A phase 1/2 study to investigate the safety and efficacy of OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with advanced solid tumors.

TPS9599 Background: Immune checkpoint inhibitors (ICI) have improved outcomes for pts with solid tumor malignancies; however, most pts relapse and treatment options are limited. Unengineered TIL cell therapy has shown promising efficacy in pts with ICI-resistant melanoma (1,2) and non-small cell lung cancer ([NSCLC] 3,4), but requires co-administration of systemic high-dose IL2, which is associated with safety risks and limits pt eligibility. OBX-115 TIL are engineered to express membrane-bound IL15 (mbIL15) under dose-dependent regulation using acetazolamide (ACZ), an FDA-approved small-molecule diuretic, avoiding the need for high-dose IL2. A first-in-human single-institution study (NCT05470283) evaluating the safety of OBX-115 in metastatic melanoma is ongoing. The current study (NCT06060613) is enrolling pts with solid tumors at multiple US sites using centralized manufacturing. Methods: This phase 1/2, single-arm, open-label, nonrandomized, multicenter study will assess the safety, tolerability, and efficacy of the OBX-115 engineered autologous TIL cell therapy regimen in pts with histologically confirmed unresectable Stage IIIC, IIID, or Stage IV metastatic melanoma (excluding uveal) with documented radiographic progression after systemic therapy containing an anti–PD‐1/PD-L1 agent (if adjuvant, progression during or within 12 wks after the last dose) and received a BRAF inhibitor ± MEK inhibitor if BRAF V600 mutation-positive OR metastatic NSCLC previously treated with an approved systemic therapy for metastatic disease (including an ICI-based regimen and/or targeted therapy where applicable) and progressed, no longer deriving benefit, or unable to continue due to treatment intolerance. Pts must have ECOG PS of 0 or 1 and life expectancy >~6 months. Pts must have ≥1 lesion suitable for OBX-115 manufacturing (≥1.5 cm) and ≥1 RECIST v1.1-measurable lesion remaining after tumor tissue procurement. Primary objectives of Phase 1 are to characterize safety and tolerability and identify a recommended Phase 2 dose of OBX-115 + ACZ; Phase 2 will evaluate efficacy of the regimen (ORR using RECIST v1.1 per investigator). Cryopreserved OBX-115 is generated from the pt’s own tumor tissue procured by surgical excision or core needle biopsy, and is infused after standard- (5 days) or low-dose (4 days) lymphodepletion (cyclophosphamide and fludarabine), based on clinical status. ACZ is administered at cohort-defined doses once daily for up to 10 days starting day of OBX-115 infusion, with optional ACZ redosing at Wk 6–8 for up to 10 days in pts with suboptimal radiographic response. No systemic high-dose IL2 is administered. Two sites are open and recruiting, with additional sites being activated. 1. Rohaan NEJM 2022. 2. Chesney JITC 2022. 3. Creelan Nat Med 2021; Schoenfeld SITC 2021. Clinical trial information: NCT06060613 .