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

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ClinicalTrials.gov Identifier: NCT02525029
Recruitment Status : Recruiting
First Posted : August 17, 2015
Last Update Posted : December 6, 2018
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota

Tracking Information
First Submitted Date  ICMJE July 14, 2015
First Posted Date  ICMJE August 17, 2015
Last Update Posted Date December 6, 2018
Study Start Date  ICMJE March 2016
Estimated Primary Completion Date August 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 9, 2015)
  • Phase I: MTD [ Time Frame: 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).
  • Phase II: Number of Patients with Complete Response [ Time Frame: 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.
  • Phase II: Number of Patients with Partial Response [ Time Frame: 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 II: Number of Patients with Mixed Response [ Time Frame: 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.
  • Phase II: Number of Patients with No Response [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 13, 2015)
  • Phase I: MTD [ Time Frame: 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).
  • Phase II: Number of Patients with Response [ Time Frame: 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.
  • Phase II: Number of Patients with Response [ Time Frame: 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 II: Number of Patients with Response [ Time Frame: 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.
  • Phase II: Number of Patients with Response [ Time Frame: 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.
Change History Complete list of historical versions of study NCT02525029 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 13, 2015)
  • Number of Participants with Adverse Events as a Measure of Safety and Feasibility of hCG Supplementation with Pregnyl® [ Time Frame: 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 [ Time Frame: Day 28 after initiation of protocol therapy ]
    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 [ Time Frame: Day 56 after initiation of protocol therapy ]
    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 [ Time Frame: Day 28 after initiation of protocol therapy ]
    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 [ Time Frame: Day 56 after initiation of protocol therapy ]
    Rate of treatment failure for acute GVHD at days 28 and 56 after initiation of protocol therapy to historical controls.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Pregnyl as Adjunct Therapy for High-Risk or Refractory Acute GVHD
Official Title  ICMJE 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
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 Provided
Study Type  ICMJE Interventional
Study Phase Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Condition  ICMJE Graft vs Host Disease
Intervention  ICMJE
  • Drug: Pregnyl®

    ARM 1: High-Risk aGVHD

    Standard of care immunosuppression, plus Pregnyl® at assigned dose subcutaneously every other day for up to 5 doses through day 7:

    • If a complete or partial response, continue protocol treatment followed by hCG maintenance twice weekly for 10 doses beginning day 9 to 12.
    • If no response, the patient will be taken off study treatment

    Doses for both arms:

    • 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.
    • Phase II: the dose of Pregnyl will be that identified as the MTD during phase I.
    Other Name: Human chorionic gonadotropin (hCG)
  • Drug: Pregnyl®

    ARM 2a: Steroid Dependent aGVHD

    Standard of care immunosuppression, plus Pregnyl® at assigned dose subcutaneously every other day for up to 5 doses through day 7:

    • If a complete or partial response, continue protocol treatment followed by hCG maintenance twice weekly for 10 doses beginning day 9 to 12.
    • If no response, the patient will be taken off study treatment

    Doses for both arms:

    • 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.
    • Phase II: the dose of Pregnyl will be that identified as the MTD during phase I.
    Other Name: Human chorionic gonadotropin (hCG)
  • Drug: Pregnyl®

    ARM 2b: Steroid-Refractory aGVHD

    Standard of care immunosuppression, plus Pregnyl® at assigned dose subcutaneously every other day for up to 7 doses through day 14:

    • If a complete or partial response, continue protocol treatment followed by hCG at the assigned dose maintenance twice weekly for 10 doses beginning day 15 to 17.
    • If no response, the patient will be taken off study treatment

    Doses for both arms:

    • 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.
    • Phase II: the dose of Pregnyl will be that identified as the MTD during phase I.
    Other Name: Human chorionic gonadotropin (hCG)
Study Arms
  • Experimental: 1: High-Risk aGVHD

    Standard of care immunosuppression, plus Pregnyl® (hCG supplementation) at assigned dose subcutaneously every other day for up to 5 doses.

    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. If the patient is enrolled in the phase I component, the event must be reported as a DLT per section 11. If the same patient experiences a second DLT, the patient will discontinue treatment.

    Continue protocol treatment through day 7. Assess response at day 7:

    1. If a complete or partial response, continue protocol treatment followed by hCG maintenance twice weekly for 10 doses beginning day 9 to 12.
    2. If no response, the patient will be taken off study treatment.
    Intervention: Drug: Pregnyl®
  • Experimental: 2a: Steroid-Dependent aGVHD

    Standard of care immunosuppression, plus Pregnyl® (hCG supplementation) at assigned dose subcutaneously every other day for up to 5 doses.

    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. If the patient is enrolled in the phase I component, the event must be reported as a DLT per section section 11. If the same patient experiences a second DLT, the patient will discontinue treatment.

    Continue protocol treatment through day 14. Assess response at day 14:

    1. If a complete or partial response, continue protocol treatment followed by hCG at the assigned dose maintenance twice weekly for 10 doses beginning day 15 to 17.
    2. If no response, the patient will be taken off study treatment
    Intervention: Drug: Pregnyl®
  • Experimental: 2b: Steroid-Refractory aGVHD

    Standard of care immunosuppression, plus Pregnyl® (hCG supplementation) at assigned dose subcutaneously every other day for up to 7 doses.

    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. If the patient is enrolled in the phase I component, the event must be reported as a DLT per section section 11. If the same patient experiences a second DLT, the patient will discontinue treatment.

    Continue protocol treatment through day 14. Assess response at day 14:

    1. If a complete or partial response, continue protocol treatment followed by hCG at the assigned dose maintenance twice weekly for 10 doses beginning day 15 to 17.
    2. If no response, the patient will be taken off study treatment
    Intervention: Drug: Pregnyl®
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 27, 2017)
66
Original Estimated Enrollment  ICMJE
 (submitted: August 13, 2015)
40
Estimated Study Completion Date March 2021
Estimated Primary Completion Date August 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender
Sexes Eligible for Study: All
Ages up to 76 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE
Contact: Timothy Krepski 612-273-2800 tkrepsk1@fairview.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02525029
Other Study ID Numbers  ICMJE 2014LS020
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Masonic Cancer Center, University of Minnesota
Study Sponsor  ICMJE Masonic Cancer Center, University of Minnesota
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Shernan Holtan, MD University of Minnesota - Clinical and Translational Science Institute
PRS Account Masonic Cancer Center, University of Minnesota
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP