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Study of Pregnyl as Adjunct Therapy for High-Risk or Refractory Acute GVHD

Primary Purpose

Graft vs Host Disease

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Pregnyl®

About this trial

This is an interventional supportive care trial for Graft vs Host Disease focused on measuring GVHD

Eligibility Criteria

undefined - 76 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Acute graft versus host disease (GVHD) fitting one of the following categories:
- High-Risk aGVHD (ARM 1): Pediatric or adult (ages 12-76 years) HCT recipients with high-risk acute GVHD, as determined by the refined MN acute GVHD risk score: http://z.umn.edu/MNAcuteGVHDRiskScore OR high risk on the basis of blood biomarkers (Ann Arbor Score 3 or amphiregulin ≥ 33 pg/ml) or
- Steroid-Refractory aGVHD (ARM 2): Pediatric or adult (ages 12-76 years) HCT recipient with grade II-IV steroid refractory or steroid-dependent acute GVHD, defined as any one of the following:
  - No response of acute GVHD after at least 4 days of systemic corticosteroids of at least 2 mg/kg prednisone or equivalent
  - Progression of acute GVHD within 3 days of systemic corticosteroids of at least 2 mg/kg prednisone or equivalent
  - Failure to improve to at least grade II acute GVHD after 14 days of systemic corticosteroids, with initial doses of at least 2 mg/kg prednisone or equivalent
  - Flare of acute GVHD of at least grade II/IV severity despite tapering dose of steroids being > 0.5 mg/kg/day.
Adequate organ function at study enrollment defined as:
- Renal: 1.73m2Serum 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
Diagnosis of a hormone responsive malignancy
Uncontrolled infection at initiation of protocol treatment
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 as assessed on baseline blood hCG level
Unwilling or unable to stop supplemental sex hormone therapy (estrogen, progesterone, and/or testosterone preparations)
Women or men of childbearing potential unwilling to take adequate precautions to avoid pregnancy from the start of protocol treatment through 28 days after the last treatment

Screening Inclusion Criteria:

Pediatric or adult (ages 0-76 years) HCT recipients
Suspected high risk GVHD
Voluntary written consent (adult or parent/guardian with minor assent for 12 through 17 year olds)

Sites / Locations

Masonic Cancer Center at University of Minnesota

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

1: High-Risk aGVHD

2a: Steroid-Dependent aGVHD

2b: Steroid-Refractory aGVHD

Arm Description

Standard of care immunosuppression, plus Pregnyl® (hCG supplementation) at assigned dose subcutaneously every other day for up to 5 doses of Pregnyl®; however dose levels -1 and -2 will be used only if dose level 1 proves too toxic. The 1st 2 patients will be enrolled in dose level 1. The next cohort of 2 patients will not begin treatment until all patients in the current cohort have reached day 21 in order to assess for dose limiting toxicity (DLT). Individual patient dose reductions: If a patient has toxicity that meets the definition of dose limiting, the patient can drop down one dose level for the next injection and continue treatment.

Standard of care immunosuppression, plus Pregnyl® (hCG supplementation) at assigned dose subcutaneously every other day for up to 5 doses of Pregnyl®; however dose levels -1 and -2 will be used only if dose level 1 proves too toxic. The 1st 2 patients will be enrolled in dose level 1. The next cohort of 2 patients will not begin treatment until all patients in the current cohort have reached day 21 in order to assess for dose limiting toxicity (DLT). Individual patient dose reductions: If a patient has a toxicity, the patient can drop down one dose level for the next injection and continue treatment.

Standard of care immunosuppression, plus Pregnyl® (hCG supplementation) at assigned dose subcutaneously every other day for up to 7 doses of Pregnyl®; however dose levels -1 and -2 will be used only if dose level 1 proves too toxic. The 1st 2 patients will be enrolled in dose level 1. The next cohort of 2 patients will not begin treatment until all patients in the current cohort has reached day 21 to assess for dose limiting toxicity (DLT). Individual patient dose reductions: If a patient has a toxicity, the patient can drop down one dose level for the next injection and continue treatment.

Outcomes

Primary Outcome Measures

Phase I: MTD

Maximum tolerated dose (MTD) of Pregnyl® when given with standard immunosuppressive therapy in pediatric and adult patients with high-risk or refractory acute graft-versus-host disease (aGVHD).

Phase II: Number of Patients with Complete Response

Percentage of complete response among surviving patients at day 28 after initiation of protocol therapy in pediatric and adult patients with high-risk (Arm 1) or refractory (Arm 2) aGVHD. Complete response is defined as a Stage of 0 for all organs with no additional intervening therapy for their GVHD.

Phase II: Number of Patients with Partial Response

Percentage of partial response among surviving patients at day 28 after initiation of protocol therapy in pediatric and adult patients with high-risk (Arm 1) or refractory (Arm 2) aGVHD. Partial response is defined as improvement by at least 1 stage in all involved organs without progression in others with no additional intervening therapy for their GVHD.

Phase II: Number of Patients with Mixed Response

Percentage of mixed response among surviving patients at day 28 after initiation of protocol therapy in pediatric and adult patients with high-risk (Arm 1) or refractory (Arm 2) aGVHD. Mixed Response is defined as improvement in one organ with deterioration in another organ manifesting symptoms of GVHD or development of symptoms of GVHD in a new organ.

Phase II: Number of Patients with No Response

Percentage of no response among surviving patients at day 28 after initiation of protocol therapy in pediatric and adult patients with high-risk (Arm 1) or refractory (Arm 2) aGVHD. No response is defined as deterioration of any organ involved.

Secondary Outcome Measures

Number of Participants with Adverse Events as a Measure of Safety and Feasibility of hCG Supplementation with Pregnyl®

Safety and feasibility of hCG supplementation with Pregnyl® in combination with standard immunosuppressive therapy in pediatric and adult patients with high-risk or refractory aGVHD.

Number of Participants with Incidence of aGVHD Flare

Incidence of acute GVHD flare after CR/PR requiring increase of steroids or other systemic treatment at days 28 and 56.

Number of Participants with Incidence of aGVHD Flare

Incidence of acute GVHD flare after CR/PR requiring increase of steroids or other systemic treatment at days 28 and 56.

Rate of participants who fail treatment at Day 28

Rate of treatment failure for acute GVHD at days 28 and 56 after initiation of protocol therapy to historical controls.

Rate of participants who fail treatment at Day 56

Rate of treatment failure for acute GVHD at days 28 and 56 after initiation of protocol therapy to historical controls.

Full Information

NCT ID

NCT02525029

First Posted

July 14, 2015

Last Updated

March 24, 2023

Sponsor

Masonic Cancer Center, University of Minnesota

1. Study Identification

Unique Protocol Identification Number

NCT02525029

Brief Title

Study of Pregnyl as Adjunct Therapy for High-Risk or Refractory Acute GVHD

Official Title

Phase I/II Study of Human Chorionic Gonadotropin and Epidermal Growth Factor Supplementation (Pregnyl®) to Support Tolerance and Repair As Adjunct Therapy in High-Risk or Refractory Acute Graft-Versus-Host Disease

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Completed

Study Start Date

March 2016 (Actual)

Primary Completion Date

May 2021 (Actual)

Study Completion Date

April 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Masonic Cancer Center, University of Minnesota

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to determine the maximum tolerated dose (MTD) of Pregnyl® when given in combination with standard immunosuppressive therapy in pediatric and adult patients with high-risk (Arm 1) or refractory/dependent (Arm 2) aGVHD.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Graft vs Host Disease

Keywords

GVHD

7. Study Design

Primary Purpose

Supportive Care

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

54 (Actual)

8. Arms, Groups, and Interventions

Arm Title

1: High-Risk aGVHD

Arm Type

Experimental

Arm Description

Arm Title

2a: Steroid-Dependent aGVHD

Arm Type

Experimental

Arm Description

Standard of care immunosuppression, plus Pregnyl® (hCG supplementation) at assigned dose subcutaneously every other day for up to 5 doses of Pregnyl®; however dose levels -1 and -2 will be used only if dose level 1 proves too toxic. The 1st 2 patients will be enrolled in dose level 1. The next cohort of 2 patients will not begin treatment until all patients in the current cohort have reached day 21 in order to assess for dose limiting toxicity (DLT). Individual patient dose reductions: If a patient has a toxicity, the patient can drop down one dose level for the next injection and continue treatment.

Arm Title

2b: Steroid-Refractory aGVHD

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Pregnyl®

Other Intervention Name(s)

Human chorionic gonadotropin (hCG)

Intervention Description

Standard of care immunosuppression, plus Pregnyl® at assigned dose subcutaneously every other day for up to 5 doses through day 7 Phase I: up to 7 dose levels of Pregnyl® will be tested; however dose levels -1 and -2 will be used only if dose level 1 proves too toxic. Study will use Continual Reassessment Method (CRM) to establish a maximum tolerated dose (MTD). Step -2: 125 USP hCG/875 pg EGF/m2 Step -1: 250 USP hCG/1,750 pg EGF/m2 Step 1 (start): 500 USP hCG/3,500 pg EGF/m2 Step 2: 1,000 USP hCG/7,000 pg EGF/m2 Step 3: 2,000 USP hCG/14,000 pg EGF/m2 Step 4 (Arm 2b only): 3,500 USP hCG/24,500 pg EGF/m2 Step 5 (Arm 2b only): 5,000 USP hCG/35,000 pg EGF/m Phase II: the dose of Pregnyl will be that identified as the MTD during phase I.

Primary Outcome Measure Information:

Title

Phase I: MTD

Description

Maximum tolerated dose (MTD) of Pregnyl® when given with standard immunosuppressive therapy in pediatric and adult patients with high-risk or refractory acute graft-versus-host disease (aGVHD).

Time Frame

Day 14 after initiation of protocol therapy

Title

Phase II: Number of Patients with Complete Response

Description

Time Frame

Day 28 after initiation of protocol therapy

Title

Phase II: Number of Patients with Partial Response

Description

Time Frame

Day 28 after initiation of protocol therapy

Title

Phase II: Number of Patients with Mixed Response

Description

Time Frame

Day 28 after initiation of protocol therapy

Title

Phase II: Number of Patients with No Response

Description

Time Frame

Day 28 after initiation of protocol therapy

Secondary Outcome Measure Information:

Title

Number of Participants with Adverse Events as a Measure of Safety and Feasibility of hCG Supplementation with Pregnyl®

Description

Safety and feasibility of hCG supplementation with Pregnyl® in combination with standard immunosuppressive therapy in pediatric and adult patients with high-risk or refractory aGVHD.

Time Frame

Day 70 after initiation of protocol therapy

Title

Number of Participants with Incidence of aGVHD Flare

Description

Incidence of acute GVHD flare after CR/PR requiring increase of steroids or other systemic treatment at days 28 and 56.

Time Frame

Day 28 after initiation of protocol therapy

Title

Number of Participants with Incidence of aGVHD Flare

Description

Incidence of acute GVHD flare after CR/PR requiring increase of steroids or other systemic treatment at days 28 and 56.

Time Frame

Day 56 after initiation of protocol therapy

Title

Rate of participants who fail treatment at Day 28

Description

Rate of treatment failure for acute GVHD at days 28 and 56 after initiation of protocol therapy to historical controls.

Time Frame

Day 28 after initiation of protocol therapy

Title

Rate of participants who fail treatment at Day 56

Description

Rate of treatment failure for acute GVHD at days 28 and 56 after initiation of protocol therapy to historical controls.

Time Frame

Day 56 after initiation of protocol therapy

10. Eligibility

Sex

All

Maximum Age & Unit of Time

76 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Acute graft versus host disease (GVHD) fitting one of the following categories: High-Risk aGVHD (ARM 1): Pediatric or adult (ages 12-76 years) HCT recipients with high-risk acute GVHD, as determined by the refined MN acute GVHD risk score: http://z.umn.edu/MNAcuteGVHDRiskScore OR high risk on the basis of blood biomarkers (Ann Arbor Score 3 or amphiregulin ≥ 33 pg/ml) or Steroid-Refractory aGVHD (ARM 2): Pediatric or adult (ages 12-76 years) HCT recipient with grade II-IV steroid refractory or steroid-dependent acute GVHD, defined as any one of the following: No response of acute GVHD after at least 4 days of systemic corticosteroids of at least 2 mg/kg prednisone or equivalent Progression of acute GVHD within 3 days of systemic corticosteroids of at least 2 mg/kg prednisone or equivalent Failure to improve to at least grade II acute GVHD after 14 days of systemic corticosteroids, with initial doses of at least 2 mg/kg prednisone or equivalent Flare of acute GVHD of at least grade II/IV severity despite tapering dose of steroids being > 0.5 mg/kg/day. Adequate organ function at study enrollment defined as: Renal: 1.73m2Serum 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 Diagnosis of a hormone responsive malignancy Uncontrolled infection at initiation of protocol treatment 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 as assessed on baseline blood hCG level Unwilling or unable to stop supplemental sex hormone therapy (estrogen, progesterone, and/or testosterone preparations) Women or men of childbearing potential unwilling to take adequate precautions to avoid pregnancy from the start of protocol treatment through 28 days after the last treatment Screening Inclusion Criteria: Pediatric or adult (ages 0-76 years) HCT recipients Suspected high risk GVHD Voluntary written consent (adult or parent/guardian with minor assent for 12 through 17 year olds)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Shernan Holtan, MD

Organizational Affiliation

University of Minnesota

Official's Role

Principal Investigator

Facility Information:

Facility Name

Masonic Cancer Center at University of Minnesota

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55455

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

32236525

Citation

Holtan SG, Hoeschen AL, Cao Q, Arora M, Bachanova V, Brunstein CG, Miller JS, Rashidi A, Slungaard A, Ustun C, Vercellotti GM, Warlick ED, Betts BC, El Jurdi N, He F, Chen C, Gandhi I, Wagner JE, Blazar BR, Jacobson PA, Shabaneh A, Wang J, Panoskaltsis-Mortari A, MacMillan ML, Weisdorf DJ. Facilitating resolution of life-threatening acute GVHD with human chorionic gonadotropin and epidermal growth factor. Blood Adv. 2020 Apr 14;4(7):1284-1295. doi: 10.1182/bloodadvances.2019001259.

Results Reference

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Study of Pregnyl as Adjunct Therapy for High-Risk or Refractory Acute GVHD

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