Once Daily Targeted Intravenous (IV) Busulfex as Part of Reduced-toxicity Conditioning for Patients With Refractory Lymphomas Undergoing Allogeneic Transplantation

Sponsor

West Virginia University (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01203020

Collaborator

(none)

Enrollment

Location

Arm

140.6

Anticipated Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a phase II study of allogeneic hematopoietic progenitor cell transplantation (HPCT) followed reduced toxicity conditioning with once daily intravenous Busulfex and fludarabine in patients with relapsed/chemotherapy refractory Hodgkin's and non-Hodgkin's lymphomas.

Condition or Disease	Intervention/Treatment	Phase
Hodgkin's Lymphoma Non-Hodgkin's Lymphoma	Drug: Busulfan Drug: Fludarabine	Phase 2

Detailed Description

This study hopes to learn if giving intravenous (IV) busulfan with fludarabine before (as a conditioning regimen) allogeneic hematopoietic progenitor cell transplantation (HPC) is safe and helps patients with Non-Hodgkin´s Lymphoma (NHL) and Hodgkin´s Lymphoma (HL). An HPC transplant takes cells from a donor´s bone marrow and, after chemotherapy treatment with a conditioning regimen, infuses the donor´s cells into the patient´s body. Busulfan is a strong drug that suppresses the immune system and fludarabine is a chemotherapy (cancer fighting) drug. These drugs can stop the growth of cancer cells by breaking the Deoxyribonucleic acid (DNA) or genetic material which is necessary for the growth of both healthy and cancer cells. The use of IV busulfan with fludarabine as a conditioning regimen prior to HPC transplant is investigational (not approved by the Food and Drug Administration [FDA]).

Busulfan is only given once daily by IV in this study, which is also not approved by the FDA. Patients in this study will go through standard procedures for their disease like medical history, physical exam, blood tests, Multi Gated Acquisition Scan (MUGA) scan or echocardiogram, bone marrow aspirate or biopsy, and lung functions test. Patients will be asked to donate additional blood and bone marrow for this study and for potential future research on their blood related to this study. Because of the normal procedures for HPC transplants patients in this study will be hospitalized for 4 to 6 weeks or longer and will make frequent trips to the clinic to visit the study doctor for supervision for at least one year. Each patient will also have to have a central venous catheter inserted into a large vein above the heart. This is used to give the drugs and to take blood samples.

Participation in this study will last about two years. The study expects to enroll 32 patients and will open to at least two collaborating institutions in the future. Upon initial Institutional Review Board (IRB) approval enrollment will only occur at West Virginia University (WVU). The IRB will be notified before enrollment occurs at other institutions.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

32 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Once Daily Intravenous Busulfex as Part of Reduced-toxicity Conditioning for Patients With Relapsed/Refractory Hodgkin's and Non-Hodgkin's Lymphomas Undergoing Allogeneic Hematopoietic Progenitor Cell Transplantation - A Multicenter Phase II Study

Actual Study Start Date :

Oct 12, 2010

Anticipated Primary Completion Date :

Dec 31, 2021

Anticipated Study Completion Date :

Jun 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Allogeneic hematopoietic progenitor cell transplant Intravenous busulfex 130mg/m2 on days -6 to -3 before transplant	Drug: Busulfan Busulfex 130 mg/m2 intravenous piggy back (IVPB) for 4 days (Day -6 to -3) pharmacokinetic (PK) samples for Busulfex dose adjustment drawn on Day -6 Other Names: Busulfex Drug: Fludarabine Fludarabine 40 mg/m2 IVPB for 4 days (Day -6 to -3) Other Names: Fludarabine Monophosphate Fludara

Arm

Intervention/Treatment

Experimental: Allogeneic hematopoietic progenitor cell transplant

Intravenous busulfex 130mg/m2 on days -6 to -3 before transplant

Drug: Busulfan

Busulfex 130 mg/m2 intravenous piggy back (IVPB) for 4 days (Day -6 to -3) pharmacokinetic (PK) samples for Busulfex dose adjustment drawn on Day -6

Other Names:

Busulfex

Drug: Fludarabine

Fludarabine 40 mg/m2 IVPB for 4 days (Day -6 to -3)

Other Names:

Fludarabine Monophosphate

Fludara

Outcome Measures

Primary Outcome Measures

To assess 1-year progression free survival (PFS) of patients with chemotherapy refractory Hodgkin's and non-Hodgkin's lymphoma (NHL) undergoing reduced-toxicity conditioning (RTC) with once daily intravenous Busulfex and fludarabine. [1 year]

Secondary Outcome Measures

To record 1 and 2 year overall survival (OS) following transplantation. [At 1 year and 2 years]
To record 2 year PFS. [12/31/13]
To assess nonrelapse mortality (NRM) following RTC transplantation at day +100 and 1-year. [12/31/13]
To assess relapse rate following transplantation at day +100 and 1-year. [12/31/13]
To assess disease response rate (RR) following transplantation at day +100 and at 1-year. [12/31/13]
To correlate OS, PFS, RR, NRM following HPCT with systemic busulfan exposure. [12/31/13]
To assess rates of acute and chronic graft versus host disease (GVHD). [12/31/13]
Time to successful neutrophil engraftment. [12/31/13]
Time to successful platelet engraftment. [12/31/13]
To assess rates of primary and secondary graft failure. [12/31/13]
To assess rates of pulmonary toxicity and venous occlusive disease (VOD) post transplantation, and assess correlation with Busulfex exposure levels. [12/31/13]
To correlate chimerism kinetics following transplantation with Busulfex exposure levels. [12/31/13]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients aged 18-70 years of age are eligible.
Eligible histologies include:

B-cell, T-cell or NK-cell NHL refractory to frontline or salvage therapy defined as failure to achieve complete or partial remission according to standard criteria.
Diffuse large B-cell lymphoma relapsing within 12 months of finishing a rituximab containing first line chemotherapy regimen (regardless of response to salvage chemotherapy)or with evidence of c-myc. Primary refractory NHL (regardless of response to salvage chemotherapy).
Hodgkin lymphoma which is chemorefractory after at least two prior therapies.
Hodgkin and NHL in an untreated relapse.
Transformed NHL or chronic lymphocytic leukemia undergoing Richter's transformation (regardless of response to last chemotherapy). Patients with chemosensitive relapsed NHLs or Hodgkin lymphoma, but considered ineligible for curative therapy with autologous transplantation, because of (a) inability to collect stem cells, (b) prior autografting, (c) presence of myelodysplasia or (d) histology not considered curable with autografting in opinion of treating physician will be eligible.

All patients must have at least one suitable HLA-matched sibling or volunteer unrelated donor available (according to institutional guidelines). HLA typing should be performed at least at serological level for HLA-A, -B, and -C and at allele level for HLA-DRB1. One antigen or allele level mismatch will be permitted between the donor and the recipient; however each donor/recipient pair must match at HLA-DRB1 at allele level.
Patient must be able to provide informed consent.
Left ventricular ejection fraction ≥ 40%. No uncontrolled arrhythmias or uncontrolled New York Heart Association class III-IV heart failure.
Bilirubin, aspartate aminotransferase (AST), and Alanine transaminase (ALT) ≤ 3 x normal; and absence of hepatic cirrhosis.
Adequate renal function as defined by a serum creatinine clearance of ≥ 40% of normal calculated by Cockcroft-Gault equation.
DLCO (diffusion capacity; corrected for hemoglobin) or forced expiratory volume (FEV1) ≥ 50% of predicted.
Karnofsky performance status ≥ 70.
A negative pregnancy test will be required for all women of child bearing potential. Breast feeding is not permitted.

Exclusion Criteria:

Patients eligible for potentially curative therapy with autologous transplantation.
Patients with lymphoblastic lymphoma.
Patients with positive human immunodeficiency virus (HIV) serology.
Clinical evidence of uncontrolled bacterial, viral or fungal infection at the time of transplant conditioning.
Prior allogeneic transplantation.