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

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ClinicalTrials.gov Identifier: NCT03532295
Recruitment Status : Not yet recruiting
First Posted : May 22, 2018
Last Update Posted : May 23, 2019
Sponsor:
Collaborator:
Incyte Corporation
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Glioma Glioblastoma Drug: Epacadostat Drug: Avelumab Drug: Bevacizumab Radiation: Radiation therapy Procedure: Peripheral blood draw Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 55 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Safety run-in and Phase II Study of Epacadostat in Combination With Radiation Therapy and Avelumab in Patients With Recurrent Gliomas
Estimated Study Start Date : August 31, 2019
Estimated Primary Completion Date : May 31, 2022
Estimated Study Completion Date : August 31, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Safety Run-In
  • Epacadostat 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
Drug: Epacadostat
-All BID doses will be taken in the morning and evening, approximately 12 hours apart

Drug: Avelumab
-In order to mitigate infusion-related reactions, patients must be premedicated with an antihistamine and with acetaminophen prior to the first 4 infusions of avelumab
Other Name: Bavencio

Drug: Bevacizumab
-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
Other Name: Avastin

Radiation: Radiation therapy
-3.5 Gy x 10 fractions (during cycle 1)

Procedure: Peripheral blood draw
  • Baseline (prior to administration of any study treatment)
  • At the end of RT
  • Cycle 2 Day 1 prior to administration of avelumab and bevacizumab
  • Cycle 6 Day 1 prior to administration of avelumab and bevacizumab
  • Cycle 12 Day 1 prior to administration of avelumab and bevacizumab or time of disease progression (if progression occurs before this time point, then collect blood at time of progression only; if no progression has occurred by this time point, the Cycle 12 will be the last collection).

Experimental: Phase II Cohort A (bevacizumab-naïve patients)
  • Epacadostat 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
Drug: Epacadostat
-All BID doses will be taken in the morning and evening, approximately 12 hours apart

Drug: Avelumab
-In order to mitigate infusion-related reactions, patients must be premedicated with an antihistamine and with acetaminophen prior to the first 4 infusions of avelumab
Other Name: Bavencio

Drug: Bevacizumab
-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
Other Name: Avastin

Radiation: Radiation therapy
-3.5 Gy x 10 fractions (during cycle 1)

Procedure: Peripheral blood draw
  • Baseline (prior to administration of any study treatment)
  • At the end of RT
  • Cycle 2 Day 1 prior to administration of avelumab and bevacizumab
  • Cycle 6 Day 1 prior to administration of avelumab and bevacizumab
  • Cycle 12 Day 1 prior to administration of avelumab and bevacizumab or time of disease progression (if progression occurs before this time point, then collect blood at time of progression only; if no progression has occurred by this time point, the Cycle 12 will be the last collection).

Experimental: Phase II Cohort B (bevacizumab-refractory patients)
  • Epacadostat 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
Drug: Epacadostat
-All BID doses will be taken in the morning and evening, approximately 12 hours apart

Drug: Avelumab
-In order to mitigate infusion-related reactions, patients must be premedicated with an antihistamine and with acetaminophen prior to the first 4 infusions of avelumab
Other Name: Bavencio

Drug: Bevacizumab
-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
Other Name: Avastin

Radiation: Radiation therapy
-3.5 Gy x 10 fractions (during cycle 1)

Procedure: Peripheral blood draw
  • Baseline (prior to administration of any study treatment)
  • At the end of RT
  • Cycle 2 Day 1 prior to administration of avelumab and bevacizumab
  • Cycle 6 Day 1 prior to administration of avelumab and bevacizumab
  • Cycle 12 Day 1 prior to administration of avelumab and bevacizumab or time of disease progression (if progression occurs before this time point, then collect blood at time of progression only; if no progression has occurred by this time point, the Cycle 12 will be the last collection).




Primary Outcome Measures :
  1. 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) ]
    • 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

  2. Phase II Cohort A only: Overall survival [ Time Frame: 9 months ]
    -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

  3. Phase II Cohort B only: Overall survival [ Time Frame: 6 months ]
    -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


Secondary Outcome Measures :
  1. Phase II only: Progression-free survival (PFS) [ Time Frame: Through 2 years after completion of treatment (estimated to be 3 years) ]
    • 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

  2. Phase II only: Neurologic functions as measured by the NANO scale [ Time Frame: Through completion of treatment (estimated to be 1 year) ]
    • 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

  3. 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) ]
    -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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03532295


Contacts
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Contact: Jian L Campian, M.D., Ph.D. 314-747-4241 campian.jian@wustl.edu

Locations
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United States, Missouri
Washington University School of Medicine Not yet recruiting
Saint Louis, Missouri, United States, 63110
Contact: Jian L Campian, M.D., Ph.D.    314-747-4241    campian.jian@wustl.edu   
Principal Investigator: Jian L Campian, M.D., Ph.D.         
Sub-Investigator: George Ansstas, M.D.         
Sub-Investigator: Milan G Chheda, M.D.         
Sub-Investigator: Matthew A Ciorba, M.D.         
Sub-Investigator: Jiayi Huang, M.D.         
Sub-Investigator: Dinesh Thotala, Ph.D.         
Sub-Investigator: Christina Tsien, M.D.         
Sub-Investigator: Jingqin (Rosy) Luo, Ph.D.         
Sponsors and Collaborators
Washington University School of Medicine
Incyte Corporation
Investigators
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Principal Investigator: Jian L Campian, M.D., Ph.D. Washington University School of Medicine

Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03532295     History of Changes
Other Study ID Numbers: 18-x110
First Posted: May 22, 2018    Key Record Dates
Last Update Posted: May 23, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Pediatric Postmarket Surveillance of a Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
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Glioblastoma
Glioma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Antibodies, Monoclonal
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Immunologic Factors