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A Phase I Study of the Pan Bcl-2 Family Inhibitor Obatoclax Mesylate in Patients with Advanced Hematologic Malignancies
Abstract
Purpose: The outcome of patients with refractory leukemia and myelodysplasia is poor, and new therapies are needed. The antiapoptotic proteins of the Bcl-2 family are overexpressed in these malignancies and are potential therapeutic targets. Therefore, we conducted a phase I clinical trial of the small-molecule pan-Bcl-2 inhibitor, obatoclax mesylate, in patients with refractory leukemia and myelodysplasia to assess its safety and define its optimal dose. Experimental Design: Forty-four patients with refractory leukemia or myelodysplasia were treated with obatoclax mesylate by continuous intravenous infusion at increasing doses and frequencies. Results: A total of 306 infusions of obatoclax mesylate were administered with a median of 5 infusions per patient. The study drug was well tolerated up to the highest dose planned without dose-limiting toxicity. Grade 1/2 central nervous system symptoms were the most common adverse events attributable to the study drug. One patient with acute myeloid leukemia with mixed lineage leukemia t(9;11) rearrangement achieved a complete remission, which lasted 8 months. Three of 14 patients with myelodysplasia showed hematologic improvement with RBC or platelet transfusion independence. Conclusions: Obatoclax mesylate is well tolerated and these results support its further investigation in patients with leukemia and myelodysplasia.
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Clinical trial data suggest that the dose-limiting toxicities of obatoclax may preclude sufficient target inhibition, in contrast to ABT-263.
“clinical trial data suggest that the dose-limiting toxicities of obatoclax may preclude sufficient target inhibition, in contrast to ABT-263 (30, 34, 35).”
From mTOR Inhibition Specifically Sensitizes Colorectal Cancers with KRAS or BRAF Mutations to BCL-2/BCL-XL Inhibition by Suppressing MCL-1 (2014) · cites this paper as [35]
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Metadata
- Authors
- Schimmer, A. D., O'Brien, S., Kantarjian, H., Brandwein, J., Cheson, B. D., Minden, M. D., Yee, K., Ravandi, F., Giles, F., Schuh, A., Gupta, V., Andreeff, M., Koller, C., Chang, H., Kamel-Reid, S., Berger, M., Viallet, J., & Borthakur, G.
- Affiliations
- Princess Margaret Cancer Centre (CA)
- 2Leukemia Department and
- 4Lombardi Cancer Center, Washington, District of Columbia; and
- The University of Texas MD Anderson Cancer Center (US)
- 1Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada;
- 5GeminX Pharmaceuticals, Malvern, Pennsylvania
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2008-12-15
- Volume
- 14
- Issue
- 24
- Pages
- 8295-8301
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2157717805
- Cited by
- 192
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 9 · 2022: 3 · 2021: 6 · 2020: 10 · 2019: 8 · 2018: 6 · 2017: 8 · 2016: 10 · 2015: 9 · 2014: 15 · 2013: 25 · 2012: 20
- FWCI
- 11.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- BCL-2 inhibitor, refractory leukemia, myelodysplastic syndrome, acute myeloid leukemia, dose-limiting toxicity, central nervous system adverse events, anti-apoptotic proteins, hematologic improvement, complete remission
- MeSH terms
- Adult, Aged, Aged, 80 and over, Electrocardiography, Female, Humans, Indoles, Leukemia, Male, Middle Aged, Pyrroles, Proto-Oncogene Proteins c-bcl-2
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