Study to Evaluate the Safety and Effectiveness of Withaferin A as a Treatment to Prevent GvHD in Transplant Patients
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
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.
調査の概要
状態
状態
条件
条件
介入・治療
介入・治療
詳細な説明
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.
研究の種類
研究の種類
入学 (推定)
入学
段階
段階
- フェーズ2
- フェーズ 1
連絡先と場所
研究連絡先
研究連絡先
- 名前：Dr Akanksha Chichra, FNB, DNB Pediatric oncology
- 電話番号：8686 91 22- 68735000
- メール：akanksha7@hotmail.com
研究連絡先のバックアップ
- 名前：Dr Sachin Punatar, MBBS MD DM Medical Oncology
- 電話番号：8686 91 22- 68735000
- メール：drsachin_punatar@yahoo.in
研究場所
-
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Maharashtra
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Navi Mumbai、Maharashtra、インド、410210
- 募集
- Advanced Centre for Treatment, Research and Education in Cancer
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コンタクト：
- Akanksha Chichra, FNB DNB Pediatric oncology
- 電話番号：09004920555
- メール：akanksha7@hotmail.com
-
コンタクト：
- sachin Punatar, MBBS DM MD Medical Oncology
- 電話番号：09833445041
- メール：drsachin_punatar@yahoo.in
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-
参加基準
適格基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
説明
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.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：防止
- 割り当て：なし
- 介入モデル：単一グループの割り当て
- マスキング：なし（オープンラベル）
アーム数
武器と介入
参加者グループ / アーム参加者グループ / アーム |
介入・治療介入・治療 |
|---|---|
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実験的：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).
|
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
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この研究は何を測定していますか？
主要な結果の測定
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Safety and tolerability of oral SWA
時間枠：Day 1 to Day 90
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Incidence of treatment-emergent adverse events (TEAEs), including Grade ≥3 adverse events assessed using CTCAE v5.0 and PRO-CTCAE v1.0
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Day 1 to Day 90
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Peak plasma concentration (Cmax) of Withaferin A
時間枠：During PK sampling (Phase I)
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Maximum observed plasma concentration following oral administration
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During PK sampling (Phase I)
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Area Under the Plasma Concentration-Time Curve (AUC)
時間枠：During PK sampling (Phase I)
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Area under the plasma concentration-time curve of Withaferin A
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During PK sampling (Phase I)
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Recommended Phase II Dose (RP2D)
時間枠：By completion of Phase I (Day 90)
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RP2D determined based on safety, tolerability and PK findings
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By completion of Phase I (Day 90)
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Cumulative incidence of clinically significant acute GvHD (Grade 2-4)
時間枠：Day 100 post-transplant
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Incidence of Grade 2-4 acute GvHD according to standard grading criteria
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Day 100 post-transplant
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二次結果の測定
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Cumulative incidence of severe acute GvHD (Grade 3-4)
時間枠：Day 100 and Day 180
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Incidence of Grade 3-4 acute GvHD
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Day 100 and Day 180
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GvHD-free and relapse-free survival (GRFS
時間枠：1 year
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Participants alive without Grade III-IV acute GvHD, chronic GvHD requiring systemic therapy, relapse, or death
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1 year
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Incidence of chronic GvHD
時間枠：1 year
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Incidence of chronic GvHD according to NIH criteria
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1 year
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Time to neutrophil engraftment
時間枠：Up to Day 30 post-transplant
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Time to neutrophil engraftment, defined as the first of three consecutive days with an absolute neutrophil count (ANC) >500 cells/mm³ following hematopoietic stem cell transplantation.
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Up to Day 30 post-transplant
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Time to platelet engraftment
時間枠：Up to Day 100 post-transplant
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Time to platelet engraftment, defined as the first day of a platelet count >20,000 cells/mm³ without platelet transfusion during the preceding 7 days.
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Up to Day 100 post-transplant
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Non-relapse mortality (NRM)
時間枠：1 year
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Death without prior disease relapse
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1 year
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Overall survival (OS)
時間枠：1 year
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Time from transplant until death from any cause
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1 year
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その他の成果指標
その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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JAK2-STAT3 pathway activity
時間枠：Baseline, Day +14, Day +30, Day +60, Day +90
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Changes in JAK2-STAT3 signaling levels following SWA prophylaxis
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Baseline, Day +14, Day +30, Day +60, Day +90
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Immune cell phenotyping
時間枠：Day +30, Day +90, Day +180, Day +365
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Changes in immune cell subsets after SWA prophylaxis
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Day +30, Day +90, Day +180, Day +365
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協力者と研究者
協力者
協力者
出版物と役立つリンク
一般刊行物
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研究記録日
主要日程の研究
研究開始 (実際)
研究開始
一次修了 (推定)
一次修了
研究の完了 (推定)
研究の完了
試験登録日
最初に提出
最初に提出
QC基準を満たした最初の提出物
QC基準を満たした最初の提出物
最初の投稿 (実際)
最初の投稿
学習記録の更新
投稿された最後の更新 (実際)
投稿された最後の更新
QC基準を満たした最後の更新が送信されました
QC基準を満たした最後の更新が送信されました
最終確認日
最終確認日
詳しくは
本研究に関する用語
その他の研究ID番号
その他の研究ID番号
- 901067
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
IPD プランの説明
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
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