A phase 2 trial of flavopiridol (Alvocidib) and cisplatin in platin-resistant ovarian and primary peritoneal carcinoma: MC0261

Abstract

Purpose: Based upon promising preclinical and phase 1 trial results, combined flavopiridol and cisplatin therapy was evaluated in patients with ovarian and primary peritoneal cancers.

Methods: A two cohort phase 2 trial of cisplatin (60 mg/m2 IV) immediately followed by flavopiridol (100 mg/m2 IV, 24 h infusion; 21 day cycles) was undertaken in patients with recurrent platin-sensitive or platin-resistant disease (progression>vs. ≤6 months following prior platin-based therapy). Measurable disease (RECIST)--or evaluable disease plus CA125>2X post-treatment nadir--and ECOG performance≤2 were required.

Results: Forty-five patients were enrolled between December 23, 2004 and February 25, 2010: 40 platin-resistant (Group 1), and 5 platin-sensitive (Group 2). In Group 1, the median number of treatment cycles was 3 (range 2-12). Only 10% of patients incurred grade 4 toxicities, but grade 3 toxicities were common (65%): neutropenia (17.5%); nausea (12.5%); vomiting, fatigue, thrombosis, anemia (10% each). Seven patients (17.5%) achieved a confirmed response (1 CR, 6 PR; median duration 118 days); ten additional patients (25%) attained maintained stable disease. Median time to progression was 4.3 months; overall survival was 16.1 months. Pilot translational studies assessed ascites flavopiridol level; surrogate marker studies were uninformative. In Group 2, although 4 of 5 patients responded (2 confirmed PRs with median time to progression, 10.8 months and median overall survival 20.6 months) the cohort was closed due to poor accrual.

Conclusions: The assessed flavopiridol and cisplatin regimen displayed clinical activity in platin resistant and sensitive ovarian/primary peritoneal cancers, meriting further study.

Trial registration: ClinicalTrials.gov NCT00083122.

Conflict of interest statement

CONFLICT OF INTEREST: None

Copyright © 2012 Elsevier Inc. All rights reserved.

Figures

Figure 1

In vitro effects of flavopiridol and cisplatin alone or in combination on viability and proliferation of OV202 (A) or CaOV3 (B) human ovarian cancer cells. Exposures of cells to all agents/combinations were of 26 hour duration (cisplatin applied 2 hours prior to combined flavopiridol/cisplatin exposure for 24 hours); cell growth assessed by observing confluence. (C) Predicted response surface for flavopiridol/cisplatin synergy model from SKOV3 human ovarian cancer cells, with Greco model parameters indicated in the adjacent table.

Figure 2

Kaplan-Meier plots of overall survival (A) or time to progression (B) for Group 1 platin-resistant patients. Waterfall plots showing best RECIST response (C, only data from the 26 measurable patients shown) or CA125 response (D, data from all 40 study patients shown); values are presented as % baseline pre-therapy measurements. Blue indicates patients attaining partial or complete responses (CR or PR), green indicates those with stable disease (STAB) and red indicate patients with progressive disease (PROG).

Figure 3

Time courses of patient CA125 values in patients attaining partial or complete responses (PR or CR, A), stable disease (STAB, B) or progressive disease (PROG, C). Values are presented as % baseline pre-therapy measurements. Solid lines indicate measurable disease while dashed lines indicate evaluable disease.

Figure 4

A. Effects of the flavopiridol/cisplatin regimen relative to initial therapy with paclitaxel/carboplatin for a patient with platin-resistant primary peritoneal carcinoma who attained a CR in conjunction with the trial. CA125 levels are plotted vs. time since diagnosis; arrows indicate times of chemotherapy administration and asterisks indicate times of radiographic disease progression. Note that the period of disease control in response to flavopiridol/cisplatin was greater than that attained from initial adjuvant therapy. B. Effects of flavopiridol alone on the ex vivo survival of tumor cells isolated from the ascites of the patient shown in A immediately prior to flavopiridol/cisplatin therapy, indicating sensitivity of her tumor cells to flavopiridol in response to achieved ascetic flavopiridol concentrations. C. Immunoblotting results comparing relative levels of selected polypeptides in paired patient study samples pre/post day 1, cycle 1, therapy (SDS-PAGE, immunoblotting; actin loading controls; samples were loaded to have equivalent pre/post protein levels; 13 representative paired patient samples are shown).