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

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

Details

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