A Phase I Trial Of The Mtor Inhibitor Temsirolimus (Tem) In Combination With Capecitabine (Cap) In Patients With Advanced Malignancies.

3095 Background: The mammalian target of rapamycin (mTOR) signaling pathway is critical for cell growth and proliferation. mTOR antagonists, such as TEM, have proven anti-cancer efficacy. Pre-clinical models and early phase clinical trials have demonstrated increased efficacy when an mTOR antagonist is combined with cytotoxic chemotherapy. Methods: Patients (pts) with advanced malignancies and adequate hepatic and renal function were eligible for enrollment. An alternating dose escalation of TEM and CAP was employed in separate q2week and q3week arms. Planned dose levels were: TEM 15 and 25mg IV weekly; and CAP 500, 750, 1000, and 1250 mg/m2 orally twice daily (BID). Restaging occurred every 4 cycles for the q2week arm, and every 3 cycles for the q3week arm. PK samples assessed serum levels of sirolimus at Day 0, 8, and 15 of the q2week arm. Archived tumor specimens were assayed by immunohistochemistry (IHC) for expression of phospho-AKT, phospo-4EBP1, phoshpo-p70S6, and PTEN. Results: Thirty-two pts were enrolled, 30 of whom were evaluable for toxicity, of which 18 were male, age range 30-72 years, 25 with colorectal cancer. Pts had received an average of 4 prior lines of therapy. The most common adverse events (AEs) were mucositis and fatigue. The most common grade 3/4 AEs were fatigue (n=4), diarrhea (n=2), and hypophosphatemia (n=2). In 16/30 pts, the dose of CAP was reduced. There were two DLTs, both hypophosphatemia in the q3week arm (TEM=25mg and CAP=1000mg/m2). For the q2week arm, the recommended phase II dose (RP2D) was TEM 25 mg + CAP 1000mg/m2. For the q3week arm, the RP2D was TEM 25mg + CAP 750mg/m2. Twenty-five pts were evaluable for response (18 for OS). There were no PRs or CRs, but 14/25 pts (56%) had SD, with 4/24 (16%) having prolonged SD of >6 months. Median TTP and OS were 3 and 7 months, respectively. Five pts are still on study. PK assessment of serum sirolimus levels, and the results of the IHC on archived tumor samples will be presented. Conclusions: The combination of TEM and CAP is safe on both a q2week and a q3week schedule. The combination demonstrated promising evidence of disease control in this highly refractory population and should be tested in disease-specific phase II trials.