Study of Pembrolizumab and M032 (NSC 733972)

Inclusion Criteria:

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 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:

1. 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.
2. Karnofsky Performance Status (KPS) ≥70% (see Appendix B).
3. Life expectancy of greater than 4 weeks.
4. Preoperatively, the lesion must be ≥1.0 cm in diameter as determined by MRI.
5. 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.
6. Ability to understand and the willingness to sign a written informed con-sent document.
7. 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.
8. Patients must have normal organ and marrow function as defined below:

   1. leukocytes……………………. \>3,000/μl
   2. absolute neutrophil count………. \>1,500/μl
   3. platelets…………………………... \>100,000/μl
   4. total bilirubin……………………. within normal institutional limits
   5. AST(SGOT)/ALT(SGPT)………… \<2.5 X institutional upper limit of normal creatinine within normal institutional limits Or
   6. creatinine clearance……………... \>60 mL/min/1.73 m2 for patients with creatinine levels above insti-tutional normal

      Exclusion Criteria:

      A Woman of Child Bearing Potential (WOCBP) who has a positive urine pregnancy test within 72 hours prior to allocation.(see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

      Has received prior therapy with an anti-PD-1, anti-PD-L1, or antiPDL2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137).

      Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to allocation.

      Note: Participants must have recovered from all adverse events (AEs) due to previous thera-pies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.

      Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.

      Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (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 (eg, FluMist®) are live attenuated vaccines and are not allowed.

      Is currently participating in or has participated in a study of an interventionally-directed investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.

      Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent or if the agent is directed at analysis and not treatment (e.g., certain PET tracers, etc.).

      Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 2 mg daily of dexamethasone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.

      Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.

      Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.

      Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pitu-tary insufficiency, etc.) is not considered a form of systemic treatment.

      Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

      Has an active infection requiring systemic therapy.

      Has a known history of Human Immunodeficiency Virus (HIV).

      Has a known history of Hepatitis B (defined as Hepatitis B surface anti-gen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.

      Has a known history of active Bacillus Tuberculosis (TB).

      Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

      Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

      Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening vis-it through 120 days after the last dose of trial treatment.

      Patients who have had chemotherapy, cytotoxic therapy, immunotherapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas), surgical resection within 4 weeks prior to entering the study, or have received experimental viral therapy or gene therapy at any time (e.g., adenovirus, retrovirus or herpes virus protocol). However, this does not preclude re-treatment with M032 at a later date.

      Patients who have not recovered from adverse events due to therapeutic interventions administered more than 4 weeks earlier.

      History of allergic reactions attributed to compounds of similar biologic composition to M032 or to IL-12.

      Tumor involvement which would require ventricular, brainstem, basal ganglia, or posterior fossa inoculation or would require access through a ventricle in order to deliver treatment.

      History of encephalitis within the past 5 years, any history of multiple sclerosis or other CNS infection. Bacterial infections associated with previous cranial operations such as bone flap infections, cerebral abscesses, etc., that have been completely treated will not be exclusions for this trial

      For Phase I, Cohort I: Required steroid increase within 2 weeks of scheduled M032 administration. All study candidates: When possible, the patient should be on a dexamethasone equivalent dose of ≤ 2mg daily at the time of treatment.

      Active herpes lesion.

      Concurrent therapy with any drug active against HSV (acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir).

      Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or any other medical condition that precludes surgery.

      Patients with known history of allergic reaction to IV contrast material that is not amenable to pre-treatment by protocol.

      Patients with pacemakers, ferro-magnetic aneurysm clips, metal infusion pumps, metal or shrapnel fragments or certain types of stents.

      Receipt of Gliadel Therapy.

      Receipt of Bevacizumab (Avastin) therapy within 4 weeks of scheduled M032 administration. (Receipt of Bevacizumab (Avastin) greater than 4 weeks of scheduled M032 administration does not exclude patient.