Phase I study of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers

Abstract

BackgroundRidaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined with paclitaxel and carboplatin in patients with solid tumor cancers.MethodsEligible patients with advanced solid tumor cancers received oral 10 to 30 mg ridaforolimus daily for 5 consecutive days per week combined with intravenous paclitaxel (175 mg/m2) and carboplatin (area under the curve [AUC] 5–6 mg/mL/min) in 3-week cycles. A standard 3 + 3 design was used to escalate doses, with predefined changes to an alternate dosing schedule and/or changes in carboplatin AUC doses based on dose-limiting toxicity (DLT). Secondary information was collected regarding response and time to progression. Patients were continued on treatment if therapy was tolerated and if stable disease or better was demonstrated.ResultsThirty-one patients were consented, 28 patients were screened, and 24 patients met eligibility requirements and received treatment. Two patients were replaced for events unrelated to drug-related toxicity, resulting in 22 DLT-evaluable patients. Two grade 4 DLTs due to neutropenia were observed at dose level 1. The next cohort was changed to a predefined alternate dosing schedule (days 1–5 and 8–12). DLTs were neutropenia, sepsis, mucositis, and thrombocytopenia. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. Twenty-four patients received a median of 4 cycles (range, 1–12). Evaluable patients for response (n = 18) demonstrated a median tumor measurement decrease of 25%. The best response in these 18 patients included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). Thirteen of these patients received treatment for 4 or more cycles.ConclusionsTreatment with ridaforolimus combined with paclitaxel and carboplatin had no unanticipated toxicities and showed antineoplastic activity. The recommended phase II dose and schedule is ridaforolimus 30 mg (days 1–5 and 8–12) plus day 1 paclitaxel (175 mg/m2) and carboplatin (AUC 5 mg/mL/min) on a 21-day cycle.Trial registration ClinicalTrials.gov Identifier: NCT01256268 (trial registration date: December 1, 2010).

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“…In a phase I/II clinical trial of everolimus combined with gemcitabine/cisplatin for metastatic triple negative breast cancer, the combination treatment did not have synergistic effects despite the majority of patients harboring PIK3CA mutations [269]. The combination of ridaforolimus with paclitaxel and carboplatin in a phase I study in patients with solid tumor cancers showed antineoplastic activity with no unanticipated toxicities [266]. In a randomized phase II study to compare the effects of monotherapy with vinorelbine, which disrupts microtubules, versus combined vinorelbine and everolimus for second-line chemotherapy in advanced HER2-negative breast cancer, the combined therapy was not superior to the monotherapy, although the treatment was well tolerated [270].…”

New therapies for advanced, recurrent, and metastatic endometrial cancers

“…mTOR inhibitors have also been combined with chemotherapy. Two phase 1 trials in solid tumors using CT with either ridaforolimus [ 121 ] or temsirolimus [ 122 ] showed response rates of 25% and 82%, respectively, in EC populations. However, a randomized phase 2 trial (GOG-86P) comparing CT with either temsirolimus or bevacizumab or carboplatin plus ixabepilone and bevacizumab to CT showed improved OS when bevacizumab, but not temsirolimus, was added to CT [ 90 ].…”

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“… 187 – 189 Ridaforolimus is another intravenous mTORC1 inhibitor, administrated at a dose of 12.5 mg daily for 5 consecutive days every 2 weeks, showing a modest therapeutic efficacy as a single agent. 190 A phase II trial studied the efficacy and tolerability of ridaforolimus in recurrent and advanced EC with an ORR of 8.8% and a SD of 52.9%. 191 Everolimus, an oral mTORC1 inhibitor (10 mg daily), was evaluated in a phase II study (NCT00087685) for the treatment of patients with recurrent or persistent EC, showing an ORR of 0% and a SD of 43%.…”