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History of Changes for Study: NCT04144036
Neihulizumab for Standard-Risk Acute GVHD
Latest version (submitted September 9, 2021) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 October 28, 2019 None (earliest Version on record)
2 January 7, 2020 Study Status
3 March 20, 2020 Study Status, Eligibility and Study Description
4 August 20, 2020 Arms and Interventions, Study Status, Study Identification and Contacts/Locations
5 November 19, 2020 Study Status
6 January 14, 2021 Recruitment Status, Study Status, Contacts/Locations and Oversight
7 May 14, 2021 Outcome Measures, Arms and Interventions and Study Status
8 September 9, 2021 Outcome Measures, Study Status and Eligibility
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Study NCT04144036
Submitted Date:  October 28, 2019 (v1)

Open or close this module Study Identification
Unique Protocol ID: PRO36517
Brief Title: Neihulizumab for Standard-Risk Acute GVHD
Official Title: A Phase I Trial of Neihulizumab for the Upfront Treatment of Standard-Risk, AA 1-2 Acute Graft vs Host Disease
Secondary IDs:
Open or close this module Study Status
Record Verification: October 2019
Overall Status: Not yet recruiting
Study Start: December 15, 2019
Primary Completion: December 15, 2020 [Anticipated]
Study Completion: August 15, 2021 [Anticipated]
First Submitted: October 28, 2019
First Submitted that
Met QC Criteria:
October 28, 2019
First Posted: October 30, 2019 [Actual]
Last Update Submitted that
Met QC Criteria:
October 28, 2019
Last Update Posted: October 30, 2019 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: Sameem M. Abedin, MD
Responsible Party: Sponsor-Investigator
Investigator: Sameem M. Abedin, MD
Official Title: Assistant Professor
Affiliation: Medical College of Wisconsin
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug: Yes
U.S. FDA-regulated Device: No
Data Monitoring: Yes
Open or close this module Study Description
Brief Summary: This is a single-center Phase I study to determine the maximum tolerated dose and safety of Neihulizumab for the treatment of Minnesota standard-risk aGVHD. Patients undergoing allogeneic transplant with either a myeloablative or non-myeloablative conditioning regimen, and recipients of all donor sources will be enrolled to this trial.
Detailed Description:

Eligible patients will receive Neihulizumab weekly, for up to four doses. Responding patients, and patients with stable disease should receive all four weekly doses. Patients with skin only disease that clinically progresses by one stage (e.g from stage 2 to stage 3), but remains less than stage 4, will receive a minimum two doses of Neihulizumab. At 72 hours after the second dose, non-responding patients will be withdrawn from the study. Responding patients should remain on study and receive four total doses. Patients with lower GI GVHD that progresses by at least one stage at 4 or more days after first dose will be withdrawn from the study. All patients receiving at least 1 dose of Neihulizumab will be evaluated for DLTs and adverse events.

Dose-escalation will be conducted according to a 3+3 design. The initial dose of Neihulizumab will be 6 mg/kg weekly (Dose level 1), and the highest dose administered will be 9 mg/kg weekly (Dose level 2). The DLT observation period will be 28 days. Patients will be entered sequentially to each dose level. For each dose level, if none of the first 3 patients at that level experiences a DLT, new patients may be entered at the next higher dose level. If 1 of 3 patients experiences a DLT, up to 3 more patients are to be treated at that same dose level. If none of the additional 3 patients at that dose level experiences a DLT, new patients may be entered at the next higher dose level. However, if 1 or more of the additional 3 patients experience a DLT, then no further patients are to be started at that dose level and the preceding dose is the MTD. If 2 of 3 of the initially dosed patients experience a DLT on the first dose level, Neihulizumab will be administered at a lower dose, 3mg/kg weekly (Dose level -1). Finally, if 0 of 3 patients experience DLT at the highest dose level, an additional 3 patients will be enrolled to ensure that 6 patients are treated at the MTD. The MTD will be defined as the highest dose level at which no more than 1 of 6 treated patients, experiences a DLT.

Upon determination of MTD, an expansion cohort of 4-7 patients will be enrolled so that a total of 10 patients are enrolled at the potential Phase II dose. This will be done to preliminarily assess efficacy.

Open or close this module Conditions
Conditions: Graft-versus-host Disease
Keywords: Graft-versus-host disease
Neihulizumab
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 1
Interventional Study Model: Sequential Assignment
Number of Arms: 2
Masking: None (Open Label)
Allocation: Non-Randomized
Enrollment: 16 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: Neihulizumab Dose Escalation
Initial dose will be 6 mg weekly and the highest dose administered will be 9 mg weekly. Patients will be entered sequentially to each dose level. If 0 of the first 3 patients at that level has a DLT, new patients may be entered at the next higher dose level. If 1 of 3 patients has a DLT, up to 3 more patients are to be treated at that same dose level. If 0 of the additional 3 patients at that dose level has a DLT, new patients may be entered at the next higher dose level. If 1 or more of the additional 3 patients experience a DLT, 0 patients are to be started at that dose level and the preceding dose is the MTD. If 2 of 3 of the dosed patients has a DLT on the first dose level, the drug will be administered at a lower dose, 3 mg weekly. If 0 of 3 patients has a DLT at the highest dose level, an additional 3 patients will be enrolled to ensure that 6 patients are treated at the MTD. The MTD is the highest dose level at which no more than 1 of 6 treated patients, experiences a DLT.
Drug: Neihulizumab
The doses for the 3 + 3 design (dose escalation phase) are listed in the arm description. The dose-expansion phase will use the maximum-tolerated dose.
Other Names:
  • AbGn 168
  • AbGn 168H
Experimental: Neihulizumab Dose Expansion
Upon determination of the maximum-tolerated dose, an expansion cohort of 4-7 patients will be enrolled so that a total of 10 patients are enrolled at the potential Phase II dose. This will be done to preliminarily assess efficacy.
Drug: Neihulizumab
The doses for the 3 + 3 design (dose escalation phase) are listed in the arm description. The dose-expansion phase will use the maximum-tolerated dose.
Other Names:
  • AbGn 168
  • AbGn 168H
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Serious adverse events.
[ Time Frame: Day 28 ]

This outcome measure is the number of serious adverse events. The study will use the NCI CTCAE v5.0 for reporting of adverse events.
2. Maximum-tolerated dose.
[ Time Frame: Up to 28 days ]

The maximum-tolerated dose will be defined as the highest dose level at which no more than one of six treated patients, experiences a DLT.
3. Cmax for Plasma
[ Time Frame: Day 1 (10 minutes predose, 1 hour and 4 hours post end of infusion), Day 5, Day 8 (predose), Day 15 (predose), Day 22 (predose) and Days 28, 35, 42, 49. ]

The Cmax will be calculated using software. The calculation will be ng/ml.
Secondary Outcome Measures:
1. Treatment response: Complete response
[ Time Frame: Day 28 ]

This outcome measures the number of patients with complete response. A complete response is GVHD that fully resolves at all sites. This will be determined by assessment of aGVHD response. Acute GVHD will be assessed by consensus criteria. Patients without an observed event will be censored at their last follow-up visit.
2. Treatment response: Partial response
[ Time Frame: Day 28 ]

This outcome measures the number of patients with partial response. A partial response is GVHD that improves by at least one stage at one site, without worsening at any other site. This will be determined by assessment of aGVHD response. Acute GVHD will be assessed by consensus criteria. Patients without an observed event will be censored at their last follow-up visit.
3. Failure rate.
[ Time Frame: Day 28 ]

This will be measured by the proportion of patients requiring high-dose steroids (1mg/kg or greater daily) by Day 28.
4. Non-relapse mortality.
[ Time Frame: 6 months ]

Non relapse mortality (NRM) is the time to death without relapse/recurrence. The Kaplan-Meier method will be used to determine the six-month non-relapse mortality. Patients without an observed event will be censored at their last follow-up visit.
5. Event-free survival.
[ Time Frame: 6 months ]

The rate of freedom from aGVHD progression, relapse, or death at 6 months will be collected. Progression is defined as worsening of GVHD at any site by one stage. The Kaplan-Meier method will be used to determine event-free survival.
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  1. Patients aged ≥ 18 years.
  2. Recipients of myeloablative and non-myeloablative, reduced-intensity conditioning allogeneic tranpslants.
  3. Recipients of all donor sources, including sibling, unrelated donor, HLA-haploidentical, and HLA-mismatched donors.
  4. Patients must have initial presentation of standard-risk aGVHD according to refined Minnesota Criteria. Standard-risk aGVHD is defined as follows:

    Single organ involvement:

    • Stage 1-3 skin
    • Stage 1 upper GI
    • Stage 1-2 lower GI

    Multiple organ involvement:

    • Stage 1-3 skin plus stage 1 upper GI
    • Stage 1-3 skin plus stage 1 lower GI
    • Stage 1-3 skin plus stage 1 lower GI plus stage 1 upper GI
    • Stage 1-3 skin plus stage 1-4 liver
    • Stage 1 lower GI plus stage 1 upper GI
  5. Patients must not have received prior systemic immune suppressive therapy for the treatment of active aGVHD (topical steroids and budesonide are permitted).
  6. Biopsy confirmation of GVHD is not required, but encouraged.
  7. Female patients must meet one of the following:
    • Postmenopausal for at least one year before the screening visit, or
    • Surgically sterile (i.e. undergone a hysterectomy or bilateral oophorectomy), or
    • If subject is of childbearing potential (defined as not satisfying either of the above two criteria), agree to practice two acceptable methods of contraception (combination methods requires use of two of the following: diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge, male or female condom, hormonal contraceptive) from the time of signing of the informed consent form through 90 days after the last dose of study agent, AND o Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptom-thermal, post ovulation methods] and withdrawal are not acceptable contraception methods).
  8. Male patients, even if surgically sterilized (i.e., status post vasectomy), must agree to one of the following:
    • Practice effective barrier contraception during the entire study period and through 60 calendar days after the last dose of study agent, OR
    • Must also adhere to the guidelines of any study-specific pregnancy prevention program, if applicable, OR o Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptom-thermal, post ovulation methods] and withdrawal are not acceptable methods of contraception.)
  9. Ability to understand a written informed consent document, and the willingness to sign it.

Exclusion Criteria:

  1. Relapse of disease which was the primary indication for transplant.
  2. Uncontrolled infections not responding to antimicrobial therapy.
  3. Active and uncontrolled human immunodeficiency virus (HIV), or chronic Hepatitis B, or Hepatitis C.
  4. Tuberculosis, history of tuberculosis or a known positive Quantiferon test.
  5. Liver dysfunction not attributable to aGVHD evidenced by a Total Bilirubin ≥ 2 x ULN.
  6. Creatinine clearance < 40mL/min calculated by Cockcroft-Gault equation.
  7. Intestinal obstruction within 3 days of enrollment
  8. Life expectancy of less than 28 days, or ECOG performance status of 4.
Open or close this module Contacts/Locations
Central Contact Person: Medical College of Wisconsin Cancer Center Clinical Trials Office
Telephone: 414-805-8900
Email: cccto@mcw.edu
Study Officials: Sameem Abedin, MD
Principal Investigator
Medical College of Wisconsin
Locations:
Open or close this module IPDSharing
Plan to Share IPD: No
Open or close this module References
Citations:
Links:
Available IPD/Information:

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