title: Study Design and Rationale for the Phase 3 Clinical Development Program of Enobosarm, a Selective Androgen Receptor Modulator, for the Prevention and Treatment of Muscle Wasting in Cancer Patients (POWER Trials).
abstract: Muscle wasting in cancer is a common and often occult condition that can occur prior to overt signs of weight loss and before a clinical diagnosis of cachexia can be made. Muscle wasting in cancer is an important and independent predictor of progressive functional impairment, decreased quality of life, and increased mortality. Although several therapeutic agents are currently in development for the treatment of muscle wasting or cachexia in cancer, the majority of these agents do not directly inhibit muscle loss. Selective androgen receptor modulators (SARMs) have the potential to increase lean body mass (LBM) and hence muscle mass, without the untoward side effects seen with traditional anabolic agents. Enobosarm, a nonsteroidal SARM, is an agent in clinical development for prevention and treatment of muscle wasting in patients with cancer (POWER 1 and 2 trials). The POWER trials are two identically designed randomized, double-blind, placebo-controlled, multicenter, and multinational phase 3 trials to assess the efficacy of enobosarm for the prevention and treatment of muscle wasting in subjects initiating first-line chemotherapy for non-small-cell lung cancer (NSCLC). To assess enobosarm's effect on both prevention and treatment of muscle wasting, no minimum weight loss is required. These pivotal trials have pioneered the methodological and regulatory fields exploring a therapeutic agent for cancer-associated muscle wasting, a process hereby described. In each POWER trial, subjects will receive placebo (n = 150) or enobosarm 3 mg (n = 150) orally once daily for 147 days. Physical function, assessed as stair climb power (SCP), and LBM, assessed by dual-energy X-ray absorptiometry (DXA), are the co-primary efficacy endpoints in both trials assessed at day 84. Based on extensive feedback from the US Food and Drug Administration (FDA), the co-primary endpoints will be analyzed as a responder analysis. To be considered a physical function responder, a subject must have ≥10 % improvement in physical function compared to baseline. To meet the definition of response on LBM, a subject must have demonstrated no loss of LBM compared with baseline. Secondary endpoints include durability of response assessed at day 147 in those responding at day 84. A combined overall survival analysis for both studies is considered a key secondary safety endpoint. The POWER trials design was established with extensive clinical input and collaboration with regulatory agencies. The efficacy endpoints are a result of this feedback and discussion of the threshold for clinical benefit in patients at risk for muscle wasting. Full results from these studies will soon be published and will further guide the development of future anabolic trials. Clinical Trial ID: NCT01355484. https://clinicaltrials.gov/ct2/show/NCT01355484 , NCT01355497. https://clinicaltrials.gov/ct2/show/NCT01355497?term=g300505&rank=1 .
authors.affiliation: Duke Cancer Institute, Duke University, Duke University Medical Center, 441 Seeley G. Mudd Building, 10 Bryan Searle Drive, Box 3476, Durham, NC, 27710, UK. crawf006@mc.duke.edu.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Crawford
authors.affiliation: Department of Agricultural, Food and Nutritional Science, University of Alberta, 4-002 Li Ka Shing Centre, Edmonton, AB, T6G 2P5, Canada.
authors.forename: Carla M M
authors.initials: CM
authors.lastname: Prado
authors.affiliation: GTx Inc., 175 Toyota Plaza, 7th Floor, Memphis, TN, 38103, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Johnston
authors.affiliation: Albert Einstein College of Medicine, Jacobi Medical Center, 1400 Pelham Parkway South, Building 1, Room 3N20, Bronx, NY, 10461, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gralla
authors.affiliation: GTx Inc., 175 Toyota Plaza, 7th Floor, Memphis, TN, 38103, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Taylor
authors.affiliation: GTx Inc., 175 Toyota Plaza, 7th Floor, Memphis, TN, 38103, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hancock
authors.affiliation: University of Michigan, College of Pharmacy, 428 Church Street, Ann Arbor, MI, 48109, USA. daltonjt@umich.edu.
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D000813:Anilides / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002100:Cachexia / Q000139:chemically induced / Q000188:drug therapy*; D017326:Clinical Trials, Phase III as Topic; D004311:Double-Blind Method; D006801:Humans; D015337:Multicenter Studies as Topic; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy*; D011944:Receptors, Androgen / Q000737:chemistry*; D012107:Research Design
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D011944:Receptors, Androgen; C547106:ostarine
keywords: Cachexia; Cachexia therapy; Cachexia treatment; Enobosarm; Muscle wasting; Non-small-cell lung cancer; Sarcopenia; Selective androgen receptor modulator