A phase I trial of flavopiridol in relapsed multiple myeloma

Abstract

Purpose: Flavopiridol is primarily a cyclin-dependent kinase-9 inhibitor, and we performed a dose escalation trial to determine the maximum tolerated dose and safety and generate a pharmacokinetic (PK) profile.

Methods: Patients with a diagnosis of relapsed myeloma after at least two prior treatments were included. Flavopiridol was administered as a bolus and then continuous infusion weekly for 4 weeks in a 6-week cycle.

Results: Fifteen patients were treated at three dose levels (30 mg/m(2) bolus, 30 mg/m(2) CIV to 50 mg/m(2) bolus, and 50 mg/m(2) CIV). Cytopenias were significant, and elevated transaminases (grade 4 in 3 patients, grade 3 in 4 patients, and grade 2 in 3 patients) were noted but were transient. Diarrhea (grade 3 in 6 patients and grade 2 in 5 patients) did not lead to hospital admission. There were no confirmed partial responses although one patient with t(4;14) had a decrease in his monoclonal protein >50 % that did not persist. PK properties were similar to prior publications, and immunohistochemical staining for cyclin D1 and phospho-retinoblastoma did not predict response.

Conclusions: Flavopiridol as a single agent given by bolus and then infusion caused significant diarrhea, cytopenias, and transaminase elevation but only achieved marginal responses in relapsed myeloma (ClinicalTrials.gov identifier NCT00112723).

Conflict of interest statement

None of the authors have a relevant conflict of interest to report.

Figures

Figure 1. Myeloma clinical response

At baseline and on day 1 of each subsequent cycle, myeloma clinical labs were repeated and response determined as determined by the International Myeloma Working Group Criteria (IMWG). Patient G had serum free light chain disease only. Patients C, F, G, M, N, O, P had only baseline laboratories drawn – patients F, O, P were replaced during cycle 1 and the remainder had non-measurable disease per IMWG criteria.

Figure 2. Plasma flavopiridol concentration versus time

Flavopiridol plasma concentration versus post-infusion initiation time semi-log plots for patients with evaluable PK profiles. A. Consists of Cycle 1 Day 1 PK profiles (14) from all dose levels; B. Consists of cycle 1 day 22 PK profiles (7) from all dose levels.

Figure 3. Comparison of AUC by dose level

A. Relationship between C1D1 AUC0-∞ and dose levels (p=0.024, ANOVA). B. Relationship between C1D1 Cmax and dose levels (p=0.16, ANOVA). Abbreviations: DL1, Dose level 1= 30/30 mg; DL2, dose level 2=30/50 mg; and DL3, dose level 3=50/50 mg. Solid line within the box represents the median, the lower and upper box borders represent the first and third quartiles, and the whiskers extend to the minimum and maximum values. The mean is marked with a dotted line. *p<0.05