Phase I study of sorafenib in combination with docetaxel and prednisone in chemo-naïve 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: Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.JNCI Journal of the National Cancer Institute 03/2000; 92(3):205-16. · 14.34 Impact Factor
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ABSTRACT: The purpose of this trial was to evaluate the antitumor activity of sorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, in patients with castration-resistant prostate cancer. This was a multicenter, two-stage, phase II study. Sorafenib 400 mg was administered orally twice daily continuously. Primary end point was prostate-specific antigen (PSA) 'response' defined as a > or =50% decrease for > or =4 weeks. In all, 28 patients were enrolled. Eastern Cooperative Oncology Group performance status was zero or one in 19 and 9 patients. Two patients had no metastases, and 26 had bone and/or lymph node disease. A median of two cycles (range 1-8) was delivered. Adverse events were typical for sorafenib. The PSA response rate was 3.6% [95% confidence interval (CI) 0.1% to 18.3%] with response occurring in one patient (baseline = 10 000 and nadir = 1643 microg/l). No measurable disease responses occurred in eight patients. Time to PSA progression was 2.3 months (95% CI 1.8-6.4). Of 16 patients who discontinued sorafenib and then did not receive any immediate therapy, 10 had postdiscontinuation PSA declines of 7%-52%. Sorafenib has limited activity using current PSA criteria. The declines in PSA observed on treatment discontinuation indicate an effect on PSA production/secretion. Further study may be warranted but needs to consider the limitations of PSA as an indicator of progression and response.Annals of Oncology 04/2008; 19(4):746-51. · 7.38 Impact Factor
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ABSTRACT: Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters. We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point. Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.Journal of Clinical Oncology 12/1999; 17(11):3461-7. · 18.04 Impact Factor