Clinical Trials /

Epacadostat in Combination With Radiation Therapy and Avelumab in Patients With Recurrent Gliomas

NCT03532295

Description:

In this study, the investigators propose to combine epacadostat with radiation therapy (RT), avelumab, and bevacizumab 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.

Related Conditions:
  • Astrocytoma
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Epacadostat in Combination With Radiation Therapy and Avelumab in Patients With Recurrent Gliomas
  • Official Title: A Safety run-in and Phase II Study of Epacadostat in Combination With Radiation Therapy and Avelumab in Patients With Recurrent Gliomas

Clinical Trial IDs

  • ORG STUDY ID: 18-x110
  • NCT ID: NCT03532295

Conditions

  • Glioma
  • Glioblastoma

Interventions

DrugSynonymsArms
EpacadostatSafety Run-In
AvelumabBavencioSafety Run-In
BevacizumabAvastinSafety Run-In

Purpose

In this study, the investigators propose to combine epacadostat with radiation therapy (RT), avelumab, and bevacizumab 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.

Trial Arms

NameTypeDescriptionInterventions
Safety Run-InExperimentalEpacadostat is an oral medication that will be taken twice a day every day without regard to food during each 21-day cycle Avelumab will be given intravenously at a dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle Bevacizumab will be given intravenously at a dose of 5 mg/kg on Days 1 and 15 of each 28-day cycle 10 fractions of radiation therapy will be given at a dose of 3.5 Gy per fraction Dosing of epacadostat will start on the first day of radiation therapy. Avelumab and bevacizumab may be started up to a week before the first day of radiation therapy but must be given no later than the first day of radiation therapy. The first cycle of treatment may be more than 28 days depending on when treatment with avelumab and bevacizumab starts. Cycle 2 will start after the participant has received 28 days of treatment with epacadostat
  • Epacadostat
  • Avelumab
  • Bevacizumab
Phase II Cohort A (bevacizumab-naïve patients)ExperimentalEpacadostat is an oral medication that will be taken twice a day every day without regard to food during each 21-day cycle Avelumab will be given intravenously at a dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle Bevacizumab will be given intravenously at a dose of 5 mg/kg on Days 1 and 15 of each 28-day cycle 10 fractions of radiation therapy will be given at a dose of 3.5 Gy per fraction Dosing of epacadostat will start on the first day of radiation therapy. Avelumab and bevacizumab may be started up to a week before the first day of radiation therapy but must be given no later than the first day of radiation therapy. The first cycle of treatment may be more than 28 days depending on when treatment with avelumab and bevacizumab starts. Cycle 2 will start after the participant has received 28 days of treatment with epacadostat
  • Epacadostat
  • Avelumab
  • Bevacizumab
Phase II Cohort B (bevacizumab-refractory patients)ExperimentalEpacadostat is an oral medication that will be taken twice a day every day without regard to food during each 21-day cycle Avelumab will be given intravenously at a dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle Bevacizumab will be given intravenously at a dose of 5 mg/kg on Days 1 and 15 of each 28-day cycle 10 fractions of radiation therapy will be given at a dose of 3.5 Gy per fraction Dosing of epacadostat will start on the first day of radiation therapy. Avelumab and bevacizumab may be started up to a week before the first day of radiation therapy but must be given no later than the first day of radiation therapy. The first cycle of treatment may be more than 28 days depending on when treatment with avelumab and bevacizumab starts. Cycle 2 will start after the participant has received 28 days of treatment with epacadostat
  • Epacadostat
  • Avelumab
  • Bevacizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Safety Run-In: histologically confirmed grade III (including those with 1p/19q
             codeletion) or IV glioma or high risk grade II glioma who were treated with radiation
             and chemotherapy previously. High risk grade II gliomas are IDH wild-type and 1p/19q
             noncodeleted astrocytoma.

          -  Phase II: histologically confirmed WHO grade IV glioblastoma or gliosarcoma.

          -  GBM variants and secondary GBM are allowed for all patients.

          -  Disease must have recurred and patient must be a candidate for re-irradiation and
             bevacizumab. Any number of recurrences are allowed.

          -  Prior use of bevacizumab is allowed for all safety run-in patients and for Cohort B
             (n=19) phase II patients. Cohort A (n=24) patients must be bevacizumab-naïve.

          -  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 ≤ 1.5 x IULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 by
                  Cockcroft-Gault for patients with creatinine levels above 1.5 x IULN

               -  Serum total bilirubin ≤ IULN OR conjugated bilirubin ≤ 2.0 x IULN for patients
                  with total bilirubin > IULN

               -  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.

          -  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).

        Exclusion Criteria:

          -  A history of other non-CNS malignancy ≤ 5 years previous with the exception of basal
             cell or squamous cell carcinoma of the skin which were treated with local resection
             only or carcinoma in situ of the cervix or other surgically cured malignancies

          -  Tumors in the brainsem or cerebellum (i.e., infratentorial)

          -  Currently receiving any other investigational agents.

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to epacadostat, avelumab, 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.

          -  Persisting toxicity related to prior therapy (CTCAE > grade 1); however, alopecia,
             sensory neuropathy ≤ grade 2, or other ≤ grade 2 not constituting a safety risk based
             on the investigator's judgment are acceptable

          -  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.

          -  Prior organ transplantation including allogeneic stem cell transplantation.

          -  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 an active infection requiring systemic therapy.

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or IDO
             inhibitor.

          -  Receiving monoamine oxidase inhibitors (MAOIs) or drug which has significant MAOI
             activity (meperidine, linezolid, methylene blue) within the 21 days before screening.

          -  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.

          -  Any history of serotonin syndrome (SS) after receiving serotonergic drugs.

          -  Has a known history of HIV (HIV 1/2 antibodies).

          -  Has known active hepatitis B (e.g., HBsAg reactive or HBV DNA detected by quant RT
             PCR) or hepatitis C (e.g. HCV RNA [qualitative] 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. ECG may be repeated in triplicate,
             and if the average QTcF is < 480 ms, the patient may participate. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety run-in only: Safety and tolerability of the regimen as measured by dose-limiting toxicities (DLTs) in cycle 1
Time Frame:Completion of cycle 1 for all patients in Safety Run-In (estimated to be 6 months)
Safety Issue:
Description:6 patients will be enrolled at the 100 mg BID dose of epacadostat during the safety run-in DLT will be defined as any of grade ≥3 non-hematological AEs considered at least possibly related to the drug regimen that occur during the first cycle of treatment, with severity graded according to the NCI/CTCAE 4.0, with the following exceptions (provided they are manageable with medication): Rash Fatigue Diarrhea Nausea

Secondary Outcome Measures

Measure:Phase II only: Progression-free survival (PFS)
Time Frame:Through 2 years after completion of treatment (estimated to be 3 years)
Safety Issue:
Description: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
Measure:Phase II only: Neurologic functions as measured by the NANO scale
Time Frame:Through completion of treatment (estimated to be 1 year)
Safety Issue:
Description: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
Measure:Safety and toxicity of regimen as measured by adverse events experienced by participant
Time Frame:90 days after completion of treatment (estimated to be 1 year and 90 days)
Safety Issue:
Description:-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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated

October 31, 2019