A Phase I/II Trial of Allogeneic Reduced-Intensity, HLA-Haploidentical Allogeneic Hematopoietic Cell Transplantation Followed by GVHD Prophylaxis With Cyclophosphamide, Bortezomib and Maraviroc for Hematologic Malignancies in People Living With HIV (PLWH)
A Phase I/II Trial of Allogeneic Reduced-Intensity, HLA-Haploidentical Allogeneic Hematopoietic Cell Transplantation Followed by GVHD Prophylaxis With Cyclophosphamide, Bortezomib and Maraviroc for Hematologic Malignancies in People Living With HIV (PLWH)
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.
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
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:
Eligibility:
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.
Peripheral blood stem cells are the only graft source allowed for this study.
GVHD prophylaxis will consist of PTCy 50 mg/kg/day IV on days plus 3 and plus 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
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 plus 1 after transplant through day plus 21, or longer as clinically indicated, such as until ANC recovery.
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:
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, when stable for >4 weeks, is associated with an HIV viral load <400 copies/mL at screening evaluations. Subsequent changes to avoid/optimize drug interactions with study drugs or essential supportive care drugs may be made to the ART regimen at any time during the eligibility assessment period, as long as the eligibility criteria were met and the regimen change is expected, by the study team and involved consultants/pharmacy, to be similarly effective for HIV control. These changes to the ART regimen are not part of the study. If changes to the ART regimen are made during the eligibility period, HIV viral load will be rechecked at least 1 week after the change but prior to protocol treatment consent.
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 percent.
Adequate organ function defined as possessing all of the following:
Estimated serum creatinine clearance of >=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.
Individuals of childbearing potential and those that can father children 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.
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:
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 potential participants: 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
INCLUSION CRITERIA - RELATED DONOR:
EXCLUSION CRITERIA - RELATED DONOR:
-Failure to qualify per institutional Standard Policies
jessenia.campos@nih.gov(301) 402-0300
mustafa.hyder@nih.gov(240) 858-3182