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

Phase 2TerminatedNCT05123040

Masonic Cancer Center, University of Minnesota10 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Acute-graft-versus-host Disease

Interventions

CorticosteroidsDRUG

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

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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

Time frame: 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

Time frame: 28 days after therapy

Secondary Outcomes

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)

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 56 days after treatment

To assess patient quality of life on study

Have participants take an overall survival survey

Time frame: 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

Time frame: 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.

Time frame: 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

Time frame: 1 year after treament