Abstract C65: Overcoming docetaxel resistance through m-TOR inhibition: A phase I study of the combination of docetaxel and temsirolimus.
2011
Background: Mechanisms of resistance to docetaxel (D) are not well defined. Preclinical work has shown that the administration of the mTOR inhibitor Temsirolimus (T) between courses of D delays the growth of PTEN deficient tumors in xenografts. ( Wu et al. Cancer Res 2005 ) The current study aims to determine the recommended phase II dose (RPTD) of D in combination with T, their toxicity profile, pharmacokinetics (PK) and preliminary clinical activity. Methods: Patients (pts) aged ≥ 18 with any advanced solid tumor refractory to standard therapy, ECOG ≤2 with adequate bone marrow, renal, pulmonary and hepatic functions were eligible. D was given once every 3 weeks with T administered initially on days 2, 9 and 16. However, the protocol was later amended and day 9 of T was omitted due to excessive hematological toxicity. A 3+3 rule dose escalation was used with the following dose levels (DL) planned: DL1: D 50mg/m2, T 15 mg; DL2: D 65mg/m2, T 15 mg; DL3: D 75mg/m2, T 15 mg; DL4: D 75mg/m2, T 25 mg. Blood samples were collected for PK studies, using a validated LC-QqQ-MS procedure. An expanded cohort for patients with castration resistance prostate cancer (CRPC) who have progressed to D is planned once the RPTD has been reached. Results: To date 13 pts have been enrolled with median age = 65 (range 35–76), 9 were male and 8 had ECOG 0, Forty-seven cycles (median: 2; range: 1–9) have been administered. The most frequent related adverse events (AEs) of all grades expressed as % of cycles were: leucopenia (80.8%), hyperglycemia (70.2%), anemia (68.1%), hypercholesterolemia (65.9%), neutropenia (53.2%) hypertriglyceridemia (53.2%) and asthenia (44.7%). The most common Grade 3–4 AEs as % of cycles were: leucopenia (27.6%), neutropenia (29.7%), hypophosphatemia (23%) and lymphopenia (17.0%). Two pts in DL2 experienced dose limiting toxicities (DLT) consisting of intolerable grade 2 mucositis and febrile neutropenia respectively. DL1 was expanded and 3 additional patients were treated with no DLTs. Clearance (litres/h) and volume of distribution (litres) for D, T, and sirolimus (S) were (mean, SD): D, 196.5 (126.1), 2345.0 (1984.0); T, 25.3 (13.3), 128.8 (60.4); S, 24.1 (23.7), 456.3 (131.9). No drug-drug PK interactions were observed. Among 13 pts evaluable for response, 6 (2 pancreatic, 2 prostate, 1 rectal and 1 sarcoma) achieved stable disease. One patient with CRPC who had previously progressed on docetaxel received 9 cycles of treatment with sustained clinical benefit. Conclusions: The combination of D and T seems clinically tolerable at reduced doses of both agents and presents no PK interactions. Additive haematological toxicity and mucositis are the limiting factors to progress on dose escalation. The RPTD is D 50 mg/m2 on day 1 with T 15 mg on days 2 and 16 of a three-weekly schedule. Preliminary antitumor activity has been observed and an expanded cohort for patients with CRPC will start recruitment soon. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C65.
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