Phase I Study of Flavopiridol in Combination with Imatinib Mesylate (STI571, Gleevec) in Bcr/Abl+ Hematological Malignancies

• Published in: Blood Vol. 106; no. 11; p. 1102
• Main Authors: Grant, Steven, Karp, Judith E., Koc, Omer N., Cooper, Brenda, Luger, Selina, Figg, William D., Egorin, Merrill, Druker, Brian J., Jacobberger, James W., Ramakrishnan, Viswanathan, Perkins, Edward B., Colevas, A. Dimitrios, Roberts, John D.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 16-11-2005
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V106.11.1102.1102

Imatinib (Im), a rationally designed inhibitor of the Bcr/Abl kinase as well as other kinases, represents the standard treatment for Bcr/Abl+ malignancies. Im as a single agent, however, is not curative. Flavopiridol (Fl), an investigational cyclin dependent kinase inhibitor, is broadly active in vitro against human leukemia cells (Blood 91:2482, 1998). Previously we have shown that simultaneous disruption of a survival signaling pathway and a cell cycle regulatory pathway results in a pronounced increase in leukemic cell death (Cancer Res. 61:5106, 2001) and in more recent preclinical studies demonstrated synergistic interactions between Im and Fl in Bcr/Abl+ leukemia cells, including some that were resistant to Im (Clin Cancer Res 8;2976, 2002). Based on these considerations, we have initiated a phase I trial to identify appropriate doses of Im+Fl for further investigation. Eligible patients (pts) have CML with a suboptimal response to prior Im, CML in blast crisis, or Bcr/Abl+ acute lymphocytic leukemia (ALL). CML-BC and ALL patients may be Im-naïve. Pts receive Im by continuous daily oral dosing and Fl by 1 hour intravenous infusion weekly x 3 repeated every 4 weeks. Targeted dose levels are (Fl/Im; mg/m2): 30/400, 30/600, 45/600, 60/600, 60/800, 60/1000. Patients are divided into 2 strata based upon blast percentage in peripheral blood or bone marrow: stratum 1, <15%; and stratum 2, ≥15%. For stratum 1 dose limiting toxicity (DLT) is defined as NCI CTCAE grade 4 ANC/platelet for > 1 week or grade ≥ 3 non-heme toxicity; for stratum 2, DLT is profound marrow hypoplasia in the absence of persistent leukemia. In stratum 1, 16 pts have been treated at 4 dose levels; in stratum 2, 5 pts in the 1st and 3rd dose level. In stratum 1, 1 DLT has occurred at dose level 4 (cholecystitis requiring cholecystectomy); in stratum 2, 1 DLT has occurred at dose level 3 (sepsis/multi-organ failure which was not clearly related to treatment). The only frequent toxicities have been hematological. 4 pts have experienced objective responses including complete hematological remissions in 2 pts in stratum 1 treated with Im/Fl 30/600 who had been previously treated with Im 800 and complete hematological remissions in 2 pts in stratum 2 (who had not received prior Im). Preliminary studies indicate no Fl impact upon Im pharmacokinetics, and variable post-treatment effects on signaling pathways in CML cells. These findings indicate that a regimen consisting of Fl and Im is tolerable and active in at least some patients with Bcr/Abl+ hematologic malignancies, including some with Im-resistant disease. Pending identification of the MTD and the recommended Phase II dose (RPTD), Phase II trials will be necessary to assess the activity of this strategy more definitively.