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.
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.
Gandhi
Leena
L
Massachusetts General Hospital, Boston, Massachusetts, USA.
Harding
Matthew W
MW
Neubauer
Marcus
M
Langer
Corey J
CJ
Moore
Melvin
M
Ross
Helen J
HJ
Johnson
Bruce E
BE
Lynch
Thomas J
TJ
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects
D010880:Piperidines; D011725:Pyridines; C106077:biricodar; D014750:Vincristine; D004317:Doxorubicin