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

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

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 Overview

• Status: Recruiting
• Conditions: Acute-graft-versus-host Disease
• Intervention / Treatment: Drug: Ruxolitinib 10 MG Oral Tablet; Drug: hCG; Drug: Corticosteroids

• Study Type: Interventional
• Enrollment (Estimated): 55
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Cancer Center Clinical Trials Office; Phone Number: 612 624 2620; Email: ccinfo@umn.edu

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Recruiting
      • Masonic Cancer Center at University of Minnesota
      • Contact: Cancer Center Clinical Trials Office; Phone Number: 612-624-2620; Email: ccinfo@umn.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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/kgDose level 2 = 0.5 mg/kgDose level 3 = 0.25 mg/kgDose level 4 = 0.1 mg/kgDose level 5 = 0 mg/kg

Drug: Ruxolitinib 10 MG Oral Tablet; By mouth twice daily through day 56, then tapered; Drug: hCG; 2,000 units/m2 SQ every other day x 3 doses, followed by twice weekly x 14 doses; Other Names: Pregnyl; Drug: Corticosteroids; 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; Other Names: Prednisone; IV methylprednisolone

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: Sherman Holtan, MD, Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2023
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): September 1, 2028

Study Registration Dates

• First Submitted: November 3, 2021
• First Submitted That Met QC Criteria: November 4, 2021
• First Posted (Actual): November 17, 2021

Study Record Updates

• Last Update Posted (Actual): June 13, 2023
• Last Update Submitted That Met QC Criteria: June 12, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: aGVHD
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Methylprednisolone; Prednisone
• Other Study ID Numbers: 2020LS098; MT2020-28 (Other Identifier: Masonic Cancer Center)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No