Phase I study of sorafenib in combination with docetaxel and prednisone in chemo-na < ve patients with metastatic castration-resistant prostate cancer
ABSTRACT We performed a dose-escalation study to investigate the safety of sorafenib in combination with docetaxel and prednisone in chemo-naïve patients with metastatic castration-resistant prostate cancer (mCRPC).
Six patients were included per dose level. Following docetaxel infusion on day 1 (75 mg/m(2)/q3 weeks), sorafenib was administered at 200 mg BID on days 2-19 (dose level 1), at 200 mg BID on days 1-21 (dose level 2), at 400 mg BID on days 2-19 (dose level 3), at 400 mg BID on days 1-21 (dose level 4). Maximal tolerated dose (MTD) was exceeded if ≥2 patients experienced dose-limiting toxicities (DLT) during cycle 1. The recommended phase 2 dose for sorafenib was defined as one dose level below MTD. If MTD was not reached, the highest feasible dose would be selected to treat an expanded cohort to confirm safety.
Two DLTs were observed during sorafenib dose-escalation consisting of grade 4 febrile neutropenia (dose level 2) and grade 3 hand-foot syndrome (HFS) (dose level 3). Our pharmacokinetic results showed an increased exposure to docetaxel across all dose levels during sorafenib comedication. The main grade ≥3 toxicities were neutropenia (35 %), HFS (27 %), and febrile neutropenia (19 %). The prostate-specific antigen (PSA) response rate was 74 %. Median overall survival was 25.2 months.
Three-weekly docetaxel and prednisone could be combined with sorafenib at 400 mg BID on days 1-21 without reaching MTD. However, we observed a pharmacokinetic interaction between sorafenib and docetaxel, associated with significant toxicities, raising concerns about the safety of this combination in mCRPC.
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ABSTRACT: PURPOSE OF REVIEW: Therapeutic options for men with metastatic prostate cancer are expanding. Here we discuss the scientific progress in this disease that led to approval of several agents in the last decade and highlight ongoing clinical investigation. RECENT FINDINGS: In androgen-sensitive disease, trials are evaluating the role of intermittent androgen-deprivation therapy, early chemotherapy, and novel targeted and hormonal therapies. For chemotherapy-naive, metastatic castration-resistant prostate cancer (mCRPC), abiraterone is effective. Trials with additional agents targeting androgen receptor (AR) signaling, such as TAK-700 and enzalutamide, are ongoing. Other agents in development target the endothelin pathway, angiogenesis, AR chaperones, and immune mechanisms. Docetaxel with prednisone remains the standard first-line chemotherapeutic regimen as trials incorporating novel agents with docetaxel have been negative. Postdocetaxel, enzalutamide improves survival. Early results with cabozantinib are encouraging, and phase III studies are ongoing. Denosumab and radium-223 reduce the risk of skeletal-related events (SREs), but only radium-223 improves survival. SUMMARY: Progress in understanding the disease biology and mechanisms of castration resistance led to significant therapeutic advancements, particularly in the setting of mCRPC in which several phase III trials, each incorporating agents with different mechanisms of action, have improved survival. As a result, new options exist, and the standard of care has changed significantly. Further advances are anticipated.Current opinion in oncology 03/2013; DOI:10.1097/CCO.0b013e32835ff161 · 3.76 Impact Factor
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ABSTRACT: The multi-kinase inhibitor sorafenib is used for the treatment of renal and hepatic carcinomas and is undergoing evaluation for treatment of breast cancer in combination with other agents. Cytochrome P450 (CYP) 3A4 converts sorafenib to multiple metabolites that have been detected in patient plasma. However, recent clinical findings suggest that combination therapy may elicit inhibitory pharmacokinetic interactions involving sorafenib that increase toxicity. While sorafenib N-oxide is an active metabolite, information on the anti-tumor actions of other metabolites is unavailable. The present study evaluated the actions of sorafenib and its five major metabolites in human breast cancer cell lines. All agents, with the exception of N'-hydroxymethylsorafenib N-oxide, decreased ATP formation in four breast cancer cell lines (MDA-MB-231, MDA-MB-468, MCF-7 and T-47D). Prolonged treatment of MDA-MB-231 cells with N'-desmethylsorafenib, N'-desmethylsorafenib N-oxide and sorafenib (10μM, 72h) produced small increases in caspase-3 activity to 128-139% of control. Sorafenib and its metabolites, again with the exception of N'-hydroxymethylsorafenib N-oxide, impaired MEK/ERK signaling in MDA-MB-231 cells and modulated the expression of cyclin D1 and myeloid cell leukemia sequence-1, which regulate cell viability. When coadministered with doxorubicin (0.5 or 1μM), sorafenib and N'-desmethylsorafenib (25μM) produced greater effects on ATP production than either treatment alone. Thus, it emerges that, by targeting the MEK/ERK pathway, multiple sorafenib metabolites may contribute to the actions of sorafenib in breast cancer. Because N'-desmethylsorafenib is not extensively metabolized and does not inhibit major hepatic CYPs, this metabolite may have a lower propensity to precipitate pharmacokinetic drug interactions than sorafenib.Biochemical pharmacology 05/2013; 86(3). DOI:10.1016/j.bcp.2013.05.014 · 4.65 Impact Factor
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ABSTRACT: Since 2010, six drugs have been approved for the treatment of castration-resistant prostate cancer, i.e., CYP17 inhibitor Abiraterone, androgen receptor antagonist Enzalutamide, cytotoxic agent Cabazitaxel, vaccine Sipuleucel-T, antibody Denosumab against receptor activator of nuclear factor kappa B ligand and radiopharmaceutical Alpharadin. All these drugs demonstrate improvement on overall survival, expect for Denosumab, which increases the bone mineral density of patients under androgen deprivation therapy and prolongs bone-metastasis-free survival. Besides further CYP17 inhibitors (Orteronel, Galeterone, VT-464 and CFG920), androgen receptor antagonists (ARN-509, ODM-201, AZD-3514 and EZN-4176) and vaccine Prostvac, more drug candidates with various mechanisms or new indications of launched drugs are currently under evaluation in different stages of clinical trials, including various kinase inhibitors and platinum complexes. Some novel strategies have also been proposed aimed at further potentiation of antitumor effects or reduction of side effects and complications related to treatments. Under these flourishing circumstances, more investigations should be performed on the optimal combination or the sequence of treatments needed to delay or reverse possible resistance and thus maximize the clinical benefits for the patients.International Journal of Molecular Sciences 07/2013; 14(7):13958-78. DOI:10.3390/ijms140713958 · 2.34 Impact Factor