Phase I trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl+ hematological malignancies
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Imatinib is an inhibitor of the Bcr-Abl tyrosine kinase; however, resistance is common. Flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, down-regulates short-lived anti-apoptotic proteins via inhibition of transcription. In preclinical studies, flavopiridol synergizes with imatinib to induce apoptosis. We investigated this novel combination regimen in patients with Bcr-Abl+ malignancies.
In a phase I dose-escalation study, imatinib was administered orally daily, and flavopiridol by 1 h intravenous infusion weekly for 3 weeks every 4 weeks. Adults with chronic myelogenous leukemia or Philadelphia chromosome-positive acute leukemia were eligible. Patients were divided into two strata based on peripheral blood and bone marrow blast counts. The primary objective was to identify the recommended phase II doses for the combination. Correlative pharmacokinetic and pharmacodynamic studies were also performed.
A total of 21 patients received study treatment. Four dose levels were evaluated before the study was closed following the approval of the second-generation Bcr-Abl tyrosine kinase inhibitors (TKIs). Five patients responded, including four sustained responses. Four patients had stable disease. All but one responder, and all patients with stable disease had previously been treated with imatinib. One patient had a complete response sustained for 30 months. Changes in expression of phospho-Bcr/Abl, -Stat5, and Mcl-1 were monitored. No major pharmacokinetic interaction was observed.
This is the first study to evaluate the combination of a CDK inhibitor and a TKI in humans. The combination of flavopiridol and imatinib is tolerable and produces encouraging responses, including in some patients with imatinib-resistant disease.
KeywordsImatinib Flavopiridol Cyclin-dependent kinase inhibitor CDK inhibitor Bcr-Abl Tyrosine kinase inhibitor Alvocidib
The authors would like to acknowledge Mary Beth Tombes, R. N., M. N. for assistance in preparing the manuscript tables, Lora Kramer for the Western blot figure, Sookyung Woo and Shawn Spencer for the manuscript and supplemental sections on flavopiridol pharmacokinetics and Brian J. Druker, Director, Knight Cancer Institute, Oregon Health and Science University, for performing correlative studies on characterization of mechanisms of resistance to imatinib in patients previously treated with imatinib. This work was supported by the following NIH grants: R01 CA93738-05, CA 100866, and R21 CA106139, NCI Cooperative Agreement U01 CA70095, Massey Cancer Center Support Grant P30 CA016059, General Clinical Research Center Grant M01 RR00065, Leukemia and Lymphoma Society of America award 6181-10, Multiple Myeloma Research Foundation, Myeloma SPORE award 1P50CA142509, and Lymphoma SPORE award 1P50CA130805. EK was supported by a scholarship from the Hellenic Society of Medical Oncology. JHB and MJE were supported by grant P30-CA47904 from the National Cancer Institute. MJE was the recipient of an American Society of Clinical Oncology Cancer Foundation Translational Research Professorship.
Conflict of interest
JHB discloses having received research support from Novartis. None of the other authors have any conflicts of interest relevant to this article to disclose.
- 30.Rathkopf DE, Ilson DH, Yi S et al (2004) A phase II trial of sequential paclitaxel and flavopiridol in patients with metastatic paclitaxel-refractory esophageal cancer. Presented at the American society of clinical oncology gastrointestinal cancers symposium, San Francisco, CA, January 22–24, 2004 (abstract 67)Google Scholar
- 31.Rathkopf DE, Fornier M, Shah MA et al (2004) A phase I dose-finding study of weekly, sequential docetaxel (Doc) followed by flavopiridol (F) in patients with advanced, solid tumors. J Clin Oncol 2004(22):213s suppl; abstr 3072Google Scholar
- 36.Karp JE, Pagel JM, Smith BD et al (2010) Randomized phase II study of two schedules of flavopiridol (alvocidib, F) given as timed sequential therapy (TST) with Ara-C and mitoxantrone (FLAM) for adults with newly diagnosed, poor-risk acute myelogenous leukemia (AML). Blood (ASH Annual Meeting Abstracts) 2010; 116 (Abstract 186)Google Scholar