Retifanlimab and Epacadostat in Combination With Radiation and Bevacizumab in Patients With Recurrent Gliomas

Study Overview
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Brief Summary
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In this study, the investigators propose to combine retifanlimab with radiation therapy (RT) and bevacizumab with or without epacadostat in the treatment of recurrent glioblastoma (GBM). The investigators hypothesize that this combination provides a powerful synergy between RT and immune modulators to produce more robust anti-tumor immune response, induce tumor regression and improve overall survival.

Official Title
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Safety and Efficacy Study of Retifanlimab and Epacadostat in Combination With Radiation and Bevacizumab in Patients With Recurrent Gliomas

Conditions
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Glioma, Glioblastoma

Intervention / Treatment
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* Drug: Epacadostat
* Drug: Bevacizumab
* Radiation: Radiation therapy
* Procedure: Peripheral blood draw
* Drug: Retifanlimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recurrent WHO grade 4 glioblastoma or gliosarcoma, including molecular features of glioblastoma and WHO grade 4 astrocytoma or WHO grade high grade glioma. Other GBM variants and secondary GBM are allowed. All grade 4 gliomas that have relapsed more than once may be included, as the prognosis of multiply recurrent grade 4 glioma patients may not differ based on IDH mutation status. Disease must have recurred, and patient must be a candidate for re-irradiation and bevacizumab. Any number of recurrences are allowed. Patients must have measurable disease per RANO criteria. Lesions will be considered measurable when they are bi-dimensional with clearly defined margins of ≥5 mm in two perpendicular diameters. Prior transient use of bevacizumab for cerebral edema or radiation necrosis is allowed without a washout period. Prior bevacizumab use is permitted if used for treatment of disease if administered more than 4 months prior to registration. At least 18 years of age. Karnofsky performance status ≥ 60% Normal bone marrow and organ function as defined below: Absolute neutrophil count ≥ 1,000/mcL Platelets ≥ 75,000/mcL Hemoglobin ≥ 9.0 g/dL or > 5.6 mmol/L (transfusion is acceptable to meet this criterion) Serum creatinine ≤ ULN or creatinine clearance ≥ 60 mL/min/1.73 m2 by Cockcroft-Gault for patients Serum total bilirubin ≤ 1.5 ULN AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN INR or PT ≤ 1.5 x IULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants aPTT ≤ 1.5 x IULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants At least 28 days from any major surgery such as craniotomy and surgical wound is fully healed, and at least 14 days from LITT or biopsy. Prior to surgery, there must be imaging evidence of measurable progressive disease (PD) per RANO criteria as noted above. Women of childbearing potential and men must agree to use highly effective 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 participating in this study, she must inform her treating physician immediately. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Prior use of the Optune device is allowed, without a washout period. However, concurrent Optune use is not permitted while on treatment for this trial. Exclusion Criteria: Currently receiving any other investigational agents. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to epacadostat, retifanlimab, bevacizumab, or other agents used in the study. Dexamethasone dose > 4 mg daily at the time of registration (higher dose of steroid for symptom control is allowed during the study). History of intracranial abscess within 6 months prior to start of study therapy. Has active autoimmune disease or syndrome (i.e. moderate or severe rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, active inflammatory bowel disease) that has required systemic treatment in the past 2 years (i.e. with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) or who are receiving systemic therapy for an autoimmune or inflammatory disease (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. Subjects are permitted to enroll if they have vitiligo, resolved childhood asthma/atopy, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger. Has a severe acute or chronic medical condition including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis, or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study. Has had an allogeneic tissue/solid organ transplant. Has an active infection requiring intravenous antibiotic therapy. Has a known history of active tuberculosis (TB; bacillus tuberculosis). Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or IDO inhibitor. If a patient is enrolled to regimen B, they are prohibited from receiving monoamine oxidase inhibitors (MAOIs) or drug which has significant MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before screening. If a patient is enrolled to regimen B, the use of any UGT1A9 inhibitor from screening through follow-up period, including acitretin, amitriptyline, androsterone, cyclosporine, dasatinib, diclofenac, diflunisal, efavirenz, erlotinib, estradiol (17-beta), flutamide, gefitinib, gemfibrozil, glycyrrhetinic acid, glycyrrhizin, imatinib, imipramine, ketoconazole, linoleic acid supplements, mefenamic acid, mycophenolic acid, niflumic acid, nilotinib, phenobarbital, phenylbutazone, phenytoin, probenecid, propofol, quinidine, ritonavir, sorafenib, sulfinpyrazone, valproic acid, and verapamil is prohibited. If a patient is enrolled to regimen B, the use of probiotics from screening through end of treatment is prohibited. If a patient is enrolled to regimen B, the use of warfarin is prohibited. If anti-coagulation is needed during the conduct of the study and non-warfarin regimens are not feasible, the participant must discontinue study therapy. Chronic use of systemic antibiotics (> 14 days) unless medical monitor review and approval. Any history of serotonin syndrome (SS) after receiving serotonergic drugs. Has uncontrolled HIV (HIV 1/2 antibodies). Well-controlled HIV is defined as CD4+ count > 300 cells, undetectable viral load, and receiving HAART/ART. Study specific HIV testing is not required for patients who do not have any prior history of HIV. Has uncontrolled active hepatitis B (e.g., HBsAg reactive or HBV DNA detected by quant RT PCR) or hepatitis C (e.g. HCsAg reactive or HCV RNA [qualitative or quantitative] is detected). Uncontrolled intercurrent illness including, but not limited to, clinically significant (i.e. active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 60 months prior to enrollment), congestive heart failure (≥ NYHA class II), unstable angina pectoris, or serious cardiac arrhythmia requiring medication. History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's opinion, is clinically meaningful. Screening QTc interval > 480 msec will require investigator's evaluation on patient's eligibility. Subjects with left bundle branch block are excluded. Presence of a gastrointestinal condition that may affect drug absorption. Receipt of live attenuated vaccine within 30 days before the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist) are live attenuated vaccines and are not allowed. Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test prior to the start of study treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regimen A: Retifanlimab+RT+bevacizumab<br>Retifanlimab will be given intravenously over the course of 30 to 60 minutes at a dose of 500 mg on Day 1 of each 28-day cycle. Bevacizumab will be given intravenously at a dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle. Ten fractions of radiation therapy will be given at a dose of 3.5 Gy per fraction Retifanlimab and bevacizumab will be started approximately two weeks before the first day of radiation therapy Treatment may continue for up to two years. | Drug: Bevacizumab<br>* -The first infusion will be over the course of 90 minutes; if tolerated, the second infusion will be over the course of 60 minutes; if tolerated, all subsequent infusions will be over 30 minutes<br>* Other names: Avastin;Radiation: Radiation therapy<br>* -The gross tumor maximum diameter (to be irradiated) to be </= 6 cm in the first 6 patients. If more than 1 target is irradiated, then the sum of all the target maximum diameters should be </= 6 cm. No more than 3 separate targets for RT is allowed.<br>Procedure: Peripheral blood draw<br>* Baseline (prior to administration of any study treatment) Before initiation of RT (up to 7 days prior to start of RT; may be on the same day as RT before RT treatment) At the end of RT and/or Cycle 2 Day 1 prior to administration of INCMGA00012 with our without epacadostat Cycle 3 Day 1 prior to administration of INCMGA00012 with or without epacadostat (+/- 7 days) Cycle 5 Day 1 prior to administration of INCMGA00012 with our without epacadostat (+/- 7 days) Time of disease progression<br>Drug: Retifanlimab<br>* -Will be supplied by Incyte<br>* Other names: INCMGA00012;|
| Experimental: Regimen B: Retifanlimab+RT+bevacizumab+epacadostat<br>Retifanlimab will be given intravenously over the course of 30 to 60 minutes at a dose of 500 mg on Day 1 of each 28-day cycle. Bevacizumab will be given intravenously at a dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle. Ten fractions of radiation therapy will be given at a dose of 3.5 Gy per fraction Retifanlimab and bevacizumab will be started approximately two weeks before the first day of radiation therapy Epacadostat will be administered orally at 400 mg BID. Treatment may continue for up to two years. | Drug: Epacadostat<br>* -All BID doses will be taken in the morning and evening, approximately 12 hours apart<br>Drug: Bevacizumab<br>* -The first infusion will be over the course of 90 minutes; if tolerated, the second infusion will be over the course of 60 minutes; if tolerated, all subsequent infusions will be over 30 minutes<br>* Other names: Avastin;Radiation: Radiation therapy<br>* -The gross tumor maximum diameter (to be irradiated) to be </= 6 cm in the first 6 patients. If more than 1 target is irradiated, then the sum of all the target maximum diameters should be </= 6 cm. No more than 3 separate targets for RT is allowed.<br>Procedure: Peripheral blood draw<br>* Baseline (prior to administration of any study treatment) Before initiation of RT (up to 7 days prior to start of RT; may be on the same day as RT before RT treatment) At the end of RT and/or Cycle 2 Day 1 prior to administration of INCMGA00012 with our without epacadostat Cycle 3 Day 1 prior to administration of INCMGA00012 with or without epacadostat (+/- 7 days) Cycle 5 Day 1 prior to administration of INCMGA00012 with our without epacadostat (+/- 7 days) Time of disease progression<br>Drug: Retifanlimab<br>* -Will be supplied by Incyte<br>* Other names: INCMGA00012;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | -Overall survival is defined as the time interval from date of treatment start to date of first documented death event (death due to any cause) or date of censoring. If a patient has not had an event, OS will be censored at the date of last follow up | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Duration of time from start of treatment to radiographic progression or death due to any cause, whichever occurs first Radiographic progression will be assessed using the RECIST 1.1. If the disease recurrence/progression assessment involves more than one date, the earliest date will be used as the event date. A patient will be censored at the date of the last radiographic disease assessment indicating a lack of disease progression, if any of the following occurs before documented disease progression: alive and lack evidence of progression at the end of study or at the time of analysis data cut-off, disease progression or death occurs right after missing data for a scheduled radiographic disease assessment, patient receives non-protocol treatment, or equivocal findings of recurrence - treatment may continue until the next scheduled assessment. If recurrence is confirmed at the next scheduled assessment, the date of recurrence should be the earlier date when recurrence was suspected | Through 2 years after completion of treatment (estimated to be 4 years) | 
| Neurologic functions as measured by the NANO scale | Neurologic Function in Neuro-Oncology (NANO) scale is a scoring assessment based on direct observation and testing performed during clinical evaluation There are 9 domains (gait, strength, ataxia, sensation, visual fields, facial strength, language, level of consciousness, and behavior The score defines overall response criteria Each domain is subdivided into 3 or 4 levels of function with scores based on discrete quantifiable measures. Thus, levels of function for each domain range from 0 to 2 or 0 to 3. A score of 0 indicates normal function, while the highest score indicates the most severe level of deficit for that domain. Levels of function are distinguished by significant and measurable differences in order to avoid misinterpretation of subtle or nonspecific changes | Through completion of treatment (estimated to be 2 years) | 
| Safety and toxicity of regimen as measured by adverse events experienced by participant | -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting | 90 days after completion of treatment (estimated to be 2 years and 90 days) |