A randomized phase II study of cediranib alone versus cediranib in combination with dasatinib in docetaxel resistant, castration resistant prostate cancer patients.

Abstract

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.

• Authors: Anna Spreafico, Kim N Chi, Srikala S Sridhar, David C Smith, Michael A Carducci, Peter Kavsak, Tracy S Wong, Lisa Wang, S Percy Ivy, Som Dave Mukherjee, Christian K Kollmannsberger, Mahadeo A Sukhai, Naoko Takebe, Suzanne Kamel-Reid, Lillian L Siu, Sebastien J Hotte
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 5 Pg. 1005-16 (Oct 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 24788563 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• Collagen Type I
• DNA, Neoplasm
• Peptides
• Protein Kinase Inhibitors
• Pyrimidines
• Quinazolines
• Taxoids
• Thiazoles
• collagen type I trimeric cross-linked peptide
• Docetaxel
• Receptors, Vascular Endothelial Growth Factor
• src-Family Kinases
• Alkaline Phosphatase
• cediranib
• Dasatinib

Topics

• Aged
• Aged, 80 and over
• Alkaline Phosphatase (blood)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacology, therapeutic use)
• Bone and Bones (enzymology)
• Collagen Type I (blood)
• DNA, Neoplasm (genetics)
• Dasatinib
• Docetaxel
• Drug Resistance, Neoplasm
• Humans
• Male
• Middle Aged
• Mutation
• Peptides (blood)
• Prostatic Neoplasms, Castration-Resistant (blood, drug therapy, genetics)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacology)
• Pyrimidines (administration & dosage, adverse effects, pharmacology)
• Quinazolines (administration & dosage, adverse effects, pharmacology)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors)
• Sequence Analysis, DNA
• Taxoids
• Thiazoles (administration & dosage, adverse effects, pharmacology)
• Treatment Outcome
• src-Family Kinases (antagonists & inhibitors)