Ruxolitinib, Human Chorionic Gonadotropin (uhCG/EGF), and Dose De-escalated Corticosteroids for Treatment of Minnesota High-Risk Acute GVHD (aGVHD): A Phase I/II Study
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Recommend the lowest possible dose for Phase II of corticosteroids when given in combination with ruxolitinib and uhCG/EGF in pediatric based on DLT frequency
研究概览
简要总结
This multi-center center phase I/II study to establish the lowest possible recommended phase 2 dose (RP2D) of corticosteroids in conjunction with ruxolitinib and uhCG/EGF (a novel combination) for high-risk aGVHD.
This is a single arm study designed to determine the lowest dose of corticosteroids required (toxicity endpoint) without impairing GVHD complete response or partial response (CR/PR) at day 28 when given in conjunction with uhCG/EGF and ruxolitinib.
After completion of the corticosteroid dose finding, the final dose will be carried forward into a two-stage phase II extension trial to confirm safety and make a preliminary determination of efficacy of this novel drug combination for high-risk aGVHD.
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
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •HCT recipients over 12 years of age within the first 7 days of initial treatment of high-risk aGVHD, defined as:
- •Newly diagnosed Minnesota high-risk aGVHD -OR-
- •Newly diagnosed Minnesota standard risk aGVHD with plasma amphiregulin ≥ 33 pg/ml tested at the UMN Cytokine Reference Lab. For amphiregulin lab ordering information, see Fairview Lab Guide: http://labguide.fairview.org/showtest.asp?testid=6766&format=long -OR-
- •Newly diagnosed Minnesota standard risk aGVHD Ann Arbor 3 biomarkers tested by Viracor. For ordering information, see: https://www.viracor-eurofins.com/test-menu/403572p-agvhd-symptomatic- onset-algorithm/
- •Renal: Serum creatinine ≤2.5x upper limit of normal (ULN)
- •Cardiac: Left ventricular ejection fraction (LVEF) ≥ 35%
- •Voluntary written consent (adult or parent/guardian with minor assent for 12 through 17-year-olds).
排除标准
- •Progressive malignancy
- •Uncontrolled bacterial, fungal, parasitic, or viral infection at initiation of protocol treatment
- •Unwilling or unable to stop supplemental sex hormone therapy (estrogen, progesterone, and/or testosterone preparations)
- •Unwilling or unable to stop GnRH antagonists, aromatase inhibitors, or anti-androgens
- •History of a hormone responsive malignancy
- •Current thromboembolic disease requiring full-dose anticoagulation - patients receiving pharmacologic prophylaxis for thromboembolic disease will be eligible
- •Active or recent (within prior 3 months) thrombus, irrespective of anticoagulation status
- •Pregnancy
- •Women or men of childbearing potential unwilling to take adequate precautions to avoid unintended pregnancy from the start of protocol treatment through 30 days after the last treatment
研究组 & 干预措施
Ruxolitinib;hCG (Pregnyl®) ;Corticosteroids
-
Ruxolitinib 10 mg by mouth twice daily (with dose adjustments as indicated) through day 56, followed by taper
-
hCG (Pregnyl®) 2,000 units/m2 SQ every other day x 3 doses, followed by twice weekly x 14 doses (total 17 doses through day 56)
-
Corticosteroids (Prednisone, or IV methylprednisolone equivalent)
-
Dose level 1 (starting dose) = 1 mg/kg
-
Dose level 2 = 0.5 mg/kg
-
Dose level 3 = 0.25 mg/kg
-
Dose level 4 = 0.1 mg/kg
-
Dose level 5 = 0 mg/kg
干预措施: Corticosteroids (Drug)
Ruxolitinib;hCG (Pregnyl®) ;Corticosteroids
-
Ruxolitinib 10 mg by mouth twice daily (with dose adjustments as indicated) through day 56, followed by taper
-
hCG (Pregnyl®) 2,000 units/m2 SQ every other day x 3 doses, followed by twice weekly x 14 doses (total 17 doses through day 56)
-
Corticosteroids (Prednisone, or IV methylprednisolone equivalent)
-
Dose level 1 (starting dose) = 1 mg/kg
-
Dose level 2 = 0.5 mg/kg
-
Dose level 3 = 0.25 mg/kg
-
Dose level 4 = 0.1 mg/kg
-
Dose level 5 = 0 mg/kg
干预措施: Ruxolitinib 10 MG Oral Tablet (Drug)
Ruxolitinib;hCG (Pregnyl®) ;Corticosteroids
-
Ruxolitinib 10 mg by mouth twice daily (with dose adjustments as indicated) through day 56, followed by taper
-
hCG (Pregnyl®) 2,000 units/m2 SQ every other day x 3 doses, followed by twice weekly x 14 doses (total 17 doses through day 56)
-
Corticosteroids (Prednisone, or IV methylprednisolone equivalent)
-
Dose level 1 (starting dose) = 1 mg/kg
-
Dose level 2 = 0.5 mg/kg
-
Dose level 3 = 0.25 mg/kg
-
Dose level 4 = 0.1 mg/kg
-
Dose level 5 = 0 mg/kg
干预措施: hCG (Drug)
结局指标
主要结局
Recommend the lowest possible dose for Phase II of corticosteroids when given in combination with ruxolitinib and uhCG/EGF in pediatric based on DLT frequency
时间窗: 28 days after therapy
Plan report patients proportions and their 95% confidence intervals of paitents who experience dose limiting toxicity. Determine best dose based on DLT criteria by CTCAE v5.0 * Thrombosis requiring anticoagulation * Ascites (grade 3-5) * Ovarian hyperstimulation syndrome
Best response of treatment in adult and children
时间窗: 28 days after therapy
proportions of complete, partial, mixed, and no response among surviving patients at days 28 after initiation of protocol therapy in pediatric and adult patients with Minnesota high-risk aGVHD
次要结局
- Incidence of acute GVHD flare after CR/PR requiring increase of steroids or other systemic treatment(56 days after treatment)
- Compare the rate of treatment failure for acute GVHD after initiation of protocol therapy to historical controls(56 days after treatment)
- To assess patient quality of life on study(6 month after treatment)
- Collect blood samples and rectosigmoid biopsies for future correlative studies(1 year after treament)
- Number of participants with treatment-related adverse events as assessed by CTCAE v5.0(30 days after treatment)
- Determine 1-year overall survival(1 year post treatment)
- Non-relapse mortality (death without recurrent or progressive disease after allo-HSCT)(1 year post treatment)
- Incidence of acute GVHD flare after CR/PR requiring increase of steroids or other systemic treatment(28 days after treatment)
- Compare the rate of treatment failure for acute GVHD after initiation of protocol therapy to historical controls(28 days after treatment)