VELCADE®-BEAM and Autologous Hematopoietic Stem Cell Transplantation for Non-Hodgkin's Lymphoma, or Mantle Cell Lymphoma

Phase 1

Completed

Interventions: Drug: Bortezomib
Drug: BEAM (carmustine (BCNU), etoposide, cytarabine, melphalan)

Brief Summary: This is a Phase I/II trial designed to study the toxicity and Maximum Tolerated Dose (MTD) of bortezomib in combination with BEAM (carmustine (BCNU), etoposide, cytarabine, melphalan) and autologous hematopoietic stem cell transplantation (ASCT) and to obtain a preliminary estimate of the response rate to this combination.

Detailed Description: Primary Objective:The primary objective of the study is to evaluate the toxicity and determine the maximum tolerated dose (MTD) of bortezomib when added to a standard BEAM (carmustine (BCNU), etoposide, cytarabine, melphalan) conditioning regimen followed by autologous hematopoietic stem cell transplantation (ASCT).

Secondary Objective: The secondary objective of the study is to obtain a preliminary estimate of the overall response rate (ORR), progression free survival (PFS), and overall survival (OS) with this regimen.

Enrolled subjects will receive bortezomib in combination with BEAM (carmustine (BCNU), etoposide, cytarabine, melphalan) and autologous hematopoietic stem cell transplantation (AHSCT). Phase I treatment will administer bortezomib in four dose cohorts,in addition to the BEAM and ASCT. Three patients will be accrued in each dose cohort with enrollment starting at dose cohort. These subjects will be evaluated to establish the maximum tolerated dose of bortezomib in combination with BEAM autologous peripheral blood stem cell transplantation. Once established, the maximum tolerated dose will be utilized in treating an additional 20 subjects.

Follow-Up: Data collected will be utilized to obtain a preliminary estimate of the overall response rate, progressions free survival and overall survival using this regimen.

Recruitment & Eligibility

Inclusion Criteria

Persistent, relapsed or refractory indolent non-Hodgkin's lymphoma (Follicular grade I, II, or III), non-Hodgkin's lymphoma, composite lymphomas with ≥ 50% of tumor showing follicular histology, transformed follicular, lymphoplasmacytic, marginal zone lymphoma, small Lymphocytic Lymphoma (including T-cell subtypes), or mantle cell lymphoma that is relapsed, refractory, or in PR1 or CR1 (MCL only for CR1).
Age >19 years.
Signed written informed consent.
Expected survival duration of > six months.
Karnofsky Performance Status > 70.
Eligible patients must have: Liver functions < 3x upper limits of normal (ULN) unless due to disease; ANC > 500 cells/mm3 and Platelet Count > 50 mm3.
Patients > age 60 or with clinical signs of heart disease must have ejection fraction ≥ 45% LVEF.
Patients with clinical signs of pulmonary insufficiency must have DLCO to be measured at > 50% of predicted value.
Able to collect > 1.2 X 106/kg CD34+ cell for transplantation.
No serious disease or condition that, in the opinion of the investigator, would compromise the patient's ability to participate in the study.
Female patients must not be pregnant or lactating.
Male and female patients of reproductive potential must follow accepted birth control measures.

Exclusion Criteria

Patients who are HIV seropositive
Serum creatinine >2.5mg/dL or calculated creatinine clearance ≤ 50ml/min
Total bilirubin >3 times upper limits of normal (unless due to Gilberts disease or malignancy), ALT and AST >4 times the upper limits of normal
Active infection at the time of transplant
Myocardial infarction within 6 months prior to enrollment or has New York Hospital Association (NYHA) Class III or IV heart failure uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
Patient has hypersensitivity to bortezomib, boron or mannitol.
Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.

Arm && Interventions

Group	Intervention	Description
Bortezomib Dose Escalation	BEAM (carmustine (BCNU), etoposide, cytarabine, melphalan)	The phase I section of the study will follow a standard 3 + 3 design to determine the maximum tolerated dose (MTD) of bortezomib when added to a standard BEAM (BCNU (carmustine), etoposide, cytarabine, melphalan) conditioning regimen followed by autologous hematopoietic stem cell transplantation (ASCT). After the MTD is defined, additional patients will enroll in Phase II to obtain preliminary estimates of survival using the Phase I regimen.
Bortezomib Dose Escalation	Bortezomib	The phase I section of the study will follow a standard 3 + 3 design to determine the maximum tolerated dose (MTD) of bortezomib when added to a standard BEAM (BCNU (carmustine), etoposide, cytarabine, melphalan) conditioning regimen followed by autologous hematopoietic stem cell transplantation (ASCT). After the MTD is defined, additional patients will enroll in Phase II to obtain preliminary estimates of survival using the Phase I regimen.

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) of Bortezomib	14 months	The maximum tolerated dose (MTD) is defined to be the dose cohort below which 3 of 6 patients experience dose limiting toxicity (DLT), or the highest dose cohort of 1.5 mg/m², if 2 DLT were not observed at any dose cohort.

Secondary Outcome Measures

Name	Time	Method
Preliminary Estimate of Overall Response Rate (ORR)	100 day post autologous hematopoietic stem cell transplantation (ASCT), one year post ASCT	To obtain a preliminary estimate of overall response rate (ORR). The overall response rate is calculated as the number of patients who achieved complete response (CR) and partial response (PR) divided by the total number of evaluable patients.
Progression-free Survival (PFS), and Overall Survival (OS)	one year post autologous hematopoietic stem cell transplantation (ASCT) , 5 years post ASCT	To obtain a preliminary estimate of PFS and OS. Overall survival (OS) is defined as time from the first chemotherapy administered on the transplant trial until death from any cause. Progression free survival (PFS)is defined as time from therapy until relapse, progression, or death from any cause.