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

Leena Gandhi, Matthew W. Harding, Marcus Neubauer, Corey J. Langer, Melvin Moore, Helen J Ross, Bruce E. Johnson, Thomas J. Lynch

Research output: Contribution to journalArticle

63 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)924-932
Number of pages9
JournalCancer
Volume109
Issue number5
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

Fingerprint

Small Cell Lung Carcinoma
Multiple Drug Resistance
Vincristine
Doxorubicin
Safety
Neutropenia
P-Glycoprotein
biricodar
Technetium Tc 99m Sestamibi
Drug Therapy
Neoplasms
Survival
Therapeutics
Up-Regulation

Keywords

  • Carcinoma
  • Clinical trials
  • Lung neoplasm
  • Multidrug resistance
  • Phase II
  • Small cell
  • VX-710

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Gandhi, Leena; Harding, Matthew W.; Neubauer, Marcus; Langer, Corey J.; Moore, Melvin; Ross, Helen J; Johnson, Bruce E.; Lynch, Thomas J.

In: Cancer, Vol. 109, No. 5, 01.03.2007, p. 924-932.

Research output: Contribution to journalArticle

Gandhi, Leena ; Harding, Matthew W. ; Neubauer, Marcus ; Langer, Corey J. ; Moore, Melvin ; Ross, Helen J ; Johnson, Bruce E. ; Lynch, Thomas J. / 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. In: Cancer. 2007 ; Vol. 109, No. 5. pp. 924-932.
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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.",
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T1 - 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

AU - Gandhi, Leena

AU - Harding, Matthew W.

AU - Neubauer, Marcus

AU - Langer, Corey J.

AU - Moore, Melvin

AU - Ross, Helen J

AU - Johnson, Bruce E.

AU - Lynch, Thomas J.

PY - 2007/3/1

Y1 - 2007/3/1

N2 - 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.

AB - 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.

KW - Carcinoma

KW - Clinical trials

KW - Lung neoplasm

KW - Multidrug resistance

KW - Phase II

KW - Small cell

KW - VX-710

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