Abstract A071: Phase I trial of the combination of bortezomib and clofarabine in adults with refractory solid tumors, lymphomas, or myelodysplastic syndromes

Abstract

Abstract Background: The NCI ALMANAC study carried out a systemic in vitro drug screen with 2.8 million dose combinations to identify drug pairs with greater than additive activity. This was followed by patient-derived xenograft models, which demonstrated that the combination of the proteasome inhibitor bortezomib and the nucleoside analog clofarabine was highly active. Both agents have been approved by FDA: bortezomib for multiple myeloma & mantle cell lymphoma, and clofarabine for acute lymphoblastic leukemia. However, neither agent is approved for solid tumors or myelodysplastic syndrome (MDS). Our pre-clinical models suggest that the activity of this drug pair may be due to modulation of DNA damage and enhancement of the intrinsic apoptotic cascade. While both drugs can initiate apoptosis, bortezomib resistance occurs when the drug fails to upregulate the apoptotic promoter BAX; however, clofarabine can stabilize BAX and facilitate apoptosis via alternate pathways (unpublished data). We are conducting an ongoing phase 1 trial to evaluate the activity of bortezomib and clofarabine in refractory solid tumors, lymphomas, and MDS. Methods: The trial uses a 3+3 design, enrolling at least one solid tumor/lymphoma and one MDS patient (pt) at each dose level. The occurrence of pre-defined hematologic dose limiting toxicity (DLT) or a second instance of a grade 2 hematologic toxicity triggers expansion of the dose level into separate cohorts: (1) solid tumor/lymphoma & (2) MDS. Starting dose of clofarabine was 1 mg/m2 administered intravenously (IV) on day (D)1-5, with bortezomib 0.8 mg/m2 SQ on D1-4 of 21-day cycles. Response was measured using RECIST 1.1, Lugano criteria, and IWG, respectively. Exploratory endpoints include DNA damage and epithelial-to-mesenchymal phenotype transition in blood and malignant tissue. Results: As of July 2019, 15 pts were enrolled with advanced solid tumors (n=11), lymphoma (1) & MDS (3). Median patient age is 62 (48-80 yrs). Median lines of prior therapy is 3 (1-7). One pt had a DLT (grade 3 anemia in a solid tumor pt at dose level 3), leading to the separation into solid tumor/lymphoma and MDS cohorts. In the MDS cohort, 2 pts had stable disease (SD) as best response (1pt with >8 months duration of response [DOR] following hypomethylating agent [HMA] failure). In the solid tumor/lymphoma cohort, 2 pts achieved a best response of SD (1pt with > 7 months DOR, with colorectal adenocarcinoma). The only toxicity possibly attributed to treatment in the MDS cohort was grade 3 neutropenia. In the solid tumor/lymphoma cohort, the grade 3 toxicities were anemia (2) and lymphopenia (4); there was one grade 4 lymphopenia, and no grade 3/4 neutropenia or thrombocytopenia. Conclusions: This unique trial design demonstrates that conducting a phase 1 study with both solid tumors and hematologic malignancies is feasible and efficient, eliminating the need for a larger sample size or two separate trials. Treatment with bortezomib and clofarabine has shown early activity in a colon cancer pt and an MDS pt post HMA failure, where treatment options are critically limited. Dose escalation and pharmacodynamic studies are ongoing. Future studies include assessment of drug pair mechanism of action using a validated apoptosis multiplex assay and next-generation sequencing. Funded by NCI Contract No. HHSN261200800001E Citation Format: Sabrina S. Khan, Geraldine O'Sullivan, Larry Rubinstein, Shivaani Kummar, Lamin Juwara, Jennifer Zlott, Arjun Mittra, Murielle Hogu, Jerry Collins, Apurva Srivastava, Brandon Miller, Ralph E. Parchment, Christopher S. Hourigan, Steven Pavletic, James Doroshow, Alice P. Chen, Naoko Takebe. Phase I trial of the combination of bortezomib and clofarabine in adults with refractory solid tumors, lymphomas, or myelodysplastic syndromes [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A071. doi:10.1158/1535-7163.TARG-19-A071