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Abstract Background/Rationale: The combination of the proteosome inhibitor bortezomib (B) and purine analog clofarabine (C) induced synergy in the NCI-ALMANAC screen of FDA-approved cancer drug combinations; preclinical xenograft studies confirmed this activity and suggested a combination mechanism of action involving greater-than-additive effects on markers of DNA damage response (DDR) and pyroptotic cell death. We conducted a phase 1 clinical trial (NCT02211755) to assess the safety of the B and C combination in patients (pts) with solid tumors and myelodysplastic syndrome (MDS), and to determine the effect of the combination on biomarkers of cell death and DDR. Due to limited MDS pt accrual, this cohort was terminated early, and MDS pt data are not included here. Objectives: The primary objective was to assess safety and maximum tolerated dose (MTD) of B and C in pts with solid tumors and MDS. Secondary objectives were to assess pharmacodynamic (PD) effects using validated assays for cell death and DDR in tumor biopsy tissue and circulating tumor cells (CTCs). Design: The dose escalation followed a 3+3 design, enrolling at least 1 pt from each group (solid tumor and MDS) per dose level until hematologic dose-limiting toxicity (DLT) was observed. Adverse events (AEs) were graded using CTCAE v4. 0. Ten planned dose levels (DL) included C ranging from 1 to 10 mg/m2 on D2-5 of cycle 1 and D1-5 from cycle 2 on and B from 0. 8 to 1. 5 mg/m2 on D1 and D4 of 21-day cycles. Response was assessed by RECIST 1. 1 every 2 cycles. Biopsies were performed on the expansion cohort pre-dose, 2-4 hours after C on C1D1, and C2D4; CTCs were collected pre-dose, C1D2, day 1 of subsequent cycles, and at progression. Results: We enrolled 25 pts with advanced solid tumors (15 male, 10 female). Median age was 62 years (range 30-81). DLT occurred in 4 pts (at DL3 1 pt, DL5 2, and DL4 1) and included Grade 4 neutropenia (3), Grade 3-4 thrombocytopenia (3), and Grade 3 anemia (1). There were no Grade 5 AEs. DL4 (B 1. 3 mg/m2 D1 and 4, C 1. 5 mg/m2 D1-5, 21-day cycles) was the MTD. Twenty-one pts were evaluable for response; the best response was stable disease (SD) for 10 pts (47. 6%). Median duration of response for pts achieving SD was 3. 5 months (range 2-7). Of note, 3 out of the 10 colorectal cancer (CRC) pts had SD 4 months. Four pts with CRC have been enrolled in an expansion cohort for biomarker evaluation; induction of pyroptosis has been measured in a limited number of paired biopsies collected to date. Conclusions: Despite preclinical evidence of synergy, the human equivalent of the efficacious preclinical combination dose could not be achieved clinically, which may account for the lack of antitumor response. Prolonged SD was observed in 3 pts with CRC. PD analyses, including of CTCs and additional cell death biomarkers, are ongoing. Funded by NCI Contract No. HHSN261201500003I. Citation Format: Andre L. De Souza, Naoko Takebe, Alice P. Chen, James H. Doroshow, Ralph E. Parchment, Apurva K. Srivastava, Lawrence Rubistein, Deborah Wilsker, Brandon L. Miller, Murielle Hogu, Geraldine O`Sullivan Coney, Shivaani Kummar, Jeevan Govindharajulu, Robert Meehan, William G. Herrick, Angie Dull, Donna Ketchum, Shaowei Li, Jiuping Ji, Richard Piekarz. Phase 1 trial of bortezomib and clofarabine combination in adults with refractory solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT120.
Souza et al. (Fri,) studied this question.