Reduced Intensity, Partially HLA Mismatched BMT to Treat Hematologic Malignancies

NCT01203722 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: J1055NA_00039823P01CA015396
• Study Type: interventional
• Target: 87
• Locations: 1 country
• Sites: 1

Brief Summary

If transplantation using mismatched unrelated donors or non-first-degree relatives could be performed with an acceptable toxicity profile, an important unmet need would be served. Towards this goal, the current study extends our platform of nonmyeloablative, partially HLA-mismatched bone marrow transplant (BMT) and Peripheral Blood Stem Cell Transplant (PBSCT) to the use of such donors, investigating up to several postgrafting immunosuppression regimens that incorporate high-dose Cy. Of central interest is the incorporation of sirolimus into this postgrafting immunosuppression regimen. The primary goal for phase 1 is to identify a transplant regimen associated with acceptable rates of severe acute GVHD and NRM by Day 100 and for phase 2 estimate the 6-month probability of survival without having had acute grade III- IV GVHD or graft failure.

Conditions

Hematologic Malignancies

Keywords

Reduced intensity; partially HLA mismatched allogeneic BMT; Acute leukemias; Chronic leukemias; Myelodysplasia; Lymphomas; Unrelated or non-first-degree related donors; Peripheral blood stem cell transplant

Outcome Measures

Primary Outcomes (3)

• Number of Participants Who Have Severe Acute Graft-versus-host-disease (GVHD)

  Two immunosuppressive regimens with Fludarabine-Cytoxan-TBI conditioning will be studied in reduced-intensity, partially HLA mismatched allogeneic BMT from unrelated or non-first-degree related donors. Transplant regimen will be determined by acceptable rates of severe acute GVHD (\< 25%).

  Study Day 100

• Number of Participants Who Have Transplant-related Nonrelapse Mortality (NRM)

  Two immunosuppressive regimens with Fludarabine-Cytoxan-TBI conditioning will be studied in reduced-intensity, partially HLA mismatched allogeneic BMT from unrelated or non-first-degree related donors. Transplant regimen will be determined by acceptable number of participants with transplant-related NRM.

  Study Day 100

• 6-month Probability of Survival as Assessed by Absence of Grade III-IV GVHD or Evidence of Graft Failure.

  Number of participants who do not have grade II-IV GVHD or evidence of graft failure will be assessed.

  6 months

Secondary Outcomes (13)

• Progression-free Survival

  2 years

• Event-free Survival

  7 years

• Overall Survival

  7 years

• Cumulative Incidence of Progression or Relapse

  7 years

• Cumulative Incidence of Non-relapse Mortality (NRM).

  7 years

Study Arms (4)

REGIMEN B

ACTIVE COMPARATOR

Pre-BMT : * Day -6 through -2: Fludarabine 30 mg/m2/day (adjusted for renal function; maximum cumulative dose, 150 mg/m2) administered IV * Day -6 and -5: Cytoxan 14.5 mg/kg/day administered IV * Day -1: 400 cGy total body irradiation (TBI) administered in a single fraction Day 0: Allogeneic blood or marrow transplantation (BMT) Post-Transplantation Immunosuppression Consisting of: * Day 3 and 4: High-dose Cytoxan 50mg/kg/day (adjusted according to IBW) administered IV * Day 5: Sirolimus loading dose 6 mg PO once * Day 5 thru Day 35: Mycophenolate Mofetil (MMF) 15 mg/kg PO TID (maximum daily dose 3 g/day) * Day 6 thru Day 180: Sirolimus maintenance dose 2 mg PO QD with dose adjustments to maintain trough of 3 - 12 ng/mL

Drug: Fludarabine; Drug: Cytoxan; Radiation: Total Body Irradiation; Procedure: Allogeneic Blood or Marrow Transplant; Drug: Mycophenolate Mofetil; Drug: Sirolimus

REGIMEN C

ACTIVE COMPARATOR

Pre-BMT: * Day -6 through -2: Fludarabine 30 mg/m2/day (adjusted for renal function; maximum cumulative dose, 150 mg/m2) administered IV * Day -6 and -5: Cytoxan 14.5 mg/kg/day administered IV * Day -1: 400 cGy TBI administered in a single fraction Day 0: BMT Post-Transplantation Immunosuppression Consisting of: * Day 3 and 4: High-dose Cytoxan 50mg/kg/day (adjusted according to IBW) administered IV * Day 5 thru Day 35: MMF 15 mg/kg PO TID (maximum daily dose 3 g/day) * Day 5 thru Day 180: Tacrolimus 1 mg administered IV QD

Drug: Fludarabine; Drug: Cytoxan; Radiation: Total Body Irradiation; Procedure: Allogeneic Blood or Marrow Transplant; Drug: Mycophenolate Mofetil; Drug: Tacrolimus

REGIMEN B2

ACTIVE COMPARATOR

Pre-PBSCT: * Day -6 through -2: Fludarabine 30 mg/m2/day (adjusted for renal function; maximum cumulative dose, 150 mg/m2) administered IV * Day -6 and -5: Cytoxan 14.5 mg/kg/day administered IV * Day -1: 400 cGy TBI administered in a single fraction Day 0: Peripheral Blood Stem Cell Transplant (PBSCT) Post-Transplantation Immunosuppression Consisting of: * Day 3 and 4: High-dose Cytoxan 50mg/kg/day (adjusted according to IBW) administered IV * Day 5: Sirolimus loading dose 6 mg PO once * Day 5 thru Day 35: MMF 15 mg/kg PO TID (maximum daily dose 3 g/day) * Day 6 thru Day 180: Sirolimus maintenance dose 2 mg PO QD with dose adjustments to maintain trough of 3 - 12 ng/mL

Drug: Fludarabine; Drug: Cytoxan; Radiation: Total Body Irradiation; Procedure: Peripheral Blood Stem Cell Transplant; Drug: Mycophenolate Mofetil; Drug: Sirolimus

REGIMEN B3: HIV patients with CCRd32 homozygous donors

ACTIVE COMPARATOR

Pre-PBSCT: * Day -6 through -2: Fludarabine 30 mg/m2/day (adjusted for renal function; maximum cumulative dose, 150 mg/m2) administered IV * Day -6 and -5: Cytoxan 14.5 mg/kg/day administered IV * Day -1: 400 cGy TBI administered in a single fraction Day 0: Peripheral Blood Stem Cell Transplant (PBSCT) Post-Transplantation Immunosuppression Consisting of: * Day 3 and 4: High-dose Cytoxan 50mg/kg/day (adjusted according to IBW) administered IV * Day 5: Sirolimus loading dose 6 mg PO once * Day 5 thru Day 35: MMF 15 mg/kg PO TID (maximum daily dose 3 g/day) * Day 6 thru Day 180: Sirolimus maintenance dose 2 mg PO QD with dose adjustments to maintain trough of 3 - 12 ng/mL

Drug: Fludarabine; Drug: Cytoxan; Radiation: Total Body Irradiation; Procedure: Peripheral Blood Stem Cell Transplant; Drug: Mycophenolate Mofetil; Drug: Sirolimus

Interventions

Fludarabine DRUG

Fludarabine 30 mg/m2/day

REGIMEN B; REGIMEN B2; REGIMEN B3: HIV patients with CCRd32 homozygous donors; REGIMEN C

Cytoxan DRUG

Pre-BMT: Cytoxan 14.5 mg/kg/day administered IV; Post-Transplantation: High-dose Cytoxan 50mg/kg/day

Also known as: High-dose Cytoxan

REGIMEN B; REGIMEN B2; REGIMEN B3: HIV patients with CCRd32 homozygous donors; REGIMEN C

Total Body Irradiation RADIATION

400 cGy TBI administered in a single fraction

Also known as: TBI

REGIMEN B; REGIMEN B2; REGIMEN B3: HIV patients with CCRd32 homozygous donors; REGIMEN C

Allogeneic Blood or Marrow Transplant PROCEDURE

Also known as: BMT

REGIMEN B; REGIMEN C

Peripheral Blood Stem Cell Transplant PROCEDURE

Also known as: PBSCT

REGIMEN B2; REGIMEN B3: HIV patients with CCRd32 homozygous donors

Mycophenolate Mofetil DRUG

15mg/kg by mouth three times daily

Also known as: MMF

REGIMEN B; REGIMEN B2; REGIMEN B3: HIV patients with CCRd32 homozygous donors; REGIMEN C

Sirolimus DRUG

Loading Dose: Sirolimus 6mg by mouth once; Maintenance dose: Sirolimus 2mg by mouth daily

REGIMEN B; REGIMEN B2; REGIMEN B3: HIV patients with CCRd32 homozygous donors

Tacrolimus DRUG

Tacrolimus 1mg intravenously, daily

REGIMEN C

Eligibility Criteria

• Age: 6 Months - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient age 0.5-75 years
• Absence of a suitable related or unrelated bone marrow donor who is molecularly matched at HLA-A, B, Cw, DRB1, and DQB1.
• Absence of a suitable partially HLA-mismatched (haploidentical), first-degree related donor. Donors who are homozygous for the CCR5delta32 polymorphism are given preference.
• Eligible diagnoses:
• Relapsed or refractory acute leukemia in second or subsequent remission, with remission defined as \<5% bone marrow blasts morphologically
• Poor-risk acute leukemia in first remission, with remission defined as \<5% bone marrow blasts morphologically:
• AML with at least one of the following:
• AML arising from MDS or a myeloproliferative disorder, or secondary AML
• Presence of Flt3 internal tandem duplications
• Poor-risk cytogenetics: Complex karyotype \[\> 3 abnormalities\], inv(3), t(3;3), t(6;9), MLL rearrangement with the exception of t(9;11), or abnormalities of chromosome 5 or 7
• Primary refractory disease
• ALL (leukemia and/or lymphoma) with at least one of the following:
• Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), or MLL rearrangement
• Clear evidence of hypodiploidy
• Primary refractory disease

You may not qualify if:

• Not pregnant or breast-feeding.
• No uncontrolled bacterial, viral, or fungal infection.
• Note: HIV-infected patients are potentially eligible. Eligibility of HIV-infected patients will be determined on a case-by-case basis.
• No previous allogeneic BMT (syngeneic BMT permissible).
• Active extramedullary leukemia or known active CNS involvement by malignancy. Such disease treated into remission is permitted.
• Potential donors consist of:
• Unrelated donors
• Second-degree relatives
• First cousins
• The donor and recipient must be identical at at least 5 HLA alleles based on high resolution typing of HLA-A, -B, -Cw, -DRB1, and -DQB1, with at least one allele matched for a HLA class I gene (HLA-A, -B, or -Cw) and at least one allele matched for a class II gene (HLA-DRB1 or -DQB1).
• Meets institutional selection criteria and medically fit to donate. 4 . Lack of recipient anti-donor HLA antibody. Note: In some instances, low level, non-cytotoxic HLA specific antibodies may be permissible if they are found to be at a level well below that detectable by flow cytometry. This will be decided on a case-by-case basis by the PI and one of the immunogenetics directors. Pheresis to reduce anti-HLA antibodies is permissible; however eligibility to proceed with the transplant regimen would be contingent upon the result.
• Donor must not be HLA identical to the recipient.
• Has not donated blood products to recipient.

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231-2410, United States

Location

Related Publications (2)

• Rappazzo KC, Zahurak M, Bettinotti M, Ali SA, Ambinder AJ, Bolanos-Meade J, Borrello I, Dezern AE, Gladstone D, Gocke C, Fuchs E, Huff CA, Imus PH, Jain T, Luznik L, Rahmat L, Swinnen LJ, Wagner-Johnston N, Jones RJ, Ambinder RF. Nonmyeloablative, HLA-Mismatched Unrelated Peripheral Blood Transplantation with High-Dose Post-Transplantation Cyclophosphamide. Transplant Cell Ther. 2021 Nov;27(11):909.e1-909.e6. doi: 10.1016/j.jtct.2021.08.013. Epub 2021 Aug 20.

  PMID: 34425261 DERIVED

• Kasamon YL, Ambinder RF, Fuchs EJ, Zahurak M, Rosner GL, Bolanos-Meade J, Levis MJ, Gladstone DE, Huff CA, Swinnen LJ, Matsui WH, Borrello I, Brodsky RA, Jones RJ, Luznik L. Prospective study of nonmyeloablative, HLA-mismatched unrelated BMT with high-dose posttransplantation cyclophosphamide. Blood Adv. 2017;1(4):288-292. doi: 10.1182/bloodadvances.2016002766. Epub 2017 Jan 6.

  PMID: 29242852 DERIVED

MeSH Terms

Conditions

Hematologic Neoplasms; Anemia, Refractory, with Excess of Blasts; Lymphoma

Interventions

fludarabine; Cyclophosphamide; Whole-Body Irradiation; Peripheral Blood Stem Cell Transplantation; Mycophenolic Acid; Sirolimus; Tacrolimus

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Anemia, Refractory; Anemia; Myelodysplastic Syndromes; Bone Marrow Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Radiotherapy; Therapeutics; Investigative Techniques; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Transplantation; Surgical Procedures, Operative; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Macrolides; Lactones

Results Point of Contact

• Title: Richard Ambinder, MD PhD
• Organization: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

rambind1@jhmi.edu

4109558839

Study Officials

• Richard Ambinder, MD

  Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 15, 2010
• First Posted: September 16, 2010
• Study Start: September 1, 2010
• Primary Completion: May 28, 2024
• Study Completion: May 28, 2024
• Last Updated: February 19, 2026
• Results First Posted: February 18, 2026

Record last verified: 2026-02

Locations

US (1)