Phase 1 first-in-human, open-label, dose-escalation (3 + 3), dose-expansion clinical trial to evaluate the safety, tolerability and preliminary clinical efficacy of M3T01 (fully human IgG4/kappa monoclonal antibody targeting FasL) in subjects with metastatic or unresectable solid tumors.
Age ≥ 18 years.
Life expectancy ≥ 12 weeks.
Provision of written informed consent (see Section 16.1 and Appendix 18.5.5) for participation in the clinical trial.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1 for subjects with solid tumors other than glioblastoma.
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.
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.
New York Heart Association (NYHA) congestive heart failure class ≥ II.
Sequential
M3T01
DrugSubjects will be treated with M3T01 through an IV infusion over 1 hour given every 3 weeks.
Pembrolizumab
DrugPembrolizumab will be given as standard of care to Cohort DL 5+ under Part 1 of the study. Subjects will receive 200 mg IV once every 3 weeks.
Chemoradiation
RadiationSubjects will be treated with standard of care chemoradiation therapy consisting of TMZ 75 mg/m2 daily with concurrent radiation therapy (60 Gy administered over 6 weeks). Following chemoradiation therapy, subjects will have a 4-week break from TMZ before starting standard adjuvant TMZ 150-200 mg/m2 days 1-5 of 28-day cycles for 6 cycles. Subjects will be treated with M3T01 at the RP2D through an IV infusion every 3 weeks that will begin concurrently with chemoradiation therapy.
FOLFOX regimen
DrugFOLFOX will be given as standard of care on 14 day cycles. Subjects will receive oxaliplatin 85 mg/m2 IV on Day 1, leucovorin 400 mg/m2 IV on Day 1, fluorouracil 400 mg/m2 IV push on Day 1, and fluorouracil 1,200 mg/m2 IV continuous infusion on Days 1-2 every 14 days for up to 9 cycles.
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Treatment groupsSee each treatment group below.
Treatment-emergent adverse events
Safety parameters including clinical assessments, vital signs, laboratory testing, and electrocardiograms (ECG) will be used to assess treatment-emergent adverse events (TEAE). Adverse events will be graded using the NCI-CTCAE v5.0. Investigators will determine relatedness of all treatment emergent adverse events (TEAE) to the investigational agent(s).
Dose-limiting toxicities
The DLT evaluation period will be defined as the first 21 days after infusion of M3T01 as monotherapy or in combination with other systemic therapies (including pembrolizumab, temozolomide, and FOLFOX). Site investigators will grade toxicities using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Serious adverse events
Clinical assessments, vital signs, laboratory testing, and electrocardiograms (ECG) will be used to assess serious adverse events (SAE) using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Immune-related adverse events
Clinical assessments, vital signs, laboratory testing, and electrocardiograms (ECG) will be used to assess immune-related adverse events (irAE) using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
PK Profile of M3T01
Serum PK parameters including the area under the curve (AUC), maximum concentration (Cmax), minimum concentration (Cmin), time to maximum concentration (Tmax), half-life (t1/2), and other serum concentration vs time parameters.
Immunogenicity of M3T01
• Incidence of anti-drug antibodies (ADA) and neutralizing antibodies (nAbs) against M3T01 and correlation with M3T01 PK parameters, toxicity, and clinical efficacy.
Antitumor Activity of M3T01
Tumor response (for all solid tumors other than glioblastoma) will be evaluated by site investigators per RECIST v1.1 to assess the objective response rate (ORR), best overall response (BOR), disease control rate (DCR), duration of response (DOR), progression free survival (PFS), and overall survival (OS). Tumor assessment CT or MRI scans will be performed every 8 weeks for the first 6 months and then every 12 weeks thereafter. Tumor assessments for subjects with glioblastoma will be performed with contrast-enhanced MRI per the Response Assessment in Neuro-Oncology (RANO 2.0) criteria.
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