In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT138-CT138
Abstract:
Background: NCI ALMANAC, a systematic in vitro combination drug screen study, identified greater-than-additive activity for the combination of the proteasome inhibitor bortezomib and the nucleoside analog clofarabine. The combination also yielded strong, greater-than-single-agent activity in human tumor xenograft models. Our preclinical findings postulate that the activity of this drug pair may be due to modulation of DNA damage and the intrinsic apoptotic cascade. In an ongoing phase I trial, we evaluate the safety and activity of bortezomib and clofarabine in refractory solid tumors, lymphomas, and myelodysplastic syndromes (MDS). Methods: This is an open-label trial with a 3+3 design, enrolling at least one solid tumor/lymphoma and one MDS patient (pt) at each dose level. Starting doses were clofarabine 1 mg/m2 intravenously (IV) on days (D) 1-5 and bortezomib 0.8 mg/m2 subcutaneously (SC) on D1 and D4 of 21-day cycles. Response was determined per RECIST 1.1, Lugano criteria, and IWG, respectively. Exploratory endpoints include markers of DNA damage and epithelial-to-mesenchymal phenotype transition in blood. Once MTD is declared, a biopsy expansion cohort will enroll to evaluate the mechanism of action for the combination using validated apoptosis multiplex and next-generation sequencing assays. Results: As of October 2020, 22 pts were enrolled with advanced solid tumors (n=18), lymphoma (1), and MDS (3). Median pt age is 62 (range 41-80). Median lines of prior therapy is 3 (range 1-8). Three pts had DLTs in the solid tumor/lymphoma cohort: grade 3 anemia at dose level (DL) 3 (clofarabine 1.5 mg/m2, bortezomib 1 mg/m2); grade 4 neutropenia and grade 4 thrombocytopenia at DL 5 (clofarabine 2 mg/m2, bortezomib 1.3 mg/m2); and grade 4 neutropenia at DL 5. In the solid tumor/lymphoma cohort, grade 3 toxicities possibly attributed to study drugs were anemia (3), lymphopenia (3), thrombocytopenia (1), and frequent premature ventricular contractions (1); grade 4 toxicities were lymphopenia (5), neutropenia without infection (2), and thrombocytopenia (1). The only toxicity possibly attributed to study drugs in the MDS cohort was grade 3 febrile neutropenia in one pt. In the solid tumor/lymphoma cohort, 6 pts achieved a best response of stable disease (SD); 3 patients experienced prolonged SD of ≥ 6 months (1 pt each with colorectal adenocarcinoma, pancreatic adenocarcinoma, and cholangiocarcinoma). In the MDS cohort, 2 pts had SD as a best response (8 months in 1 pt following hypomethylating agent failure). Pharmacodynamic analyses in circulating tumor cells are ongoing. Conclusions: Treatment with bortezomib and clofarabine demonstrated prolonged SD in one pt each with colon adenocarcinoma, pancreatic adenocarcinoma, cholangiocarcinoma, and MDS. Hematological DLTs were seen in 2 pts on DL 5. Currently, patients are enrolling on DL 4 for the solid tumor/lymphoma cohort. Funded by NCI Contract No. HHSN261200800001E. Citation Format: James Q. Nguyen, Geraldine O'Sullivan Coyne, Larry Rubinstein, Shivaani Kummar, Lamin Juwara, Jennifer Zlott, Abdul Rafeh Naqash, Murielle Hogu, Jerry Collins, Apurva Srivastava, Brandon Miller, Ralph E. Parchment, Robert Meehan, Christopher S. Hourigan, Steven Pavletic, James H. 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 American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT138.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2021-CT138
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2021
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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