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There was one patient in the primary trial who suffered from a significant decrease in the number of granulocytes in their blood. | Adverse Events 2:
Granulocytopenia 1/184 (0.54%) | Contradiction |
Only one cohort of the primary trial needs to receive manual lymph drainage prior to each cycle of anthracyclines. | INTERVENTION 1:
Exercise
an acute bout of exercise performed 24 hours prior to each cycle of anthracyclines and no exercise for 48 hours post exercise
INTERVENTION 2:
Usual Care
no exercise for 72 hours prior or 48 hours post each cycle of anthracyclines | Contradiction |
More than a dozen the primary trial participants are classified as having Pathologic Complete Response (pCR) in the Breast and Nodes. | Outcome Measurement:
Number of Participants With Pathologic Complete Response (pCR) in the Breast and Nodes
pCR was defined as no histologic evidence of invasive tumor cells in the surgical breast specimen, axillary nodes, or sentinel node identified after neoadjuvant chemotherapy.
Time frame: From the start of the study until the time of surgery (average of 221.9 days [standard deviation of 23.65 days] after study entry)
Results 1:
Arm/Group Title: AC, Followed by Weekly Paclitaxel and Concurrent Pazopanib
Arm/Group Description: Participants were treated with intravenous (IV) doxorubicin (60 milligrams per meters squared [mg/m^2]) and cyclophosphamide (AC) (600 mg/m^2) every 21 days for 4 cycles. This was followed by weekly paclitaxel (WP) 80 mg/m^2 IV on Days 1, 8, and 15 every 28 days for 4 cycles given concurrently with oral pazopanib 800 mg (2 tablets taken at the same time each day, either 1 hour before or 2 hours after a meal) taken daily and continuing until 7 days before surgery. Pazopanib was resumed at the same oral dose 4-6 weeks after surgery and was continued daily for 6 months.
Overall Number of Participants Analyzed: 93
Measure Type: Number
Unit of Measure: Participants 16 | Entailment |
64 of the study participants in the primary trial receiving lapatinib 1000mg daily and trauzumab 4mg/kg loading dose and then 2mg/kg every week experienced at least Near Complete Pathologic Response, or better, after 12 weeks. | Outcome Measurement:
Pathologic Assessment After Study Treatment
Pathologic Assessment After 12 weeks of lapatinib and trastuzumab with or without endocrine therapy. Pathologic complete response: no invasive cancer in the residual breast. Near pathologic complete response: residual disease of less than 1 cm in breast.
Time frame: 12 weeks
Results 1:
Arm/Group Title: Lapatinib + Trastuzumab
Arm/Group Description: All study participants received lapatinib 1000mg daily and trauzumab 4mg/kg loading dose and then 2mg/kg every week
Overall Number of Participants Analyzed: 64
Measure Type: Number
Unit of Measure: participants Complete Pathologic Response: 18
Near Complete Pathologic Response: 16
Not Pathologic response: 30 | Contradiction |
Black women cannot take part in the secondary trial or the primary trial. | Inclusion Criteria:
Female patients with histologically or cytologically confirmed carcinoma of the breast
Patients with advanced/metastatic disease that is not amenable to curative therapy (either surgery or radiation therapy)
Patients must have measurable disease by the RECIST criteria, defined as at least one lesion that can be accurately measured in at least one diameter (at least 10 mm in longest diameter (LD) by spiral computer tomography (CT) scan, or at least 20 mm by standard techniques; If the only measurable lesion is a lymph node, it must measure at least 20 mm in LD. If a single lesion is identified as the target lesion, a cytological or histological confirmation of breast carcinoma is required.
Patients must have had prior treatment with an anthracycline and a taxane (either sequential or in combination) and may have had prior treatment with other agents as well.
Patients must have progressed within six months of the last dose of chemotherapy, or experienced disease progression while receiving chemotherapy for advanced/metastatic disease.
Resolution of all chemotherapy or radiation-related toxicities to less than grade 1 severity
Age 18 years
Eastern Cooperative Oncology Group (ECOG) Performance Status (APPENDIX 4) of 0 or 1
Life expectancy of 3 months
Adequate renal function as evidenced by serum creatinine 1.5 mg/dL or calculated creatinine clearance 50 mL/minute (min) per the Cockcroft and Gault formula
Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) 1.5 x 10^9/L, hemoglobin 10.0 g/dL (a hemoglobin <10.0 g/dL would be acceptable if it can be corrected by growth factor or transfusion), and platelet count 100 x 10^9/L
Adequate liver function as evidenced by bilirubin 1.5 mg/dL and alkaline phosphatase, alanine transaminase (ALT), and aspartate transaminase (AST) 3 times the upper limits of normal (ULN) (in the case of liver metastases 5 x ULN)
Patients willing and able to complete the FACT-B questionnaire, Analgesic Diary, Pain VAS, and the tumor-related symptomatic assessment
Patients willing and able to comply with the study protocol for the duration of the study
A sample from the diagnostic biopsy (paraffin block) must be available
Written informed consent prior to any study-specific screening procedures with the understanding that the patient may withdraw consent at any time without prejudice
Exclusion Criteria:
Patients who have received chemotherapy, radiation, hormonal therapy, or Herceptin within 2 weeks of E7389 treatment start
Radiation therapy encompassing > 10% of marrow
Failure to recover from any chemotherapy related or other therapy related toxicity at study entry that is deemed to be clinically significant by the study investigator
Prior treatment with Mitomycin C or nitrosoureas
Prior high dose chemotherapy with hematopoietic stem cell rescue in the past two years
Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen
Active symptomatic brain metastasis; Patients with central Nervous System (CNS) metastasis are considered eligible if they have completed local therapy and discontinued from corticosteroids for at least two weeks before starting treatment with E7389
Patients with meningeal carcinomatosis
Patients who require therapeutic anti-coagulant therapy with Warfarin or related compounds; Mini dose warfarin for catheter related thrombosis prophylaxis is permitted
Women who are pregnant or breast-feeding; Women of childbearing potential with either a positive pregnancy test at Screening or no pregnancy test. Women of childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception in the opinion of the Investigator. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential.
Severe /uncontrolled intercurrent illness/infection
Significant cardiovascular impairment (history of congestive heart failure > NYHA grade II, unstable angina or myocardial infarction within the past six months, or serious cardiac arrhythmia)
Patients with organ allografts
Patients with known positive HIV status
Patients who have had a prior malignancy, other than carcinoma in situ of the cervix, or non-melanoma skin cancer, unless the prior malignancy was diagnosed and definitively treated 5 years previously with no subsequent evidence of recurrence
Patients with pre-existing neuropathy > Grade 1
Patients with a hypersensitivity to halichondrin B and/or halichondrin B chemical derivative
Patients who participated in a prior E7389 clinical trial
Patients with other significant disease or disorders that, in the Investigator's opinion, would exclude the patient from the study
PATIENT CHARACTERISTICS:
Has 1 of the following racial or ethnic backgrounds based on the patient's country of birth or the mother and father's country of birth:
Hispanic
Haitian Creole
African American
Caucasian | Contradiction |
Patients must have either AST or ALT < 1.5 ULN to participate in the primary trial. | Inclusion Criteria:
Hepatic status: Serum total bilirubin 1 x upper limit of normal (ULN; in the case of known Gilbert's syndrome, a higher serum total bilirubin [< 1.5 x ULN] is allowed), aspartate aminotransferase and alanine aminotransferase 1.5 x ULN, and alkaline phosphatase 1.5 x ULN; | Contradiction |
the primary trial and the secondary trial recorded none of the same types of adverse events | Adverse Events 1:
Total: 27/50 (54.00%)
Febrile neutropenia * 4/50 (8.00%)
Anaemia * 1/50 (2.00%)
Neutropenia * 1/50 (2.00%)
Cardiac failure * 1/50 (2.00%)
Diarrhoea * 1/50 (2.00%)
Gastritis * 1/50 (2.00%)
Nausea * 1/50 (2.00%)
Oesophagitis * 1/50 (2.00%)
Pyrexia * 7/50 (14.00%)
Mucosal inflammation * 1/50 (2.00%)
Drug hypersensitivity * 1/50 (2.00%)
Cellulitis * 2/50 (4.00%)
Adverse Events 1:
Total: 158/482 (32.78%)
Anaemia 7/482 (1.45%)
Disseminated intravascular coagulation 1/482 (0.21%)
Lymphadenopathy 0/482 (0.00%)
Neutropenia 0/482 (0.00%)
Thrombocytopenia 2/482 (0.41%)
Anaemia 28/482 (1.66%)
Disseminated intravascular coagulation 21/482 (0.21%)
Febrile neutropenia 21/482 (0.21%)
Lymphadenopathy 20/482 (0.00%)
Neutropenia 20/482 (0.00%) | Contradiction |
sufferers of hyperthyroidism and diabetes mellitus are eligible for the primary trial. | Exclusion Criteria:
Patients will not be included in the study if one of the following criteria applies:
Pregnant patients
Breast feeding patients
Patients with occupational exposure to ionizing irradiation
Patients with previous thyroid disorders | Contradiction |
Patients in the primary trial receive vorinostat at the same frequency and through the same route of administration as the secondary trial receive 6-Mercaptopurine. | INTERVENTION 1:
Treatment (Enzyme Inhibitor Therapy, AI Sensitization Therapy)
Patients receive vorinostat PO QD for 2 weeks followed by AI therapy comprising anastrozole PO QD, letrozole PO QD, OR exemestane PO QD for 6 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
vorinostat: Given PO
laboratory biomarker analysis: Correlative studies
biopsy: Optional correlative studies
F-18 16 alpha-fluoroestradiol: Correlative studies
positron emission tomography: Correlative studies
anastrozole: Given PO
letrozole: Given PO
exemestane: Given PO
gene expression analysis: Correlative studies
INTERVENTION 1:
6-Mercaptopurine and Methotrexate (6MP/MTX)
6-Mercaptopurine: 6MP 75mg/m2 body surface area, administered orally (PO) once a day (od) in the morning 1 hour after eating, on a continuous schedule. One cycle is 28 days. Treatment is given continuously until disease progression.
Methotrexate: Methotrexate 20mg/m2 will be taken orally, once a week, in the morning. One cycle is 28 days. Treatment is given continuously until disease progression.
Update: These original doses were reduced following an Urgent Safety Measure in August 2012 due to a large proportion of patients requiring a dose reduction or treatment delay due to incidences of myelo-suppression.
The reduced doses were 55mg/m2 of 6MP orally once a day, and 15mg/m2 of Methotrexate orally once a week. | Entailment |
the primary trial and the secondary trial interventions involve a variety of scans, such as CT, PET, MRI and dosimetry | INTERVENTION 1:
IPAS
Once the patient recorded in the trial, and after completion of a post-implant dosimetry scanner to analyze the dose distribution within the target volume and organs at risk, the patient is treated by irradiation and partial accelerated breast brachytherapy using high dose rate, delivering a total dose of 16 Gy in one fraction
IPAS
INTERVENTION 1:
Zr89-trastuzumab PET/CT
Zr89-trastuzumab (trastuzumab labelled with zirconium 89) for PET/CT single arm | Contradiction |
All the primary trial participants and cohort 1 participants in the secondary trial do not receive any oral capecitabine, oral lapatinib ditosylate or cixutumumab IV, however cohort 2 of the secondary trial receive all of these. | INTERVENTION 1:
Diagnostic (FLT PET)
Patients with early stage, ER positive primary breast cancer undergo FLT PET scan at baseline and 1-6 weeks after the start of standard endocrine treatment. The surgery follows 1-7 days after the second FLT PET scan.
Tracer used in the FLT PET (positron emission tomography) scanning procedure: [F18] fluorothymidine.
Positron Emission Tomography: Undergo FLT PET
Laboratory Biomarker Analysis: Correlative studies - Ki67 staining of the tumor tissue in the biopsy and surgical specimen.
INTERVENTION 1:
Arm A
Patients receive oral capecitabine twice daily on days 1-14 and oral lapatinib ditosylate once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. lapatinib ditosylate: Given PO and capecitabine: Given PO
INTERVENTION 2:
Arm B
Patients receive capecitabine and lapatinib ditosylate as in arm I. Patients also receive cixutumumab IV over 1-1½ hours on days 1, 8, and 15. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, lapatinib ditosylate: Given PO and capecitabine: Given PO | Entailment |
the primary trial only records cardiovasuclar adverse events. | Adverse Events 1:
Total: 67/349 (19.20%)
Anaemia * 3/349 (0.86%)
Leukopenia * 1/349 (0.29%)
Neutropenia * 3/349 (0.86%)
Thrombocytopenia * 1/349 (0.29%)
Atrial fibrillation * 2/349 (0.57%)
Cardiac arrest * 1/349 (0.29%)
Cardiac failure * 0/349 (0.00%)
Cardiac failure acute * 0/349 (0.00%)
Cardio-respiratory arrest * 2/349 (0.57%)
Cardiovascular insufficiency * 0/349 (0.00%) | Entailment |
children and illiterate adults are not able to take part in the primary trial. | Inclusion Criteria:
Age 18 and 85 years
Exclusion Criteria:
Inability to read and write English | Entailment |
A patient with stage 2B , pathologically confirmed PR positive breast cancer is elgible for both the primary trial and the secondary trial. | Inclusion Criteria:
Clinical locally advance breast cancer (Stage IIB or III)
Pathologically confirmed diagnosis of estrogen receptor (ER)-positive or progesterone receptor (PR)-positive breast cancer with ER or PR Allred Score > 4
Inclusion Criteria:
Premenopausal, estrogen receptor positive women, aged 20 years and over, with operable and measurable breast cancer who have provided written informed consent
Exclusion Criteria:
Medical history of chemotherapy or endocrine therapy for breast cancer, or with treatment history of radiotherapy. Unwillingness to stop taking any drug known to affect sex hormone status (including hormone replacement therapy (HRT). | Contradiction |
dosages are specified in the intervention section of the secondary trial and the primary trial | INTERVENTION 1:
Lidocaine Patch
Lidocaine patch 5% (Lidoderm®, Endo Pharmaceuticals Inc.): 1 patch was applied topically to the affected site(s) for 12 hours each day.
INTERVENTION 2:
Placebo Patch
Placebo patch: 1 patch was applied topically to the affected site(s) for 12 hours each day.
INTERVENTION 1:
Letrozole, Breast Enhancement, Safety
Single arm of healthy postmenopausal women to have two breast MRI (baseline and post-treatment). Letrozole of 12.5 mg/day is given for three successive days just prior to the second MRI. | Contradiction |
There were no instances of patients with abnormal heart rates in the primary trial. | Adverse Events 1:
Total: 3/31 (9.68%)
Edema: limb * 2/31 (6.45%)
Neutrophils/granulocytes (ANC/AGC) * 0/31 (0.00%)
Cardiac General - Other (Specify, __) * [1]0/31 (0.00%)
Cardiac General - Other (Specify, __) * [2]0/31 (0.00%)
Left ventricular diastolic dysfunction * 0/31 (0.00%)
Supraventricular and nodal arrhythmia - Atrial tachycardia/Paroxysmal Atrial Tachycardia * 0/31 (0.00%)
Adverse Events 2:
Total: 8/25 (32.00%)
Edema: limb * 1/25 (4.00%)
Neutrophils/granulocytes (ANC/AGC) * 0/25 (0.00%)
Cardiac General - Other (Specify, __) * [1]1/25 (4.00%)
Cardiac General - Other (Specify, __) * [2]0/25 (0.00%)
Left ventricular diastolic dysfunction * 1/25 (4.00%)
Supraventricular and nodal arrhythmia - Atrial tachycardia/Paroxysmal Atrial Tachycardia * 0/25 (0.00%) | Entailment |
the primary trial and the secondary trial do not use cyclical interventions. | INTERVENTION 1:
Intelligent Breast Exam, iBE
Single Arm: Additional breast exam by a FDA approved hand-held intelligent breast exam device and a clinical breast exam during their scheduled breast screening appointment. No return visit required for participation.
intelligent Breast Exam, iBE: A bilateral iBE exam will be performed on the entire breast in addition to a clinical breast exam administered by a trained individual. If the patient is selected to participate in the inter-rater reliability portion of the study, the subject will undergo both the iBE and the clinical breast exams twice sequentially performed by two different separately trained individuals during the same visit.
INTERVENTION 1:
Phase 1: Addition of Supine MRI to Conventional Imaging
Pre-operative supine MRI with intraoperative optical scanning and tracking (group MRI) | Entailment |
There is a significant difference in the Percentage of Participants Achieving a Dosimetrically Satisfactory Treatment Plan between cohort 1 and 2 of the primary trial, the increase in Gy has a huge effect. | Outcome Measurement:
Feasibility of PBI Directed External Radiotherapy as Measured by Percentage of Participants Achieving a Dosimetrically Satisfactory Treatment Plan
-The study will be deemed infeasible if more than 4 patients cannot be given treatment because her tumor is such that a dosimetrically satisfactory treatment plan cannot be devised for her.
Time frame: Within 1 year of protocol registration
Results 1:
Arm/Group Title: Cohort 1 (36 Gy)
Arm/Group Description: 36 Gy in 9 fractions BID x 4 1/2 treatment days
Partial Breast Irradiation (PBI)
Overall Number of Participants Analyzed: 50
Measure Type: Number
Unit of Measure: percentage of participants 100
Results 2:
Arm/Group Title: Cohort 2 (40 Gy)
Arm/Group Description: 40 Gy in 10 fractions BID over 5 treatment days
Partial Breast Irradiation (PBI)
Overall Number of Participants Analyzed: 50
Measure Type: Number
Unit of Measure: percentage of participants 100 | Contradiction |
There were more patients with hypotension in cohort 1 of the primary trial, than in cohort 1 of the secondary trial. | Adverse Events 1:
Total: 6/21 (28.57%)
Hypertension 3/21 (14.29%)
Edema 3/21 (14.29%)
Nausea 2/21 (9.52%)
Fracture 1/21 (4.76%)
Dizziness 3/21 (14.29%)
Syncope 2/21 (9.52%)
Headache 2/21 (9.52%)
Dyspnea 2/21 (9.52%)
Hypoxia 3/21 (14.29%)
Adverse Events 1:
Total: 1/40 (2.50%)
Hypertension 0/40 (0.00%)
Lower GI bleed 1/40 (2.50%)
Death 0/40 (0.00%)
Headache 0/40 (0.00%)
Dyspnea 0/40 (0.00%)
Sinusitis 0/40 (0.00%)
Wound Dehiscence 0/40 (0.00%) | Contradiction |
Heavy smokers (more than 5 cigarettes smoked per day) are eligible for the secondary trial and the primary trial. | Inclusion Criteria:
Female gender;
Age 18 years;
Performance Status- Eastern Cooperative Oncology Group (ECOG) 0-1
Histologically confirmed invasive breast cancer:
Primary tumor greater than 1 cm diameter, measured by clinical examination and mammography or ultrasound.
Any N,
No evidence of metastasis (M0) (isolated supra-clavicular node involvement allowed);
Over expression and/or amplification of HER2 in the invasive component of the primary tumor and confirmed by a certified laboratory prior to randomization.
Known hormone receptor status.
Hematopoietic status:
CBC not less than .75 of institutional lower limit. Absolute neutrophil count 1,5 x 10^9/L, Platelet count 100 x 10^9/L, Hemoglobin at least 9 g/dl,
Hepatic status:
Serum total bilirubin 2 x upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (< 1.5 x ULN) is allowed, Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) 3.5 times ULN, Alkaline phosphatase 2.5 times ULN, Renal status: Creatinine 1.5mg/dL,
Cardiovascular: Baseline left ventricular ejection fraction (LVEF) ³ 50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan,
Negative serum or urine β-hCG pregnancy test at screening for patients of childbearing potential within 2-weeks (preferably 7 days) prior to randomization.
Fertile patients must use effective contraception (barrier method - condoms, diaphragm - also in conjunction with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not allowed)
Signed informed consent form (ICF)
Patient accepts to make available tumor samples for submission to central laboratory to conduct translational studies as part of this protocol.
Exclusion Criteria:
Previous (less than 5 years) or current history of malignant neoplasms, except for curatively treated: Basal and squamous cell carcinoma of the skin; Carcinoma in situ of the cervix.
Patients with a prior malignancy diagnosed more than 5 years prior to randomization may enter the study.
Preexisting peripheral neuropathy grade 2
Known history of uncontrolled or symptomatic angina, clinically significant arrhythmias, congestive heart failure, transmural myocardial infarction, uncontrolled hypertension ( 180/110), unstable diabetes mellitus, dyspnea at rest, or chronic therapy with oxygen;
Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety;
Unresolved or unstable, serious adverse events from prior administration of another investigational drug;
Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of ICF;
Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded;
Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies);
Concurrent treatment with an investigational agent or participation in another therapeutic clinical trial;
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trastuzumab Emtansine, trastuzumab, lapatinib, paclitaxel, abraxane or their components;
Pregnant or lactating women;
Concomitant use of CYP3A4 inhibitors or inducers
Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
Patients have an active infection and require IV or oral antibiotics.
Pregnant or breast-feeding women
Patients unwilling or unable to comply with the protocol
Inclusion Criteria :
women with primary breast cancer, without ongoing support for substance use.
An AUDIT-C score >1 or more than one cigarette smoked per day.
Individuals able to consent to benefit of intervention focused on substance use. (Karnofsky Index >70).
Exclusion Criteria :
Patients who currently use substances for which a second-line care is already committed.
Patients with a Karnofsky index <70. | Entailment |
less than 50% of the primary trial subjects treated with Lapatinib 1500 mg had no progressive Disease at Week 12. | Outcome Measurement:
Percentage of Participants With Progressive Disease at Week 12 in Cohort 1
The percentage of participants with progressive disease (PD) 12 weeks after randomization was measured. Per Response Evaluation Criteria In Solid Tumors (RECIST), a response of PD is defined as a >=20% increase in target lesions. Participants were also classified as having PD if their response at Week 12 was unknown or missing. Response was determined by an independent radiologist and by an investigator.
Time frame: Week 12
Results 1:
Arm/Group Title: Cohort 1: Lapatinib 1500 mg
Arm/Group Description: Lapatinib 1500 milligrams (mg) administered orally once a day
Overall Number of Participants Analyzed: 72
Measure Type: Number
Unit of Measure: percentage of participants Independently Evaluated: 38.9
Investigator Evaluated: 43.1 | Contradiction |
A Female patients with a bilateral mastectomy would be excluded from the primary trial. | At least 1 healthy intact breast | Entailment |
Only men can be eligible for the primary trial. | Inclusion Criteria:
Premenopausal, estrogen receptor positive women, aged 20 years and over, with operable and measurable breast cancer who have provided written informed consent
Exclusion Criteria:
Medical history of chemotherapy or endocrine therapy for breast cancer, or with treatment history of radiotherapy. Unwillingness to stop taking any drug known to affect sex hormone status (including hormone replacement therapy (HRT). | Contradiction |
Twice as many patients in cohort 1 of the primary trial suffered from Erysipelas than Bacterial diarrhoea. | Adverse Events 1:
Erysipelas 2/167 (1.20%)
Bacterial diarrhoea 1/167 (0.60%) | Entailment |
Cohort 1 and 2 of the primary trial had the same number of patients with anaemia and Neutropenia, but Cohort 1 had 1 more case of Leukopenia than cohort 2. | Adverse Events 1:
Anaemia 1/51 (1.96%)
Leukopenia 1/51 (1.96%)
Neutropenia 1/51 (1.96%)
Adverse Events 2:
Anaemia 1/50 (2.00%)
Leukopenia 0/50 (0.00%)
Neutropenia 1/50 (2.00%) | Entailment |
the secondary trial and the primary trial accept patients in the same age range. | Inclusion Criteria:
Female breast cancer patients over the age of 18 will be recruited for this study. Patients enrolled in the study will meet standard criteria for whole breast XRT.
PATIENT CHARACTERISTICS:
Age
18 and over | Entailment |
the primary trial studies tumours response, whereas the secondary trial investigates changes in Bone Mineral Density. | Outcome Measurement:
Primary Endpoint : Compare Best Overall Response Rate (ORR) (According to Response Evaluation Criteria in Solid Tumor [RECIST] 1.1 Criteria) at Week 24 of MYL-1401O Plus Taxane Versus Herceptin® Plus Taxane in the ITT1 Population
Tumor measurements were perform by centralized blinded reviewers using RECIST 1.1 criteria. Per RECIST 1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph node must have reduction in short axis to <10 mm.Partial Response (PR): >/= 30% decrease sum of the diameters of target lesions from baseline sum diameters.
Progressive Disease (PD): </= 20% increase in the sum of the diameters of target lesions, from the smallest sum on study with at least a 5 mm absolute increase in the sum of all lesions. The appearance of one or more new lesions* denotes disease progression.
Stable Disease (SD): Neither sufficient decrease or increase. Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions. Non-complete Response/Non-Progressive Disease: Persistence of one or more non-target lesions. Progressive Disease (PD): Substantial, unequivocal progression of existing non-target lesions.
Time frame: from time of First treatment to week 24
Outcome Measurement:
Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry.
Time frame: 12 months | Entailment |
The majority of patients in the primary trial suffered from Kidney stones. | Adverse Events 1:
Total: 3/19 (15.79%)
Febrile neutropenia 1/19 (5.26%)
Colitis 1/19 (5.26%)
Pain in extremity 0/19 (0.00%)
Nephrolithiasis 0/19 (0.00%)
Pulmonary embolism 1/19 (5.26%)
Dyspnoea 0/19 (0.00%)
Haematoma 0/19 (0.00%)
Adverse Events 2:
Total: 4/30 (13.33%)
Febrile neutropenia 1/30 (3.33%)
Colitis 0/30 (0.00%)
Pain in extremity 1/30 (3.33%)
Nephrolithiasis 1/30 (3.33%)
Pulmonary embolism 0/30 (0.00%)
Dyspnoea 1/30 (3.33%)
Haematoma 1/30 (3.33%) | Contradiction |
Group 1 of the secondary trial has a higher ORR than both the Everolimus + Letrozole cohort of the primary trial and the trastuzumab cohort. | Outcome Measurement:
Objective Response Rate (ORR)
Per Response Evaluation Criteria In Solid Tumors (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Up to 2 years.
Results 1:
Arm/Group Title: NKTR-102 14 Day
Arm/Group Description: NKTR-102: NKTR-102 given on a q14 day schedule
Overall Number of Participants Analyzed: 35
Measure Type: Number
Unit of Measure: percentage of subjects 28.6 (14.6 to 46.3)
Results 2:
Arm/Group Title: NKTR-102 21 Days
Arm/Group Description: NKTR-102: NKTR-102 given on a q21 day schedule
Overall Number of Participants Analyzed: 35
Measure Type: Number
Unit of Measure: percentage of subjects 35 (14.6 to 46.3)
Outcome Measurement:
Percentage of Participants With Overall Response Rate (ORR)
Overall Response Rate (ORR) was defined as the proportion of patients whose best overall response was either complete response (CR) or partial response (PR) according to RECIST 1.0 for target lesions and assessed by CT: Complete Response (CR), disappearance of all target lesions for a period of at least one month; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (ORR) = CR + PR. Only descriptive statistics.
Time frame: From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 15 months
Results 1:
Arm/Group Title: Everolimus + Letrozole
Arm/Group Description: All patients received 2 tablets (5 mg each) of Everolimus (a total of 10 mg) + 1 tablet of Letrozole (2.5 mg) daily until disease progression or as described in the protocol.
Overall Number of Participants Analyzed: 43
Measure Type: Number
Unit of Measure: Percentage of Participants 37.2 | Contradiction |
Cyclophosphamide, Doxil and Trastuzumab were used in the secondary trial intervention, but not in the primary trial. | INTERVENTION 1:
Cabozantinib
Cabozantinib was given at a dose of 60 mg orally once per day for 21 day cycles. Treatment continued in the absence of disease progression or unacceptable toxicity.
INTERVENTION 1:
Phase I: Cyclophosphamide, Doxil, Trastuzumab
Patients receive oral cyclophosphamide once daily on days 1-28 and pegylated doxorubicin HCl liposome IV over 90 minutes on day 1. Treatment repeats every 4-6 weeks in the absence of disease progression or unacceptable toxicity. Some patients with HER2/neu 3+ disease may also receive trastuzumab IV over 30-90 minutes weekly or every 3 weeks at the discretion of the treating physician.
pegylated liposomal doxorubicin hydrochloride: Given IV
cyclophosphamide: Given orally
trastuzumab: Given IV | Entailment |
pre-menopausal patients are excluded from the secondary trial, but eligible for the primary trial. | Inclusion Criteria:
Recurrent or residual metastatic breast carcinoma
Zubrod performance status less than 2
18-60 years old
Related donor human leukocyte antigen (HLA)-compatible for allogeneic transplantation or unrelated HLA-compatible donor.
No major organ dysfunction or active infection
Exclusion Criteria: None
Inclusion Criteria:
Patient must be postmenopausal defined as meeting one or more of the following: | Entailment |
Patients with cytologically confirmed breast cancer, who's Locally recurrent disease is amenable to radiation with curative intent are not eligible for the secondary trial, but are eligible for the primary trial. | Inclusion Criteria:
Histologically or cytologically confirmed breast cancer that is either locally recurrent or metastatic.
Locally recurrent disease must not be amenable to surgical resection or radiation with curative intent.
INCLUSION CRITERIA:
Undergoing core needle biopsy for a breast abnormality suspicious for breast cancer.
Has undergone a core needle biopsy demonstrating breast cancer and has not yet had any further therapy, provided the core needle biopsy is available for analysis.
No prior therapy for breast cancer within the past 5 years.
18 years of age or older.
Ability to understand and the willingness to sign a written informed consent document.
EXCLUSION CRITERIA:
History of parathyroid disease, hypercalcemia, or kidney stones.
Supplemental vitamin D other than from a standard multiple vitamin or from standard formulations of calcium and vitamin D (eg, calcium citrate with vitamin D) within the prior 6 months.
History of renal failure requiring dialysis or kidney transplantation.
Pregnant or nursing
Receiving supplemental calcium > 1200 mg calcium per day during study.
Initial treatment of breast cancer will not be with breast-conserving surgery or mastectomy.
Locally-advanced breast cancer
Plans for neoadjuvant chemotherapy, hormonal therapy, or other systemic therapy
Plans for preoperative radiation therapy
Plans for breast cancer surgery, and does not allow for at least 10 days of vitamin D intervention.
Any condition potentially interfering with subjects ability to comply with taking study medication.
Any medical condition that would potentially interfere with vitamin D absorption, such as celiac sprue, ulcerative colitis.
Current participation in another research study that would increase risk to subject, in the opinion of the investigators | Contradiction |
the primary trial does not use trastuzumab, Tamoxifen or Exemestane in its intervention. | INTERVENTION 1:
CMRM Versus UMRM
[Not Specified] | Entailment |
Cohort 1 of the primary trial had 25% more patients experiencing adverse events than cohort 2. | Adverse Events 1:
Total: 13/24 (54.17%)
FEBRILE NEUTROPENIA 5/24 (20.83%)
HAEMATOTOXICITY 0/24 (0.00%)
NEUTROPENIA 3/24 (12.50%)
LYMPHADENOPATHY 0/24 (0.00%)
PERICARDIAL EFFUSION 1/24 (4.17%)
ATRIAL FIBRILLATION 1/24 (4.17%)
APLASIA 0/24 (0.00%)
NAUSEA 0/24 (0.00%)
PYREXIA 1/24 (4.17%)
EXTRAVASATION 0/24 (0.00%)
CHOLECYSTITIS 1/24 (4.17%)
PATHOLOGICAL FRACTURE 1/24 (4.17%)
Adverse Events 2:
Total: 6/24 (25.00%)
FEBRILE NEUTROPENIA 0/24 (0.00%)
HAEMATOTOXICITY 1/24 (4.17%)
NEUTROPENIA 0/24 (0.00%)
LYMPHADENOPATHY 1/24 (4.17%)
PERICARDIAL EFFUSION 0/24 (0.00%)
ATRIAL FIBRILLATION 0/24 (0.00%)
APLASIA 1/24 (4.17%)
NAUSEA 1/24 (4.17%)
PYREXIA 0/24 (0.00%)
EXTRAVASATION 1/24 (4.17%)
CHOLECYSTITIS 0/24 (0.00%)
PATHOLOGICAL FRACTURE 0/24 (0.00%) | Entailment |
In total only one participant of the primary trial did not achieve Pathological Complete Response. | Outcome Measurement:
Number of Patients With a Pathological Complete Response (pCR) Who Received Targeted Therapy With Trastuzumab and Pertuzumab or Bevacizumab Predicted by Genomically-derived Molecular Subtypes.
Number of patients with a pathological complete response (pCR) who received targeted therapy with trastuzumab and pertuzumab or bevacizumab predicted by genomically-derived molecular subtypes (HER2 positive or HER2 negative. pCR is defined as absence of invasive cancer in breast or lymph nodes after neoadjuvant chemotherapy.
Time frame: Up to 30 days after last cycle of treatment
Results 1:
Arm/Group Title: Cohort 1P (HER2 Positive)
Arm/Group Description: Patients receive a run-in Pertuzumab treatment of 840 mg IV over 60 minutes on day -14 followed by Trastuzumab IV over 30-60 minutes and Pertuzumab IV over 30-60 minutes, docetaxel IV, and carboplatin IV on day 1. Treatment repeats very 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed: 5
Measure Type: Count of Participants
Unit of Measure: Participants 4 80.0%
Results 2:
Arm/Group Title: Cohort 1T (HER2 Positive)
Arm/Group Description: Patients receive a run-in Trastuzumab treatment of 8 mg/kg IV over 90 minutes on day -14 followed by Trastuzumab IV over 30-60 minutes and Pertuzumab IV over 30-60 minutes, Docetaxel IV, and Carboplatin IV on day 1. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed: 6
Measure Type: Count of Participants
Unit of Measure: Participants 6 100.0% | Entailment |
the primary trial participants are given saracatinib PO every single day of the study duration. | INTERVENTION 1:
Treatment (Enzyme Inhibitor Therapy)
Patients receive saracatinib PO on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Entailment |
No participants of the primary trial had a Progression Free Survival over 1 year, but several patients had a PFS of less than 1 month. | Outcome Measurement:
Progression Free Survival
Progression free survival was based in investigator-determined progressive disease (PD) and calculated from the date of randomization to the date of PD or the date of death, whichever occurred first. Participants who had not progressed and were still alive at the time of clinical cut off were censored at the last disease assessment prior to the clinical cutoff. For PD or death with a missing interval immediately preceding the event, progression-free survival (PFS) was censored at the last disease assessment prior to the missing interval. Participants who withdrew from the study (withdrawal of consent or lost to follow-up) without progression were censored at the time of the last disease assessment.
Time frame: From the date of randomization to the date of disease progression (PD) or death, whichever occurred first (up to 8.4 years)
Results 1:
Arm/Group Title: Standard of Care (SOC)
Arm/Group Description: Participants received standard supportive care as packed red blood cells (RBC) transfusion as per Investigator's discretion.
Overall Number of Participants Analyzed: 1048
Median (95% Confidence Interval)
Unit of Measure: Months 7.4 (7.1 to 7.6)
Results 2:
Arm/Group Title: Epoetin Alfa
Arm/Group Description: Participants received SOC plus epoetin alfa 40,000 international units (IU) subcutaneously (SC) once a week.
Overall Number of Participants Analyzed: 1050
Median (95% Confidence Interval)
Unit of Measure: Months 7.4 (6.9 to 7.6) | Contradiction |
Patients' appetites were not affected in the primary trial, but at least one was affected in the secondary trial. | Adverse Events 1:
Total: 9/33 (27.27%)
Febrile neutropenia * 1/33 (3.03%)
Cardiac failure * 1/33 (3.03%)
Pyrexia * 2/33 (6.06%)
Chest pain * 1/33 (3.03%)
Medical device complication * 1/33 (3.03%)
Cellulitis * 1/33 (3.03%)
Sepsis * 1/33 (3.03%)
Hip fracture * 1/33 (3.03%)
Back pain * 1/33 (3.03%)
Menorrhagia * 1/33 (3.03%)
Thrombosis * 1/33 (3.03%)
Adverse Events 1:
Total: 10/48 (20.83%)
NEUTROPENIA 1/48 (2.08%)
THROMBOCYTOPENIA 0/48 (0.00%)
VOLUME BLOOD DECREASED 1/48 (2.08%)
FIBRILLATION ATRIAL 1/48 (2.08%)
HYPOTENSION 1/48 (2.08%)
ABDOMINAL PAIN 1/48 (2.08%)
APPETITE DECREASED 0/48 (0.00%)
DEHYDRATION 4/48 (8.33%)
DIARRHEA 4/48 (8.33%)
NAUSEA 3/48 (6.25%)
VOMITING 2/48 (4.17%)
FEVER 1/48 (2.08%)
RIGORS 0/48 (0.00%)
Adverse Events 2:
Total: 5/53 (9.43%)
NEUTROPENIA 1/53 (1.89%)
THROMBOCYTOPENIA 1/53 (1.89%)
VOLUME BLOOD DECREASED 0/53 (0.00%)
FIBRILLATION ATRIAL 0/53 (0.00%)
HYPOTENSION 0/53 (0.00%)
ABDOMINAL PAIN 0/53 (0.00%)
APPETITE DECREASED 1/53 (1.89%)
DEHYDRATION 0/53 (0.00%)
DIARRHEA 0/53 (0.00%)
NAUSEA 1/53 (1.89%)
VOMITING 1/53 (1.89%)
FEVER 1/53 (1.89%)
RIGORS 1/53 (1.89%) | Entailment |
Abraxane + Capecitabine group of the primary trial has 61 more patients with either Complete Response (CR) disappearance of all target lesions; Partial Response (PR) at least a 30% decrease in the sum of the longest diameter of target lesions than the Abraxane Alone group. | Outcome Measurement:
Objective Response Rate
Patient response rates will be measured by the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI. Responses include the following: Complete Response (CR) disappearance of all target lesions; Partial Response (PR) at least a 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) best response from the start of treatment until disease progression.
Time frame: Baseline to 6 months
Results 1:
Arm/Group Title: Abraxane + Tigatuzumab
Arm/Group Description: Patients will receive Abraxane at 100 mg/m2 X 3 doses on Days 1, 8, and 15 at 28-day intervals and tigatuzumab to be administered as a 10 mg/kg loading dose followed by 5 mg/kg for the first cycle and then every other week on Days 1 and 15 for subsequent cycles. Patients will be evaluated for response every 8 weeks. Patients with disease progression will be taken off the study.
Overall Number of Participants Analyzed: 39
Measure Type: Number
Unit of Measure: percentage of patients 28 (14.9 to 45.0)
Results 2:
Arm/Group Title: Abraxane Alone
Arm/Group Description: Patients will receive Abraxane at 100 mg/m2 weekly X 3 doses on Days 1, 8, and 15 at 28-day intervals. Abraxane will be administered on an outpatient basis by an IV infusion over 30 minutes. Patients will be evaluated for response every 2 cycles (every 8 weeks).
Overall Number of Participants Analyzed: 21
Measure Type: Number
Unit of Measure: percentage of patients 38 (18 to 61.1) | Contradiction |
the primary trial did not record any skin infections in their patients. | Adverse Events 1:
Total: 2/4 (50.00%)
Atrial fibrillation 0/4 (0.00%)
Dehydration 1/4 (25.00%)
Fatigue (asthenia, lethargy, malaise) 1/4 (25.00%)
Pain - Back 1/4 (25.00%)
Urinary tract infection 0/4 (0.00%)
Dyspnea (shortness of breath) 0/4 (0.00%)
Pericardial effusion 0/4 (0.00%)
Thrombosis 0/4 (0.00%)
Skin infection 0/4 (0.00%)
Rash: hand-foot skin reaction 0/4 (0.00%)
Adverse Events 2:
Total: 0/3 (0.00%)
Atrial fibrillation 0/3 (0.00%)
Dehydration 0/3 (0.00%)
Fatigue (asthenia, lethargy, malaise) 0/3 (0.00%)
Pain - Back 0/3 (0.00%)
Urinary tract infection 0/3 (0.00%)
Dyspnea (shortness of breath) 0/3 (0.00%)
Pericardial effusion 0/3 (0.00%)
Thrombosis 0/3 (0.00%)
Skin infection 0/3 (0.00%)
Rash: hand-foot skin reaction 0/3 (0.00%) | Entailment |
Laser Therapy is only used in cohort 1 of the primary trial, neither cohort of the secondary trial make use of this. | INTERVENTION 1:
Laser Therapy Alone
therapist administered laser treatment
laser: therapist administered laser
INTERVENTION 2:
Mld Alone
therapist administered manual lymphatic drainage
manual lymphatic drainage: therapist administered massage therapy
INTERVENTION 1:
Part A Abemaciclib: HR+, HER2+ Breast Cancer
Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or in combination with endocrine therapy (ET). Participants with hormone receptor positive HR+, HER2+ breast cancer receiving concurrent trastuzumab, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
INTERVENTION 2:
Part B Abemaciclib: HR+, HER2- Breast Cancer
Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or for in combination with endocrine therapy (ET).
Participants may continue to receive treatment until discontinuation criteria are met. | Entailment |
the primary trial and the secondary trial both record cases of Cholecystitis. | Adverse Events 1:
Total: 3/24 (12.50%)
Disseminated intravascular coagulation 0/24 (0.00%)
Death NOS 0/24 (0.00%)
Edema limbs 0/24 (0.00%)
Fatigue 0/24 (0.00%)
Hepatic failure 1/24 (4.17%)
Alanine aminotransferase increased 1/24 (4.17%)
Aspartate aminotransferase increased 1/24 (4.17%)
Blood bilirubin increased 0/24 (0.00%)
Ejection fraction decreased 1/24 (4.17%)
Adverse Events 2:
Total: 9/22 (40.91%)
Disseminated intravascular coagulation 1/22 (4.55%)
Death NOS 1/22 (4.55%)
Edema limbs 1/22 (4.55%)
Fatigue 1/22 (4.55%)
Hepatic failure 0/22 (0.00%)
Alanine aminotransferase increased 0/22 (0.00%)
Aspartate aminotransferase increased 1/22 (4.55%)
Blood bilirubin increased 1/22 (4.55%)
Ejection fraction decreased 1/22 (4.55%)
Adverse Events 1:
Total: 5/33 (15.15%)
Left Ventricular Thrombus * 1/33 (3.03%)
Nausea * 1/33 (3.03%)
Acute Cholecystitis * 1/33 (3.03%)
Renal Failure * 1/33 (3.03%)
Pneumonia * 1/33 (3.03%) | Contradiction |
There is 1 case (1.45%) of thrombocytopenia in the primary trial. | Adverse Events 1:
Total: 26/69 (37.68%)
Thrombophlebitis * 1/69 (1.45%)
Anaemia NOS * 1/69 (1.45%)
Acute febrile neutrophilic dermatosis * 1/69 (1.45%)
Cardiac failure NOS * 2/69 (2.90%)
Ejection fraction decreased * 1/69 (1.45%)
Intestinal obstruction NOS * 1/69 (1.45%)
Diarrhoea NOS * 2/69 (2.90%)
Febrile neutropenia * 12/69 (17.39%)
Mucosal inflammation NOS * 1/69 (1.45%) | Contradiction |
Participants with T4 N1 M0 breast carcinoma are eligible for the primary trial. | Tumor must be confined to either the breast or to the breast and ipsilateral axilla (Note: patinets with multifocal/multicentric tumors are eligible). Patient must have (according to TNM 7th edition rules):
T1 with T 1.0cm, T2 or T3 by at least one radiographic or clinical measurement
Either clinically positive (N1 only) or clinically negative axillary nodes (N0)
M0 | Contradiction |
Female Patients with LVEF > 50%, who have previously undergone treatment with any of the following drugs; trastuzumab emtansine, paclitaxel, abraxane or lapatinib are still eligible for the primary trial but are excluded from the secondary trial. | Inclusion Criteria:
Prospectively confirmed HER2-positive (i.e., IHC 3+ or IHC 2+ and gene amplified by fluorescence in situ hybridization [FISH] positive) as assessed on primary tumor and/or metastatic site
Documented progression of unresectable, locally advanced, or mBC, determined by the investigator
Left ventricular ejection fraction (LVEF) >/= 50% by echocardiogram (ECHO)
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
A negative serum Beta-Human Chorionic Gonadotropin (Beta-HCG) test for women of childbearing potential (premenopausal or not meeting the definition of postmenopausal i.e. >/= 12 months of amenorrhea), and women who have not undergone surgical sterilization (i.e., absence of ovaries and/or uterus)
For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use two adequate non-hormonal methods of contraception, including at least one method with a failure rate of <1% per year, during the treatment period and for at least 7 months after the last dose of study drug
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm. With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of <1% per year during the treatment period and for at least 7 months plus 90 days (a spermatogenesis cycle) after the last dose of study drug. Men must refrain from donating sperm during this same period. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 7 months after the last dose of study drug.
Exclusion Criteria:
Prior treatment with trastuzumab emtansine
Prior treatment with lapatinib or lapatinib with capecitabine or non-comparable biologic or biosimilar of trastuzumab
Peripheral neuropathy of Grade >/= 3 per the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE [version 4.03])
History of other malignancy within the previous 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 uterine cancer, synchronous or previously diagnosed HER2-positive breast cancer, or cancers with a similar curative outcome as those mentioned above
History of receiving any anti-cancer drug/biologic or investigational treatment within 21 days prior to enrollment except hormone therapy, which can be given up to 7 days prior to enrollment; recovery of treatment-related toxicity consistent with other eligibility criteria
History of exposure to cumulative doses of anthracyclines, as defined in the protocol
History of radiation therapy within 14 days of enrollment
Brain metastases that are untreated, symptomatic, or require therapy to control symptoms, as well as a history of radiation, surgery, or other therapy, including steroids, to control symptoms from brain metastases within 2 months (60 days) before enrollment
CNS only disease
History of a decrease in LVEF to < 40% or symptomatic congestive heart failure (CHF) with previous trastuzumab treatment
History of symptomatic chronic heart failure (New York Heart Association [NYHA] Classes II-IV) or serious cardiac arrhythmia requiring treatment
History of myocardial infarction or unstable angina within 6 months of enrollment
Current dyspnea at rest due to complications of advanced malignancy or requirement for continuous oxygen therapy
Current severe, uncontrolled systemic disease
Pregnancy or lactation
Concurrent, serious, uncontrolled infections or current known infection with human immunodeficiency virus (HIV) or active hepatitis B and/or hepatitis C. For patients who are known carriers of hepatitis B virus (HBV), active hepatitis B infection must be ruled out, based on negative serologic testing and/or determination of HBV DNA viral load per local guidelines
Presence of conditions that could affect gastrointestinal absorption: malabsorption syndrome, resection of the small bowel or stomach, and ulcerative colitis
History of intolerance (such as Grade 3-4 infusion reaction) or known hypersensitivity to trastuzumab or murine proteins or any component of the product
Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol
Inclusion Criteria:
Female gender;
Age 18 years;
Performance Status- Eastern Cooperative Oncology Group (ECOG) 0-1
Histologically confirmed invasive breast cancer:
Primary tumor greater than 1 cm diameter, measured by clinical examination and mammography or ultrasound.
Any N,
No evidence of metastasis (M0) (isolated supra-clavicular node involvement allowed);
Over expression and/or amplification of HER2 in the invasive component of the primary tumor and confirmed by a certified laboratory prior to randomization.
Known hormone receptor status.
Hematopoietic status:
CBC not less than .75 of institutional lower limit. Absolute neutrophil count 1,5 x 10^9/L, Platelet count 100 x 10^9/L, Hemoglobin at least 9 g/dl,
Hepatic status:
Serum total bilirubin 2 x upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (< 1.5 x ULN) is allowed, Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) 3.5 times ULN, Alkaline phosphatase 2.5 times ULN, Renal status: Creatinine 1.5mg/dL,
Cardiovascular: Baseline left ventricular ejection fraction (LVEF) ³ 50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan,
Negative serum or urine β-hCG pregnancy test at screening for patients of childbearing potential within 2-weeks (preferably 7 days) prior to randomization.
Fertile patients must use effective contraception (barrier method - condoms, diaphragm - also in conjunction with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not allowed)
Signed informed consent form (ICF)
Patient accepts to make available tumor samples for submission to central laboratory to conduct translational studies as part of this protocol.
Exclusion Criteria:
Previous (less than 5 years) or current history of malignant neoplasms, except for curatively treated: Basal and squamous cell carcinoma of the skin; Carcinoma in situ of the cervix.
Patients with a prior malignancy diagnosed more than 5 years prior to randomization may enter the study.
Preexisting peripheral neuropathy grade 2
Known history of uncontrolled or symptomatic angina, clinically significant arrhythmias, congestive heart failure, transmural myocardial infarction, uncontrolled hypertension ( 180/110), unstable diabetes mellitus, dyspnea at rest, or chronic therapy with oxygen;
Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety;
Unresolved or unstable, serious adverse events from prior administration of another investigational drug;
Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of ICF;
Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded;
Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies);
Concurrent treatment with an investigational agent or participation in another therapeutic clinical trial;
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trastuzumab Emtansine, trastuzumab, lapatinib, paclitaxel, abraxane or their components;
Pregnant or lactating women;
Concomitant use of CYP3A4 inhibitors or inducers
Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
Patients have an active infection and require IV or oral antibiotics.
Pregnant or breast-feeding women
Patients unwilling or unable to comply with the protocol | Contradiction |
the primary trial did not use overall response rate, tumour response rate or progression-free survival rate as its outcome measurement. | Outcome Measurement:
Progression-Free Survival (PFS) Rate
PFS was based on Kaplan-Meier estimates. PFS was defined as time in weeks from start of study treatment to first documentation of objective tumor progression or death due to any cause. PFS was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 7. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from death case report forms (CRFs). Percentage of participants who had not experienced progression or death by Week 16 is reported. | Contradiction |
According to the results of the primary trial the MTD of paclitaxel is approximately is 120 mg. | Outcome Measurement:
Phase I Portion: Maximum Tolerated Dose/MTD of Dasatinib When Administered in Combination With a Fixed Dose of Weekly Paclitaxel.
[Not Specified]
Time frame: Through completion of Phase I, up to 1 year
Results 1:
Arm/Group Title: Dasatinib and Paclitaxel
Arm/Group Description: The phase I portion is a standard, three-patient per cohort, dose escalation schedule will be used. Between 6 and 54 patients will likely be necessary to determine the MTD of dasatinib in combination with weekly paclitaxel.
The phase II portion of this trial has a Simon two-stage design to determine the efficacy of dasatinib when administered in combination with paclitaxel.
Dasatinib and Paclitaxel: A treatment cycle will consist of 28 days, according to the following schedule:
Dasatinib 120MG PO once daily, Weekly paclitaxel 80 mg/m2 given intravenously over 1 hour on day 1, 8, and 15 of a 28 day cycle.
The trial will initially test the combination of weekly paclitaxel and dasatinib given PO, once daily , continuously. In case of 2 dose-limiting toxicities (DLT) in the first cohort (0), the next cohort will test dasatinib given with a different schedule, 5 days on and 2 days off, omitting dasatinib the day prior and the day of administration of paclitaxel.
Overall Number of Participants Analyzed: 15
Measure Type: Number
Unit of Measure: mg of dasatinib 120 | Contradiction |
Cohort 2 of the primary trial recorded 1 incident of thrombocytopenia. | Adverse Events 2:
Anemia with trombocytopenia 1/110 (0.91%) | Entailment |
the secondary trial recorded more total occurences of gastrointestinal adverse events than the primary trial. | Adverse Events 1:
Total: 23/120 (19.17%)
Febrile neutropenia 4/120 (3.33%)
Leukopenia 2/120 (1.67%)
Neutropenia 8/120 (6.67%)
Cardiac tamponade 0/120 (0.00%)
Ventricular arrhythmia 1/120 (0.83%)
Ascites 0/120 (0.00%)
Oesophagitis 0/120 (0.00%)
Large intestine polyp 0/120 (0.00%)
Death 1/120 (0.83%)
Liver injury 1/120 (0.83%)
Pneumonia 3/120 (2.50%)
Adverse Events 2:
Total: 30/122 (24.59%)
Febrile neutropenia 3/122 (2.46%)
Leukopenia 3/122 (2.46%)
Neutropenia 9/122 (7.38%)
Cardiac tamponade 2/122 (1.64%)
Ventricular arrhythmia 0/122 (0.00%)
Ascites 1/122 (0.82%)
Oesophagitis 1/122 (0.82%)
Large intestine polyp 0/122 (0.00%)
Death 1/122 (0.82%)
Liver injury 0/122 (0.00%)
Pneumonia 5/122 (4.10%)
Adverse Events 1:
Total: 47/254 (18.50%)
Anaemia 1/254 (0.39%)
Febrile neutropenia 1/254 (0.39%)
Lymphadenopathy 1/254 (0.39%)
Acute myocardial infarction 1/254 (0.39%)
Angina pectoris 0/254 (0.00%)
Angina unstable 0/254 (0.00%)
Bundle branch block left 0/254 (0.00%)
Cardiac failure 4/254 (1.57%)
Coronary artery disease 0/254 (0.00%)
Coronary artery stenosis 1/254 (0.39%)
Adverse Events 2:
Total: 56/269 (20.82%)
Anaemia 1/269 (0.37%)
Febrile neutropenia 0/269 (0.00%)
Lymphadenopathy 0/269 (0.00%)
Acute myocardial infarction 0/269 (0.00%)
Angina pectoris 3/269 (1.12%)
Angina unstable 1/269 (0.37%)
Bundle branch block left 1/269 (0.37%)
Cardiac failure 1/269 (0.37%)
Coronary artery disease 1/269 (0.37%)
Coronary artery stenosis 0/269 (0.00%) | Contradiction |
Less than 5 patients in the primary trial experienced Earache. | Adverse Events 1:
Total: 107/383 (27.94%)
Anaemia 4/383 (1.04%)
Febrile neutropenia 7/383 (1.83%)
Haemoytique anaemia 0/383 (0.00%)
Leukopenia 1/383 (0.26%)
Neutropenia 6/383 (1.57%)
Thrombocytopenia 2/383 (0.52%)
Anginal pectoris 1/383 (0.26%)
Cardiomyopathy 0/383 (0.00%)
Ear pain 0/383 (0.00%)
Abdominal distension 1/383 (0.26%)
Abdominal pain 6/383 (1.57%)
Adverse Events 2:
Total: 85/383 (22.19%)
Anaemia 3/383 (0.78%)
Febrile neutropenia 2/383 (0.52%)
Haemoytique anaemia 0/383 (0.00%)
Leukopenia 0/383 (0.00%)
Neutropenia 1/383 (0.26%)
Thrombocytopenia 1/383 (0.26%)
Anginal pectoris 0/383 (0.00%)
Cardiomyopathy 1/383 (0.26%)
Ear pain 1/383 (0.26%)
Abdominal distension 0/383 (0.00%)
Abdominal pain 3/383 (0.78%) | Entailment |
Less than 5% of the primary trial participants achieved CR or PR. | Outcome Measurement:
Objective Response Rate (ORR)
Tumor response evaluation was performed using RECIST 1.0 using CT/MRI. Proportion of patients achieving a CR or PR is considered in the overall response.
Time frame: Assessed at the end of each even-numbered cycle (every 8 weeks), or per standard of care but no less than 4 weeks and nor more than every 12 weeks (+/- 1 week) if treatment has ended.
Results 1:
Arm/Group Title: Pralatrexate
Arm/Group Description: Study drug 190 mg/m^2 for 2 to 4 weeks.
Overall Number of Participants Analyzed: 22
Measure Type: Number
Unit of Measure: participants 1 | Entailment |
More the primary trial participants suffered Grade 1 Cardiotoxicity Events After Cycle 8 than Grade 3 events. | Outcome Measurement:
Grades of Cardiotoxicity Events in the Subset of Patients Reporting a Cardiotoxicity Event
This table summarizes the cardiotoxicity events of different grades. Grade 1 is a decline of left ventricular ejection fraction(LVEF) >=10% but <20% of baseline value. Grade 2 is LVEF below LLN (50%) or decline of LVEF >=20% of baseline value. Grade 3 is congestive heart failure responsive to treatment. Please note that only a subset of patients reported cardiotoxic events so the totals will not add up to the total number of participants.
Time frame: Baseline, after cycle 4 (~84 days), after cycle 8 (~168 days), and 30 or more days after last cycle of induction therapy
Results 1:
Arm/Group Title: Arm I: Doxorubicin and Taxotere
Arm/Group Description: Patients received PLD 30 mg/m^2 IV followed by docetaxel 60 mg/m^2 IV, one hour after PLD completion, every 3 weeks for a total of 8 cycles. Dexamthasone 8 mg orally twice a day was administered the day before, the day of, and the day following docetaxel. The maximum allowed cumulative dose of PLD was 240 mg/m^2. Pyridoxine 200 mg PO daily started on Day 1 of Cycle 1 and continued daily while the patient was on PLD.
Overall Number of Participants Analyzed: 16
Measure Type: Number
Unit of Measure: participants Grade 1 After Cycle 4 (approx. 84 days): 2
Grade 1 After Cycle 8 (approx. 168 days): 4
Grade 1 After 30 days or more after last cycle: 1
Grade 2 After Cycle 4 (approx 84 days): 3
Grade 2 After Cycle 8 (approx 168 days): 4
Grade 2 After 30 days or more after last cycle: 1
Grade 3 After Cycle 4 (approx 84 days): 1
Grade 3 After Cycle 8 (approx 168 days): 0
Grade 3 After 30 days or more after last cycle: 0 | Entailment |
To be eligible for both the secondary trial and the primary trial patients must satisfy all the following conditions; alkaline phosphatase < 2.5 x ULN, aspartate aminotransferase <= 1.5 x ULN and Hemoglobin > 10 g/dL. | The following criteria for evidence of adequate hepatic function must be met:
alkaline phosphatase must be less than 2.5 x ULN for the lab; and
aspartate aminotransferase (AST) must be less than/equal to 1.5 x ULN for the lab.
Platelet count must be greater than/equal to 100,000/mm^3.
Hemoglobin must be greater than/equal to 10 g/dL.
Platelets > 100,000/mm^3
Hemoglobin > 10 g/dL
AST < 2 times upper limit of normal (ULN)
Alkaline phosphatase < 2 times ULN | Contradiction |
A total of 3 patients in the primary trial suffered a life-threatening reaction to an infection. | Adverse Events 1:
Total: 9/90 (10.00%)
Febrile neutropenia 2/90 (2.22%)
Ascites 0/90 (0.00%)
Nausea 0/90 (0.00%)
Vomiting 0/90 (0.00%)
Death NOS 1/90 (1.11%)
Fever 0/90 (0.00%)
Other general disorders, administration site conditions 0/90 (0.00%)
Other hepatobiliary disorders 1/90 (1.11%)
Lung infection 2/90 (2.22%)
Sepsis 2/90 (2.22%)
Spinal fracture 0/90 (0.00%)
Adverse Events 2:
Total: 12/89 (13.48%)
Febrile neutropenia 0/89 (0.00%)
Ascites 1/89 (1.12%)
Nausea 1/89 (1.12%)
Vomiting 1/89 (1.12%)
Death NOS 2/89 (2.25%)
Fever 1/89 (1.12%)
Other general disorders, administration site conditions 1/89 (1.12%)
Other hepatobiliary disorders 0/89 (0.00%)
Lung infection 0/89 (0.00%)
Sepsis 1/89 (1.12%)
Spinal fracture 1/89 (1.12%) | Entailment |
The Herceptin group in the primary trial had a higher percentage of Patients Achieving partial Pathological Response than the CT-P6 and ZA group. | Outcome Measurement:
The Percentage of Patients Achieving Pathological Complete Response Defined as the Absence of Invasion Tumor Cells in the Breast and in Axillary Lymph Nodes, Regardless of Ductal Carcinoma in Situ (DCIS)
Subject who went through Neoadjuvant period completely (24 weeks), will receive surgery within 3-6 weeks after last treatment of neoadjuvant period.
The primary endpoint, Pathological complete response, will be assessed using resected bio-specimens collected in breast and axilla during a surgery.
Time frame: After Neo-adjuvant therapy and Surgery (up to 30 weeks)
Results 1:
Arm/Group Title: CT-P6
Arm/Group Description: Patient received CT-P6 at an initial dose of 8 mg/kg administered by a single IV infusion on Day 1 of Cycle 1, followed by 6 mg/kg on Day 1 of Cycles 2 through 8 (3-week cycles). Patients also received docetaxel 75 mg/m^2 during cycles 1 through 4 and FEC (fluorouracil 500mg/m^2, epirubicin 75mg/m^2, and cyclophosphamide 500mg/m^2) during Cycles 5 through 8. After a total of 8 treatment cycles of the neoadjuvant treatment, surgery was performed within 3 to 6 weeks from the last dose of study.
Overall Number of Participants Analyzed: 248
Measure Type: Number
Unit of Measure: percentage of responders 46.77 (40.43 to 53.19)
Results 2:
Arm/Group Title: Herceptin
Arm/Group Description: Patient received Herceptin at an initial dose of 8 mg/kg administered by a single IV infusion on Day 1 of Cycle 1, followed by 6 mg/kg on Day 1 of Cycles 2 through 8 (3-week cycles). Patients also received docetaxel 75 mg/m^2 during cycles 1 through 4 and FEC (fluorouracil 500mg/m^2, epirubicin 75mg/m^2, and cyclophosphamide 500mg/m^2) during Cycles 5 through 8. After a total of 8 treatment cycles of the neoadjuvant treatment, surgery was performed within 3 to 6 weeks from the last dose of study.
Overall Number of Participants Analyzed: 256
Measure Type: Number
Unit of Measure: percentage of responders 50.39 (44.10 to 56.68) | Contradiction |
None of the subjects in the primary trial are required to injest any pills, and half the subjects in the secondary trial must take a weekly tablet. | INTERVENTION 1:
Manual Lymph Drainage
Manual lymph drainage (MLD) treatment 3 times a week for 4 weeks to the lymphedematous upper limb
Manual Lymph Drainage (MLD): MLD is a practitioner-applied manual massage technique designed to decrease limb volume in patients with lymphedema by enhancing movement of lymph fluid, resulting in reductions in interstitial fluid.
INTERVENTION 2:
Negative Pressure
PhysioTouch (negative pressure massage) treatment 3 times a week for 4 weeks to the lymphedematous upper limb
PhysioTouch: The PhysioTouch is a hand-held device that administers negative pressure under the treatment head, and gently pulls the underlying skin and subcutaneous tissue into the suction cup. This suction produces a stretch to the skin and in the subcutaneous tissue space. This action is thought to facilitate lymphatic flow from the interstitium into the lymphatic vessels, and mobilizes the superficial fascia.
INTERVENTION 1:
No Exercise
Multivitamin Arm + Calcitriol Arm:Calcitriol pill taken once per week
INTERVENTION 2:
Exercise
Exercise Arm: Exercise consisting of progressive walking and resistance band training
Calcitriol+ Exercise Arm: Calcitriol pill taken once per week + Exercise | Contradiction |
The most common adverse event in cohort 1 of the primary trial is Neutropenia. | Adverse Events 1:
Total: 21/337 (6.23%)
Blood/Bone Marrow-Other 0/337 (0.00%)
Febrile neutropenia 0/337 (0.00%)
Hemoglobin 2/337 (0.59%)
Atrioventricular block - 2nd degree Mobitz Type II 0/337 (0.00%)
Cardiac-ischemia/infarction 1/337 (0.30%)
Left ventricular diastolic dysfunction 0/337 (0.00%)
Left ventricular systolic dysfunction 1/337 (0.30%)
Restrictive cardiomyopathy 1/337 (0.30%) | Contradiction |
Cohort 1 of the primary trial and Cohort 1 of the secondary trial both have less than 30% occurrence of adverse events. | Adverse Events 1:
Total: 15/52 (28.85%)
Adverse Events 1:
Total: 2/7 (28.57%) | Entailment |
Patients must be doing less than 2 hours of physical exercise per week to participate in the primary trial, however, this is not a requirement for the secondary trial. | Inclusion Criteria:
Less than 120 minutes of exercise per week
Inclusion Criteria:
The patient has provided written informed consent with HIPAA authorization before participating in the study, as has his/her responsible caregiver, if applicable.
The patient is a candidate for surgical intervention, with lymph node mapping being a part of the surgical plan.
The patient is at least 18 years of age at the time of consent.
The patient has an ECOG performance status of Grade 0 - 2 [8].
The patient has a clinical negative node status at the time of study entry.
If of child bearing potential, the patient has a negative pregnancy test within 72 hours prior to administration of Lymphoseek, has been surgically sterilized, or has been postmenopausal for at least 1 year.
The patient is currently not participating in another investigational drug study.
Melanoma Patients
The patient has a diagnosis of primary melanoma.
Breast Cancer Patients
The patient has a diagnosis of primary breast cancer.
Patients with pure ductal carcinoma in situ (DCIS) or non-invasive carcinoma if lymph node biopsy is part of the surgical plan.
Exclusion Criteria:
The patient is pregnant or lactating;
The patient has clinical or radiological evidence of metastatic cancer including palpably abnormal or enlarged lymph nodes (i.e., all patients should be any T,N0,M0);
The patient has a known hypersensitivity to Lymphazurin or Patent Bleu V.
Melanoma Patients
The patient has a tumor with a Breslow depth less than 0.75mm.;
Patients that have had preoperative chemotherapy, immunotherapy or radiation therapy;
Patients diagnosed with a prior invasive melanoma that would occur on the same body region or potentially draining to the same nodal basin or patients with truncal or extremity primary melanoma who has had a prior breast cancer potentially draining to the same axillary nodal basin;
Patients who have undergone node basin surgery of any type or radiation to the nodal basin(s) potentially draining the primary melanoma;
Patients who have undergone a wide excision for their primary melanoma (>1 cm in dimension) or complex reconstruction (rotation, free flap or skin graft of any type).
Breast Cancer Patients
The patient has bilateral primary breast cancers or multiple tumors within their breast;
Patients that have had prior surgical procedures such as breast implants, reduction mammoplasty or axillary surgery;
Patients scheduled for bilateral mastectomy for any reason;
Patients that have had preoperative radiation therapy to the affected breast or axilla | Entailment |
There were 4 cases of Febrile neutropenia in cohort 1 of the primary trial, and 0 cases of heart failure. | Adverse Events 1:
Febrile neutropenia 4/127 (3.15%)
Cardiac failure 0/127 (0.00%) | Entailment |
Arm 2 of the primary trial receive dose-intensive chemotherapy on a21 day cycle up to 3 times in the absence of disease progression or unacceptable toxicity. | INTERVENTION 1:
Arm I
Patients receive dose-intensive chemotherapy comprising doxorubicin hydrochloride IV over 10-15 minutes on day 1, oral cyclophosphamide once daily on days 1-7, and filgrastim subcutaneously on days 2-7. Courses repeat every 7 days for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Beginning 1 week later, patients then receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes once a week for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients with HER-2/neu positive disease also receive trastuzumab IV over 30-90 minutes once a week for 1 year in the absence of disease progression or unacceptable toxicity.
doxorubicin hydrochloride: Given IV
cyclophosphamide: Given orally
filgrastim: Given SC
paclitaxel albumin-stabilized nanoparticle formulation: Given IV
trastuzumab: Given IV
laboratory biomarker analysis: Correlative studies
quality-of-life assessment: Ancillary studies | Contradiction |
Only 6 patients in cohort 1 of the primary trial had Varicose Veins. | Adverse Events 1:
Varicose Vein 1/6 (16.67%) | Contradiction |
People who inherit harmful variants of the BReast CAncer gene 1 or 2 are eligible for the primary trial. | Inclusion Criteria:
Known deleterious germline mutation of BRCA1/2 (Patients in Cohorts A and A1) | Entailment |
Neither the secondary trial or the primary trial require patients to undergo any kind of medical treatment during their interventions, they are only testing effectiveness of consultations. | INTERVENTION 1:
Arm 1: BREASTChoice (Decision Tool)
Investigators recruited patients scheduled for a plastic/reconstruction consult. Investigators identified patients who completed a mastectomy, or were scheduled for one, and considering reconstruction, but didn't have an appointment with a plastic/reconstructive surgeon. A study team member called the patient to determine their interest and offered for them to come to their scheduled appointment 30 minutes early to meet a coordinator or offered them the option to complete pre-appointment procedures at home. Patients randomized using computer random assignment. If the patient didn't have an appointment, she scheduled a convenient time to complete study procedures with research staff. Patients interacted with the decision tool. They were asked to answer a survey. After the appointment, the team collected information consult duration, decision process quality, and measures of shared decision making. Patient participation was approximately 30 minutes.
INTERVENTION 2:
Arm 2: Enhanced Usual Care (Surgical Care Booklet)
Investigators recruited patients scheduled for plastic/reconstruction consultation. Investigators identified patients who completed or scheduled a mastectomy, and considering reconstruction, but didn't have an appointment with a plastic/reconstructive surgeon. A study team member called the patient to determine their interest and offered for them to come to their scheduled appointment 30 minutes early to meet a coordinator or to complete the pre-appointment procedures at home. Patients were randomized using computer random assignment. If the patient didn't have an appointment, she scheduled a convenient time to complete study procedures with research staff. Patients interacted with American Society of Plastic Surgeons booklet "Breast Reconstruction." They were asked to answer a survey. After the appointment, the team collected information about consult duration, decision process quality, and measures of shared decision making. Patient participation was approximately 30 minutes.
INTERVENTION 1:
ARM 1 Daily Boost
Radiation Therapy
Radiation Therapy: Arm 1= 15 daily radiation fractions of 2.7 Gy, Monday to Friday for 3 weeks, to the whole breast with a daily concomitant boost of 0.5 Gy to the tumor bed, for a total daily dose of 3.2 Gy to the tumor bed (2.7Gy+0.5 Gy). The overall dose will be 40.5 Gy to the breast and 48.0 Gy to the tumor bed.
Arm 2= 15 daily radiation fractions of 2.7 Gy Monday to friday for three weeks to the entire breast with a Friday boost of 2.0 Gy to the tumor bed, for a total dose to the tumor bed on each friday of 4.7 Gy (2.7 Gy+ 2.0 Gy). The overall dose will be 40.5 Gy to the breast and 46.5 gy to the tumor bed.
INTERVENTION 2:
ARM 2 Weekly Boost
Radiation Therapy
Radiation Therapy: Arm 1= 15 daily radiation fractions of 2.7 Gy, Monday to Friday for 3 weeks, to the whole breast with a daily concomitant boost of 0.5 Gy to the tumor bed, for a total daily dose of 3.2 Gy to the tumor bed (2.7Gy+0.5 Gy). The overall dose will be 40.5 Gy to the breast and 48.0 Gy to the tumor bed.
Arm 2= 15 daily radiation fractions of 2.7 Gy Monday to friday for three weeks to the entire breast with a Friday boost of 2.0 Gy to the tumor bed, for a total dose to the tumor bed on each friday of 4.7 Gy (2.7 Gy+ 2.0 Gy). The overall dose will be 40.5 Gy to the breast and 46.5 gy to the tumor bed. | Contradiction |
The the primary trial placebo group performed much better than the test group, as a lower PFS is ideal. | Outcome Measurement:
Progression-free Survival (PFS)
PFS is defined as the number of months from the date of randomization to the earlier of progressive disease (PD) or death due to any cause.
Time frame: From date of randomization to discontinuation due to disease progression or death up to primary completion date (Median follow-up 6 months)
Results 1:
Arm/Group Title: Exemestane 25 mg + Placebo
Arm/Group Description: Exemestane (Aromasin ) 25 mg tablets orally once daily plus a placebo-matching entinostat tablet orally once per week on Days 1, 8, 15 and 22 of each 28-day treatment cycle until development of progressive disease (PD) or unacceptable toxicity or closure of the study by the Sponsor, whichever occurred first.
Overall Number of Participants Analyzed: 66
Median (95% Confidence Interval)
Unit of Measure: months 2.27 (1.81 to 3.68)
Results 2:
Arm/Group Title: Exemestane 25 mg + Entinostat 5 mg
Arm/Group Description: Exemestane (Aromasin ) 25 mg tablets orally once daily plus an entinostat 5 mg tablet orally once per week on Days 1, 8, 15 and 22 of each 28-day treatment cycle until development of progressive disease (PD) or unacceptable toxicity or closure of the study by the Sponsor, whichever occurred first.
Overall Number of Participants Analyzed: 64
Median (95% Confidence Interval)
Unit of Measure: months 4.28 (3.26 to 5.36) | Contradiction |
A patient in cohort 2 of the primary trial received a Plasma transfusion. | Adverse Events 2:
Total: 17/181 (9.39%)
Disseminated intravascular coagulation 0/181 (0.00%)
Febrile neutropenia 1/181 (0.55%)
Hemoglobin decreased 13/181 (7.18%)
Lymphatics 0/181 (0.00%)
Transfusion: pRBCs 1/181 (0.55%)
Arrhythmia supraventricular 1/181 (0.55%)
Cardiac disorder 0/181 (0.00%)
Edema 0/181 (0.00%)
Left ventricular failure 1/181 (0.55%)
Myocardial ischemia 0/181 (0.00%) | Contradiction |
Adequate Hematologic, Hepatic and renal function is not necessary for participating in the primary trial. However, being pregnant is required. | Inclusion Criteria:
stage I-III breast cancer
adjuvant or neoadjuvant anthracycline-based chemotherapy
Exclusion Criteria:
under age 18
pregnancy
metastatic or inoperable (including inflammatory) breast cancer
confounding underlying medical illnesses
history of mania
history of other axis-I psychiatric disorder
other physical or psychological impairments - | Contradiction |
the primary trial did not use overall response rate, tumour response rate or preference score as its outcome measurement. | Outcome Measurement:
Progression-Free Survival (PFS) Rate
PFS was based on Kaplan-Meier estimates. PFS was defined as time in weeks from start of study treatment to first documentation of objective tumor progression or death due to any cause. PFS was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 7. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from death case report forms (CRFs). Percentage of participants who had not experienced progression or death by Week 16 is reported. | Entailment |
the secondary trial and the primary trial do not require participants to be of a particular ethnicity, sex, height or to be able to speak a specific language. | Inclusion criteria:
Female patients >=18 years with proven diagnosis of HER2-overexpressing, histologically confirmed breast cancer
Locally advanced or metastatic disease
Must have disease that can be evaluated according to RECIST 1.1 (Response Evaluation Criteria for Solid Tumours version 1.1)
For trastuzumab pre-treated patients, must have failed prior trastuzumab treatment
Investigator-confirmed diagnosis of Inflammatory Breast Cancer
Must have biopsiable disease
Exclusion criteria:
Prior treatment with HER2-targeted small molecules or antibodies other than trastuzumab (which must have been given in the trastuzumab-failure study population)
Must not have received prior vinorelbine treatment
INCLUSION CRITERIA:
Postmenopausal female.
Postmenopausal defined as no menses for at least 12 months or bilateral oophorectomy. In unclear cases, (e.g. 50 year old who has had hysterectomy) chemical confirmation of postmenopausal status may be confirmed with follicle stimulating hormone (FSH) greater than 35 U/L.
Elevated risk for developing invasive breast cancer by virtue of one of the following criteria:
Gail Model risk of greater than or equal to 1.7% over 5 years from study entry. (This is the same minimum level of risk required for a subject to be eligible for the recently completed NSABP-P1 tamoxifen breast cancer prevention trial).
Lobular neoplasia.
Atypical ductal hyperplasia.
DCIS (ductal carcinoma in situ) that has been previously treated with mastectomy or lumpectomy and radiation, +/- tamoxifen.
Deleterious mutations in BRCA1 or 2 OR A priori risk assessment of 20% chance or greater of carrying BRCA1/2 gene mutation. The BRCAPRO and Couch model will both be used to asses this risk. If a woman has a 20% risk of carrying a BRCA1/2 mutation by either model, she will meet eligibility criteria.
Prior stage I or II breast cancer at least 2 years out from treatment for invasive disease and no prior use of aromatase inhibitors.
Subjects should be willing to abstain from use of hormonal therapies (e.g. tamoxifen, hormone replacement therapy, oral contraceptive pills, hormone-containing intrauterine devices (IUDs). E-string is acceptable). Venlafaxine will be offered as supportive care for women with menopausal symptoms.
Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
Subject has been counseled regarding her options and has signed the informed consent document.
Baseline dual-emission x-ray absorptiometry (DEXA) scan with bone mineral density (BMD) T-score greater than or equal to 2.5 at antero posterior (AP) spine.
Hemoglobin greater than or equal to 11 g/dl.
Creatinine less than 1.5 times the upper limits of normal.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) less than 2.5 times upper limit of normal.
No investigational agent for the past 30 days.
If history of cancer (other than squamous or basal cell skin cancers), subject must have no evidence of disease at time of enrollment AND no history of cancer directed treatment in the 2 years preceding enrollment.
EXCLUSION CRITERIA:
Current or recent chronic use (within 3 months) of hormonal medications, e.g. oral contraceptive pills, hormone replacement therapy, tamoxifen, raloxifene, IUD with progestins or corticosteroids. (Subjects on chronic topical or inhaled steroids will be eligible for the study.) Current use of phenytoin, carbamazepine, rifampin due to increased estrogen metabolism.
History of clotting or bleeding disorder.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to exemestane (e.g. anastrozole, letrozole, formestane).
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. | Contradiction |
2 cases of hematolysis were recorded in the primary trial, none in the secondary trial. | Adverse Events 1:
Total: 9/157 (5.73%)
Blood disorder 1/157 (0.64%)
Hemoglobin decreased 1/157 (0.64%)
Hemolysis 0/157 (0.00%)
Arrhythmia 0/157 (0.00%)
Cardiac disorder 0/157 (0.00%)
Myocardial ischemia 1/157 (0.64%)
Hearing impaired 0/157 (0.00%)
Tinnitus 0/157 (0.00%)
Cataract 0/157 (0.00%)
Diplopia 0/157 (0.00%)
Glaucoma 0/157 (0.00%)
Vision blurred 0/157 (0.00%)
Adverse Events 2:
Total: 14/157 (8.92%)
Blood disorder 0/157 (0.00%)
Hemoglobin decreased 2/157 (1.27%)
Hemolysis 1/157 (0.64%)
Arrhythmia 0/157 (0.00%)
Cardiac disorder 0/157 (0.00%)
Myocardial ischemia 0/157 (0.00%)
Hearing impaired 2/157 (1.27%)
Tinnitus 1/157 (0.64%)
Cataract 1/157 (0.64%)
Diplopia 0/157 (0.00%)
Glaucoma 1/157 (0.64%)
Vision blurred 1/157 (0.64%)
Adverse Events 1:
Total: 6/168 (3.57%)
FEBRILE NEUTROPENIA 3/168 (1.79%)
ENTERITIS 1/168 (0.60%)
PERIPHERAL NEUROPATHY 2/168 (1.19%)
DEPRESSION 1/168 (0.60%) | Contradiction |
There were no cases of Cellulitis, Vertigo or Anaemia in the primary trial. | Adverse Events 1:
Total: 8/101 (7.92%)
Vertigo * 1/101 (0.99%)
Infected lymphocele * 1/101 (0.99%)
Ejection fraction decreased * 5/101 (4.95%)
Lymphoedema * 1/101 (0.99%) | Contradiction |
the primary trial only recorded three types of adverse events. | Adverse Events 1:
Total: 3/30 (10.00%)
Cholecystitis * [1]1/30 (3.33%)
Increase in diarrhea * [2]1/30 (3.33%)
Flank pain * [3]1/30 (3.33%) | Entailment |
All participants of the primary trial must have recently undergone either an echocardiography. | Inclusion Criteria:
Normal (greater than 50%) left ventricular ejection fraction (LVEF) by MUGA scan or echocardiography. | Contradiction |
postmenopausal women are eligible for the primary trial, and Premenopausal women are eligible for the secondary trial. | Inclusion Criteria:
The patient must be postmenopausal woman.
INCLUSION CRITERIA
Premenopausal, defined as any of: | Entailment |
Patients with Breast cancers that have estrogen receptors are included in the primary trial. | Inclusion Criteria:
Patients with node-negative, ER or PR-positive tumors 4 cm in size whose tumors are low risk (defined as a score of 0-17) on an Oncotype DX profile are not eligible. | Contradiction |
Patients in cohort 1 of the primary trial receive Exemestane twice as often as cohort 2 patients receive Cytoxan. | INTERVENTION 1:
A: Exemestane
ARM A: Patients will be treated with exemestane.
Exemestane: 25 mg daily by mouth for 6 to 12 months.
INTERVENTION 2:
B: Docetaxel and Cytoxan
ARM B: Patients will be treated with docetaxel and cytoxan.
Docetaxel: Docetaxel (75 mg/m²) into a vein once every 3 weeks for 6 cycles (6 times in about 24 weeks).
Cytoxan: Cytoxan (600 mg/m²) into a vein once every 3 weeks for 6 cycles (6 times in about 24 weeks). | Contradiction |
There were significantly more cases of ventricular tachycardia than Supraventricular tachycardia in cohort 2 of the primary trial. | Adverse Events 2:
Supraventricular tachycardia * 1/107 (0.93%)
Tachycardia * 1/107 (0.93%) | Contradiction |
patients with Phosphoinositide 3-kinase inhibitor based treatments are eligible for the primary trial, if this treatment ended over 5 years prior. | Exclusion Criteria:
Have received previous treatment with PI3K inhibitors | Contradiction |
the primary trial and the secondary trial do not have the same duration of intervention administration. | INTERVENTION 1:
Post-menopausal Women Using Adjuvant Letrozole
Part A Routine Care Letrozole; Part B Double Dose Letrozole in overweight/obese participants
Letrozole: Part A Monitor standard of care letrozole use for 28 days; measure blood levels of estrogens and vitamin D at start and end of period. Part B In overweight/obese participants who completed Part A, provide a double dose of letrozole and monitor use for 28 days; measure blood levels of estrogens and vitamin D at start and end of period.
INTERVENTION 1:
Neratinib 40 mg
Neratinb 40 mg qd
INTERVENTION 2:
Neratinib 80 mg
Neratinib 80 mg qd | Entailment |
the primary trial recorded the same number of occurences for every type of adverse event. | Adverse Events 1:
Total: 3/9 (33.33%)
Fatigue * 1/9 (11.11%)
Non-cardiac chest pain * 1/9 (11.11%)
Sepsis * 1/9 (11.11%)
Urinary tract infection * 1/9 (11.11%)
Syncope * 1/9 (11.11%)
Anxiety * 1/9 (11.11%)
Thromboembolic event * 1/9 (11.11%) | Entailment |
Patients in the primary trial receive a lower dose of Zometa by IV than the secondary trial patients receive of ado-trastuzumab emtansine. | INTERVENTION 1:
Zoledronic Acid 5 mg IV
Zometa (Zoledronic Acid) 5 mg IV given over 15 minutes as a one time dose. Follow-up at month 1 & every 2 months to month 12 for serum & urine markers of bone destruction (NTx & CTx).
INTERVENTION 1:
Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1)
Patients receive 250 mg PO daily PI3K inhibitor BYL719 on days 1-21 and 3.6mg/kg IV over 30-90 minutes on day 1 ado-trastuzumab emtansine (T-DM1). Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
PI3K inhibitor BYL719: Given PO
Ado-trastuzumab emtansine: Given IV
Pharmacological study: Correlative studies
Laboratory biomarker analysis: Optional correlative studies | Entailment |
Not a single patient in the primary trial suffered from Congestive Heart Failure (during active treatment). | Outcome Measurement:
Number of Patients With Congestive Heart Failure (CHF) While on Active Treatment
[Not Specified]
Time frame: 6 months
Results 1:
Arm/Group Title: AC/PTL
Arm/Group Description: Standard doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (80 mg/m^2) x 12 with concurrent standard dose trastuzumab (weekly x 12, then repeat 3 weeks for an additional 9 months) plus daily lapatinib (modified to 750 mg during Paclitaxel + Trastuzumab + Lapatinib (PTL) and 1000 mg during trastuzumab + lapatinib (TL)) for a total of 12 months.
Overall Number of Participants Analyzed: 109
Measure Type: Number
Unit of Measure: participants 0 | Entailment |
the primary trial had a total of 3 patients experiencing pancreas related adverse events, the secondary trial had 0. | Adverse Events 1:
Total: 103/1408 (7.32%)
Anaemia 1/1408 (0.07%)
Angina pectoris 1/1408 (0.07%)
Myocardial infarction 1/1408 (0.07%)
Atrial fibrillation 0/1408 (0.00%)
Sinus tachycardia 0/1408 (0.00%)
Tachycardia 0/1408 (0.00%)
Vertigo 0/1408 (0.00%)
Diarrhoea 22/1408 (1.56%)
Vomiting 12/1408 (0.85%)
Nausea 4/1408 (0.28%)
Abdominal pain 2/1408 (0.14%)
Pancreatitis 2/1408 (0.14%)
Adverse Events 2:
Total: 85/1408 (6.04%)
Anaemia 1/1408 (0.07%)
Angina pectoris 0/1408 (0.00%)
Myocardial infarction 1/1408 (0.07%)
Atrial fibrillation 1/1408 (0.07%)
Sinus tachycardia 1/1408 (0.07%)
Tachycardia 1/1408 (0.07%)
Vertigo 1/1408 (0.07%)
Diarrhoea 1/1408 (0.07%)
Vomiting 1/1408 (0.07%)
Nausea 1/1408 (0.07%)
Abdominal pain 0/1408 (0.00%)
Pancreatitis 1/1408 (0.07%)
Adverse Events 1:
Total: 46/170 (27.06%)
Anaemia 1/170 (0.59%)
Febrile neutropenia 1/170 (0.59%)
Cardiac tamponade 1/170 (0.59%)
Myocarditis 1/170 (0.59%)
Pericardial effusion 2/170 (1.18%)
Pericarditis 1/170 (0.59%)
Colitis 1/170 (0.59%)
Constipation 1/170 (0.59%)
Diarrhoea 0/170 (0.00%)
Gastroenteritis eosinophilic 0/170 (0.00%)
Intestinal obstruction 0/170 (0.00%)
Adverse Events 2:
Total: 0/1 (0.00%)
Anaemia 0/1 (0.00%)
Febrile neutropenia 0/1 (0.00%)
Cardiac tamponade 0/1 (0.00%)
Myocarditis 0/1 (0.00%)
Pericardial effusion 0/1 (0.00%)
Pericarditis 0/1 (0.00%)
Colitis 0/1 (0.00%)
Constipation 0/1 (0.00%)
Diarrhoea 0/1 (0.00%)
Gastroenteritis eosinophilic 0/1 (0.00%)
Intestinal obstruction 0/1 (0.00%)
Nausea 0/1 (0.00%) | Entailment |
the secondary trial and the primary trial give their patient cohorts Stem Cell Transplants on the first day of the study. | INTERVENTION 1:
High-dose Chemotherapy
Carboplatin + Cyclophosphamide + Thiotepa
Carboplatin : Target AUC of 20, then divided into 4 doses given by vein (IV) days -6, -5, -4, -3 prior to stem cell infusion.
Thiotepa : 120 mg/m^2 by vein days -6, -5, -4, -3 prior to stem cell infusion.
Stem Cell Transplant : Stem Cell Transplant on Day 0.
Cyclophosphamide : 1.5 gm/m^2 by vein days -6, -5, -4, -3 prior to stem cell infusion.
INTERVENTION 1:
Samarium 153-EDTMP + Stem Cell Transplant
Samarium 153-EDTMP tracer dose = 30 millicurie (mCi) intravenous Day 1; or with study drug to bones, receive higher therapy dose of 153 Sm-EDTMP 7-14 days after tracer dose. Stem Cell Transplant Day 0, about 14-21 days after Samarium 153-EDTMP. | Entailment |
Only two types of adverse events, Leukopenia and Anaemia, occurred in more than 1% of patient in cohort 1 of the primary trial. | Total: 672/2264 (29.68%)
Febrile neutropenia * 117/2264 (5.17%)
Neutropenia * 98/2264 (4.33%)
Febrile bone marrow aplasia * 14/2264 (0.62%)
Anaemia * 8/2264 (0.35%)
Leukopenia * 8/2264 (0.35%)
Thrombocytopenia * 6/2264 (0.27%)
Disseminated intravascular coagulation * 3/2264 (0.13%)
Agranulocytosis * 1/2264 (0.04%)
Bone marrow failure * 1/2264 (0.04%) | Contradiction |
Patients with aspartate aminotransferase more than 2 times the upper limit of normal are excluded from both the secondary trial but eligible for the primary trial. | Exclusion Criteria:
AST or ALT > 2.5 times the upper limit of normal (ULN)
ALT and AST 2.5 times ULN ( 5 times ULN in the presence of documented liver metastases) | Contradiction |
0/49 the primary trial Participants With HER2-expressing Metastatic and/or Unresectable Breast Cancer had a Maximum change from baseline in QTcF of <60ms. | Outcome Measurement:
Changes in QTcF After Treatment With DS-8201a in Participants With HER2-expressing Metastatic and/or Unresectable Breast Cancer
The number of participants with notable electrocardiogram changes meeting predefined criteria is being reported.
Time frame: Screening (within 7 days before enrollment) up to Cycle 3 Day 15 (each cycle is 21 days)
Results 1:
Arm/Group Title: DS-8201a
Arm/Group Description: Participants who received 6.4 mg/kg of DS-8201a as an intravenous (IV) infusion once every 3 weeks on Day 1 of each 21-day cycle.
Overall Number of Participants Analyzed: 49
Measure Type: Count of Participants
Unit of Measure: Participants Maximum change from baseline in QTcF: >30 ms: 3 6.1%
Maximum change from baseline in QTcF: >60 ms: 0 0.0% | Contradiction |
According to the results of the primary trial the MTD of dasatinib in combination with weekly paclitaxel is approximately is 120 mg. | Outcome Measurement:
Phase I Portion: Maximum Tolerated Dose/MTD of Dasatinib When Administered in Combination With a Fixed Dose of Weekly Paclitaxel.
[Not Specified]
Time frame: Through completion of Phase I, up to 1 year
Results 1:
Arm/Group Title: Dasatinib and Paclitaxel
Arm/Group Description: The phase I portion is a standard, three-patient per cohort, dose escalation schedule will be used. Between 6 and 54 patients will likely be necessary to determine the MTD of dasatinib in combination with weekly paclitaxel.
The phase II portion of this trial has a Simon two-stage design to determine the efficacy of dasatinib when administered in combination with paclitaxel.
Dasatinib and Paclitaxel: A treatment cycle will consist of 28 days, according to the following schedule:
Dasatinib 120MG PO once daily, Weekly paclitaxel 80 mg/m2 given intravenously over 1 hour on day 1, 8, and 15 of a 28 day cycle.
The trial will initially test the combination of weekly paclitaxel and dasatinib given PO, once daily , continuously. In case of 2 dose-limiting toxicities (DLT) in the first cohort (0), the next cohort will test dasatinib given with a different schedule, 5 days on and 2 days off, omitting dasatinib the day prior and the day of administration of paclitaxel.
Overall Number of Participants Analyzed: 15
Measure Type: Number
Unit of Measure: mg of dasatinib 120 | Entailment |
Patients with Leukemia, Hepatitis or Cataracts cannot be included in the primary trial. | Inclusion Criteria:
Adult women with proven diagnosis of advanced adenocarcinoma of the breast (locoregional recurrent or metastatic disease).
Women who are not of childbearing potential.
ER-positive and/or Progesterone receptor (PgR)-positive tumor based on local laboratory results (test as per local practice).
HER2-negative breast cancer based on local laboratory results (test as per local practice or local guidelines).
Patients must be appropriate candidates for letrozole therapy.
Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
Adequate bone marrow function.
Adequate liver function
Adequate renal function.
Exclusion Criteria:
Known hypersensitivity to letrozole, or any of its excipients, or to any palbociclib excipients.
Current use of food or drugs known to be potent inhibitors or inducers of CYP3A4 isoenzymes within 7 days prior to study entry.
Prior treatment with any CDK inhibitor.
Previous participation in a palbociclib clinical study.
Participation in other studies involving investigational drug(s) within 2 weeks prior to study entry and/or during study participation.
QTc >480 msec; history of QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes.
High cardiovascular risk, including, but not limited to recent myocardial infarction, severe/unstable angina and severe cardiac dysrhythmias in the past 6 months prior to enrollment.
Diagnosis of any second invasive malignancy within the last 3 years prior to enrollment. Note: patients with adequately treated basal cell or squamous cell skin cancer, a history of intraepithelial neoplasia or in situ disease (eg, carcinoma in situ of the cervix or melanoma in situ) may enter.
Active uncontrolled or symptomatic brain metastases. Previously treated and clinically stable, brain metastases are permitted.
Other severe acute or chronic medical or psychiatric conditions.
Patients who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees directly involved in the conduct of the study. | Contradiction |
the primary trial participants are treated with hypnosis, this is not used at all in the secondary trial. | INTERVENTION 1:
Hypnotherapy
Patients randomized to the hypnosis arm of the study will undergo individually three one-hour sessions with a certified hypnotherapist. These sessions will be one week apart. Patients will also be instructed on the use of self-hypnosis techniques to use at home.
INTERVENTION 2:
Gabapentin
Patients randomized to the gabapentin arm will be prescribed 900mg of the drug daily (300 mg by mouth three times daily).
INTERVENTION 1:
Digital Breast Tomosynthesis
Digital Breast Tomosynthesis + Synthetic Mammography (DBT)
The DBT was independently read by two radiologists. A consensus meeting decided whether to recall the woman or not.
Women selected for further assessment (positive screening exam) was recalled.
Digital Breast Tomosynthesis + Synthetic Mammography: Two-view tomosynthesis performed with GE SenoClaire 3D Breast Tomosynthesis.
INTERVENTION 2:
Digital Mammography
The digital mammograms was independently read by two radiologists. A consensus meeting decided whether to recall the woman or not.
Women selected for further assessment (positive screening exam) was recalled.
Digital mammography: Two-view digital mammography performed with GE SenoClaire 3D Breast Tomosynthesis. | Entailment |
the primary trial does not record any cardiac related adverse events. | Adverse Events 1:
Total: 112/458 (24.45%)
Febrile neutropenia 8/458 (1.75%)
Neutropenia 6/458 (1.31%)
Anaemia 3/458 (0.66%)
Thrombocytopenia 3/458 (0.66%)
Pancytopenia 2/458 (0.44%)
Myocardial infarction 0/458 (0.00%)
Pericardial effusion 0/458 (0.00%)
Tachycardia 0/458 (0.00%)
Acute myocardial infarction 1/458 (0.22%)
Atrial fibrillation 0/458 (0.00%)
Adverse Events 2:
Total: 39/221 (17.65%)
Febrile neutropenia 5/221 (2.26%)
Neutropenia 1/221 (0.45%)
Anaemia 2/221 (0.90%)
Thrombocytopenia 0/221 (0.00%)
Pancytopenia 0/221 (0.00%)
Myocardial infarction 2/221 (0.90%)
Pericardial effusion 2/221 (0.90%)
Tachycardia 2/221 (0.90%)
Acute myocardial infarction 0/221 (0.00%)
Atrial fibrillation 1/221 (0.45%) | Contradiction |
the primary trial had a higher occurrence rate of fistula enterovesical than the secondary trial. | Adverse Events 1:
fistula enterovesical 1/74 (1.35%)
Adverse Events 1:
Total: 11/50 (22.00%)
Anemia 3/50 (6.00%)
Febrile neutropenia 1/50 (2.00%)
Arrythmia 1/50 (2.00%)
Ileus 1/50 (2.00%)
Nausea 1/50 (2.00%)
Pain-Abdominal 1/50 (2.00%)
Vomiting 1/50 (2.00%)
Bronchial infection 1/50 (2.00%)
Sepsis 1/50 (2.00%)
Neutropenia 2/50 (4.00%)
Platelet count decreased 1/50 (2.00%)
Dehydration 1/50 (2.00%)
Arthralgia 1/50 (2.00%) | Entailment |
dosages are specified in the intervention section of the secondary trial, whereas for the primary trial these are not made clear. | INTERVENTION 1:
Lidocaine Patch
Lidocaine patch 5% (Lidoderm®, Endo Pharmaceuticals Inc.): 1 patch was applied topically to the affected site(s) for 12 hours each day.
INTERVENTION 2:
Placebo Patch
Placebo patch: 1 patch was applied topically to the affected site(s) for 12 hours each day.
INTERVENTION 1:
Letrozole, Breast Enhancement, Safety
Single arm of healthy postmenopausal women to have two breast MRI (baseline and post-treatment). Letrozole of 12.5 mg/day is given for three successive days just prior to the second MRI. | Entailment |
the primary trial and the secondary trial use completely different drugs and techniques for their interventions, however they both require trained Radiologists on site for evaluation. | INTERVENTION 1:
Fulvestrant + Anastrozole
Fulvestrant 250 mg Loading Dose Regimen + Anastrozole 1 mg
INTERVENTION 2:
Anastrozole
Anastrozole 1 mg
INTERVENTION 1:
Prone to Supine MRI Evaluated by Radiologist A
Radiologist A, number of participants successfully segmented
INTERVENTION 2:
Prone to Supine MRI Evaluated by Radiologist B
Radiologist B, number of participants successfully segmented | Contradiction |
Patients in the primary trial receive oral pazopanib once daily every day, continuing until disease progression or unacceptable toxicity. | INTERVENTION 1:
Treatment (Pazopanib Hydrochloride)
Patients receive oral pazopanib once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
pazopanib hydrochloride: Given orally
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies | Entailment |
All 4 of the CHF cases in the primary trial, were in cohort 1. | Adverse Events 1:
Cardiac failure congestive 1/32 (3.13%)
Adverse Events 2:
Cardiac failure congestive 0/20 (0.00%) | Contradiction |
the primary trial and the secondary trial have entirely different adverse event profiles. | Adverse Events 1:
Total: 28/36 (77.78%)
Lymphocytopenia 210/36 (27.78%)
Neutropenia 29/36 (25.00%)
Anemia 26/36 (16.67%)
Thrombocytopenia 24/36 (11.11%)
Hyperglycemia 27/36 (19.44%)
Nausea 213/36 (36.11%)
Diarrhea 211/36 (30.56%)
Fatigue 215/36 (41.67%)
Flu-like symptoms 26/36 (16.67%)
Hot Flashes 25/36 (13.89%)
AST/ALT elevation 211/36 (30.56%)
Arthralgia 24/36 (11.11%)
Adverse Events 1:
Total: 1/22 (4.55%)
Blood bilirubin increased 1/22 (4.55%)
Alkaline phosphatase increased 1/22 (4.55%) | Entailment |
There were 10x more patients with Left ventricular systolic dysfunction in the primary trial than in the secondary trial. | Adverse Events 1:
Left Ventricular Dysfunction 4/218 (1.83%)
Adverse Events 2:
Left Ventricular Dysfunction 13/228 (5.70%)
Adverse Events 1:
Left ventricular systolic dysfunction 1/82 (1.22%) | Entailment |
Cohort 1 and 2 of the primary trial receive 50mg of different drugs, administered orally from Day 1 to Day 21 | INTERVENTION 1:
Afatinib 50 mg
Patients received continuous daily dosing with Afatinib 50 mg orally from Day 1 to Day 21 of each treatment course. 2 treatment courses were to be given in the trial.
INTERVENTION 2:
Lapatinib 1500 mg
Patients received continuous daily dosing with Lapatinib 1500 mg orally from Day 1 to Day 21 of each treatment course. 2 treatment courses were to be given in the trial. | Contradiction |
All Progression Free Participants (After 16 Weeks of Treatment) in the primary trial were in the Afatinib 50 mg With Letrozole group. | Outcome Measurement:
Percentage of Progression Free Participants After 16 Weeks of Treatment
Progression was defined according to 1 of the following criteria: New bone lesion(s) on bone scan or on magnetic resonance imaging; Progression or occurrence of new lesion(s) according to the Response Evaluation Criteria In Solid Tumours version 1.0 (RECIST); an increase in tumour marker CA 15.3 of more than 20 percent,compared with baseline, at 2 consecutive examinations; occurrence of disease-related skeletal events. If a patient did not fulfil any criteria and was withdrawn because of clinical deterioration amounting to PD according to the Investigator, they were considered as having PD.
Time frame: 16 weeks
Results 1:
Arm/Group Title: Afatinib 50 mg With Letrozole
Arm/Group Description: Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Overall Number of Participants Analyzed: 7
Measure Type: Number
Unit of Measure: Percentage of participants 28.57 (3.67 to 70.96)
Results 2:
Arm/Group Title: Afatinib 40 mg With Letrozole
Arm/Group Description: Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Overall Number of Participants Analyzed: 13
Measure Type: Number
Unit of Measure: Percentage of participants 0.00 (0.00 to 24.71) | Entailment |