1 NCT #: NCT02431572 Protocol #: 14-421 TITLE: A pilot s tudy to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Coordina ting Center: DF/HCC *Princip al Investigator (PI): Elizabeth Gerstner , MD Version Date: June 20, 2018 Protocol A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Vers ion Date: June 20, 2018 3 SCHEMA Diseases: Metastatic cancer to the brain (Cohort A) Primary brain tumors (Cohorts B) Diseases: Primary brain tumors (Cohorts C) Immunotherapy Assess inflammation (PBR PET) Assess inflammation (PBR PET) Chemoradiation Assess inflammation (PBR PET) Follow Patients Protocol A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Vers ion Date: June 20, 2018 4 TABLE OF CONTENTS SCHEM A .........................................................................................................................................3 OBJECTIVES ..................................................................................................................................6 1.1 Study Design ............................................................................................................6 1.2 Primary Objectives ...................................................................................................6 1.3 Secondary Objectives ...............................................................................................6 BACKGROUND .............................................................................................................................6 2.1 Study Disease(s) .......................................................................................................6 2.2 IND Agent(s) ...........................................................................................................7 2.3 Other Agent(s) ..........................................................................................................7 2.4 Rationale ..................................................................................................................7 2.5 Correlative Studies Background ..............................................................................9 PARTICIPANT SELECTION .........................................................................................................9 3.1 Eligibility Criteria ....................................................................................................9 3.2 Exclusion Criteria ..................................................................................................11 3.3 Inclusion of Women and Minorities ......................................................................12 REGISTRATION PROCEDURES ...............................................................................................12 4.1 General Guidelines for DF/HCC and DF/PCC Institutions ...................................12 4.2 Registration Process for DF/HCC and DF/PCC Institutions .................................12 4.3 General Guidelines for Other Investigative Sites ..................................................13 4.4 Registration Process for Other Investigative Sites .................................................13 5. IMAGING PLAN ......................................................................................................................13 5.1 Treatment Regimen ................................................................................................13 5.2 Pre-MR-PET Scan Criteria ....................................................................................13 5.3 MR-PET Scan Procedure .....................................................................................14 5.4 General Concomitant Medication and Supportive Care Guidelines ......................15 5.5 Criteria for Taking a Participant Off Protocol Therapy .........................................15 5.6 Duration of Follow Up ...........................................................................................16 5.7 Criteria for Taking a Participant Off Study ...........................................................16 DOSING DELAYS/DOSE MODIFICATIONS ...........................................................................17 ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ........................................17 7.1 Expected Toxicities ................................................................................................17 7.2 Adverse Event Characteristics ...............................................................................17 7.3 Expedited Adverse Event Reporting ......................................................................18 7.4 Expedited Reporting to the Food and Drug Administration (FDA) ......................19 7.5 Expedited Reporting to Hospital Risk Management .............................................19 7.6 Routine Adverse Event Reporting .........................................................................19 Protocol A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy. Vers ion Date: June 20, 2018 5 IMAGING AGENT INFORMATION ..........................................................................................19 8.1 PBR ........................................................................................................................19 BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ....................................................21 9.1 Biomarker Studies ..................................................................................................21 9.2 Laboratory Correlative Studies ..............................................................................21 STUDY CALENDAR ...................................................................................................................21 MEASUREMENT OF EFFECT ....................................................................................................23 11.1 Antitumor Effect – Solid Tumors ..........................................................................23 11.2 Antitumor Effect – Hematologic Tumors ..............................................................29 11.3 Other Response Parameters ...................................................................................29 DATA REPORTING / REGULATORY REQUIREMENTS .......................................................29 12.1 Data Reporting .......................................................................................................29 12.2 Data Safety Monitoring ..........................................................................................30 12.3 Multicenter Guidelines ...........................................................................................30 12.4 Collaborative Agreements Language .....................................................................30 STATISTICAL CONSIDERATIONS ...........................................................................................30 13.1 Study Design/Endpoints .........................................................................................30 13.2 Sample Size, Accrual Rate and Study Duration ....................................................30 13.3 Stratification Factors ..............................................................................................32 13.4 Interim Monitoring Plan ........................................................................................32 13.5 Analysis of Primary Endpoints ..............................................................................32 13.6 Analysis of Secondary Endpoints ..........................................................................33 13.7 Reporting and Exclusions ......................................................................................33 PUBLICATION PLAN .................................................................................................................33 REFERENCES ..............................................................................................................................34 APPENDIX A PERFORMANCE STATUS CRITERIA ..................................................36 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 6 OBJECTIVES 1.1 Study Design This is an imaging pilot study to look at changes in primary and metastatic brain tumor inflammation using PBR PET - a tracer that highlights inflammation. Our goal is to determine if this tracer can be used to detect changes in inflammation during tumor treatment. We will study 3 populations of patients with intracranial tumors : metastatic brain tumor patients treated with immunotherapy, GBM patients undergoing chemoradiation, and GBM patients treated with immunotherapy. PBR PETs will be performed at baseline prior to therapy and then several weeks -months after start of therapy depending on therapy used. The PET studies will be performed using a simultaneous MR- PET imaging scanner . No diagnostic decisions or therapy decisions will be based on any results obtained from these PET scans, and we expect no change in the care of these patients. The success of these studies should enable methods that could be used in larger studies to more completely understand the role of inflammation in the treatment of cancer. 1.2 Primary Objectives 1. To determine whether PET imaging with [11C] PBR2 8 can measure inflammation related to immunotherapy in patients with brain tumors- specifically metastatic brain tumors and glioblastoma. . 2. To determine whether PET imaging with [11C] PBR2 8 can measure inflammation related to chemoradiation in patients with glioblastoma. 1.3 Secondary Objectives 1. NA BACKGROUND 2.1 Study Disease (s) An estimated 51,410 primary brain tumors were diagnosed in 2007, and 19% of these tumors were glioblastomas (CBTRUS - Central Brain Tumor Registry of the United S tates). GBM is the most common malignant primary brain tumor and is a uniformly fatal disease with 5 -year survival rates less than 4% despite aggressive treatment with surgery, radiation and chemotherapy. There is no curative therapy for patients with GBM. Current standard of care for patients with newly diagnosed GBM is concomitant involved field radiation and oral temozolomide chemotherapy followed by monthly temozolomide for 6-12 months. 1 If patients 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 7 relapse, there is no standard of care tr eatment. Immunotherapy is increasingly being explored as a tool to improve outcome for these patients. Metastatic tumors which have spread to the brain are incurable diseases that recently have had modest success with immunotherapy. However, duration of response in the brain is limited for unclear reasons. 2.2 IND Agent(s) 2.2.1 IND Agent #1 NA 2.2.2 IND Agent #2 NA 2.3 Other Agent(s) NA 2.4 Rationale Cancer immunotherapy is rapidly gaining traction as an effective treatment in some forms of cancer. The last several years have seen FDA approval of active cellular immunotherapy for advanced prostate cancer and immune checkpoint blockade via CTLA-4 inhibition for patients with advanced melanoma. Currently, there is great enthusiasm for PD -1 inhibition (checkpoint blockade) via monoclonal antibodies in patients with solid tumors; phase 2 results have yielded high response rates across a spectrum of cancers with relatively little toxicity. In addition, adopti ve T-lymphocyte transfer using ex vivo expanded tumor- infiltrating lymphocytes or chimeric antigen receptors (CAR’s) is showing great promise in patients with melanoma and CD19+ leukemia respectively. Also, phase 2 studies have demonstrated convincing activity of immune -based approaches for both metastatic and primary tumors in the central nervous system. For instance, the response rate for intracranial melanoma metastases is roughly equivalent to that of peripheral lesions treated with CTLA-4 blockade, and glioblastoma peptide vaccination and dendritic cell vaccination approaches are currently in randomized phase 3 and phase 2b clinical trials. Evaluating the impact of immune -based therapies in the short term has been challenging in patients with solid malignancies, including those with brain tumors. Standard imaging evaluation of tumor response, such as the RECIST or RANO criteria, may not accurately reflect what is occurring in the tumor microenvironment during immunotherapy. In essence, contrast-enhancement may reflect therapy -induced inflammation rather than tumor progression. The immunotherapy community has proposed a set of “immune- related response criteria” that may be 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 8 more applicable to these patients. However, as these measures require the si multaneous assessment of multiple lesions, they are poorly suited for understanding response in glioblastoma. There is an expanding number of cases of immunotherapy- associated pseudoprogression in which intensely enhancing and space- occupying lesions resol ve without other intervention after a few weeks. The ability to distinguish between and inflammatory response and tumor progression (which is characterized by an immunosuppressive environment) is critical for providers. There is, therefore, a need for m ore specific imaging of immunotherapy- associated inflammation in patients with intracranial tumors. The 1 8-kDa translocator protein (TSPO) is a protein that is expressed in mitochondria and is particularly prominently expressed by activated microglia, i nfiltrating macrophages, and reactive astrocytes . Thus, it is a marker of neuro-inflammation. PET tracers are being developed that bind to this receptor as a means to measure inflammation. 2 One of these tracers, [11C]PBR28, is a second generation PET tracer that binds to TSPO . This tracer has been used in many studies of CNS disease such as cocaine abuse3, neurocysticercosis4 depression5 Alzheimer’s disease6,7 multiple sclerosis8,9, and seizures10. The tracer has also been used in animal models to look at ischemia related inflammation .11 These studies have shown that this tracer is increased in areas of inflammation in the brain and is safe to use in humans. There are no reported adverse events related to the PBR28 tracer and, in 2014, the Martinos Center manufactured 83 human doses of PBR28 and there were no reports of adverse events related to the doses. Unfortunately there is little data in human brain tumors so it is unclear if this tracer will be equally useful in this patient population. Conflicting data exists regarding TSPO expression in gliomas. One study in rats using an alternate TSPO binding PET tracer suggested increased uptake in tumors 12 where as another human study showed a lack of TSPO expression in microglial associated with h igh grade gliomas .13 The rat study did not specify which cells expressed TSPO. Importantly, these studies were not designed to test the response of human gliomas to treatment or changes in TSPO expression that may occur during treatment. Thus, there is a rationale to further study the role of this tracer in human brain tumors to better characterize its utility in measuring inflammation . One goal with including both glioma patients and metastatic brain tumor patients is to determine if there are differences in PBR 28 uptake based on type of cancer which may suggest differences in TSPO expression within different tumor microenvironments and in inflammatory response to treatment . Given the limited data on this tracer in cancer, it may be more useful in one type of cancer rather than another because of the different underlying biology of tumors. There is a high number of patients with metastatic melanoma to the brain and immunotherapy is commonly used for this patient population so we elected to start with this cohort of patients but are now amending the protocol to include all cancer types as there are now immunotherapy options and clinical trials of immunotherapy for more than just melanoma pati ents. Thus, w e will evaluate [11C]PB28 PET as a tool for measuring inflammation associated with the response to immunotherapy or chemoradiation in patients with brain tumors . Having such a tool that distinguishes active tumor from inflammation will be an incredibly useful tool in the management of patients. If this tracer shows potential utility in this pilot study, we will examine 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 9 it further in separate planned phase II gliom a vaccination studies at our center, in an effort to correlate PET findings with outcome. One limitation of PBR PET is that certain people can be classified as low binders because of a genetic polymorphism. 14 These “low binders” have negligible binding to the PBR28 tracer so would not be informative to include in our study and will be excluded. Only about 10% of human subjects are low affinity binders based on prior data. 14 As part of the screening process , after informed consent has been obtained , a simple blood test will be performed to determine binding affinity of consented patients. Tho se who are low -affinity binders will be not be enrolled . In summary, we our simple goal is to perform two PBR PETs in patients with metastatic brain cancer undergoing treatment with immunotherapy and one PBR PET in patients with GBM to measure inflammatio n. This is similar to performing FDG PETs in these patients but uses a different PET tracer than FDG. Since PBR28 was first used at the Martinos Center, there have been 11 clinical trials approved using this tracer and no adverse events reported. 2.5 Correlat ive Studies Background In addition to PET imaging, MRI scans will be acquired. MRI is a very useful tool to non-invasively probe tumor response to treatment and is already part of the routine management of patients with G BM. The complicated relationship between tumor perfusion, vascular permeability, and tumor cellularity can be assessed by MRI . Dynamic susceptibility contrast (DSC) and dynamic contrast enhanced (DCE) MRI can measure vascular parameters such as cerebral blo od volume (CBV), blood flow, mean transit time, vessel size, and permeability - all of which are impacted by immunotherapy and chemoradiation. These will be exploratory analyses to see if changes in tumor vasculature/cellularity can help interpret changes in PBR uptake. PARTICIPANT SELECTION 3.1 Eligibility Criteria 3.1.1 Participants must have evidence of metastatic cancer to the brain for Cohort A or histologically confirmed GBM for Cohorts B and C . 3.1.2 Those with GBM but suspected to have pseudoprogression at any time after completion of chemoradiation can enroll in Cohort C. 3.1.3 Participants must have measurable brain disease, defined as at least one lesion that is 10 mm in diameter. 3.1.4 Age > 18 years. 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 10 3.1.5 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) 3.1.6 Life expectancy of greater than 3 months . 3.1.7 Participants must have normal organ and marrow function as defined below: − leukocytes ≥3,000/mcL − absolute neutrophil count ≥1,500/mcL − platelets ≥100,000/mcL − total bilirubin within normal institutional limits − AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal − creatinine within normal institutional limits OR − creatinine clearance ≥55 mL/min/1.73 m2 for participants with creatinine levels above institutional normal. 3.1.8 For Cohort A, only patients with metastatic cancer to the brain for whom their treating physician has planned to give immunotherapy as monotherapy are eligible for this study. This can be in the setting of a clinical trial or not. 3.1.9 For Cohort B, only patients with GBM for whom their treating physician has planned to give immunotherapy are eligible for this study . This can be in the setting of a clinical trial or not. 3.1.10 For Cohort C, patients with GBM who have completed standard temozolomide + radiation and have suspected pseudoprogression can enroll. There is no time frame from completion of chemoradiation as pseudoprogression is increasingly recognized at later time points. 3.1.11 Patient must be able to undergo MRI and PET scans. 3.1.12 Patient must be maintained on a stable corticosteroid regimen for 5 days prior each MR- PET scan. 3.1.13 High or mixed affinity binders (Ala/Ala or Ala/Thr) based on genotyping result from PBR affinity test. This blood test will be performed as part of the screening process after consent has been obtained. 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 11 3.1.14 The effects of PBR on the developing human fetus are unknown. For this reason and because radiopharmaceuticals agents are known to be teratogenic, women of child- bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immed iately. Radiopharmaceutical agents are known to be teratogenic. 3.1.15 Ability to understand and the willingness to sign a written informed consent document. 3.2 Exclusion Criteria 3.2.1 History of allergic reactions attributed to compounds of similar chemical or biologic composition to PBR . 3.2.2 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. 3.2.3 Pregnant women are excluded from this study because PBR is a radiopharmaceutical agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to exposure of the mother to PBR , breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study. 3.2.4 HIV-positive participants are excluded because their immune system is compromised and may affect the interpretation of the imaging data . 3.2.5 Patients who are no t suitable to undergo MRI or PET or use gadolinium contrast due to: • Claustrophobia • Presence of metallic objects or implanted medical devices in body (i.e. cardiac pacemaker, aneurysm clips, surgical clips, prostheses, artificial hearts, valves with steel parts, metal fragments, shrapnel, tattoos nea r the eye, or steel implants) The craniotomy patients will all have titanium but this is MRI compatible • Sickle cell disease • Renal failure • Reduced renal function, as determined by creatinine clearance < 30 mL/min based on a serum creatinine level obtained within 28 days prior to registration 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 12 3.3 Inclusion of Women and Minorities Both men and women of all races and ethnic groups are eligible for this trial.