A Phase I Study of the SMAC-Mimetic Birinapant in Adults with Refractory Solid Tumors or Lymphoma.
The inhibitor of apoptosis (IAP) family of antiapoptotic proteins has been identified as a target for small molecule inhibitors in cancer. Second mitochondrial-derived activator of caspases (SMAC) efficiently and naturally antagonizes IAPs, and preclinical studies have determined that SMAC mimetics have potent anticancer properties. Here, we report a first-in-human trial designed to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics/pharmacodynamics (PK/PD) of birinapant, a novel SMAC mimetic. Patients with advanced solid tumors or lymphoma were enrolled in a 3+3 dose escalation design with birinapant administered intravenously from 0.18 to 63 mg/m(2) once weekly every 3 of 4 weeks. Fifty patients were enrolled to 12 dose cohorts. Birinapant 47 mg/m(2) was determined to be the MTD. At 63 mg/m(2), dose-limiting toxicities included headache, nausea, and vomiting. Two cases of Bell's palsy (grade 2) also occurred at 63 mg/m(2). Birinapant had a plasma half-life of 30 to 35 hours and accumulated in tumor tissue. Birinapant suppressed cIAP1 and increased apoptosis in peripheral blood mononuclear cells and tumor tissue. Prolonged stable disease was observed in 3 patients: non-small cell lung cancer (5 months), colorectal cancer (5 months), and liposarcoma (9 months). Two patients with colorectal cancer had radiographic evidence of tumor shrinkage. In conclusion, birinapant was well tolerated with an MTD of 47 mg/m(2) and exhibited favorable PK and PD properties. Several patients demonstrated stable disease and evidence of antitumor activity. These results support the ongoing clinical trials of birinapant in patients with cancer.
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Ravi.amaravadi@uphs.upenn.edu.
Ravi K
RK
Amaravadi
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Russell J
RJ
Schilder
Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Lainie P
LP
Martin
Pediatric Infectious Diseases and Vaccine Clinical Trials, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.
Myron
M
Levin
TetraLogic Pharmaceuticals, Malvern, Pennsylvania.
Martin A
MA
Graham
TetraLogic Pharmaceuticals, Malvern, Pennsylvania.
David E
DE
Weng
Roswell Park Cancer Institute, Buffalo, New York.
Alex A
AA
Adjei
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D019540:Area Under Curve; D015153:Blotting, Western; D004151:Dipeptides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
D004151:Dipeptides; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; C582429:birinapant