A Phase IIa single arm open-label study to investigate the safety, tolerability, and PK of F-652 in combination with systemic corticosteroids in subjects who have undergone Hematopoietic Stem Cell Transplantation (HSCT) and have newly diagnosed grade II-IV lower GI acute Graft Verses Host Disease (aGVHD). Treatment with F-652 will be once a week for 4 weeks, with post treatment follow up visits on days 28, 56, 180 and 365.

This is a Phase IIa single arm open-label study to investigate the safety, tolerability, and PK of F-652 in combination with systemic corticosteroids in subjects who have undergone HSCT and have newly diagnosed grade II-IV lower GI aGVHD. The HSCT may be derived from bone marrow, peripheral blood stem cells, or cord blood. The PK of F-652 in this subject population will be investigated. Subjects may be replaced if subject withdrawal is not related to safety or treatment response.

F-652 will be administered in conjunction with prednisone (or equivalent) at the time of the onset of clinical symptoms consistent with GI and/or liver aGVHD. Prednisone (or equivalent) will be given at a dose of 2 mg/kg/day and tapered as per protocol.

F-652 will be administered intravenously at a rate of 100 mL/hour for one hour once per week for four weeks. A total of 4 doses will be administered at a dose of 45 μg/kg each. Subjects will be followed for safety and efficacy through Day 180, and subject survival status will be collected at Day 365.

In the first stage of the trial, a total of 16 subjects will be enrolled. If six or fewer have a Day 28 treatment response, the trial will close due to a lack of efficacy. If seven or more have a response, an additional 11 subjects will be enrolled into study for a total sample size of 27. During the course of a subject's therapy, dose reduction may occur on an individual basis as per protocol.

Inclusion Criteria:

1. Age ≥18 years and ≤80.
2. Newly diagnosed lower GI grade II-IV aGVHD with clinical diagnosis based on modified Keystone criteria1 following allogeneic HSCT using bone marrow, peripheral blood stem cells, or cord blood. Grading of aGVHD will be based on International Bone Marrow Transplant Registry (IBMTR) criteria.
3. Subjects are willing to undergo a biopsy to confirm lower GI aGVHD. Biopsy results are not needed to initiate treatment. However, if aGVHD is not confirmed histologically, treatment with F-652 will be discontinued.
4. Female subjects of childbearing potential who agree to practice 2 effective methods of contraception.
5. Male subjects, even if surgically sterilized (i.e. Status post-vasectomy) must agree to agree to practice contraception.
6. Have adequate renal function (Serum creatinine <3 mg/dL).
7. ANC >500/mm3.
8. Show evidence of a personally signed and dated informed consent document indicating that the subject (or legally acceptable representative) has been informed of all pertinent aspects of the trial.

Exclusion Criteria:

Subjects who met any of the following criteria were excluded from the study:

1. Evidence of relapse or progression of hematologic malignancy at the time of study enrollment.
2. Active uncontrolled infection. Subjects with a controlled infection receiving definitive therapy for 48 hours prior to enrollment were eligible.
3. Subjects requiring vasopressors or mechanical ventilation.
4. Subjects who had received previous systemic corticosteroids for the treatment of acute GI GVHD for longer than 5 days. Subjects who were treated with systemic corticosteroids for aGVHD for a prior allogeneic HSCT >12 months ago were eligible.
5. Subjects who received any corticosteroid therapy (for non-GVHD) at doses >0.5 mg/kg/day prednisone (or IV equivalent) within 7 days prior to the onset of GVHD therapy.
6. Subjects who developed aGVHD after unplanned donor lymphocyte infusion.
7. Subjects with chronic GVHD features (i.e., acute/chronic GVHD overlap syndrome or classical chronic GVHD).
8. History of psoriasis.
9. History of epithelial malignancies including melanoma or any carcinomas.
10. History or diagnosis of mantle cell lymphoma or anaplastic large cell lymphoma.
11. Subject was pregnant or breast-feeding.
12. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
13. The subject or guardian was unable to give informed consent or unable to comply with the treatment protocol including appropriate supportive care, follow-up, and research tests.
14. The subject had tested positive for the Clostridium difficile (C. difficile) toxin within 7 days of study entry.
15. Cytotoxic, biologic, or investigational agents were not permitted throughout the study. These included, but were not limited to, ATG, alemtuzumab, rituximab, photopheresis, and thalidomide. Subjects who participated in any other investigational drug trial or had exposure to any other investigational agent, device, or procedure, within 4 weeks prior to screening and throughout the entire trial, except for trials of investigational drugs administered prophylactically for GVHD or CMV post-allogeneic HSCT. In this exception, the other investigational drug must have been discontinued upon enrolling (i.e., screening/sign ICF) into this study.
16. Any serious medical or psychiatric illness that could, in the Investigator's opinion, potentially have interfered with the completion of treatment according to this protocol.

30 participants were dosed based on initial screening. Then 3 of the 30 participants were removed after receiving one dose because they failed inclusion/exclusion criteria leaving 27 participants to continue in the study. The baseline demographics were assessed based on the total initial enrolled number of participants (30). All 30 participants were exposed to study drug so they were in the safety population, but not all were in the efficacy as they did not continue in the study per protocol.

AEs/SAEs were assessed from the time of screening until the end of Day 56 and all causality for mortality was assessed up to 1 year.

All SAEs and AEs were those assessed as possibly, probably, or definitely related to F-652 by the study Investigator at each site. Please note: 30 participants were dosed based on initial screening, so they were included in the safety population.