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

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.

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.

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