Phase II, double-blinded, randomized study of enzastaurin plus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer.

Abstract

INTRODUCTION:

We examined the efficacy of enzastaurin plus pemetrexed as second-line therapy in patients with advanced (stage IIIA/B or IV) non-small cell lung cancer in a double-blinded, randomized, phase II study.

METHODS:

Patients received pemetrexed 500 mg/m intravenously on day 1 of 21-day cycles (day 8 in cycle 1) plus oral enzastaurin (250 mg two times per day; combination arm) or placebo (pemetrexed arm). Both arms received supplementation with vitamin B12, folic acid, and dexamethasone. An interim analysis was conducted to determine whether efficacy would warrant a phase III study.

RESULTS:

The interim analysis showed no evidence of improved progression-free survival with enzastaurin. At final analysis (N = 160, 80 in each arm), baseline characteristics were well balanced. There was no significant difference in progression-free survival (3.0 months, p = 0.544) or overall survival (9.6 months in combination arm and 7.4 months in pemetrexed arm, p = 0.171). Drug-related serious adverse events included cerebrovascular accident, palpitations, and renal failure (n = 1, each) in combination arm and neutropenic sepsis, thrombocytopenia, and panniculitis (n = 1, each) in pemetrexed arm. Nonhematologic drug-related grade 3/4 toxicities were similar in both arms. Grade 3/4 hematologic toxicities were higher with the combination, specifically leukopenia (6.3% versus 0%), neutropenia (15.2% versus 5.0%), and thrombocytopenia (8.9% versus 1.3%). Of the 26 deaths reported on-study or within 30 days of discontinuation (10 in combination arm and 16 in pemetrexed arm), none were drug related.

CONCLUSION:

The combination regimen of enzastaurin and pemetrexed is well tolerated but does not improve efficacy over pemetrexed and placebo as second-line treatment of unselected patients with advanced non-small cell lung cancer.

• Authors: Alberto Chiappori, Gerold Bepler, Fabrice Barlesi, Jean-Charles Soria, Martin Reck, Alessandra Bearz, Fernando Barata, Giorgio Scagliotti, Keunchil Park, Asavari Wagle, Astra M Liepa, Yan Daniel Zhao, Nadia Chouaki, Neill Iscoe, Joachim von Pawel
• Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (J Thorac Oncol) Vol. 5 Issue 3 Pg. 369-75 (Mar 2010) ISSN: 1556-1380 [Electronic] United States
• PMID: 20090562 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Glutamates
• Indoles
• Pemetrexed
• Guanine
• Folic Acid
• Vitamin B 12
• enzastaurin

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Carcinoma, Squamous Cell (drug therapy, pathology)
• Double-Blind Method
• Female
• Folic Acid (administration & dosage)
• Glutamates (administration & dosage)
• Guanine (administration & dosage, analogs & derivatives)
• Humans
• Indoles (administration & dosage)
• Lung Neoplasms (drug therapy, pathology)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Staging
• Pemetrexed
• Prognosis
• Salvage Therapy
• Survival Rate
• Vitamin B 12 (administration & dosage)