Shorter Course Tacrolimus After Nonmyeloablative, Related Donor BMT With High-dose Posttransplantation Cyclophosphamide

NCT01342289 | Completed Phase 1

• 2 other identifiers: J1151NA_00048378
• Study Type: interventional
• Target: 127
• Locations: 1 country
• Sites: 1

Brief Summary

This research is being done to learn more about nonmyeloablative bone marrow transplantation (BMT), also known as a "mini" transplant for patients with blood cancers, using bone marrow from a relative.

Conditions

Hodgkin's Lymphoma; Leukemia; Myelodysplastic Syndrome(MDS); Multiple Myeloma; Non Hodgkin's Lymphoma

Keywords

Nonmyeloablative; Allogeneic; Bone Marrow Transplant (BMT); Tacrolimus; Cyclophosphamide

Outcome Measures

Primary Outcomes (2)

• Safety of reduced-dose tacrolimus as assessed by Percentage of Participants with severe graft versus host disease (GVHD)

  Percentage of participants with severe graft versus host disease (GVHD) defined as grade III-IV acute GVHD or extensive chronic GVHD. Acute GVHD is defined by the Przepiorka criteria, which stages the degree of organ involvement in the skin, liver, and gastrointestinal (GI) tract, based on severity, with Stage 1+ being least severe and stage 4+ being the most severe. Grading of acute GVHD is as follows: Grade I (skin involvement stages 1+ to 2+, with no liver or GI involvement), Grade II (skin involvement stages 1+ to 3+, liver 1+, GI tract 1+), Grade III (skin involvement stages 2+ to 3+, liver 1+, GI tract 2+ to 4+), Grade IV (skin involvement stages 4+, Liver 4+). Chronic GVHD is defined by the NIH consensus criteria. This system gives scores from 0 to 3 for Karnofsky performance score, skin, mouth, eyes, gastrointestinal, liver, lungs, joints, and genitals, as well as an overall severity. Higher scores indicate more severe disease. Scores are not totaled or added up.

  Day 5 - Day 120

• Tolerability of tacrolimus as assessed by percentage of participants with treatment-emergent adverse events

  Percentage of participants with grade 3-4 toxicity by CTCAE 4.0 attributable to tacrolimus.

  Up to 120 days

Secondary Outcomes (8)

• Percentage of participants experiencing acute GVHD

  Up to 7 years

• Percentage of participants experiencing chronic GVHD

  Up to 7 years

• Disease relapse

  Up to 7 years

• Non-relapse mortality

  Up to 7 years

• Use of immunosuppression

  Up to 2 years

Study Arms (3)

Tacrolimus 60

EXPERIMENTAL

Non-myeloablative bone marrow transplant with fludarabine, cyclophosphamide, total body irradiation conditioning regimen and cyclophosphamide, mycophenolate mofetil, and tacrolimus prophylaxis for graft-versus-host disease (GVHD). Tacrolimus was given for 60 days.

Drug: Cyclophosphamide; Drug: Fludarabine; Radiation: Total body irradiation; Drug: Mycophenolate Mofetil; Drug: Tacrolimus 60; Biological: Bone marrow transplant

Tacrolimus 90

EXPERIMENTAL

Non-myeloablative bone marrow transplant with fludarabine, cyclophosphamide, total body irradiation conditioning regimen and cyclophosphamide, mycophenolate mofetil, and tacrolimus prophylaxis for graft-versus-host disease (GVHD). Tacrolimus was given for 90 days.

Drug: Cyclophosphamide; Drug: Fludarabine; Radiation: Total body irradiation; Drug: Mycophenolate Mofetil; Drug: Tacrolimus 90; Biological: Bone marrow transplant

Tacrolimus 120

EXPERIMENTAL

Non-myeloablative bone marrow transplant with fludarabine, cyclophosphamide, total body irradiation conditioning regimen and cyclophosphamide, mycophenolate mofetil, and tacrolimus prophylaxis for graft-versus-host disease (GVHD). Tacrolimus was given for 120 days.

Drug: Cyclophosphamide; Drug: Fludarabine; Radiation: Total body irradiation; Drug: Mycophenolate Mofetil; Drug: Tacrolimus 120; Biological: Bone marrow transplant

Interventions

Cyclophosphamide DRUG

Days -6 and -5: 14.5 mg/kg/day IV. Days 3 and 4: 50 mg/kg/day IV.

Also known as: Cytoxan

Tacrolimus 120; Tacrolimus 60; Tacrolimus 90

Fludarabine DRUG

Days -6, -5, -4, -3, and -2: 30 mg/m\^2/day IV.

Also known as: Fludara

Tacrolimus 120; Tacrolimus 60; Tacrolimus 90

Total body irradiation RADIATION

Day -1: 200 centigray in one fraction.

Also known as: TBI

Tacrolimus 120; Tacrolimus 60; Tacrolimus 90

Mycophenolate Mofetil DRUG

Days 5 to 35: 15 mg/kg PO three times per day; max daily dose 1 g.

Also known as: MMF, CellCept

Tacrolimus 120; Tacrolimus 60; Tacrolimus 90

Tacrolimus 60 DRUG

Begin dosing at 1 mg IV daily on Day 5. Dose is titrated according to serum levels. Stop at Day 60.

Also known as: FK-506, Prograf

Tacrolimus 60

Tacrolimus 90 DRUG

Begin dosing at 1 mg IV daily on Day 5. Dose is titrated according to serum levels. Stop at Day 90.

Also known as: FK-506, Prograf

Tacrolimus 90

Tacrolimus 120 DRUG

Begin dosing at 1 mg IV daily on Day 5. Dose is titrated according to serum levels. Stop at Day 120.

Also known as: FK-506, Prograf

Tacrolimus 120

Bone marrow transplant BIOLOGICAL

Donor stem cells infused IV on Day 0.

Also known as: BMT

Tacrolimus 120; Tacrolimus 60; Tacrolimus 90

Eligibility Criteria

• Age: 6 Months - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• years
• Suitable first-degree related, HLA haploidentical or HLA-matched donor
• Eligible diagnoses:
• a. Low-grade non-Hodgkin's lymphoma or plasma cell neoplasm with either of the following, and with stable disease or better prior to transplantation: i. Progressed during multiagent therapy, failed at least two prior therapies (excluding single agent rituximab), or there is evidence of prior transformation ii. SLL or CLL with 11q or 17p deletion or with progression \< 6 months after a purine analog-containing regimen
• b. Relapsed, refractory, or progressive aggressive non Hodgkin's lymphoma (including mantle cell lymphoma), with PR or better prior to transplantation, and autologous BMT is not recommended. Note: Patients with Burkitt's, atypical Burkitt's, or acute lymphoblastic lymphoma must be in CR.
• c. Relapsed, refractory, or progressive Hodgkin's lymphoma meeting one of the following criteria, and autologous BMT is not recommend: i. PR or better prior to transplantation. ii. Stable disease prior to transplantation, provided that the disease is low-volume and disease control is regarded as sufficient to proceed with BMT. Eligibility of such patients will be determined on a case-by-case basis with the PI or co-PI.
• d. One of the following poor-risk lymphomas or plasma cell neoplasms, in PR or better prior to transplantation: i. Transformed lymphoma ii. T-cell PLL iii. Peripheral T-cell lymphoma iv. NK or NK/T-cell lymphoma v. Blastic/blastoid mantle cell lymphoma vi. Plasma cell leukemia
• e. For patients with SLL, CLL, or PLL, \< 20% of bone marrow cellularity involved by this process (to lower risk of graft rejection).
• f. Relapsed, refractory, or progressive acute leukemia in second or subsequent remission, with remission defined as \<5% bone marrow blasts morphologically.
• g. Poor-risk acute leukemia in first remission, with remission defined as \<5% bone marrow blasts morphologically: i. 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 Primary refractory disease ii. ALL (leukemia and/or lymphoma) with at least one of the following: Poor-risk cytogenetics Clear evidence of hypodiploidy Primary refractory disease iii. Biphenotypic leukemia
• h. MDS with at least one of the following poor-risk features: i. Poor-risk cytogenetics ii. IPSS score of INT-2 or greater iii. Treatment-related or secondary MDS iv. MDS diagnosed before age 21 years v. Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy vi. Life-threatening cytopenias, including those requiring frequent transfusions
• i. Interferon- or imatinib-refractory CML in first chronic phase, or CML in second or subsequent chronic phase
• j. Philadelphia chromosome negative myeloproliferative disease (including myelofibrosis)
• k. Chronic myelomonocytic leukemia
• l. Juvenile myelomonocytic leukemia

You may not qualify if:

• Active extramedullary leukemia or known active Central Nervous System (CNS) involvement by malignancy.
• Previous Bone marrow transplant (BMT) less than 3 months prior to start of conditioning.
• Inadequate end-organ function as measured by:
• Left ventricular ejection fraction less than or equal to 35% or shortening fraction less than 25%
• Bilirubin greater than or equal to 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST greater than or equal to 5 x ULN
• FEV1 and FVC less than or equal to 40% of predicted; or if unable to perform pulmonary function tests due to young age, oxygen saturation less than 92% on room air
• Previous allogeneic BMT (syngeneic BMT permissible).
• Pregnant or breast-feeding.
• Uncontrolled infection.

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead

Study Sites (1)

Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21231, United States

Location

Related Publications (1)

• Kasamon YL, Fuchs EJ, Zahurak M, Rosner GL, Symons HJ, Gladstone DE, Huff CA, Swinnen LJ, Brodsky RA, Matsui WH, Borrello I, Shanbhag S, Cooke KR, Ambinder RF, Luznik L, Bolanos-Meade J, Jones RJ. Shortened-Duration Tacrolimus after Nonmyeloablative, HLA-Haploidentical Bone Marrow Transplantation. Biol Blood Marrow Transplant. 2018 May;24(5):1022-1028. doi: 10.1016/j.bbmt.2018.01.011. Epub 2018 Jan 17.

  PMID: 29353109 DERIVED

MeSH Terms

Conditions

Hodgkin Disease; Leukemia; Myelodysplastic Syndromes; Multiple Myeloma; Lymphoma, Non-Hodgkin

Interventions

Cyclophosphamide; fludarabine; fludarabine phosphate; Whole-Body Irradiation; Mycophenolic Acid; Tacrolimus; Bone Marrow Transplantation

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Hematologic Diseases; Bone Marrow Diseases; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

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

Study Officials

• Richard Jones, M.D.

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

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

Model Details: Participants were initially enrolled on the 90-day arm. When that arm completed enrollment, participants were enrolled on the 120-day arm while safety of the 90-day arm was evaluated. The 90-day arm was found to be safe, so participants were then enrolled on the 60-day arm for the remainder of the study.

Study Record Dates

• First Submitted: April 21, 2011
• First Posted: April 27, 2011
• Study Start: August 1, 2011
• Primary Completion: March 1, 2018
• Study Completion: March 1, 2018
• Last Updated: October 17, 2018

Record last verified: 2018-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)