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Keywords:

  • multidrug resistance;
  • VX-710;
  • lung neoplasm;
  • carcinoma;
  • small cell;
  • clinical trials;
  • Phase II

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 99mTc-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. Cancer 2007 © 2007 American Cancer Society.