Allogeneic Transplant in HIV Patients (BMT CTN 0903)

NCT ID: NCT01410344

Last Updated: 2022-12-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-09-30
• Study Completion Date: 2018-06-30

Brief Summary

The rationale for this trial is to demonstrate the feasibility and safety of allogeneic HCT for patients with chemotherapy-sensitive hematological malignancies and coincident HIV-infection. In particular, the trial will focus on the 100-day non-relapse mortality as an indicator of the safety of transplant in this patient population. Correlative assays will focus upon the incidence of infectious complications in this patient population, the evolution of HIV infection and immunological reconstitution. Where feasible (and when this can be accomplished without compromise of either the donor quality or the timeliness of transplantation), an attempt will be made to identify donors who are homozygotes for the delta32 mutation for CCR5.

Detailed Description

The study is designed to evaluate the feasibility and safety of reduced-intensity and fully-ablative allogeneic hematopoietic cell transplantation (HCT) for patients with hematological malignancies or myelodysplastic syndromes (MDS) who have HIV infection. The goal of the study is to assess the 100 day Non-relapse Mortality as well as immunological reconstitution in this patient population. Where feasible, an attempt will be made to identify human leukocyte antigen (HLA)-compatible hematopoietic stem cell donors who are homozygotes for the delta32 mutation of the chemokine receptor 5 (CCR5delta32). Patients will undergo a treatment plan review prior to registration on the trial. All patients will undergo allogeneic HCT from a matched sibling or unrelated donor.

Conditions

Leukemia; Lymphoma; HIV

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Allogeneic Transplant

One regimen from either reduced-intensity conditioning (RIC) (Fludarabine and Busulfan; or Fludarabine and Melphalan) or myeloablative conditioning (MAC) (Busulfan and Fludarabine; or Cyclophosphamide and Total Body Irradiation) will be administered prior to allogeneic hematopoietic cell transplantation (HCT).

Group Type: OTHER

Fludarabine and Busulfan

Intervention Type: DRUG

RIC Regimen (Flu/Bu): Fludarabine total dose: 120-180 mg/m^2, Busulfan: ≤ 8 mg/kg PO or 6.4 mg/kg IV). Recommended regimen:

• Days -6 to -2: Flu (30 mg/m^2/day, total dose of 150 mg/m^2)
• Days -5 to -4: Busulfan (4mg/kg/day PO or 3.2 mg/kg IV, 130 mg/m^2/day, total dose of 8 mg/kg PO or 6.4 mg/kg IV, or 260 mg/m^2 IV, respectively)

Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction in Fludarabine dosage.

Busulfan will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs more than 125 percent of IBW, in which case the drug will be dosed according to the adjusted IBW.

Fludarabine and Melphalan

Intervention Type: DRUG

RIC Regimen (Flu/Mel): Fludarabine total dose: 120-180 mg/m^2, Melphalan total dose: less than or equal to 150 mg/m^2. Recommended regimen:

• Days -5 to -2: Flu (30mg/m^2/day, total dose of 120 mg/m^2)
• Day -1: Mel (140mg/m^2)

Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction in Fludarabine dosage.

Busulfan and Fludarabine

Intervention Type: DRUG

MAC Regimen (Bu/Flu): Fludarabine total dose: 120-180mg/m^2 Busulfan total dose less than or equal to 16mg/kg PO or 12.8 mg/kg IV. Recommended regimen:

• Days -5 to -2: Busulfan (4 mg/kg/day PO with Bu Css 900 plus/equal to 100 ng/mL (or per institutional standard), 3.2 mg/kg/day IV or 130 mg/m^2/day IV; total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m^2, respectively)
• Days -5 to -2: Flu (30 mg/m^2/day, total dose of 120 mg/m^2)

Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction in Fludarabine dosage.

Busulfan will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs more than 125 percent of IBW, in which case the drug will be dosed according to the adjusted IBW.

Cyclophosphamide and Total Body Irradiation

Intervention Type: DRUG

MAC Regimen (Cy/TBI): Cyclophosphamide total dose: 120 mg/kg, Fractionated TBI total dose: 1200-1420 cGy Recommended regimen:

• Days -7 to -4: TBI (total dose of 1200-1420 cGy)
• Days -3 to -2: Cy (60 mg/kg/day, total dose of 120 mg/kg)

Cyclophosphamide will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs less than IBW, in which case the drug will be dosed according to the actual body weight.

Interventions

Fludarabine and Busulfan

RIC Regimen (Flu/Bu): Fludarabine total dose: 120-180 mg/m^2, Busulfan: ≤ 8 mg/kg PO or 6.4 mg/kg IV). Recommended regimen:

• Days -6 to -2: Flu (30 mg/m^2/day, total dose of 150 mg/m^2)
• Days -5 to -4: Busulfan (4mg/kg/day PO or 3.2 mg/kg IV, 130 mg/m^2/day, total dose of 8 mg/kg PO or 6.4 mg/kg IV, or 260 mg/m^2 IV, respectively)

Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction in Fludarabine dosage.

Busulfan will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs more than 125 percent of IBW, in which case the drug will be dosed according to the adjusted IBW.

Intervention Type: DRUG

Fludarabine and Melphalan

RIC Regimen (Flu/Mel): Fludarabine total dose: 120-180 mg/m^2, Melphalan total dose: less than or equal to 150 mg/m^2. Recommended regimen:

• Days -5 to -2: Flu (30mg/m^2/day, total dose of 120 mg/m^2)
• Day -1: Mel (140mg/m^2)

Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction in Fludarabine dosage.

Intervention Type: DRUG

Busulfan and Fludarabine

MAC Regimen (Bu/Flu): Fludarabine total dose: 120-180mg/m^2 Busulfan total dose less than or equal to 16mg/kg PO or 12.8 mg/kg IV. Recommended regimen:

• Days -5 to -2: Busulfan (4 mg/kg/day PO with Bu Css 900 plus/equal to 100 ng/mL (or per institutional standard), 3.2 mg/kg/day IV or 130 mg/m^2/day IV; total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m^2, respectively)
• Days -5 to -2: Flu (30 mg/m^2/day, total dose of 120 mg/m^2)

Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction in Fludarabine dosage.

Busulfan will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs more than 125 percent of IBW, in which case the drug will be dosed according to the adjusted IBW.

Intervention Type: DRUG

Cyclophosphamide and Total Body Irradiation

MAC Regimen (Cy/TBI): Cyclophosphamide total dose: 120 mg/kg, Fractionated TBI total dose: 1200-1420 cGy Recommended regimen:

• Days -7 to -4: TBI (total dose of 1200-1420 cGy)
• Days -3 to -2: Cy (60 mg/kg/day, total dose of 120 mg/kg)

Cyclophosphamide will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs less than IBW, in which case the drug will be dosed according to the actual body weight.

Intervention Type: DRUG

Other Intervention Names

Fludara and Busulfex; Fludara and Alkeran; Busulfex and Fludara; Cytoxan® and radiation

Eligibility Criteria

Inclusion Criteria

1. HIV-1 infection, as documented by a rapid HIV test or any FDA-Approved HIV-1 Enzyme or Chemiluminescence Immunoassay (E/CIA) test kit and confirmed by Western Blot at any time prior to study entry. HIV antigen, plasma HIV-1 RNA, or a secondary antibody test by a method other than rapid HIV and E/CIA is acceptable as an alternative test. Alternatively, if a rapid HIV test or any FDA-Approved HIV-1 Enzyme or Chemiluminescence Immunoassay (E/CIA) test is not available, two HIV-1 RNA values ≥ 2000 copies/mL at least 24 hours apart performed by any laboratory that has CLIA certification, or its equivalent, may be used to document infection.

2. Patients must be willing to comply with effective Antiretroviral Therapy.

3. Patients must be ≥ 15 years of age.

4. Hematological malignancy associated with a poor prognosis with medical therapy alone. Diagnoses to be included:

1. Patients with the diagnosis of Acute Myeloid or Lymphocytic Leukemia (AML or ALL) in first or second complete remission.

3. Hodgkin Lymphoma beyond first remission achieving at least a partial response to most recent therapy with no evidence of progression prior to transplant.

4. Non-Hodgkin Lymphoma beyond first remission achieving at least a partial response to most recent therapy with no evidence of progression prior to transplant.

5. Donor/Recipient HLA Matching:

1. Related donor: must be an 8/8 match at HLA-A, -B, -C, (serologic typing or higher resolution) and -DRB1 (at high resolution using DNA based typing). A 7/8 related donor match is permitted only if an 8/8 unrelated donor cannot be identified.

2. Unrelated donor: must be a 7/8 or 8/8 match at HLA-A, -B, -C, and -DRB1 (at high resolution using DNA based typing).

6. Patients with adequate organ function as measured by:

1. Cardiac: Left ventricular ejection fraction at rest ≥ 40% demonstrated by Multi Gated Acquisition Scan (MUGA) or echocardiogram. Patients with known heart disease must have a functional status no worse than American Heart Association Class I defined as patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.

2. Hepatic:

i. Total Bilirubin < 2.0 mg/dL (except for isolated hyperbilirubinemia attributed to Gilbert syndrome or antiretroviral therapy as specified in Appendix E) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5x the upper limit of normal.

ii. Concomitant Hepatitis: Patients with chronic hepatitis B or C may be enrolled on the trial providing the above bilirubin and transaminase criteria are met. In addition, there must be no clinical or pathologic evidence of irreversible chronic liver disease, and there must be no active viral replication as evidenced by an undetectable hepatitis viral load by a PCR-based assay.

c) Renal: Creatinine clearance (calculated creatinine clearance is permitted) > 40 mL/min.

d) Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1), or forced vital capacity (FVC) ≥ 45% of predicted (corrected for hemoglobin).

7. Signed Informed Consent

Exclusion Criteria

1. Karnofsky/Lansky performance score < 70%.

2. Active central nervous system (CNS) malignancy; however, patients with a history of positive Cerebrospinal fluid (CSF) cytology that has become negative with intrathecal chemotherapy are eligible.

3. Uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression or no clinical improvement).

4. Active Cytomegalovirus (CMV) retinitis or other CMV-related organ dysfunction.

5. AIDS related syndromes or symptoms that pose a perceived excessive risk for transplantation-related morbidity as determined by the principal investigator.

6. Untreatable HIV infection due to multidrug antiretroviral resistance. Patients with a detectable viral load > 750 copies/ml should be evaluated with an HIV drug resistance test (HIV-1 genotype). The results should be included as part of the Antiretroviral Review (described in Appendix D). This Review Committee will make the final determination as to whether HIV viremia could potentially be suppressed with alternate antiretroviral therapy. .

7. Pregnant (positive β-HCG) or breastfeeding.

8. Fertile men or women unwilling to use contraceptive techniques from the time of initiation of mobilization until six-months post-transplant.

9. Prior allogeneic HCT.

10. Patients with psychosocial conditions that would prevent study compliance and follow-up, as determined by the principal investigator.

11. T-cell depletion (including ATG or alemtuzumab) is not allowed.

12. Use of cord blood as the source of hematopoietic cells is not allowed.

• Minimum Eligible Age: 15 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Blood and Marrow Transplant Clinical Trials Network

NETWORK

Sponsor Role: collaborator

National Marrow Donor Program

OTHER

Sponsor Role: collaborator

Medical College of Wisconsin

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mary Horowitz, MD

Role: STUDY_DIRECTOR

Center for International Blood and Marrow Transplant Research

Locations

Mayo Clinic - Phoenix

Phoenix, Arizona, United States

City of Hope National Medical Center

Duarte, California, United States

University of CA, SF

San Francisco, California, United States

H. Lee Moffitt Cancer Center

Tampa, Florida, United States

Blood & Marrow Transplant Program at Northside Hospital

Atlanta, Georgia, United States

Johns Hopkins

Baltimore, Maryland, United States

Mayo Clinic - Rochester

Rochester, Minnesota, United States

University of Pennsylvania Cancer Center

Philadelphia, Pennsylvania, United States

University of Texas/MD Anderson CRC

Houston, Texas, United States

Texas Transplant Institute

San Antonio, Texas, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, Maziarz RT, Warlick ED, Fernandez HF, Alyea EP, Hamadani M, Bashey A, Giralt S, Geller NL, Leifer E, Le-Rademacher J, Mendizabal AM, Horowitz MM, Deeg HJ, Horwitz ME. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol. 2017 Apr 10;35(11):1154-1161. doi: 10.1200/JCO.2016.70.7091. Epub 2017 Feb 13.

Reference Type: RESULT

PMID: 28380315 (View on PubMed)

Ambinder RF, Wu J, Logan B, Durand CM, Shields R, Popat UR, Little RF, McMahon DK, Cyktor J, Mellors JW, Ayala E, Kaplan LD, Noy A, Jones RJ, Howard A, Forman SJ, Porter D, Arce-Lara C, Shaughnessy P, Sproat L, Hashmi SK, Mendizabal AM, Horowitz MM, Navarro WH, Alvarnas JC. Allogeneic Hematopoietic Cell Transplant for HIV Patients with Hematologic Malignancies: The BMT CTN-0903/AMC-080 Trial. Biol Blood Marrow Transplant. 2019 Nov;25(11):2160-2166. doi: 10.1016/j.bbmt.2019.06.033. Epub 2019 Jul 4.

Reference Type: DERIVED

PMID: 31279752 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Informed Consent Form

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

U01HL069294

Identifier Type: NIH

Identifier Source: secondary_id

View Link

BMT CTN 0903

Identifier Type: OTHER

Identifier Source: secondary_id

5U24CA076518

Identifier Type: NIH

Identifier Source: secondary_id

View Link

BMTCTN0903

Identifier Type: -

Identifier Source: org_study_id