Study of PRO 140 for Prophylaxis of Acute GVHD in Patients Undergoing RIC Allogenic Stem-Cell Transplantaton (GVHD)

• Sponsor: CytoDyn, Inc.
• Collaborator: Amarex Clinical Research
• Information provided by (Responsible Party): CytoDyn, Inc.

Study Description

Brief Summary:

This is an Open-Label, Single-Arm, Phase II Multicenter Study of the Safety and Efficacy of PRO 140 for Prophylaxis of Acute Graft-Versus-Host Disease (GVHD) in Patients Undergoing Reduced Intensity Conditioning (RIC) Allogeneic Stem-Cell Transplantation.

Condition or disease	Intervention/treatment	Phase
Graft Vs Host Disease	Drug: PRO 140	Phase 2

Detailed Description:

This is an open-label, single-arm, phase II, multicenter 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 undergoing RIC allogeneic HCT.

In this study, up to 60 subjects will be enrolled. PRO 140 will be administered as a 525 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 up to 100±7 days. Subjects will return to the clinic for three Follow-up visits at 2 weeks after the last treatment visit, 30 days after the last treatment visit and one year after the first treatment visit.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	60 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	An Open-Label, Single-Arm, Phase II Multicenter Study of the Safety and Efficacy of PRO 140 for Prophylaxis of Acute Graft-Versus-Host Disease (GVHD) in Patients Undergoing Reduced Intensity Conditioning (RIC) Allogeneic Stem-Cell Transplantation
Study Start Date :	November 2016
Estimated Primary Completion Date :	December 2019
Estimated Study Completion Date :	December 2019

Arms and Interventions

Arm

Intervention/treatment

Experimental: PRO 140; up to 60 subjects will be enrolled. PRO 140 will be administered as a 525 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 up to 100±7 days. Subjects will return to the clinic for three Follow-up visits at 2 weeks after the last treatment visit, 30 days after the last treatment visit and one year after the first treatment visit.

Drug: PRO 140; Two 1 mL injections, 175mg/ml each, of PRO 140 to opposite sides of the abdomen.; Other Name: Humanized monoclonal antibody to CCR5

Outcome Measures

Primary Outcome Measures :

1. Incidence of Grade II , Grade III or Grade IV acute GVHD by Day-100 [ Time Frame: 100 Days post treatment ]
   Primary Efficacy Endpoint

Secondary Outcome Measures :

1. Incidence of severe and life-threatening (Grade III and Grade IV) acute GVHD by Day-100 [ Time Frame: 100 Days post-treatment ]
   Secondary Efficacy Endpoint
2. Incidence of organ-specific acute GVHD by Day-100 [ Time Frame: 100 Days post-treatment ]
   Secondary Efficacy Endpoint
3. Donor engraftment evaluated by T-cell and myeloid chimerism in peripheral blood [ Time Frame: 365 days post-treatment (+/- 14 days) ]
   Secondary Efficacy Endpoint
4. Neutrophil and Platelet count recovery [ Time Frame: 100 Days post treatment ]
   Secondary Efficacy Endpoint
5. Changes in ECOG performance score [ Time Frame: 100 Days post treatment ]
   Secondary Efficacy Endpoint
6. GVHD-free survival (GFS) [ Time Frame: 100 Days post treatment ]
   Secondary Efficacy Endpoint
7. 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 [ Time Frame: 365 days post-treatment (+/- 14 days) ]
   Safety Assessment
8. Frequency of treatment emergent adverse events and serious adverse events [ Time Frame: 100 Days post treatment ]
   Safety Assessment
9. Hematologic malignancy relapse rate by Day-100 [ Time Frame: 100 Days post treatment ]
   Safety Assessment
10. Changes and shifts in laboratory measurements over time [ Time Frame: 365 days post-treatment (+/- 14 days) ]

    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
11. Changes in Electrocardiogram (ECG) parameters over time [ Time Frame: 365 days post-treatment (+/- 14 days) ]
    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).

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 65 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria

Subjects may be included in the study only if they meet all of the following inclusion criteria:

1. Patients ≥18 years of age with a hematologic malignancy other than aplastic anemia or primary myelofibrosis, scheduled to undergo RIC allogeneic SCT with a peripheral blood stem cell graft, using Fludarabine/Busulfan (Flu/Bu) conditioning and Tacrolimus/ Methotrexate (Tac/MTX) GVHD prophylaxis. The following diagnoses are included:

   • Acute leukemia - Acute myelogenous leukemia (AML), Acute lymphoblastic leukemia (ALL) or acute bi-phenotypic leukemia.

   Note: Patients should have documentation of complete remission within 6 weeks prior to their transplant. Complete remission is defined as <5% blasts on a bone marrow biopsy and absence of any known extramedullary disease.

   • Chronic myelogenous leukemia (CML) in any stage, but with documentation of <5% blasts on a bone marrow biopsy within 6 weeks prior to transplant.
   • Myelodysplastic syndrome (MDS) of any subtype, but with documentation of <5% blasts on a bone marrow biopsy within 6 weeks prior to transplant.
   • Myeloproliferative disorders other than primary myelofibrosis.
   • Lymphoma - All types of lymphoma are eligible.
   • Chronic lymphocytic leukemia (CLL) and Prolymphocytic leukaemia (PLL).

2. Patients who meet institutional eligibility criteria for allogeneic SCT:

   • Renal function: Serum creatinine ≤ 2.
   • Hepatic function: Baseline direct bilirubin, ALT or AST lower than three times the upper limit of normal.
   • Pulmonary: FVC or FEV1 ≥ 40% predicted.
   • Cardiac ejection fraction ≥ 40%.
   • Clinically normal resting 12-lead ECG at screening visit or, if abnormal, considered not clinically significant by the PI Note: Prior documented echocardiogram and pulmonary function tests within the last 3 months of the Screening Visit is acceptable. If these are not performed within last 3 months, then these tests must be completed within the Screening Phase. In case the test is repeated between the Screening Visit and the First Treatment Visit, the most recent results will be used for the eligibility assessment.
3. HLA matched sibling or URD at least 7/8 HLA-A, -B, -C and -DRB1 matching by high-resolution molecular typing and will meet eligibility criteria to serve as a peripheral blood stem-cell donor.
4. Karnofsky scores ≥ 70% at the time of screening.
5. Capacity to understand and sign the study informed consent form.
6. Negative pregnancy test. Women of childbearing potential (not having had a hysterectomy, a bilateral oophorectomy or bilateral tubal ligation, or be post-menopausal with a total cessation of menses of > 1 year) must agree to use documented reliable method(s) of contraception. Men should agree to use condoms during the study period.
7. Co-enrollment in other clinical trials that do not include experimental GVHD therapies is allowed.

Inclusion Criteria

Subjects may be included in the study only if they meet all of the following inclusion criteria:

1. Patients ≥18 years of age with a hematologic malignancy other than aplastic anemia or primary myelofibrosis, scheduled to undergo RIC allogeneic SCT with a peripheral blood stem cell graft, using Fludarabine/Busulfan (Flu/Bu) conditioning and Tacrolimus/ Methotrexate (Tac/MTX) GVHD prophylaxis. The following diagnoses are included:

   • Acute leukemia - Acute myelogenous leukemia (AML), Acute lymphoblastic leukemia (ALL) or acute bi-phenotypic leukemia.

   Note: Patients should have documentation of complete remission within 6 weeks prior to their transplant. Complete remission is defined as <5% blasts on a bone marrow biopsy and absence of any known extramedullary disease.

   • Chronic myelogenous leukemia (CML) in any stage, but with documentation of <5% blasts on a bone marrow biopsy within 6 weeks prior to transplant.
   • Myelodysplastic syndrome (MDS) of any subtype, but with documentation of <5% blasts on a bone marrow biopsy within 6 weeks prior to transplant.
   • Myeloproliferative disorders other than primary myelofibrosis.
   • Lymphoma - All types of lymphoma are eligible.
   • Chronic lymphocytic leukemia (CLL) and Prolymphocytic leukaemia (PLL).

2. Patients who meet institutional eligibility criteria for allogeneic SCT:

   • Renal function: Serum creatinine ≤ 2.
   • Hepatic function: Baseline direct bilirubin, ALT or AST lower than three times the upper limit of normal.
   • Pulmonary: FVC or FEV1 ≥ 40% predicted.
   • Cardiac ejection fraction ≥ 40%.
   • Clinically normal resting 12-lead ECG at screening visit or, if abnormal, considered not clinically significant by the PI Note: Prior documented echocardiogram and pulmonary function tests within the last 3 months of the Screening Visit is acceptable. If these are not performed within last 3 months, then these tests must be completed within the Screening Phase. In case the test is repeated between the Screening Visit and the First Treatment Visit, the most recent results will be used for the eligibility assessment.
3. HLA matched sibling or URD at least 7/8 HLA-A, -B, -C and -DRB1 matching by high-resolution molecular typing and will meet eligibility criteria to serve as a peripheral blood stem-cell donor.
4. Karnofsky scores ≥ 70% at the time of screening.
5. Capacity to understand and sign the study informed consent form.
6. Negative pregnancy test. Women of childbearing potential (not having had a hysterectomy, a bilateral oophorectomy or bilateral tubal ligation, or be post-menopausal with a total cessation of menses of > 1 year) must agree to use documented reliable method(s) of contraception. Men should agree to use condoms during the study period.
7. Co-enrollment in other clinical trials that do not include experimental GVHD therapies is allowed.

Exclusion Criteria

Subjects will be excluded from the study if they meet one or more of the following exclusion criteria:

1. Patients with aplastic anemia or primary myelofibrosis. Patients with marrow fibrosis secondary to MDS, AML or a myeloproliferative disorder other than primary myelofibrosis are eligible.
2. Patients who are not expected to be available for follow-up in our institution for at least 180 days after the transplant.
3. Prior allogeneic SCT.
4. Uncontrolled bacterial, viral or fungal infections.
5. Prior use of any experimental or approved CCR5 modulators including maraviroc and PRO 140
6. Patients receiving other investigational drugs for GVHD.
7. Patients with prior malignancies are excluded unless treated with curative intent and known to be free of disease for at least 2 years.
8. Presence of fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated
9. Patients who are HIV positive
10. Females who are pregnant, lactating, or breastfeeding, or who plan to become pregnant during the study
11. Any other clinical condition that, in the Investigator's judgment, would potentially compromise study compliance or the ability to evaluate safety/efficacy

Contacts and Locations

Contacts

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Contact: Kush Dhody, MBBS, MS	301-956-2536	kushd@amarexcro.com

Locations

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

Sponsors and Collaborators

CytoDyn, Inc.

Amarex Clinical Research

More Information

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Responsible Party:	CytoDyn, Inc.
ClinicalTrials.gov Identifier:	NCT02737306 History of Changes
Other Study ID Numbers:	PRO 140_CD 03_GVHD
First Posted:	April 13, 2016
Last Update Posted:	August 15, 2018
Last Verified:	August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

Keywords provided by CytoDyn, Inc.:

RIC Allogeneic Stem-Cell Transplantation

Additional relevant MeSH terms:

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Graft vs Host Disease; Immune System Diseases; PRO-140 monoclonal antibody; HIV Antibodies; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; Molecular Mechanisms of Pharmacological Action	Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; Immunologic Factors; Physiological Effects of Drugs