A phase 2a safety run-in and preliminary efficacy study of liposomal gemcitabine (FF-10832) in combination with pembrolizumab in patients with advanced solid tumors.
Authors: Langer Corey J. , Curti Brendan D. , Farber Charles Michael , Wheeler Catherine A. , Wages David S. , Matsumoto Takeshi , Shimoyama Susumu , Mori Mikinaga , Yamada Naoki , Subach Ruth Ann , Madden Timothy , Johansen Mary , Maier Gary , Cheung Kin , Chaney Marya F. , Galsky Matt D. 
Published: June 2024

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Background: FF-10832 (FF832) [liposomal gemcitabine (GEM)] has demonstrated superior activity preclinically compared to GEM via preferential tumor accumulation & induction of antitumor immune responses. Further enhanced activity has been shown in combination with immune checkpoint inhibitors. We evaluated the tolerability & preliminary efficacy of FF832 in combination with the PD-1 antibody pembrolizumab (PEM) in a Phase 2a safety run-in study in patients (pts) with advanced solid tumors. Methods: Pts received 200 mg PEM followed by 40 mg/m2 FF832 on Day 1 of a 21-day cycle to validate the recommended Phase 2 dose (RP2D) for combination therapy; treatment was continued until disease progression or unacceptable toxicity. Response was assessed by RECIST 1.1 every 2 cycles. Tumor PD-L1 expression, mutational burden, and modulation of circulating immune cells were assessed, & population PK modeling performed. Results: Twelve pts [NSCLC (6), urothelial cancer, UC (4), renal cell carcinoma (2); 6M/6F; median age, 69 (42-82) & median # prior therapies, 5 (1-7); prior GEM (5), prior PEM (9)] received a median of 2 (1-8) cycles FF832+PEM. Median time on study was 6.1 (1.1–23.7) weeks. FF832+PEM was well-tolerated. Common AEs related to FF832 were Gr≤2 fatigue (50%) with 1 Gr 3, anemia (33%) with 2 Gr 3, & Gr ≤2 decreased appetite, diarrhea, ↑AST, ↑AlkPhos, muscular weakness, nausea, and pyrexia (25% each). Common AEs related to FF832+PEM were Gr≤2 fatigue (33%) & nausea (25%). Three pts had Gr≤2 infusion reactions with the first FF832 infusion; all resolved & were successfully rechallenged. FF832 dose was reduced to 30 mg/m2 after Cycle 1 in 3 pts due to Gr 3 rash (1), Gr 2 fatigue (1), & one DLT of Gr 3 malaise, pain, and arthralgia. Of 9 pts evaluable for response, one achieved an unconfirmed PR after one cycle (UC, prior GEM/PEM, 42%↓ in target lesions). Five pts had a best response of SD with 2 maintained for 6-8 cycles. Median PFS was 6 weeks (95%CI: 3.1–NR); median OS was 23.3 weeks (95%CI: 4–NR). An extended plasma t1/2 (~30 hours) & exposures consistent with FF832 monotherapy at the RP2D were observed. As with FF832 monotherapy, multi-log decreases were observed in circulating Ki67+ Tregs relative to total CD4+ cells while CD8+ cells increased, suggesting FF832+PEM could enhance shifts to a more immunocompetent tumor microenvironment. Conclusions: The safety and preliminary efficacy of FF832+PEM was demonstrated in heavily pre-treated pts with solid tumors whose disease progressed on prior GEM and/or PEM. Continuous GEM exposure from FF832 along with immune checkpoint blockade may improve antitumor activity. Evaluation of FF832 at the RP2D/schedule of 40 m/gm2 Q 21 days alone and in combination with PEM is ongoing in a randomized expansion study in pts with metastatic NSCLC and UC with prior disease progression on PD-1/L1 therapy. Clinical trial information: NCT05318573 .