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.

Abstract

BACKGROUND:

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).

METHODS:

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).

RESULTS:

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 (99m)Tc-sestamibi uptake in tumor tissue was observed with the addition of VX-710 in this study.

CONCLUSIONS:

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.

• Authors: Leena Gandhi, Matthew W Harding, Marcus Neubauer, Corey J Langer, Melvin Moore, Helen J Ross, Bruce E Johnson, Thomas J Lynch
• Journal: Cancer (Cancer) Vol. 109 Issue 5 Pg. 924-32 (Mar 01 2007) ISSN: 0008-543X [Print] United States
• PMID: 17285598 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study)

Chemical References

• Piperidines
• Pyridines
• biricodar
• Vincristine
• Doxorubicin

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carcinoma, Small Cell (drug therapy)
• Doxorubicin (administration & dosage, adverse effects)
• Drug Resistance, Multiple
• Female
• Humans
• Lung Neoplasms (drug therapy)
• Male
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy)
• Piperidines (administration & dosage, adverse effects)
• Pyridines (administration & dosage, adverse effects)
• Vincristine (administration & dosage, adverse effects)