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

Phase 1

Completed

Conditions: Graft vs Host Disease

Interventions: Drug: Pregnyl®

Registration Number: NCT02525029

Lead Sponsor: Masonic Cancer Center, University of Minnesota

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 53

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Arm 1: Phase 1 Dose Level -2: 125 USP hCG/875 pg EGF/m^2	Pregnyl®	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. 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 1: Phase I Dose Level -1: 250 USP hCG/1,750 pg EGF/m^2	Pregnyl®	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. 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 1: Phase 1 Dose Level 1 500 USP hCG/3,500 pg EGF/m^2	Pregnyl®	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 1: Phase 1 Dose Level 2 1,000 USP hCG/7,000 pg EGF/m^2	Pregnyl®	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 1: Phase 1 Dose Level 3 2,000 USP hCG/14,000 pg EGF/m^2	Pregnyl®	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 2A: Phase 1 Dose Level -2: 125 USP hCG/875 pg EGF/m^2	Pregnyl®	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.
Arm 2A: Phase I Dose Level -1: 250 USP hCG/1,750 pg EGF/m^2	Pregnyl®	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.
Arm 2A: Phase 1 Dose Level 1 500 USP hCG/3,500 pg EGF/m^2	Pregnyl®	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.
Arm 2A: Phase 1 Dose Level 2 1,000 USP hCG/7,000 pg EGF/m^2	Pregnyl®	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.
Arm 2A: Phase 1 Dose Level 3 2,000 USP hCG/14,000 pg EGF/m^2	Pregnyl®	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.
Arm 2B: Phase 1 Dose Level -2: 125 USP hCG/875 pg EGF/m^2	Pregnyl®	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.
Arm 2B: Phase I Dose Level -1: 250 USP hCG/1,750 pg EGF/m^2	Pregnyl®	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.
Arm 2B: Phase 1 Dose Level 1 500 USP hCG/3,500 pg EGF/m^2	Pregnyl®	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.
Arm 2B: Phase 1 Dose Level 2 1,000 USP hCG/7,000 pg EGF/m^2	Pregnyl®	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.
Arm 2B: Phase 1 Dose Level 3 2,000 USP hCG/14,000 pg EGF/m^2	Pregnyl®	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.
Arm 2B: Phase 1 Dose Level 4 3,500 USP hCG/24,500 pg EGF/m^2	Pregnyl®	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.
Arm 2B: Phase 1 Dose Level 5 5,000 USP hCG/35,000 pg EGF/m^2	Pregnyl®	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.
Arm 1: Phase 2 MTD	Pregnyl®	After completion of the dose finding trial for each arm, the final doses will be carried forward into a two-stage phase II extension trial to confirm safety and make a preliminary determination of the activity level for Arm 1 and Arm 2. If the phase I trial enrolls fewer than 13 patients at the MTD, we will employ Simon's Minmax two-stage design with the possibility to discontinue after the 1st stage if the response rate is low
Arm 2A: MTD	Pregnyl®	After completion of the dose finding trial for each arm, the final doses will be carried forward into a two-stage phase II extension trial to confirm safety and make a preliminary determination of the activity level for Arm 1 and Arm 2. If the phase I trial enrolls fewer than 13 patients at the MTD, we will employ Simon's Minmax two-stage design with the possibility to discontinue after the 1st stage if the response rate is low
Arm 2B: MTD	Pregnyl®	After completion of the dose finding trial for each arm, the final doses will be carried forward into a two-stage phase II extension trial to confirm safety and make a preliminary determination of the activity level for Arm 1 and Arm 2. If the phase I trial enrolls fewer than 13 patients at the MTD, we will employ Simon's Minmax two-stage design with the possibility to discontinue after the 1st stage if the response rate is low

Primary Outcome Measures

Name	Time	Method
Phase I: MTD (USP hCG)	Day 14 after initiation of protocol therapy	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). Dosage measured as (USP hCG/pg EGF/mm\^2).
Number of Patients With Complete Response	Day 28 after initiation of protocol therapy	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.
Number of Patients With Partial Response	Day 28 after initiation of protocol therapy	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 I: MTD (pg EGF/m^2)	Day 14 after initiation of protocol therapy	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). Dosage measured as (USP hCG/pg EGF/m\^2).
Number of Patients With Mixed Response	Day 28 after initiation of protocol therapy	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.
Number of Patients With No Response	Day 28 after initiation of protocol therapy	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

Name	Time	Method
Rate of Participants Who Fail Treatment at Day 56	Day 56 after initiation of protocol therapy	Rate of treatment failure for acute GVHD at day 56 after initiation of protocol therapy to historical controls.
Number of Participants With Adverse Events as a Measure of Safety and Feasibility of hCG Supplementation With Pregnyl®	Day 70 after initiation of protocol therapy	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	Day 56 after initiation of protocol therapy	Incidence of acute GVHD flare after CR/PR requiring increase of steroids or other systemic treatment at day 56.
Rate of Participants Who Fail Treatment at Day 28	Day 28 after initiation of protocol therapy	Rate of treatment failure for acute GVHD at day 28 after initiation of protocol therapy to historical controls.