OPTIMIZE: A Phase II Study of Reduced Dose Post Transplantation Cyclophosphamide As GVHD Prophylaxis in Adult Patients with Hematologic Malignancies Receiving HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation

Background:

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative option for many hematologic malignancies, but disparities in access to matched unrelated donors exist based upon patient ancestry. NMDP is committed to expanding access to HCT by improving outcomes using mismatched unrelated donors (MMUD), thereby enabling more patients to receive this life-saving therapy.

NMDP has sponsored two completed CIBMTR (Center for International Blood and Marrow Transplant Research)-led studies in adults using post-transplantation cyclophosphamide (PTCy)-based GVHD prophylaxis in the MMUD setting. One-year overall survival (OS) was 76% in 15-MMUD (NCT02793544), which studied 4-7/8 MMUD bone marrow (BM) in adult patients with hematologic malignancies following myeloablative (MAC) or reduced intensity conditioning (RIC) and PTCy, mycophenolate mofetil (MMF), and sirolimus as GVHD prophylaxis (Shaw et al. TCT 2023). ACCESS (NCT04904588) used 4-7/8 MMUD peripheral blood stem cell (PBSC) allografts followed by PTCy, MMF, and tacrolimus in adult patients and recently reported a 1-year OS of 79% in the RIC stratum (n=70)(Al Malki et al. ASCO 2024).

PTCy at standard doses, 50 mg/kg on days 3 (D3) and 4 (D4), can cause life-threatening acute and long-term toxicities like prolonged pancytopenia, cardiac dysfunction, and infections. OPTIMIZE (NCT06001385) seeks to mitigate such toxicity by studying safety and feasibility of reduced dose PTCy (RD-PTCy) (25 mg/kg on D3 and D4) in combination with MMF and tacrolimus following 4-7/8 MMUD PBSC transplant in adults with hematologic malignancies.

Study Design and Methods:

OPTIMIZE is a CIBMTR-led prospective, multi-center, non-randomized, two-stage, Phase II study in the U.S. Patients are stratified based on conditioning intensity (MAC, RIC) with a third stratum for patients diagnosed with myelofibrosis. Included are adults with hematological malignancy and any HCT-CI score in the RIC stratum but HCT-CI <5 in the MAC stratum. Exclusion criteria include availability of a suitable HLA-matched related or 8/8 URD and the presence of donor-specific HLA antibodies to any mismatched allele/antigen with mean fluorescence intensity >3000. URDs must be 18-40 years old and matched at 4-7/8 alleles (HLA-A, -B, -C, and -DRB1).

The study includes a dose run-in phase for patients receiving 4-6/8 HLA MMUD PBSC allografts and either MAC or RIC followed by intermediate dose PTCy (ID-PTCy) (37.5 mg/kg on D3 and D4), MMF and tacrolimus. The run-in phase will evaluate 20 subjects without myelofibrosis from the <7/8 population at ID-PTCy before using RD-PTCy in the <7/8 population.

The primary endpoint is D100 infection-free survival (IFS) defined as survival without grades 2-3 infections per Blood and Marrow Transplant Clinical Trials Network criteria or subsequent transplant. The two-stage design includes an interim futility analysis of IFS after Stage I enrollment of 39 subjects into each stratum 1 and 2. If IFS is estimated to be greater than 44.8% for a given stratum, additional subjects will be enrolled to complete that stratum (36 for MAC stratum, 43 for RIC stratum).

Safety stopping rules include D28 graft failure, D100 non-relapse mortality, D14 cytokine release syndrome, and D100 grades 3-4 acute GVHD. Select secondary and exploratory endpoints include GVHD-free, relapse-free survival (GRFS) and OS at 1-year, cumulative incidence of BK-virus hemorrhagic cystitis at 1-year, incidence of patient-reported toxicities and symptoms, immune repertoire and reconstitution, and impact of HLA match grade and donor age on 1-year IFS and OS.

Study Accrual and Subject Characteristics

As of July 2024, 16 of 30 planned sites are open to enrollment, 14 of which have consented or enrolled at least one subject. Accrual to both the MAC and RIC strata have exceeded projections by 57% and 60%, respectively. The study is targeting accrual of 187 subjects.

Consistent with 15-MMUD and ACCESS, 65% of enrolled patients are racially/ethnically diverse. AML has been the most common diagnosis. Reported infusion products have been fresh (91%) versus cryopreserved (9%).

Future Directions:

OPTIMIZE enrolled the first patient in January 2024 and has since seen robust enrollment supporting that studies using MMUD address unmet patient needs. Interim analysis for the RIC stratum is anticipated to occur Fall 2024, and the full study is targeting complete accrual by January 2026.