Clinical Trials /

Avelumab With Hypofractionated Radiation Therapy in Adults With Isocitrate Dehydrogenase (IDH) Mutant Glioblastoma

NCT02968940

Description:

The purpose of this study is to test how safe and effective treatment with the combination of Avelumab and radiation is for IDH mutant gliomas that have transformed to glioblastoma after chemotherapy.

Related Conditions:
  • Glioma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Avelumab With Hypofractionated Radiation Therapy in Adults With Isocitrate Dehydrogenase (IDH) Mutant Glioblastoma
  • Official Title: A Phase II, Open-label, Single Arm, Multicenter Study of Avelumab With Hypofractionated Radiation in Adult Subjects With Transformed IDH Mutant Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: 16-01179
  • NCT ID: NCT02968940

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
AvelumabMSB0010718CAvelumab and hypofractionated radiation therapy(HFRT)

Purpose

The purpose of this study is to test how safe and effective treatment with the combination of Avelumab and radiation is for IDH mutant gliomas that have transformed to glioblastoma after chemotherapy.

Detailed Description

      The active pharmaceutical ingredient in Avelumab (MSB0010718C) is a fully human antibody of
      the immunoglobulin gamma-1 (IgG1) isotype that specifically targets and blocks the Programmed
      death-ligand 1(PD-L1) for Programmed cell death protein 1 (PD-1).

      Avelumab binds PD-L1 and blocks the interaction between PD-L1 and PD-1. This removes the
      suppressive effects of PD-L1 on anti-tumor cluster of differentiation 8 (CD8)+ T cells,
      resulting in the restoration of cytotoxic T cell response.
    

Trial Arms

NameTypeDescriptionInterventions
Avelumab and hypofractionated radiation therapy(HFRT)ExperimentalAvelumab 10 mg/kg intravenously (IV) every 2 weeks. Hypofractionated radiation therapy to a total dose of 30 Gy, delivered in 6 Gy per fraction for 5 consecutive daily fractions

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Male or female subjects aged ≥18 years.
    
              2. Documentation of IDH1 or IDH2 mutation in any tumor specimen.
    
              3. Pathologic evidence (either diagnostic pathology slides or pathology report) of a
                 diagnosis of WHO grade II or III glioma prior to treatment with temozolomide or PCV
                 chemotherapy.
    
              4. Histopathological evidence of glioblastoma (WHO grade IV) on a progressive tumor
                 specimen after treatment with temozolomide or PCV chemotherapy. The diagnosis of
                 glioblastoma must be confirmed on central review by a study-designated
                 neuropathologist at NYULMC at screening.
    
            Exceptions to this eligibility include the following:
    
            a. Any progressive glioma with IDH1 or IDH2 mutation, regardless of WHO grade,
            histopathological diagnosis, or prior therapy, will be eligible if the progressive tumor
            specimen is found to have one of the genetic alterations below:
    
              1. ≥20 somatic mutations per Mb by whole-exome sequencing
    
              2. High mutation burden or microsatellite instability (MSI) identified by Foundation
                 Medicine panel next-generation sequencing (FoundationOne®, FoundationOne CDx™).
                 Foundation Medicine's threshold for high mutation burden (HMB) in their panel NGS
                 assays is ≥20 somatic mutations per Mb. Foundation Medicine's panel NGS assay has been
                 validated by whole-exome and whole-genome sequencing to correlate tightly with tumor
                 mutation burden (R2 = 0.94).96
    
              3. Mutation in a mismatch repair gene or other genes known to be associated with
                 hypermutator phenotypes or microsatellite instability, including but not limited to
                 MSH2, MSH6, MLH1, POLE, PMS2, POLD as determined by validated methods.
    
              4. Microsatellite instability as identified by polymerase chain reaction (PCR) or other
                 validated methods.
    
                 b. Progressive oligodendroglioma (with 1p/19q codeletion) that has hallmark
                 histopathological features of glioblastoma (i.e. necrosis, pseudopalisading necrosis,
                 or microvascular proliferation) is eligible as IDH1/2 mutant, 1p/19q codeleted
                 oligodendrogliomas that have progressed after chemotherapy have been shown to develop
                 hypermutation phenotype.
    
              5. Availability of a paraffin-embedded or frozen tumor-tissue block with a minimum of 1
                 cm2 of tumor surface area from a tissue specimen that demonstrates pathological
                 transformation to glioblastoma (WHO grade IV) or a progressive specimen that harbors
                 one of the genetic alterations specified in Inclusion Criteria 4a. a. If a tumor block
                 cannot be submitted, then 20 unstained slides (preferably 10 slides from two different
                 tumor blocks from the same surgery) from the tumor specimen must be submitted.
    
              6. Patients must have had treatment with temozolomide, lomustine (CCNU) or PCV
                 [procarbazine, lomustine (CCNU), vincristine] chemotherapy prior to histopathologic
                 transformation to glioblastoma or prior to identification of one of the genetic
                 alterations specified in Inclusion
    
            Criteria 4a. Notes or records from the treating oncologist are required for documentation
            of treatment history. Prior treatment with at least one of the following chemotherapy
            schedules is required to be eligible:
    
              1. At least one 6 week course of continuous daily temozolomide
    
              2. At least six 28-day cycles given in one of the following schedules:
    
                   1. Daily for 5 days of a 28-day cycle
    
                   2. Daily for 21 days of a 28-day cycle
    
                   3. Daily for 14 days of a 28-day cycle
    
                   4. Alternating 7 days on/7 days per 28-day cycle
    
                   5. Continuous daily dosing of a 28-day cycle.
    
              3. Other schedules of temozolomide may be considered after discussion with the overall
                 Principal Investigator.
    
              4. At least 3 cycles of PCV or lomustine (CCNU) chemotherapy. 7. Patients who received
                 anti-tumor therapy after histopathologic transformation to glioblastoma must have
                 shown unequivocal radiographic evidence of tumor progression by contrast-enhanced MRI
                 scan (or CT scan if MRI is contraindicated).
    
                 8. Patients must have had prior CNS radiotherapy for their glioma, including standard
                 doses for lowgrade or high-grade glioma as well as non-standard dose and
                 fractionation, including hypofractionated regimens, stereotactic radiosurgery, etc.
    
                 9. Patients can have had any number of prior therapies, including but not limited to
                 molecularly targeted therapies and anti-angiogenic therapies, however they must have
                 had prior chemotherapy with either temozolomide or lomustine as per Eligibility
                 Criteria 6.
    
                 10. Karnofsky performance status of ≥60. 11. Interval of at least 6 months from the
                 completion of any prior radiotherapy and registration. If patients have not passed an
                 interval of at least 6 months, they may still be eligible if they meet one or more of
                 the following criteria:
    
            a. New areas of tumor outside the original radiotherapy fields as determined by the
            investigator, or b. Histologic confirmation of tumor through biopsy or resection, or c.
            Nuclear medicine imaging, MR spectroscopy, or MR perfusion imaging consistent with true
            progressive disease, rather than pseudoprogression or radiation necrosis obtained within 28
            days of registration AND an interval of at least 90 days between completion of radiotherapy
            and registration.
    
            12. The following time periods must have elapsed prior to start of study treatment, the
            following time periods must have elapsed:
    
              1. 5 half-lives from any investigational agent
    
              2. 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from
                 nitrosoureas)
    
              3. 6 weeks from antibodies
    
              4. Prior treatment with other immune modulating agents within fewer than 4 weeks prior to
                 the first dose of Avelumab. 1. Examples of immune modulating agents include blockers
                 of CTLA-4, 4-1BB (CD137), OX-40, therapeutic vaccines, or cytokine treatments.
    
              5. 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies.
    
                 13. An interval of at least 2 weeks (to start of study agent) between prior surgical
                 resection or one week for stereotactic biopsy.
    
                 14. Adequate hematologic, hepatic, and renal function defined by absolute neutrophil
                 count ≥1.5 x 109/L, hemoglobin >9 g/dL, platelet count ≥ 100 x 109/L (may have been
                 transfused), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5
                 x upper limit of normal (ULN), total bilirubin ≤1.5 x ULN, and estimated creatinine
                 clearance (CrCl) ≥ 30 mL/min according to the Cockcroft-Gault formula or local
                 institutional standard method.
    
                 15. Women of child-bearing potential (WOCBP) and men able to father a child must agree
                 to use highly effective contraception while on study drug and for 30 days after the
                 last dose of Avelumab. WOCBP must have a negative pregnancy test within 28 days of
                 initiation of dosing.
    
            Highly effective contraceptive measures include: stable use of oral contraceptives such as
            combined estrogen and progestogen and progestogen only hormonal contraception or other
            prescription pharmaceutical contraceptives for 2 or more menstrual cycles prior to
            screening; intrauterine device [IUD]; intrauterine hormone-releasing system (IUS);
            bilateral tubal ligation; vasectomy and sexual abstinence.
    
              1. Contraception is not required for men with documented vasectomy.
    
              2. Postmenopausal women must be amenorrheic for at least 12 months in order not to be
                 considered of childbearing potential.
    
              3. Pregnancy testing and contraception are not required for women with documented
                 hysterectomy or tubal ligation.
    
                 16. Willing to and capable of providing written informed consent prior to any study
                 related procedures.
    
                 17. Ability and willingness to comply with all study requirements, including scheduled
                 visits, treatment plans, laboratory tests, and other study-related procedures.
    
            Exclusion Criteria:
    
              1. Investigational drug use within 28 days of the first dose of Avelumab.
    
              2. Planned participation in another study of an investigational agent or investigational
                 device or use of a therapeutic device intended for therapy of glioma.
    
              3. Prior therapy with an agent that blocks the PD-1/PD-L1 pathway.
    
              4. Primary brainstem or spinal cord tumor.
    
              5. Diffuse leptomeningeal disease at recurrence
    
              6. Recurrent infratentorial tumor
    
              7. Prior re-irradiation or stereotactic radiosurgery for recurrent disease at the same
                 tumor location intended for HFRT in this study.
    
              8. Maximal tumor diameter >4 cm
    
              9. Patients with evidence of significant intracranial mass effect that requires >4 mg of
                 dexamethasone or bioequivalent per day for 5 consecutive days for management of
                 symptoms at any time within 14 days of registration.
    
                   1. Subjects on a standard high-dose steroid taper after craniotomy may receive a
                      higher dose of corticosteroids within 14 days of registration, however must be at
                      a dose ≤4 mg of dexamethasone or bioequivalent per day within 5 days prior to
                      registration.
    
                   2. Administration of steroids through a route known to result in a minimal systemic
                      exposure [i.e., intranasal, intraocular, inhaled, topical, or local injection
                      (e.g., intra-articular injection) corticosteroids (<5% of body surface area)] are
                      permitted.
    
                   3. Subjects requiring hormone replacement with corticosteroids are eligible if the
                      steroids are at doses ≤ 10 mg prednisone or bioequivalent per day.
    
                   4. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                      premedication) are allowed.
    
             10. Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory
                 agent. The following are not exclusions:
    
                 a. Patients with diabetes type I, vitiligo, hypo- or hyperthyroid diseases, or
                 psoriasis not requiring systemic immunosuppressive treatment are eligible.
    
             11. Prior organ transplantation, including allogeneic stem cell transplantation.
    
             12. Known history of, or any evidence of active, non-infectious pneumonitis within the
                 last 5 years.
    
             13. Known prior, severe hypersensitivity (NCI-CTCAE v4.03 Grade 3 or 4) to investigational
                 product or any component in its formulations including known severe hypersensitivity
                 reactions to monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma
                 (that is, 3 or more features of partially controlled asthma).
    
             14. Active infection requiring systemic therapy.
    
             15. Known history of testing positive for human immunodeficiency virus (HIV) or known
                 acquired immunodeficiency syndrome.
    
             16. Positive test for Hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus
                 (HCV antibody) at screening indicating acute or chronic infection.
    
             17. Vaccination within 4 weeks of the first dose of avelumab and while on trials is
                 prohibited except for administration of inactivated vaccines. Note: Seasonal influenza
                 vaccines for injection are generally inactivated flu vaccines and are allowed; however
                 intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are
                 not allowed.
    
             18. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
                 accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months
                 prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart
                 Association Classification Class II), or serious cardiac arrhythmia requiring
                 medication.
    
             19. Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 4.03; however,
                 alopecia and sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a
                 safety risk based on investigator's judgment, are acceptable.
    
             20. Patients with another active cancer [excluding basal cell carcinoma, cervical
                 carcinoma in situ or melanoma in situ]. Prior history of other cancer is allowed, as
                 long as there was no active disease within the prior 2 years.
    
             21. Pregnant or breastfeeding (negative serum or urine pregnancy test required for women
                 of childbearing potential), or unable to maintain use of contraception while on study
                 and for 30 days after the last dose of Avelumab.
    
             22. Known alcohol or drug abuse
    
             23. All other unstable, severe, or chronic medical conditions 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.
    
             24. Any condition that would prohibit the understanding or rendering of informed consent.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Safety (adverse events) of the protocol therapy
    Time Frame:From beginning of protocol therapy to 28 days after the end of radiation therapy
    Safety Issue:
    Description:The adverse events are evaluated per Common Terminology Criteria for Adverse Events (CTCAE) 4

    Secondary Outcome Measures

    Measure:Overall survival (OS)
    Time Frame:Up to 12 months
    Safety Issue:
    Description:OS will be determined from the time of treatment initiation until the time of death, with OS being censored at last follow-up if the patient remained alive
    Measure:Median PFS
    Time Frame:Up to 12 months
    Safety Issue:
    Description:PFS, defined as the time between treatment initiation and first occurrence of disease progression or death, will be censored at last follow-up if the patient remained alive without disease progression
    Measure:Response Rate
    Time Frame:Up to 12 months
    Safety Issue:
    Description:The radiographic response rate will be estimated with exact 95% confidence intervals
    Measure:Median duration of response
    Time Frame:Up to 12 months
    Safety Issue:
    Description:The radiographic response rate will be estimated with exact 95% confidence intervals

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:New York University School of Medicine

    Trial Keywords

    • Programmed cell death protein 1 (PD-1)
    • Programmed death-ligand 1 (PD-L1)
    • Immunotherapy
    • Hypofractionated Radiotherapy (HFRT)
    • Isocitrate dehydrogenase (IDH)
    • Glioma

    Last Updated

    March 16, 2018