Phase I/II Study De-intensifying Exposure of Post-transplantation Cyclophosphamide as GVHD Prophylaxis After HLA-haploidentical Hematopoietic Cell Transplantation for Hematologic Malignancies

Description

Background

Post-transplantation cyclophosphamide (PTCy) reduces rates of severe acute and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) and safely facilitates human leukocyte antigen (HLA)-haploidentical HCT

When clinically translated, the dose (50 mg/kg) and timing (days +3 and +4) of PTCy used were partly extrapolated from murine major histocompatibility complex (MHC)-matched skin allografting models and were partly empirical

In both MHC-haploidentical and MHC-disparate murine HCT models, a dose of 25 mg/kg/day was superior to 50 mg/kg/day on days +3 and +4 in terms of GVHD severity and mortality

In the MHC-haploidentical HCT model, a dose of 25 mg/kg on day +4 was equivalent to 25 mg/kg/day on days +3 and +4

In addition to better GVHD prevention, lower dosing of PTCy is associated with less broad reduction of T-cell numbers after PTCy

Mycophenolate mofetil (MMF), used as adjunct immunosuppression with standard dose PTCy, can have substantial gastrointestinal toxicity and can impede immune reconstitution and pathogen-specific immunity.

Objectives

Determine whether a dose of PTCy 25 mg/kg on day +3 and +4 or on day +4 only can maintain adequate protection against grade III-IV acute GVHD.

Determine whether a reduced duration of MMF, in combination with PTCy 25 mg/kg/day on days +3 and +4, can maintain adequate protection against grade III-IV acute GVHD.

Eligibility

Histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation including one of the following:

Acute myeloid leukemia (AML) of intermediate or adverse risk disease by the 2017 European LeukemiaNet criteria in first morphologic complete remission

AML of any risk in second or subsequent morphologic complete remission

B-cell acute lymphoblastic leukemia in first or subsequent complete remission

T-cell acute lymphoblastic leukemia with minimal residual disease detected after first line therapy and/or adverse genetics

Myelodysplastic syndrome of intermediate or higher score by the Revised International Prognostic Scoring System (IPSS-R)

Primary myelofibrosis of intermediate-2 or higher risk by the Dynamic International Prognostic Scoring System (DIPSS)

Chronic myelomonocytic leukemia

Chronic myelogenous leukemia resistant to or intolerant of >=3 tyrosine kinase inhibitors or with prior history of accelerated phase or blast crisis

B-cell lymphoma including Hodgkin lymphoma that has relapsed within 1 year of completion of primary treatment

Chronic lymphocytic leukemia with 17p deletion and/or unmutated IgHV or refractory to or intolerant of both BTK and PI3K inhibitors

Mature T or NK neoplasms as defined in the WHO guidelines of sufficient type and severity for allogeneic HCT based on the Prognostic Index for T-cell lymphoma (PIT) score of low-intermediate risk or higher or on recently published clinical practice guidelines

Hematologic malignancy of dendritic cell or histiocytic cell type

Multiple myeloma, stage III, relapsing after therapy with both a proteasome inhibitor and an immunomodulatory drug (IMiD)

Age 15-65.

At least one potentially suitable HLA-haploidentical donor.

Karnofsky performance score >=60

Adequate organ function

Design

Open-label, single-center, non-randomized, phase I/II study

All patients will receive myeloablative conditioning, HLA-haploidentical bone marrow HCT, and GVHD prophylaxis with PTCy, MMF (depending on cohort), and sirolimus.

A small pilot of 5 evaluable patients will receive the standard PTCy 50 mg/kg on days +3/+4 to obtain a limited amount of comparative pharmacokinetic and T-cell immunophenotyping and repertoire data.

Then the study will proceed to a small, two-level [1) 25 mg/kg/day on days +3 and +4, 2) 25 mg/kg on day +4 only] phase I dose de-escalation study based on the standard 3+3 approach

Patients will be evaluated for development of grade III-IV acute GVHD (aGVHD) at day +60 as the dose-limiting toxicity and then phase II will proceed with the shorter duration of the days of treatment (+3/+4 or +4) which is associated with 0-1 of 6 patients with grade III-IV aGVHD at day +60 and with the least amount of toxicity

Simon optimal two-stage phase II trial design, to rule out excess grade III-IV acute GVHD with this decreased PTCy exposure, will be used in the phase II portion of the study which will enroll an additional 14 patients to see if this lower PTCy exposure is associated with a similar rate of grade III-IV acute GVHD as is expected with 50 mg/kg on days +3/+4

Following completion of the phase II portion of the trial evaluating PTCy 25 mg/kg/day on days +3/+4, a dose de-escalation will be conducted to determine if the dose of MMF (standardly days +5 to +35) may be reduced without meaningful impact on avoidance of grade III-IV acute GVHD. The tested dose levels will be 1) MMF from days +5 to +18 and 2) no MMF. This will be followed by a second Simon optimal two-stage phase II trial design, to rule out excess grade III-IV acute GVHD with decreased MMF exposure, which will expand on the lowest MMF dose that is associated with acceptable toxicity and enroll an additional 14 patients to see if this lower MMF is associated with a similar rate of grade III-IV acute GVHD as is expected with full 30 day MMF treatment.

Details