case report form). CTCAE SOC Adverse Event Grade Hospitalization/ Prolongation of Hospitalization Attribution Comments Protocol A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Version Date: June 20, 2018 19 7.4 Expedited Reporting to the Food and Drug Administration (FDA) NA 7.5 Expedited Reporting to Hospital Risk Management Participating investigators will report to their local Risk Management office any participant safety reports or sentinel events that require reporting according to institutional policy. 7.6 Routine Adverse Event Reporting All Adverse Events must be reported in routine study data submissions to the Overall PI on the toxicity case report f orms . AEs reported through expedited processes (e.g., reported to the IRB, FDA, etc.) must also be reported in routine study data submissions. Any AEs related to the PET imaging will also be reported to the RDRC. IMAGING AGENT INFORMATION A list of the adverse events and potential risks associated with the investigational or other agents administered in this study can be found in Section 7.1. 8.1 PBR 8.1.1 Description The chemical name is: N-acetyl -N-(2-methoxybenzyl) -2-phenoxy-5- pyridinamine . 8.1.2 Form PBR is an intravenous injection. The radiopharmaceutical product, PBR , is the only active ingredient and it is dissolved in a solution of ≤10 mL of 95% isotonic saline: 5% ethanol (v:v). PBR is provided as a ready to use isotonic, sterile, pyrogen- free, clear, and colorless solution. PBR is typically packaged in a glass vial and does not contain any preservatives. 8.1.3 Storage and Stability Protocol A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Version Date: June 20, 2018 20 The PBR will be produced onsite the day of the scheduled PET scan at the Martinos Center under the auspicious of the Radiation Drug Review Committee ( RDRC). Proper transportation will take place according to Martinos Center policies. The Martinos Center policies include standard operating procedures for the tracer. These SOP’s have been developed by radiochemist, nuclear medicine experts and the MGH RDRC that oversees all studies using novel PET tracers. Following synthesis and quality control, the radiopharmaceutical will be used within 2 hours of the end of synthesis. 8.1.4 Compatibility NA 8.1.5 Handling Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the environment, should undertake the preparation, handling, and safe disposal of the chemotherapeut ic agent in a self -contained and protective environment. These personnel have undergoing training and certification in the handling of radiolabeled tracers (ex. qualified nuclear medicine technicians) . 8.1.6 Availability PBR will be produced onsite. 8.1.7 Preparation PBR will be produced onsite as a fully prepared agent ready for intravenous administration. Radioactivity dose can be adjusted by modifying the injection volume. No other changes in constitution should be made. Preparation will follow the SO Ps of the Martinos center that have been developed by radiochemist, nuclear medicine experts and the MGH RDRC that oversees all studies using novel PET tracers. All personnel involved have undergoing training and any necessary certification in the handling of radiolabeled tracers. 8.1.8 Administration PBR will be administered by intravenous injection by bolus by a qualified nuclear medicine technician . 8.1.9 Ordering PBR will be prepared on a single injection basis as dictated by MR-PET scheduling of studies at the Martinos Center. Protocol A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Version Date: June 20, 2018 21 8.1.10 Accountability The investigator, or a responsible party designated by the investigator, should maintain a careful record of the inventory and disposition of the agent using the NCI Drug Accountability Record Form (DARF) or another comparable drug accountability form. (See the NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage.) 8.1.11 Destruction and Return At the end of the study, unused supplies of PBR should be decayed in storage according to institutional policies. This will be documented in the PBR individual batch record and scan log. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 9.1 Biomarker Studies NA 9.2 Laboratory Correlative Studies NA STUDY CALENDAR Screening evaluations are to be conducted within 4 week s prior to start of protocol therapy. In the event that the participant’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. Assessments must be performed prior to administration of any study agent . Study assessments and agents should be administered within + 3 days of the protocol- specifi ed date, unless otherwise noted. GBM Patients with suspected Pseudoprogression Pre- Study Post- chemoradiation PET + MRI Xa Informed consent X Medical History X Physical exam X Protocol A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Version Date: June 20, 2018 22 (Ht, Wt, VS) Steroid dose X Xb KPS X Genotyping for Ala/Ala or Ala/Thr statusc X CBC with diff X CMPd X B-HCGe X X Adverse event evaluationf 3.5 hours post -PET scan Follow -upg a – at any point during therapy that a GBM patients has suspected pseudoprogression but within 4 weeks of consent b- Record steroids dose at time of PET scan c – this test will be performed as part of screen after informed consent is obtained. The blood will be sent to Partners HealthCare Personalized Medicine Translational Genomics Core located at 65 Landsdown street at Cambridge. This lab performs this testing for all other current PBR PET studies conducted at MGH. d - Sodium, potassium, chloride, glucose, BUN, creatinine, calcium, total protein, albumin, total bilirubin, SGOT [AST], SGPT [ALT], alkaline phosphatase. e – Serum pregnancy test (for w omen of childbearing potential) to be performed at baseline and prior to each PET. See http://healthcare.partners.org/phsirb/Guidance/Pregnancy_Testing_in_Research_Involving_Radiation.1.0 9.pdf f – Per NCI Adverse Event Reporting Requirements related to PET tracers , the window to collect adverse event is 3.5 hours post PET scan (i.e. 10 t½ of radiotracer) . Patient will be contacted by phone call or clinic visit within 24 hours of scan to assess for adverse event during this window. g – Follow- up every 3 months will assess subsequent treatments, tumor response to treatment, and survival For patients undergoing immunotherapy Pre-Study Pre- Immunotherapy During - Immunotherapy PET + MRI Xa Xb Informed consent X Medical History X Physical exam (Ht, Wt, VS) X Steroid dose X Xc Xc KPS X Protocol A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Version Date: June 20, 2018 23 Genotyping for Ala/Ala or Ala/Thr statusd X CBC with diff X CMPe X B-HCGf X X X Adverse event evaluationg 3.5 post -PET scan 3.5 post -PET scan Follow -uph a – 1-7 days prior to surgery or immunotherapy b – 0-5 days prior to cycle 4 of immunotherapy for metastatic brain cancer patients or prior to cycle 3 of immunotherapy for GBM patients c- Record steroids dose at time of PET scan d– This test will be performed as part of screen after informed consent is obtained. The blood will be sent to Partners HealthCare Personalized Medi cine Translational Genomics Core located at 65 Landsdown street at Cambridge. This lab performs this testing for all other current PBR PET studies conducted at MGH. e - Sodium, potassium, chloride, glucose, BUN, creatinine, calcium, total protein, albumin, total bilirubin, SGOT [AST], SGPT [ALT], alkaline phosphatase. f – Serum pregnancy test (for women of childbearing potential) to be performed at baseline and prior to each PET. See http://healthcare.partners.org/phsirb/Guidance/Pregnancy_Testing_in_Research_Involving_Radiation.1.0 9.pdf g– Per NCI Adverse Event Reporting Requirements related to PET tracers , the window to collect adverse event is 3.5 hours post PET scan (i.e. 10 t½ of radiotracer). Patient will be contacted by phone call or clinic visit within 24 hours of scan to assess for adverse event during this window. h – Follow- up every 3 months will assess subsequent treatments, tu mor response to treatment, and survival MEASUREMENT OF EFFEC T Measurement of effect will be determined by the treating physician per standard of care . The following is only included as reference for the treating physician. 11.1 Antitumor Effect – Solid Tumors RANO criteria ar e recommended to assess response . 15RECIST is recommended for the metastatic brain tumor patients. 11.1.1 Definitions Evaluable for Target Disease response. Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re -evaluated will be considered evaluable for target disease response. These participants will have their response classified according to the definitions stated below. (Note: Participants who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Protocol A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Version Date: June 20, 2018 24 Evaluable Non- Target Disease Response. Participants who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re- evaluated will be considered evaluable for non- target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions. 11.1.2 Disease Parameters Per RANO or RECIST guidelines as appropriate. Measurable disease. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by chest x -ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam . All tumor measurements must be recorded in millimeters (or decimal fractions of centimeter s). Note: Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable. If the investigator thinks it appropriate to include them, the conditions under which such lesions should be considered must be defined in the protocol. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non -measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all considered non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non- measurable) since they are, by definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same participant, these are preferred for selection as target lesions. Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported Protocol A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Version Date: June 20, 2018 25 as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions. All othe r lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as non- target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow up. 11.1.3 Metho ds for Evaluation of Disease All measurements should be taken and recorded in metric notation using a ruler, calipers , or a digital measurement tool. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow- up. Imaging -based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 11.1.4 Response Criteria 11.1.4.1 Evaluation of Target Lesions Per RANO or RECIST guidelines as appropriate. Complete Response (CR) : Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR) : At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) : At lea st a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Protocol A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Version Date: June 20, 2018 26 Stable Disease (SD) : Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. RANO Criteria (JCO 2010; 28:1963-1972) 11.1.4.2 Evaluation of Non- Target Lesions Per RANO or RECIST guidelines as appropriate. Complete Response (CR): Disappearance of all non -target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Non-CR/Non -PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Protocol A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Version Date: June 20, 2018 27 Progressive Disease (PD) : Appearance of one or more new lesions and/or unequivocal progression of existing non- target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treati ng physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator). 11.1.4.3 Evaluation of New Lesions The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning technique, imaging modality, or findings thought to represent something other than tumor (for example, some ‘new’ bone lesions may be simply healing or flare of pre -existing lesions). However, a lesion identified on a follow-up scan in an anatomical location that was not scanned at baseline is considered new and will indicate PD. If a new lesion is equivocal (because of small size etc.), follow -up evaluation will clarify if it truly represents new disease and if PD is confirmed, progression should be declared using the date of the initial scan on which the lesion was discovered. 11.1.4.4 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. For Participants with Measurable Disease ( i.e., Target Disease) Target Lesions Non-Target Lesions New Lesions Overall Response Best Overall Response when Confirmation is Required* CR CR No CR >4 wks Confirmation** CR Non-CR/Non - PD No PR >4 wks Confirmation** CR Not evaluated No PR PR Non-CR/Non - PD/not evaluated No PR SD Non-CR/Non - PD/not No SD Documented at least once >4 wks from baseline** Protocol A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Version Date: June 20, 2018 28 evaluated PD Any Yes or No PD no prior SD, PR or CR Any PD*** Yes or No PD Any Any Yes PD ∗ See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. ** Only for non-randomized trials with response as primary endpoint. *** In exceptional circumstances, unequivocal progression in non- target lesions may be accepted as disease progression. Note : Participants with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort should be made to document the objective progression even after discontinuation of treatment. For Participants with Non -Measurable Disease ( i.e., Non- Target Disease) Non-Target Lesions New Lesions Overall Response CR No CR Non-CR/non -PD No Non-CR/non -PD* Not all evaluated No not evaluated Unequivocal PD Yes or No PD Any Yes PD ∗ ‘Non -CR/non -PD’ is preferred over ‘stable disease’ for non -target disease since SD is increasingly used as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised 11.1.5 Duration of Response Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started , or death due to any cause. Participants w ithout events reported are censored at the last disease evaluation ). Duration of overall complete response: The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is obj ectively documented , or death due to any cause. Participants without events reported are censored at the last disease evaluation . Protocol A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Version Date: June 20, 2018 29 Duration of stable disease : Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements. 11.1.6 Progression -Free Survival Overall Survival : Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. Progression-Free Survival : Progression -Free Survival (PFS) is defined as the time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation. Time to Progression: Time to Progression (TTP) is defined as the time from randomization (or registration) to progression, or censored at date of last disease evaluation for those without progression reported. 11.1.7 Response Review NA 11.2 Antitumor Effect – Hematologic Tumors NA 11.3 Other Response Parameters NA DATA REPORTING / REGULATORY REQUIREME NTS Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: List and Reporting Requirements). 12.1 Data Reporting 12.1.1 Method The QACT will collect, manage, and perform quality checks on the data for this study. 12.1.2 Responsibility for Data Submission Protocol A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Version Date: June 20, 2018 30 Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data forms to the QACT according to the schedule set by the QACT. 12.2 Data Safety Monitoring The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual data from this study . The committee is composed of clinical specialists with experience in oncology and who have no direct relationship with the study. Information that raises any questions about participant safety will be addressed with the Overall PI and study team. The DSMC will review each protocol up to four times a year or more often if required to review toxicity and accrual data. Information to be pr ovided to the committee may include: up -to-date participant accrual; current dose level information; DLT information; all grade 2 or higher unexpected adverse events that have been reported; summary of all deaths occurring with 30 days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths while being treated and during active follow-up; any response information; audit results, and a summary provided by the study team. Other information (e.g.