A Phase I/II Trial of Allogeneic Reduced-Intensity, HLA-Haploidentical Bone Marrow Transplantation Followed by GVHD Prophylaxis With Cyclophosphamide, Bortezomib and Maraviroc for Hematologic Malignancies in People Living With HIV (PLWH)

• Status: Not yet recruiting
• Trial end date: 2027-07-30
• Target enrollment: 0
• Participant gender: All

Summary

Background:

• Human Immunodeficiency Virus (HIV) infection should not be considered a barrier to hematopoietic cell transplantation (HCT) in patients who otherwise have a standard indication for HCT.

• The main historical barriers include the risk of opportunistic infections, drug interactions, and lack of donor availability.

• This study addresses these barriers by requiring adequate HIV control with anti-retroviral therapies which do not interact with the transplant medications and by utilizing HLA- haploidentical donors.

• Cellular reservoirs that harbor latent HIV are cells of hematopoietic origin, and thus HCT is a potential cure for HIV if all hematopoietic/immune cells can convert to fully donors without HIV infection of these cells.

• CCR5 receptor and CXCR4 are chemokine co-receptors that enable HIV entry into cells.

• Obtaining a CCR5-delta-32 homozygous donor lacks feasibility for the majority of people living with HIV (PLWH) requiring HCT, particularly those of minority ethnic backgrounds.

• Agents used to prevent graft-versus-host disease (GVHD) include post-transplantation cyclophosphamide (PTCy), maraviroc, and bortezomib

• PTCy expands the donor pool by allowing HLA-mismatched donor HCT with good engraftment and low rates of GVHD. PTCy typically combined with other agents as adjuncts for GVHD prophylaxis, standardly a calcineurin inhibitor and mycophenolate mofetil

• Bortezomib has been used in combination with PTCy as GVHD prophylaxis and may additionally inhibit HIV infection of donor cells

• Maraviroc is used as GVHD prophylaxis, but not previously in combination with PTCy and bortezomib, and is additionally a CCR5 receptor blocker, which may inhibit HIV infection of donor cells. Maraviroc is an HIV medication used in modern ART regimens.

• This protocol is a step-wise evaluation of a GVHD prophylaxis regimen of PTCy and bortezomib in recipients of HLA-haploidentical grafts among those who are on maraviroc, followed by a de-escalation of maraviroc to serve purely as GVHD prophylaxis

• Plerixafor is used in HCT to promote hematopoietic recovery, akin to the use of G-CSF, and is also a CXCR4 blocker, which may inhibit HIV infection of donor cells

Objective:

• To determine a safe and recommended phase II dose level regimen.

• To determine whether a PTCy-based GVHD prophylaxis regimen including maraviroc and bortezomib can maintain adequate protection against grades III-IV acute GVHD (aGVHD), evaluated at day +100.

Eligibility:

• Transplant recipient: age >= 18 years

• Transplant recipient must be HIV seropositive

• Transplant recipient must have histologically or cytologically confirmed hematologic malignancy with a standard indication for allogeneic HCT, or hematologic malignancy with a standard indication for autologous transplant without access to autologous transplant

• There must be at least one potentially suitable HLA-haploidentical donor.

Design:

• Open-label, single institution, non-randomized, single arm phase II study

• CCR5-delta-32 status will be tested among donor options and homozygous donors will be used, if available

• Conditioning will consist of eATG 40 mg/kg/day IV on days -14 and -13, pentostatin 4 mg/m^2/day IV on days -11 and -7, low-dose cyclophosphamide 5 mg/kg/day orally daily on days -11 through -4; busulfan IV, pharmacokinetically dosed, on days -3 and -2.

• Bone marrow is the only graft source allowed for this study.

• GVHD prophylaxis will consist of PTCy 50 mg/kg/day IV on days +3 and +4, bortezomib 1.3 mg/m^2 IV in 2 doses at 6 and 72 hours after graft infusion for all participants. The phase I will include 2 dose levels of de-escalated maraviroc

• Dose level 1 - PLWH on a maraviroc-containing ART regimen that starts at least 4 weeks before enrollment and continues at least through day +100

• Dose level 2 - PLWH not on a maraviroc-containing ART regimen, treated with maraviroc 300 mg orally twice daily starting day -3 and given through day +30 purely for GVHD prophylaxis

• If successful completion of dose level 2, dose level 3 will substitute plerixafor in lieu of G- CSF to the dose level 2 regimen. Plerixafor will be given subcutaneously at 240 microgram/kg every other day, beginning at day +1 after transplant through day +21, or longer as clinically indicated, such as until ANC recovery.

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

Details

• Lead Sponsor: National Cancer Institute (NCI)
• Treatments: Maraviroc; Plerixafor

Criteria

• ELIGIBILITY CRITERIA:

Inclusion Criteria - Recipient:

• Participants must have a histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation including, but not limited to, one of the following:

• Acute myeloid leukemia in morphologic complete remission (<5% blasts in the bone marrow, no detectable abnormal peripheral blasts, and no extramedullary disease)

• Any secondary and/or treatment related myeloid neoplasm with antecedent history of myeloid neoplasm or previous chemotherapy/radiation

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

• T-cell 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 Dynamic IPSS-Plus (DIPSS-Plus)

• 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/progressed within 1 year of completion of primary treatment, after autologous transplantation or has progressed through at least 2 lines of therapy

• Burkitt or lymphoblastic lymphoma: high-risk disease in first remission, progression/relapse after >= 1 previous regimen

• Chronic lymphocytic leukemia with 17p deletion and/or unmutated IgHV or refractory 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 published clinical practice guidelines

• T-Prolymphocytic leukemia progressing/relapsing after alemtuzumab and at least one other regimen

• B-Prolymphocytic leukemia progressing/relapsing after fludarabine and at least one other salvage regimen

• Hematologic malignancy of dendritic cell or histiocytic cell type

• Multiple myeloma that relapses after therapy with both a proteasome inhibitor and an immunomodulatory drug (IMiD), relapses after autologous transplantation, or manifests as plasma cell leukemia

In addition to standard indications for HCT: Participant with a hematologic malignancy eligible for consolidation of first remission with autologous transplantation, if autologous transplantation is not accessible to the participant.

• HIV seropositive, with ART regimen that is stable for >4 weeks and HIV viral load <400 copies/mL

• Dose level 1: ART regimen must include maraviroc

• Dose level 2 and 3: ART regimen must not include maraviroc and there must be no history of maraviroc intolerance or resistance

• Age >= 18 years

• At least one potentially suitable HLA-haploidentical first degree or collateral related donor. Recipients with donor-specific anti-HLA antibodies (DSAs) to all potential donors must have at least one potential donor option where the DSA strength has a mean fluorescence intensity of < 5000 and antibodies are not complement-fixing.

• Karnofsky performance score >=50% (see APPENDIX A: Performance Status Criteria).

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

• Cardiac ejection fraction by 2D ECHO of >=40%

• Forced expiratory volume-1 (FEV-1), forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLco, adjusted for hemoglobin) all of >=40% predicted. If unable to perform pulmonary function tests, there should be no evidence of dyspnea at rest, no requirement for supplemental oxygen, and oxygen saturation >92% on room air. Calculations will be based on the USA-ITS-NIH reference.

• Total bilirubin <=3.0 mg/dL (unless due to Gilbert s or hemolysis), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <= 5x the upper ma glutamyl transferase (GGT) <= 5x the upper limit of normal

• Estimated serum creatinine clearance of (Bullet)50 mL/min/1.73m2 calculated using eGFR in the clinical lab

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

• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for at least one-year post-allo HCT.

Inclusion criteria - Related Donor:

• Related donor (age >=12) deemed suitable and eligible, and willing to donate, per clinical evaluations, who are additionally willing to donate blood and/or bone marrow 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:

Exclusion Criteria - Recipient:

• Participants who are receiving any other investigational agents that cannot be discontinued/completed at least 2 weeks prior to the date of beginning conditioning.

• Poorly controlled malignant indication for transplantation, defined as:

• Leukemia not having achieved morphologic remission (i.e. bone marrow blasts >5% or active extramedullary disease)

• Lymphoma not having achieved at least a partial response to prior chemotherapy or radiation by clinical and/or radiologic assessment

• Multiple myeloma not in complete remission, as determined by negative immunofixation in serum and urine and disappearance of any soft tissue plasmacytomas and <= 5% plasma cells in the bone marrow.

• Uncontrolled intercurrent illness that in the opinion of the PI would make it unsafe to proceed with transplantation.

• Study team is unable to identify an adequate antiretroviral regimen to adequately suppress the HIV viral load <400 copies/mL that is compatible with study drugs

• Pregnancy

• For lactating women: unwilling to discontinue lactation prior to the start of study treatment on day -14.

• Prohibitive allergy to a study drug or to compounds of similar chemical or biologic composition of the agents (eATG, steroids, cyclophosphamide, busulfan, pentostatin, maraviroc, bortezomib, plerixafor (dose level 3 only)) used in the study.

• Lack of central access potential sufficient for transplant

• Active psychiatric disorder which is deemed by the PI to have significant risk of compromising compliance with the transplant protocol and/or antiretroviral therapy

• Grade 3-4 motor or sensory neuropathy per CTCAE version 5.0

Exclusion Criteria - Related Donor:

-Failure to qualify per institutional Standard Policies