Matthew W. Harding is an employee of Vertex Pharmaceuticals.
A phase II study of the safety and efficacy of the multidrug resistance inhibitor VX-710 combined with doxorubicin and vincristine in patients with recurrent small cell lung cancer
Article first published online: 6 FEB 2007
Copyright © 2007 American Cancer Society
Volume 109, Issue 5, pages 924–932, 1 March 2007
How to Cite
Gandhi, L., Harding, M. W., Neubauer, M., Langer, C. J., Moore, M., Ross, H. J., Johnson, B. E. and Lynch, T. J. (2007), A phase II study of the safety and efficacy of the multidrug resistance inhibitor VX-710 combined with doxorubicin and vincristine in patients with recurrent small cell lung cancer. Cancer, 109: 924–932. doi: 10.1002/cncr.22492
- Issue published online: 22 FEB 2007
- Article first published online: 6 FEB 2007
- Manuscript Accepted: 1 DEC 2006
- Manuscript Revised: 17 NOV 2006
- Manuscript Received: 26 SEP 2006
- multidrug resistance;
- lung neoplasm;
- small cell;
- clinical trials;
- Phase II
Tumors with multidrug resistance (MDR) frequently up-regulate efflux proteins, including MDR-associated protein (MRP-1) and P-glycoprotein (Pgp). MDR represents an obstacle to successful chemotherapy treatment and is reversible in Pgp- or MRP-1-expressing cells by the inhibitor VX-710. A Phase II study was designed to evaluate VX-710 in combination with doxorubicin and vincristine in patients with sensitive, recurrent small cell lung cancer (SCLC).
Eligible patients had recurrent SCLC after a response to first-line chemotherapy. Stage 1 safety evaluation was completed with planned expansion if 9 responses were confirmed in the first 35 patients. Patients were treated every 21 days until progression or intolerable adverse events (AEs).
Thirty-six patients were enrolled from 1998 to 2000. Neutropenia was the major toxicity, occurring in 26 of 36 patients (72%). Neutropenia was more severe (30% vs 20% grade 4) and developed earlier (58% vs 38% in Cycle 1) among the 15 patients who were enrolled prior to an amendment that required neutropenia prophylaxis. Four patients died on study: 2 from infections likely related to therapy and 2 from cancer progression. Seven of 36 patients (19%) had partial responses; 6 patients sustained responses through 6 cycles of treatment, with 1 response lasting 3 years. Three additional patients had unconfirmed responses, and 4 patients had stable disease. The median survival was 6 months. No correlative 99mTc-sestamibi uptake in tumor tissue was observed with the addition of VX-710 in this study.
The addition of VX-710 to doxorubicin and vincristine therapy did not significantly enhance antitumor activity or survival. Although there were durable responses, criteria were not met to proceed with Stage 2 expansion. Cancer 2007 © 2007 American Cancer Society.