A phase I open-label dose-escalation study of intravenous BI 2536 together with pemetrexed in previously treated patients with non-small-cell lung cancer.
BACKGROUND
BI 2536 is a potent, highly selective inhibitor of polo-like kinase (Plk) 1. This open-label, phase I study investigated the maximum tolerated dose (MTD), safety, efficacy, and pharmacokinetics (PK) of BI 2536 IV in combination with standard-dose pemetrexed in previously treated advanced or metastatic non-small-cell lung cancer.


METHODS
A standard 3 + 3 design was used. The patients received 500 mg/m(2) pemetrexed and escalating doses of BI 2536 on day 1 every 3 weeks. The primary objective was the MTD of BI 2536 combined with pemetrexed. Secondary endpoints were response rate (Response Evaluation Criteria in Solid Tumors), overall safety, and PK.


RESULTS
Forty-one patients received BI 2536 (100-325 mg). Two dose-limiting toxicities (DLT) occurred at BI 2536 325 mg (grade 3 pruritus and rash; grade 4 neutropenia). Therefore, the MTD for BI 2536 in combination with pemetrexed was 300 mg. After expanding the MTD dose level, 3 additional patients experienced DLTs, which resulted in expansion of the 250 mg cohort, in which 4 of the 13 additional patients experienced DLTs. Therefore, the recommended dose of BI 2536 was 200 mg. Most frequently reported drug-related adverse events were fatigue (71%), nausea (37%), and rash (34%). Two patients had durable confirmed partial responses; 21 (54%) patients had stable disease after the treatment cycle 2. PK analysis showed that BI 2536 and pemetrexed exposure were not altered when coadministered.


CONCLUSIONS
BI 2536 200 mg combined with standard-dose pemetrexed has an acceptable safety profile in relapsed non-small-cell lung cancer. The antitumor activity observed is encouraging and supports further investigation of Plk inhibitors.
Juravinski Cancer Centre, Hamilton, Ontario, Canada. peter.ellis@jcc.hhsc.ca
Peter M
PM
Ellis
Quincy S
QS
Chu
Natasha
N
Leighl
Scott A
SA
Laurie
Holger
H
Fritsch
Birgit
B
Gaschler-Markefski
Steve
S
Gyorffy
Gerd
G
Munzert
D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D018572:Disease-Free Survival; D003875:Drug Eruptions / Q000209:etiology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D000068437:Pemetrexed; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D011537:Pruritus / Q000139:chemically induced; D011621:Pteridines / Q000008:administration & dosage; D016896:Treatment Outcome; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D005971:Glutamates; D006147:Guanine; D000068437:Pemetrexed; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536