Trial of Allogeneic Reduced-Intensity, HLA-Haploidentical Bone Marrow Transplantation Followed by Graft-versus-Host-Disease (GVHD) Prophylaxis With Cyclophosphamide, Bortezomib and Maraviroc for Hematologic Malignancies in People Living With HIV

HIV Clinical Trial

Official title: 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 Suspended

Clinical Trial Summary

Background:

People living with HIV(PLWH) are at a higher risk for cancers that may be curable with a bone marrow transplant. HIV infection itself is no longer a reason to not get a transplant, for patients who otherwise have a standard reason to need transplant.

Objective:

This study is being done to see if a new combination of drugs (cyclophosphamide, maraviroc, and bortezomib) is both safe and effective at protecting against graft-versus-host disease after bone marrow transplant. The study will also test the transplant s impact on your survival and control of your cancer.

Eligibility:

People aged 18 years and older living with HIV and a blood cancer that is eligible for a transplant. Healthy family members aged 12 or older who are half matched to transplant recipients are also needed to donate bone marrow.

Design:

The study will be done in 2 phases. The first phase will be to see if we can safely use a new combination of drugs to prevent GVHD. If the combination is safe in the first phase, the study will proceed to the second phase. In the second phase, we will see if this new combination can better protect against GVHD after transplant.

Participants will be screened. Their diagnoses, organ function and eligibility will be confirmed.

Participants will have a catheter inserted into a vein in their chest or neck. Medications and transfusions will be given through the catheter; blood will be drawn from it.

Participants will be in the hospital for 6 weeks or longer.

They will receive various drugs for 2 weeks to prep their body for the transplant.

The transplant cells will be administered through the catheter.

Participants will continue to receive drug treatments after the transplant.

Blood transfusions may also be needed.

Participants will return 1-2 times per week for follow-up visits for 3 months after discharge.

Participants will have visits 6, 12, 18, 24 months after transplant, then once a year for 5 years.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Hematologic Malignancies
• Hematologic Neoplasms
• HIV
• Neoplasms

• NCT number: NCT05470491
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Suspended
• Phase: Phase 1/Phase 2
• Start date: January 26, 2023
• Completion date: July 30, 2027