Neihulizumab for Standard-Risk Acute Graft Versus Host Disease (GVHD)

• ClinicalTrials.gov Identifier: NCT04144036
• Recruitment Status: Recruiting
• First Posted: October 30, 2019
• Last Update Posted: February 17, 2023
• Sponsor: Sameem M. Abedin, MD
• Information provided by (Responsible Party): Sameem M. Abedin, MD, Medical College of Wisconsin

Tracking Information

• First Submitted Date: October 28, 2019
• First Posted Date: October 30, 2019
• Last Update Posted Date: February 17, 2023
• Actual Study Start Date: December 14, 2020
• Estimated Primary Completion Date: August 1, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 9, 2021)

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 dose-limiting toxicity.

Original Primary Outcome Measures (submitted: October 28, 2019)

• 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.
• 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.
• 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.

Current Secondary Outcome Measures (submitted: September 9, 2021)

• 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 Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm.
• 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 Acute GVHD will be assessed by Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm.
• Use of High Dose Steroids [ Time Frame: Day 28 ]
  The number of subjects requiring high-dose steroids (1mg/kg or greater daily) by Day 28.
• Non-relapse mortality. [ Time Frame: 6 months ]
  The number of subjects who expire without relapse.

Original Secondary Outcome Measures (submitted: October 28, 2019)

• 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.
• 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.
• 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.
• 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.
• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Neihulizumab for Standard-Risk Acute Graft Versus Host Disease (GVHD)
• Official Title: A Phase I Trial of Neihulizumab for the Upfront Treatment of Standard-Risk, Ann Arbor Scoring 1-2 Acute Graft vs Host Disease
• 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 dose-limiting toxicities (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 maximum-tolerated dose (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.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Graft-versus-host Disease

Intervention

• Biological: Neihulizumab, 3 mg/kg
  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
• Drug: Neihulizumab, 6 mg/kg
  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
• Drug: Neihulizumab, 9 mg/kg
  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
• Drug: Neihulizumab
  This arm will receive the Maximum Tolerated Dose determined in the Drug Escalation phase.
  Other Names:

  • AbGn 168
  • AbGn 168H

Study Arms

• Experimental: Neihulizumab Dose Escalation, 3 mg/kg
  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.
  Intervention: Biological: Neihulizumab, 3 mg/kg
• Experimental: Neihulizumab Dose Escalation, 6 mg/kg
  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.
  Intervention: Drug: Neihulizumab, 6 mg/kg
• Experimental: Neihulizumab Dose Escalation, 9 mg/kg
  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.
  Intervention: Drug: Neihulizumab, 9 mg/kg
• 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.
  Intervention: Drug: Neihulizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 28, 2019): 16
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 30, 2024
• Estimated Primary Completion Date: August 1, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Patients aged ≥ 18 years.
2. Recipients of myeloablative and non-myeloablative, reduced-intensity conditioning allogeneic transplants.
3. Recipients of all donor sources, including sibling, unrelated donor, human leukocyte antigen (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 upper limit of normal (ULN).
6. Creatinine clearance < 40 mL/min calculated by Cockcroft-Gault equation.
7. Intestinal obstruction within three days of enrollment.
8. Life expectancy of less than 28 days, or Eastern Cooperative Oncology Group (ECOG) performance status of 4.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Medical College of Wisconsin Cancer Center Clinical Trials Office; 866-680-0505 ext 8900; cccto@mcw.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04144036
• Other Study ID Numbers: PRO36517
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Sameem M. Abedin, MD, Medical College of Wisconsin
• Original Responsible Party: Same as current
• Current Study Sponsor: Sameem M. Abedin, MD
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Sameem Abedin, MD; Medical College of Wisconsin

• PRS Account: Medical College of Wisconsin
• Verification Date: February 2023