An Open-label, Phase 1/2, Multicenter Study of Belumosudil in Children Aged 1 to <18 Years Requiring Systemic Treatment for Active Moderate-to-severe Chronic Graft Versus Host Disease (cGVHD)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Sanofi
- 入组人数
- 37
- 试验地点
- 48
- 主要终点
- Phase 1: AUC
研究概览
简要总结
This is an open-label, single group, Phase 1/2, 1-arm study for treatment of children aged 1 to <18 years with active moderate-to-severe cGVHD that is refractory to or recurred after at least 2 prior lines of systemic therapy for cGVHD.
The purpose of Phase 1 is to determine the PK profiles and to establish the Recommended Pediatric Equivalent Dose (RPED) of belumosudil in participants aged 1 to <12 years with active moderate to severe cGVHD. Upon completion and evaluation of Phase 1, Phase 2 will commence with the purpose of determining safety and efficacy (ORR by 24 weeks) of belumosudil in participants aged 1 to <18 years.
Study details include:
The end of study is defined as 3 years after the last participant is recruited or all participants have discontinued treatment, or have died, whichever comes first.
Minimum of 6 participants ages 1 to 6 years will be enrolled for each phase of study
Individual participant duration on study will consist of:
Up to 4 weeks for screening. Treatment until clinically significant progression of cGVHD, relapse/recurrence of the underlying disease, start of a new systemic treatment for cGVHD, experience of an unacceptable adverse event, request from participant or Investigator, or until the end of the study is reached, whichever comes first.
30 days of post treatment safety follow-up. Long-term follow-up until death or end of study, whichever occurs first.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant must be 1 to <18 years of age, at the time the consent/assent is signed. For Phase 1: participant must be 1 to <12 years of age, at the time the consent/assent is signed. For Phase 2: participant must be 1 to <18 years of age, at the time the consent/assent is signed.
- •Participant has undergone an allogeneic HCT
- •Has active moderate to severe cGVHD, defined using the NIH Consensus diagnosis and staging criteria for which systemic therapy is required
- •cGVHD is refractory to or has recurred after at least 2 prior lines of systemic treatment
- •Has received at least two lines of prior systemic therapy for cGVHD, but no more than 5 lines.
- •If participant receives corticosteroid therapy for cGVHD, the dose must be stable for at least 2 weeks prior to the first dose of the IMP
- •Has a Lansky-Play (if aged <16 years) or Karnofsky (if aged ≥16 years) performance scale of ≥60
- •Body weight of 8 kg and above
- •Contraceptive use by sexually active male and female should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
- •The participant or their legally authorized representative (LAR) must be capable of giving signed informed consent
- •Life expectancy of >6 months
- •Participants can take the IMP orally or via a nasogastric tube
排除标准
- •Progressive underlying disease or post-transplant lymphoproliferative disease within 4 weeks prior to the first dose of the IMP.
- •Diagnosed with another malignancy (other than malignancy for which transplant was performed) within 3 years prior to the first dose of the IMP
- •History or other evidence of severe illness or any other conditions that would make the participant, in the opinion of the Investigator, unsuitable for the study (such as malabsorption syndromes, active, uncontrolled infections, or poorly controlled psychiatric disease)
- •Has a forced expiratory volume (in the first second; FEV1) ≤39% or has lung score of 3
- •Female participants who are pregnant or breastfeeding
- •Participants who meet any of the following criteria regarding systemic GVHD treatments:
- •Participants who newly initiated any systemic GVHD treatment within 14 days prior to the first dose of belumosudil.
- •Participants receiving systemic GVHD treatments ibrutinib, ruxolitinib, mycophenolate (MMF), methotrexate, rituximab, axatilimab, or imatinib who are unable to meet the following requirements:
- •No dose increases from 14 days prior to belumosudil initiation and continuing for the first 14 days of belumosudil treatment (dose reductions and discontinuations are permitted during this period)
- •Ability to discontinue these therapies within 14 days after initiating belumosudil (allowing for a maximum overlap period of up to 14 days with belumosudil treatment)
- •Participants receiving other systemic GVHD treatments (apart from corticosteroids and calcineurin inhibitors) including investigational treatments who have not completed a washout period of at least 28 days or 5 half-lives (whichever is shorter) prior to the first dose of belumosudil. No washout period is required for extracorporeal photopheresis (ECP) or sirolimus therapy, but these must be discontinued before study treatment initiation.
- •Note: Corticosteroids and calcineurin inhibitors may continue throughout the study.
- •The use of herbal and recreational drugs within 7 days before the start of study intervention
- •Participant has had previous exposure to belumosudil
- •Administration of live or live-attenuated vaccines is prohibited within 28 days or 5 elimination half-lives of the respective vaccine, whichever is longer, prior to IMP administration and until study intervention discontinuation
- •Treatment with any non-GVHD investigational agent, or any investigational device or procedure, within 28 days (or 5 half-lives, whichever is longer) of enrollment, prior to the first dose of the IMP
- •For Phase 1 only: Administration with strong CYP3A4 inducers is not allowed within 14 days or 5 half-lives (whichever is longer) of the first dose of IMP until the study intervention discontinuation.
- •For Phase 1 only: PPIs are not allowed within 1 day or 5 half-lives (whichever is longer) of the first dose of IMP and Day 15 of Cycle
- •They can be restarted on Cycle 1 Day
- •Absolute neutrophil count <1.0 × 109/L. The use of granulocyte-colony stimulating factor (G-CSF) is not allowed within 7 days prior to the ANC test to reach this level during screening
- •Platelet count <25 × 109/L. Platelet transfusions are not allowed within 72 hours before hematology screening test. Participants with platelet transfusion refractoriness will be excluded. (Participants who have suboptimal responses to at least 2 transfusions will be considered as platelet transfusion refractory)
- •Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >3× upper limit of normal (ULN) (> 5x ULN if abnormalities are due to cGVHD)
- •Total bilirubin >1.5 × ULN (>3 x ULN if Gilbert's syndrome or if abnormalities are due to cGVHD)
- •Glomerular filtration rate (GFR) <30 mL/min/1.73 m2 using the revised Bedside Schwartz calculator
- •Participants with an active viral disease including hepatitis B virus (HBV) and hepatitis C virus (HCV)
- •Active uncontrolled Cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection
- •Known history of human immunodeficiency virus (HIV)
- •Not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures
- •The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
研究组 & 干预措施
belumosudil
Participant will take IMP with a meal approximately the same time each morning. IMP dose will be according to weight and will be increased to daily dose of twice a day (BID) in participants who concomitantly receive proton pump inhibitors (PPIs) or strong CYP3A4 inducers. No concomitant PPIs are allowed during Phase 1 up to and including Cycle 1 Day 15. From Day 16 onwards, PPIs will be permitted, resulting in an increased dose of Belumosudil to BID. No concomitant strong CYP3A4 inducers are allowed during Phase 1.
干预措施: Belumosudil (Drug)
结局指标
主要结局
Phase 1: AUC
时间窗: Cycle 1 Day 15 after the last participant dosed in the phase 1 part.
PK parameter (AUC at steady state)
Proportion of participants who achieve an overall response (partial response [PR] or complete response [CR]) by Week 25 or Cycle 7 Day 1 whichever is first
时间窗: Up to 3 years after the last participant enrolled
Proportion of participants who achieve an overall response (partial response \[PR\] or complete response \[CR\]) by Week 25 or Cycle 7 Day 1 whichever is first, as defined by the National Institute of Health (NIH) Consensus response criteria
Phase 1: AUC
时间窗: Cycle 1 Day 15 after the last participant dosed in the phase 1 part.
PK parameter (AUC at steady state)
次要结局
- Phase 1: AUC0-6h(Cycle 1 Day 15 after the last participant dosed in the phase 1 part)
- Phase 1: Number of participants with treatment-emergent adverse events [TEAEs], serious TEAEs, and adverse events of special interest (AESIs)(Up to 3 years after the last participant enrolled)
- Phase 1: ORR(Up to 3 years after the last participant enrolled)
- Phase 1: DOR(Up to 3 years after the last participant enrolled)
- Phase 1: Cmax(Cycle 1 Day 15 after the last participant dosed in the phase 1 part)
- Phase 1: response by organ(Up to 3 years after the last participant enrolled)
- Phase 1: failure-free survival (FFS)(Up to 3 years after the last participant enrolled)
- Phase 1: overall survival (OS)(Up to 3 years after the last participant enrolled)
- Phase 2: Ctrough of belumosudil(Cycle 2 Day 1 and Cycle 4 Day 1 after the last participant enrolled)
- Phase 1: time to response (TTR)(Up to 3 years after the last participant enrolled)
- Phase 2: Number of participants with treatment-emergent adverse events [TEAEs], serious TEAEs, and adverse events of special interest (AESIs)(Up to 3 years after the last participant enrolled)
- Phase 2: DOR(Up to 3 years after the last participant enrolled)
- Phase 2: response by organ(Up to 3 years after the last participant enrolled)
- Phase 2: FFS(Up to 3 years after the last participant enrolled)
- Phase 2: OS(Up to 3 years after the last participant enrolled)
- Phase 2: time to response (TTR)(Up to 3 years after the last participant enrolled)