A phase II trial of the Src-kinase inhibitor AZD0530 in patients with advanced castration-resistant prostate cancer: a California Cancer Consortium study.
Prostate cancer cells undergo neuroendocrine differentiation during androgen deprivation and secrete neuropeptides, hence activating androgen receptor-regulated genes. Src-family protein kinases are involved in neuropeptide-induced prostate cancer growth and migration. A phase II trial of AZD0530, an oral Src-family kinase inhibitor, in patients with advanced castration resistant prostate cancer was conducted. The primary endpoint was prostate cancer-specific antigen (PSA) response rate, defined as a 30% or greater decrease. A two-stage Simon design was used. Eligibility criteria included documentation of castration resistance (including antiandrogen withdrawal), adequate end-organ function, and performance status, and not more than one prior taxane-based chemotherapy regimen. AZD0530 was given at 175 mg orally once daily continuously. Rapid accrual led to 28 patients registering in the first stage. Median age was 67 years. Sixteen patients had performance status (PS) 0, eight patients had PS 1, and four patients had PS 2. Nine patients (32%) had prior docetaxel-based chemotherapy. Five patients had transient PSA reductions not meeting PSA response criteria. Median progression-free survival time was 8 weeks. Treatment was generally well tolerated. AZD0530, a potent oral Src kinase inhibitor, is feasible and tolerable in this pretreated patient population but possessed little clinical efficacy as monotherapy. Strong preclinical evidence warrants further investigation of AZD0530 in earlier-stage prostate cancer or as combination therapy.
Lara
Primo N
PN
University of California Davis Cancer Center, Sacramento, California 95817, USA. primo.lara@ucdmc.ucdavis.edu
Longmate
Jeff
J
Evans
Christopher P
CP
Quinn
David I
DI
Twardowski
Przemyslaw
P
Chatta
Gurkamal
G
Posadas
Edwin
E
Stadler
Walter
W
Gandara
David R
DR
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D052117:Benzodioxoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000601:surgery; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D052117:Benzodioxoles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C515233:saracatinib; D019061:src-Family Kinases; D017430:Prostate-Specific Antigen