Study of Standardized Withaferin-A for the Treatment of Steroid Refractory Acute Graft Versus Host Disease.

Summary

Study Design Prospective, single center, single arm, Phase II study. Research aims and objectives Aim: To evaluate the efficacy and safety of standardized Withaferin A in steroid refractory acute GvHD in patients post allogeneic stem cell transplantation Primary Objective: To evaluate the objective Response Rate (ORR) at Day 28 from the start of SWA defined as the proportion of patients achieving Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR). Methodology Treatment plan and Interventions Administration of study treatment Name of the intervention: Standardized WA (standardized root extract of Withania somnifera. This will be provided free of cost to the trial patients. Formulation: The standardized root extract of W. somnifera contains 5% of WA w/w. SWA is available as a 500 mg capsule (AshwaMAX) that contains 25 mg of WA. Route of administration: Per-oral (P/O) Dose schedule: The dose of SWA is 1500mg/day. It will be administered as 3 capsules of 500 mg once a day. Duration of treatment: * Every patient will receive treatment for at least 12 weeks followed by a taper as per physician's discretion. WA can be tapered after 12 weeks if the patient has achieved CR or VGPR and has discontinued corticosteroids for at least 4 weeks. * Dose adjustments/modifications: If the patient experiences any grade ≥3 toxicities related to SWA, further administration of SWA will be withheld immediately. Once the severity of the adverse event reduces to grade ≤1, the study agent will be rechallenged with 25% dose reduction. The same strategy will be adopted for successive grade ≥3 toxicities. If the drug is not tolerated at 25% of original dose (100 mg), no further rechallenge will be attempted. * Corticosteroid tapering will be done as per the treating physician's discretion and clinical condition of the patient.

Timeline

Start

2023-09-23

Primary completion

2028-01-09

Completion

2028-09-25

Publications

• Background Martin PJ, Inamoto Y, Flowers ME, Carpenter PA. Secondary treatment of acute graft-versus-host disease: a critical review. Biol Blood Marrow Transplant. 2012 Jul;18(7):982-8. doi: 10.1016/j.bbmt.2012.04.006. Epub 2012 Apr 14.
• Results Pires N, Gota V, Gulia A, Hingorani L, Agarwal M, Puri A. Safety and pharmacokinetics of Withaferin-A in advanced stage high grade osteosarcoma: A phase I trial. J Ayurveda Integr Med. 2020 Jan-Mar;11(1):68-72. doi: 10.1016/j.jaim.2018.12.008. Epub 2019 Mar 21.
• Results Mehta M, Gohil D, Khattry N, Kumar R, Sandur S, Sharma D, Checker R, Agarwal B, Jha D, Majumdar A, Gota V. Prevention of acute graft-versus-host-disease by Withaferin a via suppression of AKT/mTOR pathway. Int Immunopharmacol. 2020 Jul;84:106575. doi: 10.1016/j.intimp.2020.106575. Epub 2020 May 13.
• Results Jagasia M, Perales MA, Schroeder MA, Ali H, Shah NN, Chen YB, Fazal S, Dawkins FW, Arbushites MC, Tian C, Connelly-Smith L, Howell MD, Khoury HJ. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. 2020 May 14;135(20):1739-1749. doi: 10.1182/blood.2020004823.
• Results Socie G, Vigouroux S, Yakoub-Agha I, Bay JO, Furst S, Bilger K, Suarez F, Michallet M, Bron D, Gard P, Medeghri Z, Lehert P, Lai C, Corn T, Vernant JP. A phase 3 randomized trial comparing inolimomab vs usual care in steroid-resistant acute GVHD. Blood. 2017 Feb 2;129(5):643-649. doi: 10.1182/blood-2016-09-738625. Epub 2016 Nov 29.
• Results Zeiser R, Blazar BR. Acute Graft-versus-Host Disease - Biologic Process, Prevention, and Therapy. N Engl J Med. 2017 Nov 30;377(22):2167-2179. doi: 10.1056/NEJMra1609337. No abstract available.
• Results Martin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C, Litzow MR, Nieto Y, Savani BN, Schriber JR, Shaughnessy PJ, Wall DA, Carpenter PA. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2012 Aug;18(8):1150-63. doi: 10.1016/j.bbmt.2012.04.005. Epub 2012 Apr 14.
• Results Dignan FL, Clark A, Amrolia P, Cornish J, Jackson G, Mahendra P, Scarisbrick JJ, Taylor PC, Hadzic N, Shaw BE, Potter MN; Haemato-oncology Task Force of British Committee for Standards in Haematology; British Society for Blood and Marrow Transplantation. Diagnosis and management of acute graft-versus-host disease. Br J Haematol. 2012 Jul;158(1):30-45. doi: 10.1111/j.1365-2141.2012.09129.x. Epub 2012 Apr 26.
• Results Westin JR, Saliba RM, De Lima M, Alousi A, Hosing C, Qazilbash MH, Khouri IF, Shpall EJ, Anderlini P, Rondon G, Andersson BS, Champlin R, Couriel DR. Steroid-Refractory Acute GVHD: Predictors and Outcomes. Adv Hematol. 2011;2011:601953. doi: 10.1155/2011/601953. Epub 2011 Nov 3.
• Results Ruutu T, Gratwohl A, de Witte T, Afanasyev B, Apperley J, Bacigalupo A, Dazzi F, Dreger P, Duarte R, Finke J, Garderet L, Greinix H, Holler E, Kroger N, Lawitschka A, Mohty M, Nagler A, Passweg J, Ringden O, Socie G, Sierra J, Sureda A, Wiktor-Jedrzejczak W, Madrigal A, Niederwieser D. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Transplant. 2014 Feb;49(2):168-73. doi: 10.1038/bmt.2013.107. Epub 2013 Jul 29.
• Results Shohat B, Gitter S, Lavie D. Effect of withaferin A on Ehrlich ascites tumor cells--cytological observations. Int J Cancer. 1970 Mar 15;5(2):244-52. doi: 10.1002/ijc.2910050212. No abstract available.
• Results Gambhir L, Checker R, Sharma D, Thoh M, Patil A, Degani M, Gota V, Sandur SK. Thiol dependent NF-kappaB suppression and inhibition of T-cell mediated adaptive immune responses by a naturally occurring steroidal lactone Withaferin A. Toxicol Appl Pharmacol. 2015 Dec 1;289(2):297-312. doi: 10.1016/j.taap.2015.09.014. Epub 2015 Sep 25.
• Results Przepiorka D, Luo L, Subramaniam S, Qiu J, Gudi R, Cunningham LC, Nie L, Leong R, Ma L, Sheth C, Deisseroth A, Goldberg KB, Blumenthal GM, Pazdur R. FDA Approval Summary: Ruxolitinib for Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease. Oncologist. 2020 Feb;25(2):e328-e334. doi: 10.1634/theoncologist.2019-0627. Epub 2019 Oct 22.
• Results Rizvi TF, Razauddin M, Rahman SR. Immunomodulatory effect of Ashwagandha against doxorubicin toxicity. Eur J Pharma Med Res. 2016;3:463-7.
• Results Furmanowa M, Gajdzis-Kuls D, Ruszkowska J, Czarnocki Z, Obidoska G, Sadowska A, Rani R, Upadhyay SN. In vitro propagation of Withania somnifera and isolation of withanolides with immunosuppressive activity. Planta Med. 2001 Mar;67(2):146-9. doi: 10.1055/s-2001-11494.
• Results Schroeder MA, DiPersio JF. Mouse models of graft-versus-host disease: advances and limitations. Dis Model Mech. 2011 May;4(3):318-33. doi: 10.1242/dmm.006668.
• Results Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009 May 2;373(9674):1550-61. doi: 10.1016/S0140-6736(09)60237-3. Epub 2009 Mar 11.
• Results Qian L, Wu Z, Shen J. Advances in the treatment of acute graft-versus-host disease. J Cell Mol Med. 2013 Aug;17(8):966-75. doi: 10.1111/jcmm.12093. Epub 2013 Jun 26.

Drugs

Indications