A Study to Evaluate Safety and Efficacy of ACT001 and Anti-PD-1 in Patients With Surgically Accessible Recurrent Glioblastoma Multiforme

The current design provides a window to analyze the impact of the ACT001+Pembrolizumab combination on the tumor microenvironment and disease outcomes.

Phase 1b: The identified RP2D of combined ACT001 with Pembrolizumab will be determined by standard 3+3 dose escalation methodology among three ACT001 dosages (200mg, 400mg and 800mg, BID) with standard Pembrolizumab dosage. Patients will be dosed approximately 2 weeks prior to surgical resection with a single dose of Pembrolizumab and ACT001. Tumor resection will be performed and a biopsy will be obtained from the resected tumor tissue to evaluate the impact of the study drugs on the TME. After recovery from surgery, patients will resume ACT001 and Pembrolizumab until tumor progression (assessed by iRANO) or an AE requiring discontinuation of study drug. The Safety Monitoring Committee (SMC) will review the data available from all evaluable patients at each dose level prior to recommending escalation to the next dose level.

Phase 2a: Using the same dosing schedule and ACT001 dosage as determined in Phase 1b. Patients will be randomized to receive either Pembrolizumab only treatment (Arm A, 10 patients) or ACT001 plus Pembrolizumab treatment (Arm B, 20 patients).

Eligibility Criteria:
Inclusion Criteria:

1. Patient has provided written informed consent.
2. ≥ 18 years old at time of screening visit.
3. Histologically confirmed GBM at the time of diagnosis.
4. First or second relapse by the time of consenting.
5. Tumor progression (magnetic resonance imaging \[MRI\], defined by RANO) post prior treatments.
6. Feasibility for re-surgery.
7. Karnofsky Performance Status ≥ 70% (requires occasional assistance, but able to care for most of their needs, equivalent to \< ECOG 2).
8. Must be ≥ 4 weeks from administration of last dose of cancer therapy (including radiation therapy or chemotherapy). The patient must have recovered from all treatment-related toxicities to less than grade 2 per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
9. Life expectancy of ≥ 3 months.
10. Adequate organ function (absolute neutrophil count ≥1.5 x 109 /L, lymphocytes ≥ 0.5 x 109 /L, platelets ≥ 75 x 109 /L, hemoglobin ≥ 10 g/dl; total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5.0 x ULN if liver metastasis); plasma creatinine ≤ 1.5 x ULN; QTc \< 450 ms (male), \< 470 ms (female).
11. Female patients are eligible if they are of:

    1. Non-childbearing potential, defined as

       * Previous hysterectomy or bilateral oophorectomy
       * Previous bilateral tubal ligation
       * Post-menopausal (total cessation of menses for ≥ 1 year)
    2. Childbearing potential with a negative serum pregnancy test at screening (within 7 days of the first investigational product administration) and uses a highly effective method contraception before study entry and throughout the study until 28 days after the last investigational product administration. Highly effective contraception (\<1% failure rate per year), when used consistently and in accordance with both the product label and the instructions of the physician, are defined as follows:

       * Vasectomized partner who is sterile prior to the female patient's enrolment and is her sole sexual partner
       * An intrauterine device with a documented failure rate of less than 1% per year
       * Double barrier contraception defined as condom with a female diaphragm
12. Male patients, if sexually active, must agree to use a highly effective method of contraception (\< 1% failure rate per year) with their female partners from screening until 28 days following the last study drug administration.
13. Absence of deteriorating neurological symptoms, new onset of seizures and the need for increasing doses of corticosteroids.
14. Absence of toxicity from prior therapy (excluding alopecia) that has not resolved to ≤ Grade 1 unless otherwise specified.
15. Absence of other clinically significant concomitant active medical disorder, based on the investigator's judgement

Exclusion Criteria:

1. The patient has uncontrolled infection.
2. The patient has serious diseases such as unstable angina pectoris, myocardial infarction in the past 6 months, heart failure (New York Heart Association class \> II) or stroke within 6 months prior to the enrollment.
3. A gastrointestinal absorption disorder that would limit the bioavailability of oral drugs or if patient cannot take oral drugs.
4. Uncontrolled brain metastases or spinal cord compression. Patients who were treated with surgical resection or radiation therapy completing at least 4 weeks earlier are eligible if they are neurologically stable, not taking glucocorticoids and have a follow-up. MRI scan performed within the previous 4 weeks showing no tumor progression.
5. Pre-existing allergy to ACT001 or related compounds.
6. A patient has active autoimmune disease managed by systemic treatments in the past 2 years (i.e. the use of corticosteroids, immunosuppressive drugs or other disease modifying agents). Of note, a replacement therapy, e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, is not considered a form of systemic treatment.
7. A known history of, or any evidence of an active non-infectious pneumonitis.
8. Treatment with cancer therapies such as chemotherapy or radiation therapy either currently or within 4 weeks of ACT001 dosing. An exception is focal radiation for symptomatic bone metastases, which must not be within 2 weeks of ACT001 dosing.
9. History of treatment with immune CPB and Avastin (or other antiangiogenic or anti-vascular endothelial growth factor agents).
10. High dose of corticosteroids (\> 4mg/day of dexamethasone or equivalent for at least 3 consecutive days) within two weeks of enrolment for GBM treatment.
11. A patient has received other systemic immunosuppressive treatments such as mTOR inhibitor everolimus four weeks prior to registration.
12. A patient has a diagnosis of ongoing immunodeficiency due to other diseases such as human immunodeficiency virus (HIV) infection.
13. Unresolved toxicity from prior antitumor therapy, defined as toxicities (excluding alopecia) that have not resolved to \< Grade 2 as scored using the CTCAE current version. Exceptions may be allowed for stable toxicities after discussion with the investigator and sponsor.
14. Major surgery within 30 days of commencing first study therapy.
15. Pregnant or breast-feeding females.
16. A history of infection with HIV or hepatitis B or C viruses.
17. The patient has participated in other drug clinical studies \< 4 weeks prior to obtaining the informed consent.
18. The patient is, in the opinion of the investigator, unsuitable for any other reason.