Phase 1/2a Open-Label, Dose-Escalation, Multicenter, FIH, Consecutive-Cohort, Clinical Trial of BI-1808, a Monoclonal Antibody to TNFR 2 As a Single Agent and in Combination with Pembrolizumab (MK-3475-D20) in Subjects with Advanced Malignancies
The goal of this first in human clinical trial is to test BI-1808 administered as single agent and in combination with pembrolizumab in subjects with advanced malignancies whose disease has progressed after standard therapy. The main questions it aims to answer are: * how safe and tolerable is BI-1808 * what is maximum tolerated or administrated dose * to determine recommended dose for further clinical trials. Participants will receive infusions of BI-1808 alone or combination with pembrolizumab every 3 weeks. For the purpose of this study, subjects with advanced malignancies includes subjects with advanced solid tumors and subjects with T-cell lymphoma (TCL),
• Is willing and able to provide written informed consent for the trial.
• Is ≥18 years of age on the day of signing informed consent.
• Has a histologically confirmed advanced malignancy. Subjects with CTCL \[MF or SS\] who satisfy the Phase 2a, Cohort 3-specific eligibility criteria may be enrolled into the Phase 1 part of the study.
• Is intolerant of, refuses, or is not eligible for standard antineoplastic therapy.
• Has at least 1 measurable disease lesion as defined by RECIST.
• Is able to safely undergo a baseline tumor tissue biopsy prior to first dose of BI-1808 (on non previously irradiated lesions only). The biopsy must be performed at least 4 weeks following the last dose of tumor directed therapy.
• Has a life expectancy of ≥12 weeks.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Has adequate organ function as confirmed by laboratory values.
⁃ Phase 2a Expansion Cohort-Specific Inclusion Criteria:
⁃ Ovarian Cancer:
⁃ Histologically confirmed and documented recurrent ovarian, fallopian tube, and peritoneal cancer.
⁃ TCL:
• histologically confirmed diagnosis
• Stable doses of systemic steroids (≤20 mg prednisone equivalent) and of low-to-medium potency topical steroids permitted (no change in preceding 4 weeks).
• Stage IB-IV with failure of at least 1 systemic therapy.
• No current large cell transformation for subjects with CTCL.
• Prior therapy - No prior allo hematopoietic stem cell transplantation (HSCT); \>90 days since auto HSCT; \>4 weeks since systemic therapy and \>2 weeks since skin-directed therapy.
• Stable doses of systemic steroids (≤20 mg prednisone equivalent) and of low-to-medium potency topical steroids permitted (no change in preceding 4 weeks).
• Previous systemic therapies include brentuximab vedotin, bexarotene, extracorporeal photopheresis (ECP), methotrexate, mogamulizumab, romidepsin, vorinostat, or systemic therapy with localized radiation treatment or skin-directed therapy.
⁃ Melanoma:
• Histologically confirmed diagnosis of unresectable or metastatic melanoma.
• Subjects in Part A:
• Required prior therapies will include anti-programmed death-ligand 1 (PD-1) therapy either as monotherapy or as part of a combination regimen.
• For subjects with a known BRAF V600-activating mutation combination targeted therapy will be required in addition to anti-PD-1/programmed death-ligand 1 (PD-L1) therapy.
• Subjects in part B:
• Subjects with prior lines of treatment are not eligible.
⁃ All Tumor Types:
⁃ Locally advanced unresectable, recurrent or metastatic immune checkpoint inhibitor-naïve solid tumors, likely to benefit from immune checkpoint inhibitor treatment, based on Investigator opinion.
⁃ b. Subjects must have received prior standard therapy appropriate for their tumor type and stage of disease, or in the opinion of the Investigator, would be unlikely to tolerate or derive clinical benefit from appropriate standard of care therapy.
⁃ c. Subjects with known activation mutations must have prior target therapy.