A Study of Acute Graft-Versus-Host Disease (GVHD) in Patients Undergoing Allogeneic Stem-Cell Transplantation (GVHD)

A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of PRO 140 for Prophylaxis of Acute Graft-Versus-Host Disease in Patients With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS)

This is a Phase II, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study of the Safety and Efficacy of PRO 140 for Prophylaxis of Acute Graft-Versus-Host Disease in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS) Undergoing Allogeneic Stem-Cell Transplantation.

Study Overview

• Status: Terminated
• Conditions: Graft Vs Host Disease
• Intervention / Treatment: Drug: PRO 140; Drug: Placebo

Detailed Description

This is a Phase II, randomized, double-blind, placebo-controlled, multi-center study to evaluate the feasibility of the use of PRO 140 as an add-on therapy to standard GVHD prophylaxis treatment for prevention of acute GVHD in adult patients with AML or MDS undergoing allogeneic HCT.

In this study, 60 subjects will be randomized to receive either PRO 140 or placebo in a 1:1 ratio (i.e., 30 subjects per arm). PRO 140 or placebo will be administered as a 350 mg subcutaneous injection on Day -3 or Day -2 prior to stem cell infusion, on the day of stem cell infusion (Day 0), and then weekly for 30 days (at Week 1, Week 2, Week 3 and Week 4) after which it will be administered every two weeks for up to 100±7 days (at Week 6, Week 8, Week 10, Week 12 and Week 14). Subjects will return to clinic for two Follow-up visits at 2 weeks after the last treatment visit, and one year after the first treatment visit.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center Cardinal Bernardin Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55409
      • University Of Minnesota
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Texas
    • San Antonio, Texas, United States, 78229
      • Texas Transplant Institute Methodist Hospital
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

Subjects must meet all of the following criteria to be included in the study:

1. Patients diagnosed with AML or MDS per below:

   • Patients with a history of histologically or pathologically confirmed diagnosis of AML and < 5% blasts in the peripheral blood or bone marrow (per bone marrow aspiration and/or biopsy within 6 weeks prior to screening) scheduled to undergo allogeneic stem-cell transplantation
   • Patients with a histologically or pathologically confirmed diagnosis of MDS with < 10% blasts in the bone marrow (per bone marrow aspiration and/or biopsy within 6 weeks prior to screening) scheduled to undergo allogeneic stem-cell transplantation
2. Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2

3. Patients must have normal organ function as defined below:

   Myeloablative allogeneic HCT:

   • Males and females, age ≥18 and ≤ 65 years of age
   • Total bilirubin ≤ 2 mg/dL (except in patients with Gilbert's Syndrome)
   • AST/ALT ≤ 3 times institutional upper limit of normal (except in patients with leukemic infiltration of liver)
   • Serum creatinine ≤ 2 mg/dL and creatinine clearance ≥ 60 ml/hr
   • Diffusing capacity of the lung for carbon monoxide (DLCO) > 50% predicted with no symptomatic pulmonary disease
   • Cardiac ejection fraction ≥ 50%. If between 40-49% a cardiology consult is required
   • Clinically normal resting 12-lead ECG at screening visit or, if abnormal, considered not clinically significant by the PI
4. Patients must have a reasonable expectation of ≥ 6 months survival

5. The donor-recipient HLA match criteria required for participation in this protocol are not research subjects in this study and they must meet criteria as National Marrow Donor Program (NMDP) donors. Procedures for selection of donors and stem cell dose will follow FDA requirements for Blood Products (21 CFR 640) and Human Cellular and Tissue Based Products (21 CFR 1271). The standard institutional practices for stem cell transplants also will be followed. The donors are:

   • HLA-Identical Sibling (6/6): Minimal typing necessary is serologic typing for class I (AB) and molecular typing for class II (DRB1)
   • Matched Unrelated Donor (8/8): Molecular identity at HLA A, B, C and DRB1 by high-resolution typing
   • Matched Related and Unrelated Donor (7/8): high-resolution molecular typing at the following loci is required: HLA A, B, C and DRB1
6. Both male and female patients and their partners of childbearing potential must agree to use appropriate birth control methods (birth control pills, barriers, or abstinence) throughout the study duration (excluding women who are not of childbearing potential and men who have been sterilized). Females of childbearing potential must have a negative serum pregnancy test at Screening visit and negative urine pregnancy test prior to receiving the first dose of study drug.
7. Patients must understand and voluntarily sign an informed consent form

Exclusion Criteria

Subjects meeting any of the following criteria will be excluded from the study:

1. Patients not expected to be available for follow-up for at least 114 days after transplant
2. Patients who have received prior allogeneic stem cell-transplantation
3. Patients who receive post-transplant high dose cyclophosphamide
4. Patients with active central nervous system (CNS) involvement by malignant cells
5. Patients receiving other investigational drugs for GVHD. Co-enrollment in other clinical trials that do not include experimental GVHD therapies is allowed.
6. Prior use of any experimental or approved CCR5 modulator including maraviroc and PRO 140
7. Patients with uncontrolled bacterial, viral or fungal infections including diagnosis of acute viral hepatitis (defined as any active infection with hepatitis A or a new diagnosis of hepatitis B or C within 24 weeks of dosing)
8. Currently active second malignancy other than non-melanoma skin cancers
9. Presence of fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated
10. Patients who are HIV positive
11. Females who are pregnant, lactating, or breastfeeding, or who plan to become pregnant during the study
12. Subjects on chronic steroid therapy > 5 mg/day within 2 weeks of screening except for inhaled, nasal, or topical steroids
13. Any other clinical condition that, in the Investigator's judgment, would potentially compromise study compliance or the ability to evaluate safety/efficacy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; In this study, 60 subjects will be randomized to receive either PRO 140 or placebo in a 1:1 ratio (i.e. 30 subjects per arm). PRO 140 or placebo will be administered as a 350 mg subcutaneous injection. Placebo will be administered -2/-3 days before the stem cell infusion, on the day of stem cell infusion (Day 0) and thereafter on days 7, 14, 21, 28, 42, 56, 70, 84 and 98 as per the study schedule of assessments. Each vial of the Placebo contains 5mM Histidine, 15 mM Glycine, 95 mM Sodium Chloride, 0.3% (w/v) Sorbitol, 0.005% (w/v) Polysorbate 20 at a pH of 5.5. Each 350 mg dose of placebo consist of 2 SC injections of placebo (5mM Histidine, 15 mM Glycine, 95 mM Sodium Chloride, 0.3% (w/v) Sorbitol, 0.005% (w/v) Polysorbate 20 at a pH of 5.5) of 2 X 1 mL/inj. on opposite sides of abdomen.	Drug: Placebo; Placebo in parenteral solution.
Experimental: 350 mg Pro140; In this study, 60 subjects will be randomized to receive either PRO 140 or placebo in a 1:1 ratio (i.e.,30 subjects per arm). PRO 140 or placebo will be administered as a 350 mg subcutaneous injection. PRO 140 will be administered -2/-3 days before the stem cell infusion, on the day of stem cell infusion (Day 0) and thereafter on days 7, 14, 21, 28, 42, 56, 70, 84 and 98 as per the study schedule of assessments. Each vial of the PRO 140 product contains 1.4 mL antibody at 175 mg/ml in a buffer containing 5 mM L-histidine, 15.0 mM glycine, 95 mM sodium chloride, 0.3% (w/v) sorbitol, 0.005% (w/v) polysorbate 20 (Tween 20®), and sterile water for injection, at pH of 5.5. Each 350 mg dose of PRO 140 will consist of 2 SC injections of PRO 140 (2 X 1 mL/inj.) on opposite sides of abdomen.	Drug: PRO 140; PRO 140 is a humanized IgG4,κ monoclonal antibody (mAb) to the chemokine receptor CCR5.; Other Names: Humanized monoclonal antibody to CCR5

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Acute GVHD by Day 100	Incidence of Grade II, Grade III or Grade IV acute GVHD by Day-100	100 days from first treatment (100 Days post treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Severe and Life-threatening (Grade III and Grade IV) Acute GVHD by Day-100	The number and percentages of subjects with severe and life-threatening (Grade III and Grade IV) acute GVHD by Day-100 will be presented. Chi-square/ Fisher's exact test will be used to compare the incidence between the treatment groups.	100 Days post-treatment
Incidence of Organ-specific Acute GVHD by Day-100	The number and percentages of subjects with organ-specific acute GVHD by Day-100 will be presented by organ category. Chi-square/ Fisher's exact test will be used to compare the incidence between the treatment groups.	100 Days post-treatment
Donor Engraftment Evaluated by T-cell and Myeloid Chimerism in Peripheral Blood	The number and percentages of subjects with donor engraftment failure evaluated by T-cell and myeloid chimerism in peripheral blood will be presented by different treatment groups. Chi-square/ Fisher's exact test will be used to compare the incidence of donor engraftment failure.	365 days post-initial treatment (T1 Visit) (+/- 14 days)
Neutrophil and Platelet Count Recovery	The number and percentages of subjects with neutrophil and platelet count recovery will be presented. Chi-square/ Fisher's exact test will be used to compare the incidence of neutrophil recovery and of platelet recovery between treatment groups.	100 Days post treatment
Changes in ECOG Performance Score	The raw and change from baseline in ECOG performance score will be summarized for each assessment scheduled visit (i.e., Screening visit, Treatment Visits 1, 4, 7, 9, 11, Follow-up Visit 1and Unscheduled Visit(s)). Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) will be presented by treatment group. If the Normality assumption is met, t-test will be used to compare the mean of ECOG performance score between the treatment groups and if the Normality assumption is not met, a non-parametric method will be used.	100 Days post treatment visit 1
GVHD-free Survival (GFS)	GFS will be defined as the elapsed time between the date of transplant until GVHD related death. GVHD-free survival will be compared between the treatment groups using Log-rank test and Kaplan-Meier methods will be used to depict the survival curves.	100 Days post treatment visit T1
Tolerability of Repeated Subcutaneous Administration of PRO 140 as Assessed by Study Participants (Using Visual Analogue Scale) and by Investigator-evaluation of Injection Site Reactions	All data from tolerability assessments of repeated subcutaneous administration of PRO 140 as assessed by study participants and by investigator-evaluation of injection site reactions will be summarized using n, mean, Standard Deviation (SD), minimum and maximum values.	365 days post-treatment (+/- 14 days)
Frequency of Treatment Emergent Adverse Events and Serious Adverse Events	Frequency of treatment emergent adverse events and treatment emergent serious adverse events.	100 Days post treatment
AML or MDS Relapse Rate by Day-100	AML or MDS relapse rate by Day-100 will be summarized and present by treatment groups.	100 Days post treatment
Changes and Shifts in Laboratory Measurements Over Time	Safety Assessment- The laboratory measurements will include Routine CBC, Biochemistry and Urinalysis.; Routine CBC includes hemoglobin, hematocrit (HCT), red blood cell (RBC) count, white blood cell (WBC) count, WBC differential count (%), absolute neutrophils count (ANC) and platelets count.; Biochemistry profile includes assessment of Hepatic function indicators: total and direct bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, Lactate dehydrogenase (LDH); Renal function indicators: Blood Urea Nitrogen (BUN), creatinine; Electrolytes: sodium, potassium, chloride, calcium and bicarbonate; Other: glucose (random), cholesterol (total); Urinalysis for color, appearance, specific gravity, pH, protein, glucose, occult blood, ketones, RBC, WBC, epithelial cells, bacteria, casts, crystals	365 days post-treatment (+/- 14 days)
Changes in Electrocardiogram (ECG) Parameters Over Time	Safety Assessment-The following ECG parameters will be evaluated: ventricular rate (beats per minute), PR interval (msec), QRS interval (msec), QT interval (msec), and QTc interval (msec).	365 days post-treatment (+/- 14 days)

Collaborators and Investigators

• Sponsor: CytoDyn, Inc.
• Collaborators: Amarex Clinical Research

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2017
• Primary Completion (Actual): April 14, 2021
• Study Completion (Actual): September 30, 2021

Study Registration Dates

• First Submitted: March 29, 2016
• First Submitted That Met QC Criteria: April 12, 2016
• First Posted (Estimated): April 13, 2016

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: February 14, 2024
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Transplantation; Allogeneic; Stem Cell
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; Leronlimab
• Other Study ID Numbers: PRO 140_CD 03_GVHD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No