A randomized phase II study of cediranib alone versus cediranib in combination with dasatinib in docetaxel resistant, castration resistant prostate cancer patients.
BACKGROUND
Activation of the vascular endothelial growth factor receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of castration-resistant prostate cancer (CRPC) in preclinical models. Cediranib and dasatinib are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of cediranib and dasatinib in CRPC have shown single agent activity.


METHODS
Docetaxel-pretreated CRPC patients were randomized to arm A: cediranib alone (20 mg/day) versus arm B: cediranib (20 mg/day) plus dasatinib (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12-week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed. Results A total of 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles =4 in arm A (range 1-12) and 2 in arm B (range 1-9). Twelve-week PFS was 73 % in arm A versus 18 % in arm B (p = 0.03). Median PFS in months (arm A versus B) was: 5.2 versus 2.6 (95 % CI: 1.9-6.5 versus 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in either arm.


CONCLUSIONS
Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in patients with CRPC. ClinicalTrials.gov number: NCT01260688.
Princess Margaret Cancer Center, Toronto, ON, Canada.
Anna
A
Spreafico
Kim N
KN
Chi
Srikala S
SS
Sridhar
David C
DC
Smith
Michael A
MA
Carducci
Peter
P
Kavsak
Tracy S
TS
Wong
Lisa
L
Wang
S Percy
SP
Ivy
Som Dave
SD
Mukherjee
Christian K
CK
Kollmannsberger
Mahadeo A
MA
Sukhai
Naoko
N
Takebe
Suzanne
S
Kamel-Reid
Lillian L
LL
Siu
Sebastien J
SJ
Hotte
D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000097:blood; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001842:Bone and Bones / Q000201:enzymology; D024042:Collagen Type I / Q000097:blood; D004273:DNA, Neoplasm / Q000235:genetics; D000069439:Dasatinib; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010455:Peptides / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D017422:Sequence Analysis, DNA; D043823:Taxoids; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D016896:Treatment Outcome; D019061:src-Family Kinases / Q000037:antagonists & inhibitors; D007211:Indoles
D000469:Alkaline Phosphatase; D024042:Collagen Type I; D004273:DNA, Neoplasm; D000069439:Dasatinib; D000077143:Docetaxel; D010455:Peptides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; D043823:Taxoids; D013844:Thiazoles; D019061:src-Family Kinases; C052929:collagen type I trimeric cross-linked peptide; C500926:cediranib; D007211:Indoles