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

Inclusion Criteria

• Patient has provided written informed consent.
• ≥ 18 years old at time of screening visit.
• Histologically confirmed GBM at the time of diagnosis.
• First or second relapse by the time of consenting.
• Tumor progression (magnetic resonance imaging [MRI], defined by RANO) post prior treatments.
• Feasibility for re-surgery.
• Karnofsky Performance Status ≥ 70% (requires occasional assistance, but able to care for most of their needs, equivalent to < ECOG 2).
• 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.
• Life expectancy of ≥ 3 months.
• 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).
• Female patients are eligible if they are of:
• Non-childbearing potential, defined as
• Previous hysterectomy or bilateral oophorectomy
• Previous bilateral tubal ligation
• Post-menopausal (total cessation of menses for ≥ 1 year)
• 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
• 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.
• Absence of deteriorating neurological symptoms, new onset of seizures and the need for increasing doses of corticosteroids.
• Absence of toxicity from prior therapy (excluding alopecia) that has not resolved to ≤ Grade 1 unless otherwise specified.
• Absence of other clinically significant concomitant active medical disorder, based on the investigator's judgement

Exclusion Criteria

• The patient has uncontrolled infection.
• 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.
• A gastrointestinal absorption disorder that would limit the bioavailability of oral drugs or if patient cannot take oral drugs.
• 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.
• Pre-existing allergy to ACT001 or related compounds.
• 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.
• A known history of, or any evidence of an active non-infectious pneumonitis.
• 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.
• History of treatment with immune CPB and Avastin (or other antiangiogenic or anti-vascular endothelial growth factor agents).
• High dose of corticosteroids (> 4mg/day of dexamethasone or equivalent for at least 3 consecutive days) within two weeks of enrolment for GBM treatment.
• A patient has received other systemic immunosuppressive treatments such as mTOR inhibitor everolimus four weeks prior to registration.
• A patient has a diagnosis of ongoing immunodeficiency due to other diseases such as human immunodeficiency virus (HIV) infection.
• 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.
• Major surgery within 30 days of commencing first study therapy.
• Pregnant or breast-feeding females.
• A history of infection with HIV or hepatitis B or C viruses.
• The patient has participated in other drug clinical studies < 4 weeks prior to obtaining the informed consent.
• The patient is, in the opinion of the investigator, unsuitable for any other reason.