Study to Evaluate the Safety and Effectiveness of Withaferin A as a Treatment to Prevent GvHD in Transplant Patients

Official title

A Phase I/II Trial to Assess Safety and Activity of Standardized Withaferin A as GvHD Prophylaxis in Patients Undergoing Matched Related Donor Hematopoietic Stem Cell Transplant

Overview

What is acute Graft versus host disease (aGvHD)? GvHD is a complication that can occur after an allogeneic stem cell transplant resulting in damage to some organs. The death rate of GvHD patients is 15-40%. In GvHD, the donated peripheral blood stem cells or bone marrow view the recipient's body as foreign, and the donated cells/bone marrow harm the body. aGvHD usually develops in skin, liver or gastrointestinal tract, and symptoms might appear within few weeks after transplant. Symptoms of acute GvHD are observed as 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 the current prevention used for GvHD? To prevent development of GvHD many standard drugs like cyclosporine (CSA), tacrolimus (TAC), methotrexate (MTX), mycophenolate mofetil (MMF), rapamycin and cyclophosphamide are given. What is standardized Withaferin-A (SWA)? Withaferin-A (WA) is the main 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 of this drug, when added to the standard drugs used for prophylaxis of GvHD, 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, GvHD is a difficult complication of allogeneic stem cell transplant which can lead to increased hospital stay and deaths post-transplant. The standard drugs for prevention of GvHD are cyclosporine (CSA), tacrolimus (TAC), methotrexate (MTX), mycophenolate mofetil (MMF), rapamycin and cyclophosphamide. These drugs also have some side effects during the course of transplant. This points out the need for new preventive drugs that are safe and effective. SWA is an oral formulation of WA which seems to be beneficial in the early studies done in the Clinical Pharmacology Laboratory, ACTREC. SWA has also been found to be safe at very high doses. SWA will be given along with the standard drugs given to prevent GvHD. Despite of consuming these drugs, about 40 - 60% patients still develop GvHD. The investigators aim to add SWA to these standard drugs during transplant to reduce significant aGvHD. How will SWA be given? Participants who agree to participate in this trial and are found to be eligible will be given SWA as a capsule at a dose of 500 mg/day (2 capsules of 250 mg) to 3000 mg/day (6 capsules of 250 mg) as per the dose level allotted to the Patient. The drug will be given for a total duration 90 days starting from Day +1 of transplant. 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 blood samples will be collected at 0, 1, 2, 4, 8 hours on the day of start of SWA (Day +1) and Day +7. Checking immune cell profile and cytokines (which are markers of - immunity levels) will be done at Day+30, Day +90, Day+180, Day+365 from the start of SWA which is also the part of routine care. Blood sample of 5 ml will also be taken at Day 0, Day +14, Day +30, Day +60 and Day +90 after start of drug to see level of some special protein called JAK2 STAT3 protein. What are the risks involved in participation? According to available literature and information, SWA is a safe and well tolerated drug. In a phase 1 study, Standardized Withaferin-A was administered to Patients with advanced stage osteosarcoma. The drug was well tolerated by Patient up to a dose of 4800 mg. No severe side effects were observed. Increase in liver enzymes and skin rash were the most common side effects. Other side effects included fatigue, fever, swelling, and diarrhea. What is the possible impact of this trial? If indeed SWA works and prevents GvHD effectively then this could be a breakthrough in treatment. It would help many Pateints to prevent 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.

Detailed description

Background :Acute graft versus host disease (aGvHD) is one of the most serious complications of allogeneic hematopoietic stem cell transplant (AHSCT) leading to high non relapse mortality (NRM). Withaferin A (WA) is the principal active component of Withania somnifera (Ashwagandha) and is known to have anti-inflammatory and immunomodulatory activity.

WA use in GvHD prophylaxis may be beneficial, with the evidence from preclinical models. We designed this study to evaluate the efficacy and safety of oral WA in addition to the standard GvHD prophylaxis backbone in MRD transplants.

Study design :Prospective, single arm, Phase I/II, non-randomized interventional study.

Study population :Patients ≥ 18 years with any hematological malignancy, planned for MRD (10/10 match on high resolution typing) transplant will be enrolled .

Treatment: SWA will be started from Day +1 to Day +90 in addition to the standard GvHD prophylaxis backbone of calcineurin inhibitor and methotrexate. Following standard dose escalation design, patients will be enrolled at 4 dose levels (500 mg OD, 1000 mg OD, 1500 mg OD and 1500 mg BD). Based on the toxicity, pharmacokinetic data and acute GvHD rates the dose will be fixed for the rest of the patients enrolled in the Phase 2 arm Note: Dose escalation: The dose escalation to the next dose level will be made after completion of Day + 30 of all three patients. The 30 days is the safety evaluation period for the determination of MTD which is standard for phase 1 trials Study assessments:1. Baseline CBC, biochemistry, PFT, 2D ECHO/MUGA, GFR and NCCT thorax will be done pre transplant 2. Till Day +100 - Twice weekly OPD follow up with CBC, biochemistry, CMV PCR, clinical evaluation for aGvHD features and toxicity features, engraftment details and chimerism assessment 3. Post-transplant Day 100-Day 365 - Weekly OPD follow up with CBC, biochemistry, CMV PCR, clinical evaluation for GvHD features and chimerism assessment on D+180, D+360 and then yearly basis.

4\. Disease status assessment by Bone marrow assessment / PET Scan on Day+90 and then at 1 year.

Interventions

• Drug SWA (standardized root extract of Withania somnifera)
  SWA will be started from Day +1 to Day +90 in addition to the standard GvHD prophylaxis backbone of calcineurin inhibitor and methotrexate. Following standard dose escalation design, patients will be enrolled at 4 dose levels (500 mg OD, 1000 mg OD, 1500 mg OD and 1500 mg BD). Based on the toxicity, pharmacokinetic data and acute GvHD rates the dose will be fixed for the rest of the patients enrolled in the Phase 2 arm Note: Dose escalation: The dose escalation to the next dose level will be mad

Primary outcome measures

• Safety and tolerability of oral SWA [Time frame: Day 1 to Day 90]
• Peak plasma concentration (Cmax) of Withaferin A [Time frame: During PK sampling (Phase I)]
• Area Under the Plasma Concentration-Time Curve (AUC) [Time frame: During PK sampling (Phase I)]
• Recommended Phase II Dose (RP2D) [Time frame: By completion of Phase I (Day 90)]
• Cumulative incidence of clinically significant acute GvHD (Grade 2-4) [Time frame: Day 100 post-transplant]

Secondary outcome measures (7)

• Cumulative incidence of severe acute GvHD (Grade 3-4) [Time frame: Day 100 and Day 180]
• GvHD-free and relapse-free survival (GRFS [Time frame: 1 year]
• Incidence of chronic GvHD [Time frame: 1 year]
• Time to neutrophil engraftment [Time frame: Up to Day 30 post-transplant]
• Time to platelet engraftment [Time frame: Up to Day 100 post-transplant]
• Non-relapse mortality (NRM) [Time frame: 1 year]
• Overall survival (OS) [Time frame: 1 year]

Eligibility criteria

Inclusion criteria

• ECOG performance score of 0 or 1
• Adequate liver function (Total serum bilirubin < twice upper normal limit or Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 3-fold higher than laboratory upper normal limits)
• Adequate renal function (creatinine clearance > 50 ml/min)
• Adequate cardiac function (LVEF>40%)
• Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration.
• Signed, written informed consent

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
• Pregnancy, lactation, or inadequate contraception.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Prevention

Study locations

India · 2 centers

• Advanced Centre for Treatment, Research and Education in Cancer — Navi Mumbai
• Advanced Centre for Treatment, Research and Education in Cancer — Navi Mumbai

Publications

• Yco LP, Mocz G, Opoku-Ansah J, Bachmann AS. Withaferin A Inhibits STAT3 and Induces Tumor Cell Death in Neuroblastoma and Multiple Myeloma. Biochem Insights. 2014 Nov 9;7:1-13. doi: 10.4137/BCI.S18863. eCollection 2014. PMID 25452693
• Um HJ, Min KJ, Kim DE, Kwon TK. Withaferin A inhibits JAK/STAT3 signaling and induces apoptosis of human renal carcinoma Caki cells. Biochem Biophys Res Commun. 2012 Oct 12;427(1):24-9. doi: 10.1016/j.bbrc.2012.08.133. Epub 2012 Sep 12. PMID 22982675
• 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. PMID 32160294
• Abboud R, Choi J, Ruminski P, Schroeder MA, Kim S, Abboud CN, DiPersio JF. Insights into the role of the JAK/STAT signaling pathway in graft-versus-host disease. Ther Adv Hematol. 2020 Jun 2;11:2040620720914489. doi: 10.1177/2040620720914489. eCollection 2020. PMID 32537114
• 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. PMID 30904387
• Gupta SK, Jadhav S, Gohil D, Panigrahi GC, Kaushal RK, Gandhi K, Patil A, Chavan P, Gota V. Safety, toxicity and pharmacokinetic assessment of oral Withaferin-A in mice. Toxicol Rep. 2022 May 18;9:1204-1212. doi: 10.1016/j.toxrep.2022.05.012. eCollection 2022. PMID 36518386
• Das R, Rauf A, Akhter S, Islam MN, Emran TB, Mitra S, Khan IN, Mubarak MS. Role of Withaferin A and Its Derivatives in the Management of Alzheimer's Disease: Recent Trends and Future Perspectives. Molecules. 2021 Jun 17;26(12):3696. doi: 10.3390/molecules26123696. PMID 34204308
• Xia Y, Wang P, Yan N, Gonzalez FJ, Yan T. Withaferin A alleviates fulminant hepatitis by targeting macrophage and NLRP3. Cell Death Dis. 2021 Feb 11;12(2):174. doi: 10.1038/s41419-020-03243-w. PMID 33574236

Identifiers

NCT: NCT07724873 · 901067

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗