A Phase I/II Study of Pembrolizumab and M032 (NSC 733972), a Genetically Engineered HSV-1 Expressing IL-12, in Patients with Recurrent/Progressive and Newly Diagnosed Glioblastoma Multiforme, Grade 3 or Grade 4 Astrocytoma, or Gliosarcoma
This Phase I (Cohort I and Cohort II) and Phase II trial is designed to confirm the safety and tolerability of Pembrolizumab when given in conjunction with M032, an Oncolytic Herpes Simplex Virus (oHSV) that expresses IL-12 and perform the Phase II portion using a Recommended Phase 2 Dose (RP2D) of M032 (provided by the Phase I) when given in conjunction with Pembrolizumab for recurrent malignant glioma (glioblastoma multiforme, anaplastic astrocytoma, or glio-sarcoma).
⁃ Phase I/Cohort I: Participants are eligible to be included in the study only if all of the following criteria apply:
⁃ Patients must have histologically or cytologically confirmed glioblastoma multiforme, anaplastic astrocytoma, or gliosarcoma, and is deemed a potential candidate for resection of the recurrent tumor.
⁃ Prior therapy: Patients must have failed external beam radio-therapy to the brain, and if eligible and tolerated, undergone appropriate treatment with temozolomide chemotherapy. All radiation and additional chemotherapies must have been completed at least 4 weeks prior to enrollment. Prior therapy with nitrosoureas must have been completed at least 6 weeks prior to enrollment.
⁃ Phase I/Cohort II or Phase II: Participants are eligible to be included in the study only if all of the following criteria apply:
⁃ Patient must have MRI findings consistent with probable malignant glioma, have no previous diagnosis of glioma, and have had either no history of any surgery for brain tumor. The exception to this requirement is that patients who have under-gone biopsy for diagnosis only and have not received any other treatment. All patients must be potential candidates for resection of the probably malignant glioma tumor.
⁃ Should a patient in Phase I/Cohort II or Phase II be found on final pathologic diagnosis to not have a glioblastoma multiforme, anaplastic astrocytoma, or gliosarcoma, he/she will receive no other doses of M032 other than that administered at the time of craniotomy, nor will he/she receive any doses of Pembrolizumab. He/she will be followed for evidence of toxicity of M032 only and will be considered off-study for all efficacy and other secondary endpoints.
⁃ All newly diagnosed patients, whether in Phase I/Cohort II or Phase II shall also be required to meet the following eligibility and be subject to the exclusion criteria below:
• Age ≥18 years. Because no dosing or adverse event data are currently available on the use of M032 in patients \<16 years of age, children are excluded from this study but will be eligible for future pediatric phase 1 single-agent trials.
• Karnofsky Performance Status (KPS) ≥70% (see Appendix B).
• Life expectancy of greater than 4 weeks.
• Preoperatively, the lesion must be ≥1.0 cm in diameter as determined by MRI.
• The effects of M032 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for six months after receiving the final dose of M032. Because it is currently unknown if M032 can be transmitted by sexual contact, a barrier method of birth control must be employed and for six (6) months following the administration of the last dose of this study drug. Should a woman become pregnant while participating in this study, she should inform her treating physician immediately. Subjects should also refrain from donating blood during the trial.
• Ability to understand and the willingness to sign a written informed con-sent document.
• Females of childbearing potential must not be pregnant; this will be con-firmed by a negative serum pregnancy test within 14 days prior to starting study treatment.