Phase I/II Trial to Determine the Lowest Effective Dose of Post-Transplantation Cyclophosphamide in Combination With Sirolimus and Mycophenolate Mofetil as Graft-Versus-Host Disease Prophylaxis After Reduced Intensity Conditioning and Peripheral Blo

• Status: Not yet recruiting
• Trial end date: 2027-07-02
• Target enrollment: 0
• Participant gender: All

Summary

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 protection against GVHD severity and mortality. Lower dosing of PTCy also was associated with less broad reduction of T-cell numbers after PTCy and lower toxicity than higher dosing.

• In patients on an NIH study using myeloablative conditioning and bone marrow as the graft source, a dose of 25 mg/kg/day on days +3/+4 has been associated with more rapid engraftment, less toxicity, and potentially better immune function without an increase in acute GVHD.

• The optimal dosing of PTCy potentially may differ depending on the graft source (bone marrow versus peripheral blood stem cells) and HLA disparity (HLA-matched vs. HLA-partially mismatched).

Objective:

• Phase I: Determine the lowest effective dose of post-transplantation cyclophosphamide (PTCy) in combination with sirolimus and mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis after reduced intensity conditioning and peripheral blood stem cell transplantation (PBSCT), as assessed by primary graft failure AND Grade III-IV acute GVHD as the dose limiting toxicities (DLTs). This lowest effective dose will be evaluated in parallel for HLA-matched and HLA-haploidentical HCT in different arms of the study.

• Phase II: Evaluate the efficacy of PTCy, at the lowest dose determined for each HLA-matching arm from phase I, as assessed by 1-year GVHD-free relapse-free survival (GRFS) rate.

Eligibility:

-Recipient Participant:

• Histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation

• Age >= 50 years or 18-49 years but considered ineligible for myeloablative conditioning.

• At least one potentially suitable HLA-haploidentical or 10/10 (HLA-A, B, C, DR, DQ) related or unrelated donor.

• Karnofsky performance score >= 70

• Adequate organ function

Design:

• Open-label, multi-center, non-randomized, phase I/II study.

• All recipient participants will receive reduced intensity conditioning, peripheral blood stem cell (PBSC) HCT, and GVHD prophylaxis with PTCy, MMF, and sirolimus.

• There will be two parallel arms: one using HLA-haploidentical donors and one using HLA-matched related or unrelated donors.

• A small pilot of 5 evaluable participants per arm will receive the standard PTCy 50 mg/kg/day on days +3/+4 to obtain a limited amount of comparative clinical, pharmacokinetic, and T-cell immunophenotyping data.

• Then the study will proceed to a novel phase I time-to-event Bayesian optimal interval (TITE-BOIN) trial design to find the lowest acceptable dose of PTCy for each arm. Primary graft failure and grade III-IV aGVHD at day +100 post-transplant are defined PTCy dose-limiting toxicities.

• Three dose levels of PTCy: 35, 25, and 15 mg/kg/day on days +3 and +4 are planned in each arm of phase I.

• Recipient participants will be evaluated for development of grade III-IV acute GVHD (aGVHD) and primary graft failure at day +100 as the dose-limiting toxicities. Once the optimal PTCy dose for PBSC transplantation is determined for each arm, we will conduct a phase II expansion for each arm to estimate the efficacy of PTCy in combination with sirolimus and mycophenolate mofetil as GVHD prophylaxis. 1-year GRFS rate will be the primary endpoint during the phase II part.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: National Cancer Institute (NCI)
• Treatments: Cyclophosphamide; Fludarabine; Melphalan; Sirolimus

Criteria

• INCLUSION CRITERIA:

Recipient

• Participants must have a histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation limited to 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 (<5% blasts in the bone marrow, no detectable abnormal peripheral blasts, and no extramedullary disease)

• AML of any risk in second or subsequent morphologic complete remission

• Acute lymphoblastic leukemia in first or subsequent complete remission

• 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 DIPSS

• Chronic myelomonocytic leukemia

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

• B-cell lymphoma including Hodgkin lymphoma that has relapsed within 1 year of completion of primary treatment, relapsed after autologous transplantation, or has progressed through at least 2 lines of therapy

• 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 >= 50 years or age 18-49 years and also meeting one of the following criteria:

• Prior myeloablative HCT

• Prior exposure to inotuzumab, gemtuzumab, or other agent that increases the risk for sinusoidal obstruction syndrome.

• Hematopoietic Cell Transplantation- Comorbidity Index (HCT-CI) >= 3

• Karnofsky performance score <80

• Co-morbidity considered by the treating physician to be exclusionary of myeloablative conditioning

• At least one potentially suitable HLA-haploidentical or 10/10 (HLA-A, B, C, DR, DQ) related or unrelated donor for HCT

• Karnofsky performance score >= 70

• Adequate organ function defined as possessing all of the following:

• Cardiac ejection fraction >= 45% by 2D ECHO;

• Forced expiratory volume-1 (FEV-1), forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) all of >= 50% predicted;

• Estimated serum creatinine clearance of >= 60 ml/minute/1.73m^2 calculated using eGFR in the clinical lab;

• Total bilirubin <= 2X the upper limit of normal;

• Alanine aminotransferase and aspartate aminotransferase <= 3X the upper limit of normal.

• Women of child-bearing potential (WOCBP) and men must agree to use highly effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for at least one year post-transplant.

• WOCBP must have a negative serum or urine pregnancy test within 7 days prior to initiation of conditioning regimen.

• Ability of participant to understand and the willingness to sign a written informed consent document.

Donor

• Related donor (age >= 12) deemed suitable and eligible, and willing to donate, per clinical evaluations, who are additionally willing to donate blood, saliva, oral swab, and stool for research. Related donors will be evaluated in accordance with existing institutional Standard Policies and Procedures for determination of eligibility and suitability for clinical donation.

• Ability of participant or parent/legal guardian to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

Recipient

• Participants who are receiving any other investigational agents. Prior experimental therapies must have been completed at least 2 weeks prior to the date of beginning conditioning.

• Active breastfeeding.

• Active malignancy of non-hematopoietic type (excluding non-melanoma skin cancers) which is: metastatic, or relapsed/refractory to treatment, or locally advanced and not amenable to curative treatment, or limited disease treated with curative intent treatment within the last 2 years. This excludes non-melanoma skin cancers.

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents.

• Uncontrolled intercurrent illness (e.g., severe endocrinopathy, disseminated intravascular coagulation, profound electrolyte disturbance, active infectious hepatitis, uncontrolled dental infection) that in the opinion of the Site PI would make it unsafe to proceed with transplantation.

Donor

None