A First-in-Human Phase 1/2, Dose Escalation and Dose Expansion Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of TROP2-Directed Antibody-Drug Conjugate LCB84, as a Single Agent and in Combination with Pembrolizumab, in Patients with Advanced Solid Tumors
The study population in dose escalation (Phase 1) consists of patients with advanced solid tumors refractory to standard of care, or for whom no standard of care exists. After the MTD and/or RP2D for single agent LCB84 is determined, dose escalation cohorts with select tumor types will be enrolled. Combination LCB84 and anti-PD-1 Ab will be evaluated in dose escalation after a minimum of 2 dose levels of single agent LCB84 have established DLT safety, to determine the MTD and/or RP2D of combination LCB84 and anti-PD-1 Ab, and to continue into dose expansion cohorts in select tumor types.
Eligibility: Inclusion Criteria
• Key Inclusion Criteria:
• Phase 1 Dose Escalation: histologically or cytologically confirmed advanced solid tumors refractory to standard of care treatment.
• Phase 2 Dose Expansion*: select histologically or cytologically confirmed advanced solid tumors refractory to standard of care treatment.
• *expansion cohort indications to be prioritized based on data from Phase 1 dose escalation.
• Prior treatment with TROP2-directed therapy is permitted.
• Measurable disease as defined by RECIST v1.1 or RANO-BM.
• Willingness to provide archival tumor tissue when available or to undergo pre-treatment biopsy if not available.
• Mandatory pre- and on-treatment biopsies for enrichment cohorts in Phase 1 dose escalation and Phase 2 expansion cohorts if deemed medically feasible and safe.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate organ function as defined by:
• Absolute neutrophil count (ANC) >=1.5 x 109/L (1500/µL), without colony-stimulating factor support for the past 14 days
• Platelets >=100.0 x 109/L (100 000/µL)
• Hemoglobin >=9.0 g/dL
• Aspartate aminotransferase (AST) =2.5 x ULN; alanine aminotransferase (ALT) =2.5 x ULN (AST, ALT =5 x ULN if liver metastases present)
• Key
Exclusion Criteria
• Active or progressing central nervous system (CNS) metastases or any evidence of leptomeningeal disease.
• Note: Patients with stable or treated CNS metastases may be eligible if all of the following criteria are met: 1) localized treatment for brain metastases completed at least 4 weeks prior to the first dose of study drug 2) no new or progressive neurologic symptoms and without need for immediate local therapy, steroids or anticonvulsants for symptom control (stable or decreasing steroid dose (a stable dose of =4 mg dexamethasone oral or equivalent) is permitted) 3) stable brain metastases for at least 1 month prior to screening (baseline) brain MRI.
• Persistent toxicities from previous systemic antineoplastic treatments >Grade 1, excluding alopecia and vitiligo.
• Systemic antineoplastic therapy (including antiestrogen therapy) within 5 half-lives or 4 weeks, whichever is shorter, prior to first dose of the study drug.
• Concomitant use of systemic steroids at dose of >10 mg of prednisone or its equivalent per day (exception for brain metastases, as described in exclusion criteria #1 above).