A randomized phase II (RP2) trial of ridaforolimus (R) compared with progestin (P) or chemotheraphy (C) in female adult patients with advanced endometrial carcinoma.

347

261

Section: Inhibitors Of the Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

Section: Inhibitors Of the Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

The PI3K/AKT/mTOR Pathway as a Therapeutic Target in Endometrial Cancer

Slomovitz

Coleman

2012

347

261

“…Objective response rates range from 0%-30% depending upon the clinical population; clinical response rates are higher in populations that have not received prior chemotherapy and response occurs across histologic subtypes including endometroid, high-grade papillary serous, and clear cell cancers. Importantly, there is a subset, albeit small, of patients with complete and/or durable responses (32)(33)(34)(35)(36)(37).…”

Section: The Rapalogsmentioning

confidence: 99%

New Strategies in Endometrial Cancer: Targeting the PI3K/mTOR Pathway—The Devil Is in the Details

Myers

2013

Endometrial cancer is the most common gynecologic malignancy in the developed world and affects approximately 40,000 women in the United States each year. The phosphoinositide 3-kinase (PI3K) signaling pathway regulates key aspects of cancer biology including glucose uptake and metabolism, cellular growth, and survival. Endometrial cancers harbor the highest rates of PI3K pathway alterations reported to date. The PI3K pathway is highly druggable and several classes of agents are in clinical development including rapalogs, pan-PI3K inhibitors, PI3K isoform-specific inhibitors, dual PI3K/mTOR catalytic inhibitors, mTOR-specific catalytic inhibitors, and AKT inhibitors. It has been 10 years since the initiation of the first studies of rapalogs as anticancer agents. There are more than 20 registered clinical trials of PI3K/mTOR inhibitors as single agents or in therapeutic combinations for the treatment of endometrial cancers. What have we learned from the completed studies? What can we expect to learn from ongoing studies? What should we anticipate moving forward?

“…In preclinical studies, ridaforolimus displayed antiproliferative activity against a variety of human tumor cells lines in vitro and tumor xenograft models in vivo, with additive or synergistic activity when combined with other anticancer agents (14,15). In phases 2 and 3 clinical trials, ridaforolimus has shown promising activity in adults with advanced sarcomas and other malignancies (16)(17)(18)(19)(20)(21). In a large phase 2 study evaluating 212 patients with advanced sarcomas, clinical benefit with intravenously (i.v.)…”

Section: Introductionmentioning

confidence: 99%

A Multicenter, First-in-Pediatrics, Phase 1, Pharmacokinetic and Pharmacodynamic Study of Ridaforolimus in Patients with Refractory Solid Tumors

Gore

Trippett

Katzenstein

et al. 2013

Purpose: Ridaforolimus (MK-8669, AP23573) is a potent and selective mammalian target of rapamycin (mTOR) inhibitor. Preclinically, ridaforolimus displays antiproliferative activity against a variety of human tumors in vitro and tumor xenograft models in vivo, with additive or synergistic activity when combined with other anticancer agents. Antitumor activity has been confirmed in adults. This phase I study determined the safety, pharmacological, biologic, and toxicity profiles of ridaforolimus in pediatric patients with refractory malignancies.Experimental Design: Eligible children ages 1 to 18 years with advanced solid tumors were enrolled in a 3 þ 3 dose escalation design, to determine the safety, tolerability, and maximum tolerated dose (MTD)/ dose-limiting toxicity (DLT) of ridaforolimus. Toxicities, pharmacokinetics, and pharmacodynamics were characterized.Results: Fifteen patients were treated. No DLT was observed at any dose level tested; therefore, an MTD was not identified. Most adverse events were mild to moderate; the most common grades 3 and 4 adverse events were hematologic, including thrombocytopenia and anemia. Nonhematologic adverse events were mostly electrolyte disturbances. The observed pharmacokinetic profile of ridaforolimus in children was consistent with that previously showed in adults. Pharmacodynamic confirms that the dose range tested has pharmacological/pharmacodynamic activity. Forty percent of patients achieved stable disease including four of six with central nervous system tumors and two of eight with sarcomas.Conclusions: This first-in-pediatrics study shows that the second-generation mTOR inhibitor ridaforolimus is well tolerated in heavily pretreated children with refractory solid tumors. No DLTs were observed over the dose range tested. Ridaforolimus may represent a therapeutic option for use in pediatric malignancies.