Ruxolitinib, Human Chorionic Gonadotropin (uhCG/EGF), and Dose De-escalated Corticosteroids

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Acute-graft-versus-host Disease

Intervention / Treatment
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* Drug: Ruxolitinib 10 MG Oral Tablet
* Drug: hCG
* Drug: Corticosteroids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ruxolitinib;hCG (Pregnyl®) ;Corticosteroids<br>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 | Drug: Ruxolitinib 10 MG Oral Tablet<br>* By mouth twice daily through day 56, then tapered<br>Drug: hCG<br>* 2,000 units/m2 SQ every other day x 3 doses, followed by twice weekly x 14 doses<br>* Other names: Pregnyl;Drug: Corticosteroids<br>* 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 • If dose level 1 is determined to be below the Recommended Phase 2 Dose (RP2D), the dose will be escalated: Dose level -1 = 1.5 mg/kg Dose level -2 = 2 mg/kg<br>* Other names: IV methylprednisolone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 28 days after therapy | 
| Best response of treatment in adult and children | 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 | 28 days after therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | Report any type of adverse event caused by a drug cause by dose of steroids in combination of ruxolitinib and uhCG/EGF. Due to the complex medical condition of the GVHD patient, monitoring for adverse events will focus on the following events beginning with the date consent is signed and continuing for 30 days after the subject has completed or discontinued from the study or has taken last dose of the study drug. Rehospitalization Death Hematologic (grade 3-5 cytopenia) Infections (grade 3-5) Hyperglycemia (grade 3-5) Steroid myopathy (grade 3-5) | 30 days after treatment | 
| Incidence of acute GVHD flare after CR/PR requiring increase of steroids or other systemic treatment | Find proportion of incidence of acute GVHD | 28 days after treatment | 
| Incidence of acute GVHD flare after CR/PR requiring increase of steroids or other systemic treatment | Find proportion of incidence of acute GVHD | 56 days after treatment | 
| Compare the rate of treatment failure for acute GVHD after initiation of protocol therapy to historical controls | Compare count of treatment failure to other number of failures in other historical protocols | 28 days after treatment | 
| Compare the rate of treatment failure for acute GVHD after initiation of protocol therapy to historical controls | Compare count of treatment failure to other number of failures in other historical protocols | 56 days after treatment | 
| To assess patient quality of life on study | Have participants take an overall survival survey | 6 month after treatment | 
| Determine 1-year overall survival | Provide proportions and their 95% confidence intervals of patients still alive at one year post-treatment | 1 year post treatment | 
| Non-relapse mortality (death without recurrent or progressive disease after allo-HSCT) | Provide proportions and their 95% confidence intervals of patients who expedience a non-relapse mortality. | 1 year post treatment | 
| Collect blood samples and rectosigmoid biopsies for future correlative studies | Give a count of the number of patients who had blood and rectosigmoid biopsies | 1 year after treament | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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aGVHD