Study of Pregnyl as Adjunct Therapy for High-Risk or Refractory Acute GVHD
Status and phase
Completed
Phase 2
Phase 1
Conditions
Graft vs Host Disease
Treatments
Drug: Pregnyl®
Study type
Interventional
Funder types
Other
Identifiers
Details and patient eligibility
About
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.
Enrollment
53 patients
Sex
All
Ages
Under 76 years old
Volunteers
No 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)
Trial design
Primary purpose
Supportive Care
Allocation
Non-Randomized
Interventional model
Sequential Assignment
Masking
None (Open label)
53 participants in 20 patient groups
Arm 1: Phase 1 Dose Level -2: 125 USP hCG/875 pg EGF/m^2
Experimental group
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.
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.
Treatment:
Drug: Pregnyl®
Arm 1: Phase I Dose Level -1: 250 USP hCG/1,750 pg EGF/m^2
Experimental group
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.
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.
Treatment:
Drug: Pregnyl®
Arm 1: Phase 1 Dose Level 1 500 USP hCG/3,500 pg EGF/m^2
Experimental group
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.
Treatment:
Drug: Pregnyl®
Arm 1: Phase 1 Dose Level 2 1,000 USP hCG/7,000 pg EGF/m^2
Experimental group
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.
Treatment:
Drug: Pregnyl®
Arm 1: Phase 1 Dose Level 3 2,000 USP hCG/14,000 pg EGF/m^2
Experimental group
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.
Treatment:
Drug: Pregnyl®
Arm 2A: Phase 1 Dose Level -2: 125 USP hCG/875 pg EGF/m^2
Experimental group
Description:
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.
Treatment:
Drug: Pregnyl®
Arm 2A: Phase I Dose Level -1: 250 USP hCG/1,750 pg EGF/m^2
Experimental group
Description:
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.
Treatment:
Drug: Pregnyl®
Arm 2A: Phase 1 Dose Level 1 500 USP hCG/3,500 pg EGF/m^2
Experimental group
Description:
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.
Treatment:
Drug: Pregnyl®
Arm 2A: Phase 1 Dose Level 2 1,000 USP hCG/7,000 pg EGF/m^2
Experimental group
Description:
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.
Treatment:
Drug: Pregnyl®
Arm 2A: Phase 1 Dose Level 3 2,000 USP hCG/14,000 pg EGF/m^2
Experimental group
Description:
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.
Treatment:
Drug: Pregnyl®
Arm 2B: Phase 1 Dose Level -2: 125 USP hCG/875 pg EGF/m^2
Experimental group
Description:
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.
Treatment:
Drug: Pregnyl®
Arm 2B: Phase I Dose Level -1: 250 USP hCG/1,750 pg EGF/m^2
Experimental group
Description:
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.
Treatment:
Drug: Pregnyl®
Arm 2B: Phase 1 Dose Level 1 500 USP hCG/3,500 pg EGF/m^2
Experimental group
Description:
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.
Treatment:
Drug: Pregnyl®
Arm 2B: Phase 1 Dose Level 2 1,000 USP hCG/7,000 pg EGF/m^2
Experimental group
Description:
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.
Treatment:
Drug: Pregnyl®
Arm 2B: Phase 1 Dose Level 3 2,000 USP hCG/14,000 pg EGF/m^2
Experimental group
Description:
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.
Treatment:
Drug: Pregnyl®
Arm 2B: Phase 1 Dose Level 4 3,500 USP hCG/24,500 pg EGF/m^2
Experimental group
Description:
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.
Treatment:
Drug: Pregnyl®
Arm 2B: Phase 1 Dose Level 5 5,000 USP hCG/35,000 pg EGF/m^2
Experimental group
Description:
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.
Treatment:
Drug: Pregnyl®
Arm 1: Phase 2 MTD
Experimental group
Description:
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
Treatment:
Drug: Pregnyl®
Arm 2A: MTD
Experimental group
Description:
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
Treatment:
Drug: Pregnyl®
Arm 2B: MTD
Experimental group
Description:
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
Treatment:
Drug: Pregnyl®
Trial contacts and locations
1
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