Study of Standardized Withaferin-A for the Treatment of Steroid Refractory Acute Graft Versus Host Disease. (Withaferin_A)
A Phase II Clinical Trial of Standardized Withaferin-A for the Treatment of Steroid Refractory Acute Graft Versus Host Disease
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.
Studieoversigt
Status
Intervention / Behandling
Detaljeret beskrivelse
Secondary Objectives:
- To evaluate the ORR at other defined time points (Day 14 and Day 56) from initiation of SWA
- To study the Non relapse Mortality (NRM) at 1 year post transplant
- To study the Relapse rate at 1 year post transplant
- To study the Overall Survival (OS) at 1 year post transplant
- To study the incidence of chronic GvHD at 1 year post transplant
- To study the incidence of adverse effects attributed to SWA
Exploratory Objectives:
- Reduction of steroid dose by ≥30% from baseline will be calculated for all patients on day 28 after start of SWA.
- To measure the JAK2-STAT3 levels, JAK2-STAT3 receptor kinetics at baseline (pre- conditioning) and post initiation of WA.
- Immune cell phenotype, cytokine profile and pharmacokinetics of WA in patients post treatment with SWA at baseline, Day +7, Day +14, Day +28, Day+56, Day+90 and Day +180 post HSCT.
What is acute Graft versus host disease (GvHD)? GvHD is a complication that can occur after an allogeneic stem cell transplant resulting in damage to internal organs. Patients with GvHD have a mortality rate of 15-40%. In GvHD, the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow harm the body. Acute GvHD usually develops in the skin, liver or gastrointestinal tract, and symptoms might appear within weeks after transplant. Symptoms of acute GvHD are skin rash or reddened areas on the skin, yellow discoloration of the skin and/or eyes, and abnormal blood test results, nausea, vomiting, diarrhea, or abdominal cramping.
What is steroid refractory acute GvHD (SR GvHD)? Most of patients who develop acute GvHD are successfully treated with corticosteroids, a type of medicine that suppress the donor cells from attacking the recipient's organs. If steroids are unsuccessful, it is termed as acute SR GvHD. Acute SR GvHD is a condition with poor outcomes as effective treatments are not available.
What is the current treatment for SR GvHD? The only treatment that is US-FDA approved for the treatment of SR GvHD is ruxolitinib. Ruxolitinib is expensive and hence not affordable for most patients. It also has its own set of side effects which include low blood counts. Although, there are other medicines that have shown to be effective in this condition, none of them have been approved by the regulatory authorities.
What is standardized Withaferin-A (SWA)? Withaferin-A (WA) is the principal active component of Withania somnifera (Ashwagandha). It has been shown in many studies to have properties of healing and immune-modulation (improving the immune system). Studies have been done in our Clinical Pharmacology Laboratory that have shown a significant beneficial effect on reducing the risk of acute GvHD. The drug has also been tested and proven to be very safe in humans.
What is the rationale of this trial? As has been described earlier, SR GvHD is a difficult complication of allogeneic stem cell transplant which can lead to increased hospital stay and deaths post-transplant. The only approved drug for steroid refractory GvHD (Ruxolitinib) is expensive and out of reach for most patients. It also has side effects which can lead to its discontinuation. SWA is an oral formulation of WA which seems to be beneficial in the early studies done in the Clinical Pharmacology Laboratory. SWA has also been found to be safe at very high doses. Whether SWA will actually patients undergoing allogeneic stem cell transplant who develop SR GvHD has not been proven as this can only be done by conducting a systematic trial. This trial is being conducted to see if SWA is beneficial in SR GvHD which will give us a drug which is easily available, oral and inexpensive to treat SR GvHD.
How will SWA be given? Patients who agree to participate in this trial and are found to be eligible will be given SWA as a capsule at a dose of 1500 mg/day orally. The drug will be given for a total duration of 12 weeks after which the dose will be reduced and stopped. All other standard treatments which are part of a transplant procedure will be carried out without any change.
Participants will be monitored clinically for any adverse events and followed up as per standard protocols post-transplant.
What additional tests will be carried out? Additional blood sampling to study the levels of the drug WA, checking immune cell profile and cytokines (which are markers of your immunity levels) will be done at baseline, Day+7, Day +14, Day+28, Day+56, Day+90, Day +180 from the start of SWA
. What are the risks involved in participation? According to available literature and information, SWA is a safe and well tolerated drug. There is a possibility that rifaximin can have interaction with cyclosporine (immunosuppressant) and antifungal (Azole) drugs which are used in BMT, although studies done in bone marrow transplant (BMT) with rifaximin have not documented such an interaction. Drug levels of azole antifungals and cyclosporine in the blood are monitored as a standard of care (i.e. these will be done irrespective of the decision to take part in this study) in BMT which will help to take corrective action in case there is such an interaction, which will mitigate any potential risk due to this.
What is the possible impact of this trial? If indeed SWA works and treats SR GvHD effectively then this could be a major breakthrough in treatment. It would help many patients who develop SR GvHD post allogeneic stem cell transplant and would be a safe, easily available, inexpensive and oral drug for the same. This possibly could benefit and help future patients who undergo bone marrow transplant (BMT) to have better chances of survival and reduce their financial burden.
Undersøgelsestype
Tilmelding (Anslået)
Fase
- Fase 2
Kontakter og lokationer
Studiekontakt
- Navn: Dr Akanksha Chichra, DNB
- Telefonnummer: 5404 27405000
- E-mail: akanksha7@hotmail.com
Undersøgelse Kontakt Backup
- Navn: Dr.Sachin Punatar, DM
- Telefonnummer: 5404 27405000
- E-mail: drsachin_punatar@yahoo.in
Studiesteder
-
-
Maharashtra
-
Navi Mumbai, Maharashtra, Indien, 410210
- Rekruttering
- Advanced Centre for Treatment, Research and Education in Cancer
-
Kontakt:
- Akanksha Chichra, FNB DNB Pediatric oncology
- Telefonnummer: 09004920555
- E-mail: akanksha7@hotmail.com
-
Kontakt:
- sachin Punatar, MBBS DM MD Medical Oncology
- Telefonnummer: 09833445041
- E-mail: drsachin_punatar@yahoo.in
-
Ledende efterforsker:
- Dr Akanksha Chichra, FNB DNB Pediatric oncology
-
-
Deltagelseskriterier
Berettigelseskriterier
Aldre berettiget til at studere
- Barn
- Voksen
- Ældre voksen
Tager imod sunde frivillige
Beskrivelse
Inclusion Criteria:
- Patients age ≥ 12 years with a hematological malignancy who have undergone allogeneic stem cell transplant with matched related donor (MRD), Haploidentical (Haplo) donor or matched unrelated donor (MUD)
- Evidence of myeloid engraftment (eg, absolute neutrophil count ≥0.5 × 109 /L for 3 consecutive days)
- ECOG performance score of 0 or 1
- Patients with steroid-refractory aGvHD, defined as any of the following:
- Patients with progressive GvHD (ie, increase in stage in any organ system or any new organ involvement) after 3 days of primary treatment with methylprednisolone ≥2 mg/kg/d (or equivalent)
- Patients with GvHD that has not improved (ie, decrease in stage in at least 1 involved organ system) after 7 days of primary treatment with methylprednisolone ≥2 mg/kg/d (or equivalent)
- Patients who previously began corticosteroid therapy at a lower dose (≥1 mg/kg/d methylprednisolone) for treatment of skin GvHD or skin GvHD accompanied by upper gut GvHD but develop new GvHD in another organ system
- Patients who cannot tolerate a corticosteroid taper, that is, begin corticosteroids at 2.0 mg/kg/d, demonstrate response, but progress before a 50% decrease from the initial starting dose of corticosteroids is achieved
Exclusion Criteria:
- Known hypersensitivity or contraindications against Withaferin-A.
- Presence of an active uncontrolled infection defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs, or radiographic findings attributable to infection.
- Any medical or psychiatric illness which precludes the participant from giving informed consent.
Studieplan
Hvordan er undersøgelsen tilrettelagt?
Design detaljer
- Primært formål: Behandling
- Tildeling: N/A
- Interventionel model: Enkelt gruppeopgave
- Maskning: Ingen (Åben etiket)
Våben og indgreb
Deltagergruppe / Arm |
Intervention / Behandling |
|---|---|
|
Eksperimentel: Standardized Withaferin A (SWA)
Withaferin-A Standardized WA (standardized root extract of Withania somnifera Dose schedule: The dose of SWA is 1500mg/day. It will be administered as 3 capsules of 500 mg once a day. Route :Oral Duration: 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. |
Withaferin-A (standardized root extract of Withania somnifera ) 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.
Andre navne:
|
Hvad måler undersøgelsen?
Primære resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
|
OBJECTIVE RESPONSE RATE (ORR)
Tidsramme: Day 28 after initiation of standardized Withaferin A (SWA)
|
OBJECTIVE RESPONSE RATE (ORR)
|
Day 28 after initiation of standardized Withaferin A (SWA)
|
Sekundære resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
|
Overall response rate
Tidsramme: Day 14 and Day 56 after initiation of standardized Withaferin A
|
Overall response rate at Day 14 and Day 56
|
Day 14 and Day 56 after initiation of standardized Withaferin A
|
|
Non-relapse mortality (NRM)
Tidsramme: Up to 1 year post-transplant
|
The non-relapse mortality (NRM) at 1 year post transplant.
|
Up to 1 year post-transplant
|
|
Overall survival (OS)
Tidsramme: Up to 1 year post-transplant
|
The overall survival (OS) at 1 year post transplant
|
Up to 1 year post-transplant
|
|
Incidence of chronic graft versus host disease
Tidsramme: Up to 1 year post-transplant
|
The incidence of chronic graft versus host disease (GVHD) at 1 year post transplant.
|
Up to 1 year post-transplant
|
|
Incidence of adverse effects
Tidsramme: until 12 weeks after last dose of Investigational product
|
The incidence of adverse effects attributed to standardized Withaferin A (SWA).
|
until 12 weeks after last dose of Investigational product
|
|
Relapse rate
Tidsramme: upto 1 year post transplant
|
Relapse rate 1 year post transplant
|
upto 1 year post transplant
|
Andre resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
|
Number of participants with a ≥30% reduction in corticosteroid dose from baseline
Tidsramme: Day 28 after initiation of standardized Withaferin A(SWA).
|
Number of participants achieving a reduction of ≥30% in corticosteroid dose from baseline after initiation of standardized Withaferin A (SWA).
|
Day 28 after initiation of standardized Withaferin A(SWA).
|
|
Change in JAK2 and STAT3 biomarker levels from baseline
Tidsramme: Baseline (before initiation of SWA), Day +7 and Day +28 after initiation of SWA.
|
Change in JAK2 and STAT3 biomarker levels from baseline (before initiation of standardized Withaferin A [SWA])
|
Baseline (before initiation of SWA), Day +7 and Day +28 after initiation of SWA.
|
|
Change in JAK2-STAT3 receptor kinetics from baseline
Tidsramme: Baseline (before initiation of SWA), Day +7 and Day +28 after initiation of SWA.
|
Change in JAK2-STAT3 receptor kinetics from baseline (before initiation of standardized Withaferin A [SWA])
|
Baseline (before initiation of SWA), Day +7 and Day +28 after initiation of SWA.
|
|
Change in immune cell subset frequencies from baseline
Tidsramme: Baseline, Day +7 , Day +14 ,Day +28 , and Day +100 post hematopoietic stem cell transplantation (HSCT)
|
Change in the frequency of predefined immune cell subsets
|
Baseline, Day +7 , Day +14 ,Day +28 , and Day +100 post hematopoietic stem cell transplantation (HSCT)
|
|
Change in serum cytokine concentrations from baseline
Tidsramme: Baseline, Day +7 , Day +14 , Day +28, and Day +100 post transplant
|
Change in the concentrations of the predefined cytokines from baseline
|
Baseline, Day +7 , Day +14 , Day +28, and Day +100 post transplant
|
|
Maximum plasma concentration (Cmax) of Withaferin A
Tidsramme: Pharmacokinetic sampling time points from baseline through Day +100 , post transplant
|
Maximum observed plasma concentration (Cmax) of Withaferin A following administration of standardized Withaferin A (SWA).
|
Pharmacokinetic sampling time points from baseline through Day +100 , post transplant
|
Samarbejdspartnere og efterforskere
Sponsor
Efterforskere
- Ledende efterforsker: Dr.Akanksha Chichra, DNB, Advanced Centre for Treatment, Research and Education in Cancer
Publikationer og nyttige links
Generelle publikationer
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Rizvi TF, Razauddin M, Rahman SR. Immunomodulatory effect of Ashwagandha against doxorubicin toxicity. Eur J Pharma Med Res. 2016;3:463-7.
- 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.
- 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.
- 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.
Datoer for undersøgelser
Studer store datoer
Studiestart (Faktiske)
Primær færdiggørelse (Anslået)
Studieafslutning (Anslået)
Datoer for studieregistrering
Først indsendt
Først indsendt, der opfyldte QC-kriterier
Først opslået (Faktiske)
Opdateringer af undersøgelsesjournaler
Sidste opdatering sendt (Faktiske)
Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier
Sidst verificeret
Mere information
Begreber relateret til denne undersøgelse
Nøgleord
Yderligere relevante MeSH-vilkår
Andre undersøgelses-id-numre
- 900937
Plan for individuelle deltagerdata (IPD)
Planlægger du at dele individuelle deltagerdata (IPD)?
IPD-planbeskrivelse
Lægemiddel- og udstyrsoplysninger, undersøgelsesdokumenter
Studerer et amerikansk FDA-reguleret lægemiddelprodukt
Studerer et amerikansk FDA-reguleret enhedsprodukt
Disse oplysninger blev hentet direkte fra webstedet clinicaltrials.gov uden ændringer. Hvis du har nogen anmodninger om at ændre, fjerne eller opdatere dine undersøgelsesoplysninger, bedes du kontakte register@clinicaltrials.gov. Så snart en ændring er implementeret på clinicaltrials.gov, vil denne også blive opdateret automatisk på vores hjemmeside .
Kliniske forsøg med Standardized Withaferin A (SWA)
-
Sham Sunder KakarUniversity of LouisvilleRekrutteringTilbagevendende kræft i æggestokkeneForenede Stater