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Safety Study of Bone Marrow Transplant Using Mismatched Tissue Followed by Chemotherapy

Primary Purpose

MDS, Leukemias, Lymphomas

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Busulfan

Cyclophosphamide

Total body irradiation

About this trial

This is an interventional treatment trial for MDS focused on measuring Leukemia, Lymphoma, Hematologic malignancies, ALL, AML, MDS, Transplantation, Mismatched, Haploidentical, Busulfan, Cyclophosphamide, Cellcept, Tacrolimus, TBI, CMMOL, CML, JMML

Eligibility Criteria

6 Months - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Acute lymphocytic leukemia in high risk CR1
Acute myeloid leukemia in CR1
Therapy-related AML
RAEB with >5% and <20% bone marrow blasts
Chronic myelogenous leukemia beyond 1st chronic phase; Patients cannot be in blast crisis
CMMoL
JMML
Chemotherapy-resistant Hodgkins Lymphoma or intermediate or high grade Non-Hodgkins lymphoma (Less than a PR after standard or salvage chemotherapy)
Mantle cell lymphoma: chemotherapy refractory (Less than a PR after standard or salvage chemotherapy) or patients beyond CR1 with chemosensitive disease
Follicular Lymphoma, Grade 3
Transformed indolent lymphomas

Exclusion Criteria:

Poor cardiac function: left ventricular ejection fraction <45% as determined by MUGA or ECHO. For pediatric patients LVEF <45% or a shortening fraction below normal limits for age.
Poor pulmonary function: FEV1 and FVC <50% predicted for patients who have not received thoracic or mantle irradiation. For patients who have received thoracic or mantle irradiation, FEV1 and FVC <70% predicted or DLCO < 50 of predicted. For children unable to perform PFTs because of developmental stage pulse oximetry < 85% on RA
Poor liver function: bilirubin >2 mg/dl (not due to hemolysis, Gilbert's or primary malignancy)
Poor renal function: Creatinine >2.0mg/dl or creatinine clearance
HIV-positive
Positive leukocytotoxic crossmatch
Women of childbearing potential who currently are pregnant or who are not practicing adequate contraception
Uncontrolled viral, bacterial, or fungal infections Patients with symptoms consistent with RSV, influenza A, B, or parainfluenza at the time of enrollment will be assayed for the above viruses and if positive are not eligible for the trial until they are no longer symptomatic (patients may have continued assay positivity for a period of time post resolution of symptoms secondary to the nature of the assay.
Indolent lymphomas (Follicular Grade 1 and 2, marginal zone, chronic lymphocytic leukemia, small lymphocytic lymphoma, MALT)

Sites / Locations

Sidney Kimmel Comprehensive Cancer Center
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Myeloablative haploidentical BMT

Arm Description

All participants except those with acute lymphoblastic leukemia and lymphoblastic lymphoma: Busulfan will be administered 1 mg/kg oral (or 0.8 mg/kg IV) four times per day for four days, followed by cyclophosphamide 50 mg/kg once per day for two days. Participants with acute lymphocytic leukemia or lymphoblastic lymphoma: Cyclophosphamide will be administered 50 mg/kg once per day for two days, followed by total body irradiation at 300 cGy per day for four days.

Outcomes

Primary Outcome Measures

Engraftment as Measured by Donor Chimerism

Percentage of participants who achieved donor chimerism >=95%.

Secondary Outcome Measures

Non-relapse Mortality

Number of participants deceased for reasons other than disease relapse or progression.

Acute GVHD

Percentage of participants who experience grade II-IV or III-IV acute graft-versus-host-disease (GVHD) by Przepiorka criteria. The stages are defined as follows: Stage II: Rash on >50% of skin, bilirubin 2-3 mg/dL, or diarrhea 500-1000 mL/day Stage III: Bilirubin 3-15 mg/dL or diarrhea >1000 mL/day Stage IV: Generalized erythroderma with bullae or bilirubin >15 mg/dL This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999)

Chronic GVHD

Percentage of participants who experience chronic GVHD. Chronic GVHD is graded using NIH consensus criteria and Seattle criteria. This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999)

Survival

Percentage of participants alive (overall survival) and alive without disease relapse, progression, or diagnosis of myeloid malignancy (event-free survival). Estimated using Kaplan-Meier method.

Relapse

Percentage of participants who experienced disease progression or relapse. This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999)

Full Information

NCT ID

NCT00796562

First Posted

November 20, 2008

Last Updated

March 13, 2019

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborators

Otsuka Pharmaceutical Co., Ltd., National Center for Research Resources (NCRR)

1. Study Identification

Unique Protocol Identification Number

NCT00796562

Brief Title

Safety Study of Bone Marrow Transplant Using Mismatched Tissue Followed by Chemotherapy

Official Title

A Phase II Trial of Myeloablative Conditioning and Transplantation of Partially HLA-mismatched Bone Marrow for Patients With Hematologic Malignancies

Study Type

Interventional

2. Study Status

Record Verification Date

March 2019

Overall Recruitment Status

Completed

Study Start Date

December 2008 (Actual)

Primary Completion Date

June 2014 (Actual)

Study Completion Date

November 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborators

Otsuka Pharmaceutical Co., Ltd., National Center for Research Resources (NCRR)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to see if giving high dose chemotherapy and total body irradiation before and repeating high dose chemotherapy after a bone marrow transplant could reduce the incidence of graft rejection and disease for patients with blood cancers

Detailed Description

Allogeneic blood or marrow transplantation (alloBMT), following either marrow-ablative or nonmyeloablative conditioning, is a potentially curative treatment for a variety of hematologic malignancies and non-malignant hematologic disorders. Of all the potential sources of allografts, transplantation of stem cells from a human leukocyte antigen (HLA)-matched sibling has generally produced the best overall outcomes, i.e. overall and progression-free survival. Unfortunately, only about a third of candidates for alloBMT have HLA-matched siblings. For patients who lack HLA-matched siblings, there are three alternative sources of stem cells for alloBMT: 1) volunteer unrelated donors; 2) umbilical cord blood; and 3) partially HLA-mismatched, or haploidentical, related donors. Since any patient shares exactly one HLA haplotype with each biological parent or child and half of siblings, an eligible haploidentical donor can be identified rapidly in nearly all cases. However, haploidentical BMT has been associated with significant risks of graft rejection and severe GVHD, which are manifestations of excessive alloreactivity by host and donor T cells, respectively. The risk of severe GVHD may be reduced in intensively conditioned recipients of grafts that have been rigorously depleted of mature T cells or selectively depleted of alloreactive T cells, but the risks of serious infection and death from prolonged immune compromise in these patients remains high. Cyclophosphamide(Cy) is a highly immunosuppressive antineoplastic agent that has an established role in conditioning for alloBMT. Typically, the drug is administered prior to transplantation to prevent graft rejection by suppressing the host immune system. However, pre-transplantation conditioning with Cy increases the risk of GVHD following allogeneic T cell infusion in mouse models. In contrast, administration of a properly timed, high dose of Cy after BMT inhibits both graft rejection and GVHD.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

MDS, Leukemias, Lymphomas

Keywords

Leukemia, Lymphoma, Hematologic malignancies, ALL, AML, MDS, Transplantation, Mismatched, Haploidentical, Busulfan, Cyclophosphamide, Cellcept, Tacrolimus, TBI, CMMOL, CML, JMML

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

107 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Myeloablative haploidentical BMT

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Busulfan

Intervention Description

Participant will receive Busulfan injections, 4 times a day for 4 days with dilantin prophylaxis (in patients 10 years of age or older). Busulfan levels in the blood will be measured and dose adjusted, if needed.

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

Cy, Cytoxan, CTX

Intervention Description

Patient will receive Cy by IV once a day for 2 days.

Intervention Type

Radiation

Intervention Name(s)

Total body irradiation

Other Intervention Name(s)

TBI

Intervention Description

Patients will receive TBI once a day for 4 days.

Primary Outcome Measure Information:

Title

Engraftment as Measured by Donor Chimerism

Description

Percentage of participants who achieved donor chimerism >=95%.

Time Frame

Day 60

Secondary Outcome Measure Information:

Title

Non-relapse Mortality

Description

Number of participants deceased for reasons other than disease relapse or progression.

Time Frame

Day 100, 1 year

Title

Acute GVHD

Description

Time Frame

Day 100

Title

Chronic GVHD

Description

Time Frame

6 months, 12 months

Title

Survival

Description

Percentage of participants alive (overall survival) and alive without disease relapse, progression, or diagnosis of myeloid malignancy (event-free survival). Estimated using Kaplan-Meier method.

Time Frame

1 year, 2 years, 3 years

Title

Relapse

Description

Time Frame

1 year, 3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

6 Months

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Acute lymphocytic leukemia in high risk CR1 Acute myeloid leukemia in CR1 Therapy-related AML RAEB with >5% and <20% bone marrow blasts Chronic myelogenous leukemia beyond 1st chronic phase; Patients cannot be in blast crisis CMMoL JMML Chemotherapy-resistant Hodgkins Lymphoma or intermediate or high grade Non-Hodgkins lymphoma (Less than a PR after standard or salvage chemotherapy) Mantle cell lymphoma: chemotherapy refractory (Less than a PR after standard or salvage chemotherapy) or patients beyond CR1 with chemosensitive disease Follicular Lymphoma, Grade 3 Transformed indolent lymphomas Exclusion Criteria: Poor cardiac function: left ventricular ejection fraction <45% as determined by MUGA or ECHO. For pediatric patients LVEF <45% or a shortening fraction below normal limits for age. Poor pulmonary function: FEV1 and FVC <50% predicted for patients who have not received thoracic or mantle irradiation. For patients who have received thoracic or mantle irradiation, FEV1 and FVC <70% predicted or DLCO < 50 of predicted. For children unable to perform PFTs because of developmental stage pulse oximetry < 85% on RA Poor liver function: bilirubin >2 mg/dl (not due to hemolysis, Gilbert's or primary malignancy) Poor renal function: Creatinine >2.0mg/dl or creatinine clearance HIV-positive Positive leukocytotoxic crossmatch Women of childbearing potential who currently are pregnant or who are not practicing adequate contraception Uncontrolled viral, bacterial, or fungal infections Patients with symptoms consistent with RSV, influenza A, B, or parainfluenza at the time of enrollment will be assayed for the above viruses and if positive are not eligible for the trial until they are no longer symptomatic (patients may have continued assay positivity for a period of time post resolution of symptoms secondary to the nature of the assay. Indolent lymphomas (Follicular Grade 1 and 2, marginal zone, chronic lymphocytic leukemia, small lymphocytic lymphoma, MALT)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Heather Symons, M.D.

Organizational Affiliation

Johns Hopkins University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Sidney Kimmel Comprehensive Cancer Center

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21231

Country

United States

Facility Name

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21231

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

Citation

Fine J.P. and Gray, R.J. (1999), A proportional hazards model for the subdistribution of a competing risk, Journal of the American Statistical Association, 94:496-509.

Results Reference

background

PubMed Identifier

32813874

Citation

Symons HJ, Zahurak M, Cao Y, Chen A, Cooke K, Gamper C, Klein O, Llosa N, Zambidis ET, Ambinder R, Bolanos-Meade J, Borrello I, Brodsky R, DeZern A, Gojo I, Showel M, Swinnen L, Smith BD, Luznik L, Jones RJ, Fuchs EJ. Myeloablative haploidentical BMT with posttransplant cyclophosphamide for hematologic malignancies in children and adults. Blood Adv. 2020 Aug 25;4(16):3913-3925. doi: 10.1182/bloodadvances.2020001648.

Results Reference

derived

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Safety Study of Bone Marrow Transplant Using Mismatched Tissue Followed by Chemotherapy

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