RGI-2001 for the Prevention of Graft Versus Host Disease in Patients with Hematological Malignancies after Stem Cell Transplantation
This phase I trial investigates how well RGI-2001 works in preventing graft versus host disease in patients with hematological malignancies after a stem cell transplantation. Graft versus host disease is a very common condition that patients experience after receiving a stem cell transplant. It is a condition in which cells from the donor’s tissue attack the organs. RGI-2001 may work by altering the donor’s immune system in the transplanted blood to help it adjust to the body tissues. Giving RGI-2001, in combination with standard of care interventions, may prevent graft versus host disease in patients after undergoing blood stem cell transplantation.
Inclusion Criteria
- Men or women >= 18 and =< 80 years old
- Diagnosis of hematological malignancy: * Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in morphologic complete remission * Myelodysplastic syndrome (MDS), myeloproliferative disorders (MPN), or chronic myelomonocytic leukemia (CMML) with < 5% blasts in blood or bone marrow * Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) with complete response, partial response, or no response/stable disease to pre-transplant therapy. Patients with progressive HL or NHL disease will not meet eligibility for treatment
- Patients must be undergoing haploidentical allogeneic hematopoietic cell transplantation, defined as 1st or 2nd degree relative with at least 5/10 matching at HLA-A, -B, -C, DR, and DQ
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Left ventricular ejection fraction at rest must be >= 40%, or shortening fraction > 25%
- Total bilirubin =< 2.5 mg/dL, except for patients with Gilbert's syndrome or hemolysis
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase < 3 x upper limit of normal (ULN)
- Serum creatinine within normal range, or if serum creatinine is outside normal range, then renal function (measured or estimated creatinine clearance or glomerular filtration rate [GFR]) => 40 mL/min/1.73m^2
- Carbon monoxide diffusing capability test (DLCO) (corrected for hemoglobin), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) >= 50% predicted
- Ability to understand and the willingness to sign a written informed consent document
- DONOR: Donors will be considered eligible if screening shows that the donor is free from risk factors for, and clinical evidence of, infection due to relevant communicable disease agents and diseases, and is free from communicable disease risks associated with transplantation (test results for relevant communicable disease agents are negative or nonreactive)
Exclusion Criteria
- Anti-donor human leukocyte antigen (HLA) antibodies. Positive anti-donor HLA antibody is defined as a positive crossmatch test of any titer (by complement-dependent cytotoxicity or flow cytometric testing) or the presence of anti-donor HLA antibody to the high expression loci HLA-A, -B, -C, or –DRB1 with mean fluorescence intensity > 1000 by solid phase immunoassay
- Prior allogeneic hematopoietic stem cell transplantation. (Patients who have received a prior autologous hematopoietic stem cell transplant are eligible)
- Participants who are receiving any other investigational agents within 14 days prior to RGI-2001 dosing. Thus, participants must stop investigational agents by day -9 prior to transplant
- Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, recent myocardial infarction or stroke, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Patients with active or uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy
- Planned use of prophylactic donor lymphocyte infusion (DLI) therapy
- Pregnant and breast-feeding women are ineligible because they are not eligible for hematopoietic stem cell transplantation
- Known human immunodeficiency virus (HIV) infection
- Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients with positive serology must have negative viral load results for HBV and HCV within 28 days prior to transplant
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04473911.
PRIMARY OBJECTIVE:
I. To determine the feasibility of this novel treatment regimen for haploidentical transplantation.
SECONDARY OBJECTIVES:
I. To characterize the safety of liposomal alpha galactosylceramide (RGI-2001) when used in combination with post-transplant cyclophosphamide, sirolimus, and mycophenolate mofetil.
II. To estimate the cumulative incidence of grades II-IV and III-IV acute graft-versus-host-disease (GVHD) by 6 months.
III. To estimate the cumulative incidence of moderate-severe chronic GVHD by 12 months.
IV. To estimate the cumulative incidence of chronic GVHD requiring the addition of systemic immunosuppression by 12 months.
V. To estimate day 100, 6-month and 12-month non-relapse mortality.
VI. To estimate the cumulative incidence of disease relapse at 12 months.
VII. To estimate progression-free survival at 12 months.
VIII. To estimate overall survival at 12 months.
IX. To estimate GVHD-free, relapse-free, survival (GRFS) at 12 months where endpoints include any of the following: mortality, overall grade 3-4 acute GVHD, disease relapse and chronic GVHD requiring systemic immunosuppression.
EXPLORATORY OBJECTIVE:
I. To longitudinally assess changes in regulatory T cell (Treg) subsets.
OUTLINE: Patients are assigned to 1 of 3 groups.
GROUP A: Patients receive fludarabine intravenously (IV) once daily (QD) over 30-60 minutes on days -6 to -2, cyclophosphamide IV QD over 1-2 hours on days -6 and -5, and undergo total body irradiation (TBI) on day -1. Patients then undergo haploidentical hematopoietic cell transplantation on day 0. Patients also receive cyclophosphamide IV QD over 1-2 hours on days 3 and 4, sirolimus orally (PO) QD on days 5-180, mycophenolate mofetil PO three time daily (TID) or IV TID over 2 hours on days 5-35, and RGI-2001 IV over 30 minutes on day 5 and then weekly for 5 weeks in the absence of disease progression or unacceptable toxicity.
GROUP B: Patients receive fludarabine IV QD over 30-60 minutes on days -5 to -2, melphalan IV QD over on day -6, and undergo TBI on day -1. Patients then undergo haploidentical hematopoietic cell transplantation on day 0. Patients also receive cyclophosphamide IV QD over 1-2 hours on days 3 and 4, sirolimus PO QD on days 5-180, mycophenolate mofetil PO TID or IV TID over 2 hours on days 5-35, and RGI-2001 IV over 30 minutes on day 5 and then weekly for 5 weeks in the absence of disease progression or unacceptable toxicity.
GROUP C: Patients receive cyclophosphamide IV QD over 1-2 hours on day -6, pentostatin IV QD on days -4 to -3, and undergo TBI on day -1. Patients then undergo haploidentical hematopoietic cell transplantation on day 0. Patients also receive cyclophosphamide IV on days 3 and 4, sirolimus PO QD on days 5-180, mycophenolate mofetil PO TID or IV TID over 2 hours on days 5-35, and RGI-2001 IV over 30 minutes on day 5 and then weekly for 5 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study, patients are followed up at 30 and 60 days and 3, 6, 9, and 12 months.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorZachariah Michael DeFilipp
- Primary ID19-336
- Secondary IDsNCI-2020-06321
- ClinicalTrials.gov IDNCT04473911