Patient case: 64-year-old male with Cholangiocarcinoma. Genetic variant: IDH1 (R132H). Other conditions: Neuropathy.

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

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.

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.

Eligibility: Inclusion Criteria:
  1. Male or female subjects aged ≥18 years.
  2. Documentation of IDH1 or IDH2 mutation in any tumor specimen.
  3. Pathologic evidence (diagnostic pathology slides available 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:
  1. Any progressive glioma with IDH1 or IDH2 mutation, regardless of WHO grade or histopathological diagnosis, may be eligible contingent on approval by the overall Principal Investigator 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. 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.
  3. Microsatellite instability as identified by polymerase chain reaction (PCR) or other validated methods 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 can not 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 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 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 can have had any number of prior therapies. 9. Karnofsky performance status (Attachment 2) of ≥60. 10. 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.
  11. 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 PD-1/PD-L1, 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.
  12. An interval of at least 2 weeks (to start of study agent) between prior surgical resection or one week for stereotactic biopsy.
  13. 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).
  14. 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 60 days after the last dose of Avelumab. WOCBP must have a negative pregnancy test within 28 days of initiation of dosing. (Note: The effects of the trial drug on the developing human fetus are unknown; thus, WOCBP and men able to father a child must agree to use 2 highly effective contraception methods). Women may be included if they are either surgically sterile (hysterectomy or bilateral oophorectomy at least 6 weeks prior with confirmation of reproductive status by follow up hormone level assessment) or are postmenopausal (natural, spontaneous amenorrhea with an appropriate clinical profile for ≥1 year or 6 months with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL). Highly effective contraception is defined as a method with a failure rate of less than 1 % per year, including but not limited to:
  a. True Abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
  b. Sterilization: Surgical bilateral oophorectomy (with or without hysterectomy) as above, or tubal ligation at least six weeks prior.
  c. Male Partner Sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female subjects on the study, the vasectomised male partner should be the sole partner for that participant.
  d. Use of a combination of any two of the following:
  1. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 2. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository e. Appropriate hormonal contraceptives (including any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent - including oral, subcutaneous, intrauterine, or intramuscular agents) 15. Willing to and capable of providing written informed consent, or have an acceptable surrogate capable of giving consent on the subject's behalf, prior to any study related procedures.
  16. 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. Prior re-irradiation or stereotactic radiosurgery for recurrent disease at the same tumor location intended for HFRT in this study.
  6. 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 7 days prior to registration.
  2. Administration of steroids through a route known to result in a minimal systemic exposure (i.e., intranasal, intraocular, inhaled or topical corticosteroids (<5% of body surface area) for the treatment of mild/moderate asthma, allergies or dermatitis) are permitted.
  3. Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg prednisone or bioequivalent per day.
  7. Known immunosuppressive disease, active autoimmune disease requiring chronic immunosuppressive therapy, prior organ transplant, including allogeneic stem cell transplantation. The following are not exclusions:
  1. Diabetes type I, Vitiligo, hypo- or hyperthyroid, or psoriasis that does not require systemic immunosuppressive treatment are eligible
  2. Prior corneal transplant may be allowed to enroll following approval from the overall Principal Investigator.
  8. Known history of, or any evidence of active, non-infectious pneumonitis within the last 5 years.
  9. Known severe (NCI-CTCAE v4.03 Grade 3 or 4) infusion-related allergy or acute hypersensitivity reaction attributed to any monoclonal antibody, any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma)
  10. Active infection requiring systemic therapy, including known infection with human immunodeficiency virus (HIV), or known active infection with hepatitis B or hepatitis C virus.
  11. Has received a live vaccine within 4 weeks of the first dose of avelumab or while on trial. 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.
  12. Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 4.03; however, alopecia and sensory neuropathy Grade ≤ 2 is acceptable
  13. 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.
  14. Unstable or severe intercurrent medical or psychiatric conditions or uncontrolled infection.
  15. Pregnant or breastfeeding (negative pregnancy test required), or unable to maintain use of contraception while on study and for 60 days after the last dose of Avelumab.
  16. Known alcohol or drug abuse
  17. All other significant diseases (for example, inflammatory bowel disease, uncontrolled asthma), which, in the opinion of the Investigator, might impair the subject's tolerance of trial treatment.
  18. Any psychiatric condition that would prohibit the understanding or rendering of informed consent

Relevance to patient case: not relevant