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Cancer Chemother Pharmacol. 2011 Oct;68(4):889-96. doi: 10.1007/s00280-011-1567-2. Epub 2011 Feb 3.

Accelerated disease progression in prostate cancer and bone metastases with platelet-derived growth factor receptor inhibition: observations with tandutinib.

Author information

1
Department of Genitourinary Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA. pmathew@tuftsmedicalcenter.org

Abstract

BACKGROUND:

Activated platelet-derived growth factor receptor (p-PDGFR) is frequently expressed in bone metastases of castration-resistant prostate cancer (CRPC). Phase II study of tandutinib was conducted to assess the effects of a continuously administered highly potent PDGFR inhibitor in this disease state.

METHODS:

Men with progressive CRPC, bone metastases, and prior taxane chemotherapy were treated with oral tandutinib 500 mg twice daily until disease progression under a two-stage design with the 8-week freedom-from-progression (FFP) rate as the primary endpoint. The trial was designed to have 87% power to reject a null FFP rate of 10% when the true rate was 33% (type I error rate = 0.02). Secondary endpoints included tumor expression of p-PDGFR, bone marker (urine N-telopeptide, serum bone-specific alkaline phosphatase) kinetics, in vivo monitoring of PDGFR inhibition in peripheral blood leukocytes, and correlation with survival.

RESULTS:

Among 18 patients registered (aged 47-81, median 66 years), 15 were evaluable for efficacy. Five of 6 evaluable tumors were p-PDGFR positive. Mean urine N-telopeptide declined from 123.7 (baseline) to 41.0 (Cycle 2 Day 1) nmol/mmol Cr (P = 0.012). Probability of decrease in peripheral blood leukocyte p-PDGFR >0.5 versus <0.5 was associated with progression-free survival of 6 versus 8 weeks (P = 0.03, log-rank) and overall survival, 26.6 versus 42.9 weeks, respectively (P = 0.09, log-rank).

CONCLUSIONS:

In vivo PDGFR inhibition with tandutinib correlated with accelerated disease progression. This observation raises the hypothesis that PDGF contributes to the homeostasis of bone metastases from prostate cancer.

PMID:
21290244
DOI:
10.1007/s00280-011-1567-2
[Indexed for MEDLINE]

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