Inclusion Criteria:
1. Age ≥ 18 years.
2. Life expectancy ≥ 12 weeks.
3. Provision of written informed consent (see Section 16.1 and Appendix 18.5.5) for
participation in the clinical trial.
4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1 for
subjects with solid tumors other than glioblastoma.
5. Karnofsky Performance Status of ≥ 70% for subjects with glioblastoma.
6. Tumor tissue from a surgical or core needle biopsy must be provided to the sponsor
(fine needle aspirate or cytology specimens are not acceptable). Archival formalin
fixed paraffin embedded (FFPE) tissue is acceptable. If archival tumor tissue is not
available, a fresh tumor biopsy must be performed.
7. Subjects must have a tumor accessible for biopsy while on treatment. If the subject
does not have a tumor that is safely accessible for biopsy, the subject may still
participate in the clinical trial following authorization from the sponsor. NOTE:
Subjects with glioblastoma are not required to have tumor accessible for biopsy and
will not undergo a protocol specified biopsy on study.
8. Eligible tumor types in Part 1 Dose Escalation will include subjects with
histologically or cytologically confirmed metastatic or unresectable solid tumors
who have developed disease progression following standard systemic therapy in the
unresectable or metastatic setting. Subjects with cancers that harbor a molecularly
defined oncogenic target for which an FDA approved therapy is available (including
but not limited to EGFR, ROS1, ALK, BRAF, RET, NTRK, KRAS G12C, etc.) should have
received this therapy.
9. Measurable disease.
- - Subjects with solid tumors other than glioblastoma must have measurable disease
per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- - Subjects with glioblastoma: Part 1: must have measurable disease per Response
Assessment in Neuro-Oncology (RANO 2.0); Part 2: measurable disease at baseline
is not required as these subjects will have undergone maximal safe resection
prior to enrollment.
10. Adequate organ function as defined by the following:
- - Absolute neutrophil count (ANC) ≥ 1.2 x 109/L.
- - Hemoglobin ≥ 9.0 g/dL (without a blood transfusion 2 weeks prior to the
hemoglobin measurement).
- - Platelet count ≥ 100 x 109/L (without a platelet transfusion 2 weeks prior to
the platelet measurement).
- - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN.
- - Total bilirubin ≤ 1.5 x ULN (or ≤ 3 x ULN for subjects with Gilbert's
syndrome).
- - International normalized ratio (INR) ≤ 1.5 x ULN and activated partial
thromboplastin time (aPTT) ≤ 1.5 x ULN (unless the subject is being treated
with anticoagulant medication).
- - Serum albumin ≥ 2.8 g/dL.
- - Creatinine clearance (measured or calculated) ≥ 30 mL/min.
11. Female subjects of reproductive potential who are sexually active with a male
partner must:
- - Have a negative serum beta-human chorionic gonadotropin (β-HCG) test within 3
days of cycle 1 day 1.
- - Agree to use highly effective contraceptive measures (as defined in protocol)
from the time of enrollment through 3 months after the last dose of study drug
in the clinical trial.
- - Female subjects are considered to be of non-reproductive potential if they:
have been amenorrheic for greater than 1 year or have undergone surgical
sterilization through tubal ligation, oophorectomy or hysterectomy.
12. Male subjects with a female partner of reproductive potential must agree to use
highly effective contraception (as defined in protocol) from the time of enrollment
through 3 months after the last dose of study drug administration.
13. Subjects must agree to not donate sperm or eggs (ova, oocytes) for the purpose of
reproduction from the time of enrollment through 3 months after the last dose of
study drug administration.
14. Toxicities from prior anti-cancer therapy must have resolved to grade ≤ 1.
- - Exceptions include vitiligo, endocrinopathies managed with hormone replacement
therapy, alopecia, and grade 2 neuropathy or hearing loss.
Exclusion Criteria:
1. Treatment with anticancer therapy within 14 days or 5 half-lives (whichever is
shorter) of cycle 1 day 1. Palliative radiation therapy to a non-CNS metastasis is
permitted if completed at least 14 days prior to cycle 1 day 1.
2. History of other active malignancy that required treatment within 2 years of
enrollment. Exceptions include the following:
- - Early-stage/localized tumors that have received definitive/curative treatment
and have low risk of recurrence (including but not limited to cutaneous
squamous cell or basal cell carcinoma, in situ cervical or bladder cancer, and
early-stage prostate cancer).
- - Early-stage prostate cancer in which observation without treatment is
recommended.
3. Clinically significant cardiovascular conditions as defined by the following:
- - New York Heart Association (NYHA) congestive heart failure class ≥ II.
- - Left ventricular ejection fraction ≤ 50%.
- - Clinically significant cardiac arrhythmia requiring treatment within 3 months
of enrollment.
Subjects with cardiac arrhythmias on stable management for over
3 months prior to enrollment are permitted.
- - Prolonged QTcF interval > 480 ms.
- - Myocardial infarction, stroke, or pulmonary embolism within 3 months of
enrollment.
4. CNS metastases or leptomeningeal carcinomatosis (applicable to subjects with solid
tumors other than glioblastoma). Subjects with brain metastases are eligible for
participation if one of the following criteria are met:
- - CNS metastases have been treated with surgical resection or radiation therapy
and have remained stable for at least 4 weeks (repeat imaging required at least
4 weeks following resection or last radiation therapy) prior to cycle 1 day 1.
- - The subject is neurologically asymptomatic and there are ≤ 4 CNS metastases no
larger than 1 cm.
5. Treatment with immunosuppressive medications.
- - Treatment with corticosteroids greater than the equivalent of prednisone 10
mg/day within 2 weeks of cycle 1 day 1 is exclusionary.
Exceptions include:
Premedication with corticosteroids for iodine contrasted CT scans; Chronic use
of ≤ 10 mg/day of prednisone (or equivalent). Topical, inhaled, and
intra-articular corticosteroid use is allowed; Subjects with glioblastoma are
permitted to be on ≤ 3 mg/day dexamethasone (or equivalent).
6. History of severe pulmonary disease defined as either of the following:
- - History of interstitial lung disease, non-infectious pneumonitis (including
immune checkpoint inhibitor induced pneumonitis), or pulmonary fibrosis.
- - Currently dependent on supplemental oxygen.
7. History of allogeneic stem cell or solid organ transplantation.
8. History of autoimmune disease that required systemic immunosuppressive therapy
within 2 years of enrollment. Subjects with autoimmune diseases managed with hormone
replacement or topical therapies are eligible.
9. History of an immune-mediated adverse event from treatment with an immune checkpoint
inhibitor that resulted in treatment discontinuation.
- - Subjects who discontinued treatment with ipilimumab due to toxicity and
subsequently tolerated treatment with an anti-PD-(L)1 inhibitor without
treatment-limiting toxicity are eligible.
10. History of severe hypersensitivity reaction (≥ grade 3) to infusion of a therapeutic
monoclonal antibody.
11. Any major surgery within 4 weeks of receiving the first dose of the investigational
treatment.
12. Women who are pregnant or breast feeding.
13. Subjects with active (acute or chronic) bacterial, viral, or fungal infection at the
time of enrollment are ineligible with the following exceptions:
- - Subjects with human immunodeficiency virus (HIV) are eligible for participation
if the following criteria are met: CD4+ T cell count ≥350 cells/µL, No history
of AIDS-defining opportunistic infections within 12 months of enrollment,
Subjects must be on antiretroviral therapy for at least 4 weeks and have an HIV
viral load less than 400 copies/mL prior to enrollment.
- - Subjects with chronic hepatitis B (HBV) who are on suppressive antiviral
therapy prior to enrollment are eligible.
Subjects with chronic HBV who are not
eligible for treatment with suppressive antiviral therapy are ineligible.
- - Subjects with a history of hepatitis C (HCV) infection who have completed
curative antiviral treatment and have an HCV viral load below the limit of
quantification are eligible.
14. Ongoing drug or alcohol abuse at the time of enrollment.
15. Any medical or psychiatric illness or social circumstance that could jeopardize
compliance with the protocol directed treatment and safety assessments.
Additional Exclusion Criteria Specific for the Part 2A
- - Newly Diagnosed MGMT
Unmethylated Glioblastoma Cohort:
1.
Subjects with recurrent or secondary GBM.
2. Subjects who underwent biopsy only without maximal safe resection.
3. Subjects with a contraindication to MRI scans.
4. Subjects with IDH-1 or IDH-2 mutations or H3 K27M diffuse midline glioma.
5. Subjects with unresolved CNS hemorrhage, leptomeningeal or spinal metastases or
ventricular invasion.
6. Subjects treated with a carmustine wafer implant.
7. Subjects treated with Tumor Treating Fields (TTF).
