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)

Jeffrey Crawford, Carla M M Prado, Mary Ann Johnston, Richard J Gralla, Ryan P Taylor, Michael L Hancock, James T Dalton, Jeffrey Crawford, Carla M M Prado, Mary Ann Johnston, Richard J Gralla, Ryan P Taylor, Michael L Hancock, James T Dalton

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://ichgcp.net/clinical-trials-registry/NCT01355484 , NCT01355497. https://ichgcp.net/clinical-trials-registry/NCT01355497?term=g300505&rank=1 .

Keywords: Cachexia; Cachexia therapy; Cachexia treatment; Enobosarm; Muscle wasting; Non-small-cell lung cancer; Sarcopenia; Selective androgen receptor modulator.

Figures

Fig. 1
Fig. 1
POWER 1 and POWER 2 study design

References

    1. Prado CM, Maia YL, Ormsbee M, Sawyer MB, Baracos VE. Assessment of nutritional status in cancer—the relationship between body composition and pharmacokinetics. Anti Cancer Agents Med Chem. 2013;13(8):1197–203. doi: 10.2174/18715206113139990322.
    1. Prado CM. Body composition in chemotherapy: the promising role of CT scans. Curr Opin Clin Nutr Metab Care. 2013;16(5):525–33. doi: 10.1097/MCO.0b013e328363bcfb.
    1. Prado CM, Baracos VE, McCargar LJ, Reiman T, Mourtzakis M, Tonkin K, et al. Sarcopenia as a determinant of chemotherapy toxicity and time to tumor progression in metastatic breast cancer patients receiving capecitabine treatment. Clinical cancer research: an official journal of the American Association for Cancer Research. 2009;15(8):2920–6. doi: 10.1158/1078-0432.CCR-08-2242.
    1. Baracos VE, Reiman T, Mourtzakis M, Gioulbasanis I, Antoun S. Body composition in patients with non-small cell lung cancer: a contemporary view of cancer cachexia with the use of computed tomography image analysis. Am J Clin Nutr. 2010;91(4):1133s–7s. doi: 10.3945/ajcn.2010.28608C.
    1. Bruera E. ABC of palliative care. Anorexia, cachexia, and nutrition. BMJ (Clinical research ed) 1997;315(7117):1219–22. doi: 10.1136/bmj.315.7117.1219.
    1. Tan BH, Fearon KC. Cachexia: prevalence and impact in medicine. Curr Opin Clin Nutr Metab Care. 2008;11(4):400–7. doi: 10.1097/MCO.0b013e328300ecc1.
    1. Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, Guttridge D, et al. Cachexia: a new definition. Clinical nutrition (Edinburgh, Scotland) 2008;27(6):793–9. doi: 10.1016/j.clnu.2008.06.013.
    1. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12(5):489–95. The framework for the definition and classification of cancer cachexia was presented in this paper.
    1. Radbruch L, Elsner F, Trottenberg P, Strasser F, Baracos V, Fearon K. Clinical practice guidelines on cancer cachexia in advanced cancer patients with a focus on refractory cachexia. Department of Palliative Medicinen/European Palliative Care Research Collaborative. 2010.
    1. Evans WJ. Skeletal muscle loss: cachexia, sarcopenia, and inactivity. Am J Clin Nutr. 2010;91(4):1123s–7s. doi: 10.3945/ajcn.2010.28608A.
    1. Prado CM, Sawyer MB, Ghosh S, Lieffers JR, Esfandiari N, Antoun S, et al. Central tenet of cancer cachexia therapy: do patients with advanced cancer have exploitable anabolic potential? Am J Clin Nutr. 2013;98(4):1012–9. This study highlights that contrary to popular belief, muscle wasting in cancer is reversible; therapy should nonetheless include patients earlier on in disease trajectory when the window for anabolism is opened.
    1. Basaria S, Wahlstrom JT, Dobs AS. Clinical review 138: anabolic-androgenic steroid therapy in the treatment of chronic diseases. J Clin Endocrinol Metab. 2001;86(11):5108–17. doi: 10.1210/jcem.86.11.7983.
    1. Lesser GJ, Case D, Ottery F, McQuellon R, Choksi JK, Sanders G, et al. A phase III randomized study comparing the effects of oxandrolone (Ox) and megestrol acetate (Meg) on lean body mass (LBM), weight (wt) and quality of life (QOL) in patients with solid tumors and weight loss receiving chemotherapy. J Clin Oncol. 2008;26(suppl):9513.
    1. Mwamburi DM, Gerrior J, Wilson IB, Chang H, Scully E, Saboori S, et al. Comparing megestrol acetate therapy with oxandrolone therapy for HIV-related weight loss: similar results in 2 months. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2004;38(6):895–902. doi: 10.1086/381977.
    1. Mulligan K, Zackin R, Clark RA, Alston-Smith B, Liu T, Sattler FR, et al. Effect of nandrolone decanoate therapy on weight and lean body mass in HIV-infected women with weight loss: a randomized, double-blind, placebo-controlled, multicenter trial. Arch Intern Med. 2005;165(5):578–85. doi: 10.1001/archinte.165.5.578.
    1. Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y, et al. Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. J Med Chem. 2009;52(12):3597–617. doi: 10.1021/jm900280m.
    1. Negro-Vilar A. Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium. J Clin Endocrinol Metab. 1999;84(10):3459–62. doi: 10.1210/jcem.84.10.6122.
    1. Ribaudo JM, Cella D, Hahn EA, Lloyd SR, Tchekmedyian NS, Von Roenn J, et al. Re-validation and shortening of the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire. Qual Life Res Int J Qual Life Asp Treat Care Rehab. 2000;9(10):1137–46. doi: 10.1023/A:1016670403148.
    1. Webster K, Cella D, Yost K. The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System: properties, applications, and interpretation. Health Qual Life Outcomes. 2003;1:79. doi: 10.1186/1477-7525-1-79.
    1. Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST, et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachex Sarcopenia Muscle. 2011;2(3):153–61. doi: 10.1007/s13539-011-0034-6.
    1. Kim J, Wu D, Hwang DJ, Miller DD, Dalton JT. The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-prop ionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators. J Pharmacol Exp Ther. 2005;315(1):230–9. doi: 10.1124/jpet.105.088344.
    1. Dobs AS, Boccia RV, Croot CC, Gabrail NY, Dalton JT, Hancock ML, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol. 2013;14(4):335–45. This study was the first clinical trial to examine safety and efficacy of a selective androgen receptor modulator for cancer-induced muscle wasting.
    1. Antoun S, Birdsell L, Sawyer MB, Venner P, Escudier B, Baracos VE. Association of skeletal muscle wasting with treatment with sorafenib in patients with advanced renal cell carcinoma: results from a placebo-controlled study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(6):1054–60. doi: 10.1200/JCO.2009.24.9730.
    1. American Cancer Society. Cancer Facts & Figures. Atlanta, GA: 2012.
    1. American Cancer Society. What is non-small cell lung cancer? Atlanta, GA: 2012.
    1. World Health Organization GLOBOCAN 2012 . Estimated cancer incidence, mortality, and prevalence worldwide in 2012. 2012.
    1. Kwon S, Perera S, Pahor M, Katula JA, King AC, Groessl EJ, et al. What is a meaningful change in physical performance? Findings from a clinical trial in older adults (the LIFE-P study) J Nutr Health Aging. 2009;13(6):538–44. doi: 10.1007/s12603-009-0104-z.
    1. Perera S, Mody SH, Woodman RC, Studenski SA. Meaningful change and responsiveness in common physical performance measures in older adults. J Am Geriatr Soc. 2006;54(5):743–9. doi: 10.1111/j.1532-5415.2006.00701.x.
    1. Goodman AD, Brown TR, Krupp LB, Schapiro RT, Schwid SR, Cohen R, et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet. 2009;373(9665):732–8. doi: 10.1016/S0140-6736(09)60442-6.
    1. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353(20):2148–57. doi: 10.1056/NEJMoa050010.
    1. Moyle GJ, Daar ES, Gertner JM, Kotler DP, Melchior JC, O’Brien F, et al. Growth hormone improves lean body mass, physical performance, and quality of life in subjects with HIV-associated weight loss or wasting on highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2004;35(4):367–75. doi: 10.1097/00126334-200404010-00006.
    1. Bean JF, Kiely DK, LaRose S, Alian J, Frontera WR. Is stair climb power a clinically relevant measure of leg power impairments in at-risk older adults? Arch Phys Med Rehabil. 2007;88(5):604–9. doi: 10.1016/j.apmr.2007.02.004.
    1. Roig M, Eng JJ, MacIntyre DL, Road JD, Reid WD. Associations of the stair climb power test with muscle strength and functional performance in people with chronic obstructive pulmonary disease: a cross-sectional study. Phys Ther. 2010;90(12):1774–82. doi: 10.2522/ptj.20100091.
    1. Abate N, Burns D, Peshock RM, Garg A, Grundy SM. Estimation of adipose tissue mass by magnetic resonance imaging: validation against dissection in human cadavers1. J Lipid Res. 1994;35:1490–6.
    1. Rössner S, Bo WJ, Hiltbrandt E, Hinson W, Karstaedt N, Santafo P, et al. Adipose tissue determinations in cadavers-a comparison between cross-sectional planimetry and computed tomography. Int J Obes. 1990;14:893–902.
    1. Slosman DO, Casez J, Pichard C, Rochat T, Fery F, Rizzoli R, et al. Assessment of whole body composition with dual-energy X-ray absorptiometry1. Radiology. 1992;185:593–8. doi: 10.1148/radiology.185.2.1410379.
    1. Ioannidou E, Padilla J, Wang J, Heymsfield SB, Thornton JC, Horlick M, et al. Pencil-beam versus fan-beam dual-energy X-ray absorptiometry comparisons across four systems: appendicular lean soft tissue. Acta Diabetol. 2003;40:S83–S5. doi: 10.1007/s00592-003-0034-x.
    1. Prado CM, Wells JC, Smith SR, Stephan BC, Siervo M. Sarcopenic obesity: a critical appraisal of the current evidence. Clin Nutr. 2012;31(5):583–601. doi: 10.1016/j.clnu.2012.06.010.
    1. Prado CM, Heymsfield SB. Lean tissue imaging: a new era for nutritional assessment and intervention. JPEN J Parenter Enteral Nutr. 2014;38(8):940–53. doi: 10.1177/0148607114550189.
    1. Blake GM, Fogelman I. Role of dual-energy X-ray absorptiometry in the diagnosis and treatment of osteoporosis. J Clin Densitom. 2007;10:102–10. doi: 10.1016/j.jocd.2006.11.001.
    1. Liu H, Paige NM, Goldzweig CL, Wong E, Zhou A, Suttorp MJ, et al. Screening for osteoporosis in Men: a systematic review for an American College of Physicians Guideline. Ann Intern Med. 2008;148:685–701. doi: 10.7326/0003-4819-148-9-200805060-00009.
    1. Fuller NJ, Hardingham CR, Graves M, Screaton N, Dixon AK, Ward LC, et al. Assessment of limb muscle and adipose tissue by dual-energy X-ray absorptiometry using magnetic resonance imaging for comparison. Int J Obes. 1999;23:1295–302. doi: 10.1038/sj.ijo.0801070.
    1. Glickman SG, Marn CS, Supiano MA, Dengel DR. Validity and reliability of dual-energy X-ray absorptiometry for the assessment of abdominal adiposity. J Appl Physiol. 2004;97:509–14. doi: 10.1152/japplphysiol.01234.2003.
    1. Levine JA, Abboud L, Barry M, Reed JE, Sheedy PF, Jensen MD. Measuring leg muscle and fat mass in humans: comparison of CT and dual-energy X-ray absorptiometry. J Appl Physiol. 2000;88:452–6.
    1. Lane JT, Mack-Shipman LR, Anderson JC, Moore TE, Erickson JM, Ford TC, et al. Comparison of CT anddual-energy DEXA using a modified trunk compartment in the measurement of abdominal fat. Endocrine. 2005;27:295–9. doi: 10.1385/ENDO:27:3:295.
    1. Visser M, Fuerst T, Lang T, Salamone L, Harris TB. Validity of fan-beam dual-energy X-ray absorptiometry for measuring fat-free mass and leg muscle mass. Health, aging, and body composition study-dual-energy X-ray absorptiometry and body composition working group. J Appl Physiol. 1999;87:1513–20.
    1. Heymsfield SB, Gallagher D, Kotler DP, Wang Z, Allison DB, Heshka S. Body-size dependence of resting energy expenditure can be attributed to nonenergetic homogeneity of fat-free mass. Am J Physiol Endocrinol Metab. 2002;282(1):E132–8.
    1. Gordon JN, Trebble TM, Ellis RD, Duncan HD, Johns T, Goggin PM. Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial. Gut. 2005;54(4):540–5. doi: 10.1136/gut.2004.047563.
    1. Mantovani G, Maccio A, Madeddu C, Serpe R, Antoni G, Massa E, et al. Phase II nonrandomized study of the efficacy and safety of COX-2 inhibitor celecoxib on patients with cancer cachexia. J Mol Med. 2010;88(1):85–92. doi: 10.1007/s00109-009-0547-z.
    1. Mantovani G, Maccio A, Madeddu C, Serpe R, Massa E, Dessi M, et al. Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia. Oncologist. 2010;15(2):200–11. doi: 10.1634/theoncologist.2009-0153.
    1. Stewart Coats AJ, Srinivasan V, Surendran J, Chiramana H, Vangipuram SR, Bhatt NN, et al. The ACT-ONE trial, a multicentre, randomised, double-blind, placebo-controlled, dose-finding study of the anabolic/catabolic transforming agent, MT-102 in subjects with cachexia related to stage III and IV non-small cell lung cancer and colorectal cancer: study design. J Cachexia Sarcopenia Muscle. 2011;2(4):201–7. doi: 10.1007/s13539-011-0046-2.
    1. . Oxandrolone compared with megestrol in preventing weight loss in patients receiving chemotherapy for cancer 2012 [updated June 22, 2012; cited 2012 September 6]. NCT00070148]. Available from: .
    1. Prado CM, Siervo M, Mire E, Heymsfield SB, Stephan BC, Broyles S, et al. A population-based approach to define body-composition phenotypes. Am J Clin Nutr. 2014;99(6):1369–77. doi: 10.3945/ajcn.113.078576.
    1. Bossola M, Muscaritoli M, Costelli P, Grieco G, Bonelli G, Pacelli F, et al. Increased muscle proteasome activity correlates with disease severity in gastric cancer patients. Ann Surg. 2003;237(3):384–9.
    1. Prado CM, Birdsell LA, Baracos VE. The emerging role of computerized tomography in assessing cancer cachexia. Curr Opin Support Palliat Care. 2009;3(4):269–75. doi: 10.1097/SPC.0b013e328331124a.
    1. MacDonald N. Terminology in cancer cachexia: importance and status. Curr Opin Clin Nutr Metab Care. 2012;15(3):220–5. doi: 10.1097/MCO.0b013e328352a895.
    1. Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733–42. doi: 10.1056/NEJMoa1000678.
    1. Fearon KC, Glass DJ, Guttridge DC. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab. 2012;16(2):153–66. doi: 10.1016/j.cmet.2012.06.011.
    1. Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med. 1980;69(4):491–7. doi: 10.1016/S0149-2918(05)80001-3.
    1. Baracos VE. Management of muscle wasting in cancer-associated cachexia: understanding gained from experimental studies. Cancer. 2001;92(6 Suppl):1669–77. doi: 10.1002/1097-0142(20010915)92:6+<1669::AID-CNCR1495>;2-S.
    1. Morley JE, Thomas DR, Wilson MM. Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr. 2006;83(4):735–43.

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