Avelumab With Hypofractionated Radiation Therapy in Adults With Isocitrate Dehydrogenase (IDH) Mutant Glioblastoma
Condition: Glioblastoma
MeSH terms: Glioblastoma
Intervention: Avelumab; Hypofractionated radiation therapy (HFRT)
Intervention description: Avelumab 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
Intervention MeSH terms: Avelumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Programmed cell death protein 1 (PD-1); Programmed death-ligand 1 (PD-L1); Immunotherapy; Hypofractionated Radiotherapy (HFRT); Isocitrate dehydrogenase (IDH); Glioma

Summary:

      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.
    

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.