Non-hodgkin's Lymphoma, Mantle Cell Lymphoma
Conditions
Keywords
non-hodgkin's lymphoma, mantle cell lymphoma, BEAM, Velcade
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.
Interventions
DRUGBortezomib
Patients will receive bortezomib in four dose cohorts ( .8. 1.0, 1.3, 1.5 mg/m²). Patients will receive bortezomib on days -11, -8, -5, and -2 before infusion of autologous stem cells.
All study patients will receive BEAM per the standard institution protocol: BCNU (carmustine): 300 mg/m²on day -5 etoposide 100 mg/m² twice daily on days -5, -4, -3, and -2 cytarabine 100 mg/m² twice daily on days -5, -4, -3, -2 melphalan: 140 mg/m² on day -1 before infusion of autologous stem cells.
Sponsors
Millennium Pharmaceuticals, Inc.
University of Nebraska
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Subjects were screened and enrolled at an academic medical center in the United States.
Participants by arm
| Arm | Count |
|---|---|
| Phase I/II In Phase 1 of the study, bortezomib was administered in 4 dose cohorts: 0.8 mg/m², 1.0 mg/m², 1.3 mg/m² and 1.5 mg/m². Bortezomib was given on days -11, -8, -5, and -2. All study patients received BEAM conditioning: carmustine (BCNU) 300 mg/m² on day -5, etoposide 100 mg/m² twice daily on days -5, -4, -3, and -2, cytarabine 100 mg/m² twice daily on days -5, -4, -3, and -2, and melphalan 140 mg/m² on day -1 before infusion of autologous stem cells. The objective of phase 1 was to determine the maximum tolerated dose (MTD) of bortezomib in this setting. The MTD was defined by observing any nonhematologic transplantation-related toxicity higher than grade 2 on the Bearman scale occurring between day -11 and engraftment. After the MTD was defined, patients were enrolled in Phase II to obtain a preliminary estimate of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) using this regimen. | 42 |
| Total | 42 |
Baseline characteristics
| Characteristic | Phase I/II |
|---|---|
| Age, Continuous | 58 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 13 | 29 / 29 |
| serious Total, serious adverse events | 0 / 13 | 1 / 29 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Bortezomib
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.
Time frame: 14 months
Population: The MTD in Phase I was initially determined to be 1.5 mg/m2 but was later decreased to 1 mg/m2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I | Maximum Tolerated Dose (MTD) of Bortezomib | 1.5 mg/m² |
| Phase II | Maximum Tolerated Dose (MTD) of Bortezomib | 1.0 mg/m² |
Secondary
Preliminary Estimate of Overall Response Rate (ORR)
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.
Time frame: 100 day post autologous hematopoietic stem cell transplantation (ASCT), one year post ASCT
Population: One hundred days after autologous hematopoietic stem cell transplantation (ASCT), 40 participants were evaluable for response.~At year one post ASCT, 38 participants were evaluable for response. Participants evaluable for the secondary endpoints (Phase II) are those who complete the transplant procedure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I | Preliminary Estimate of Overall Response Rate (ORR) | Overall Response Rate (100 days after transplant) | 38 participants |
| Phase I | Preliminary Estimate of Overall Response Rate (ORR) | Overall Response Rate (1 year after transplant) | 33 participants |
Secondary
Progression-free Survival (PFS), and Overall Survival (OS)
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.
Time frame: one year post autologous hematopoietic stem cell transplantation (ASCT) , 5 years post ASCT
Population: There were 38 evaluable patients at one year post autologous hematopoietic stem cell transplantation (ASCT).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I | Progression-free Survival (PFS), and Overall Survival (OS) | Progression Free Survival 1 year after transplant | 83 percentage of participants |
| Phase I | Progression-free Survival (PFS), and Overall Survival (OS) | Overall Survival 1 year after transplant | 91 percentage of participants |
| Phase I | Progression-free Survival (PFS), and Overall Survival (OS) | Progression Free Survival 5 years after transplant | 32 percentage of participants |
| Phase I | Progression-free Survival (PFS), and Overall Survival (OS) | Overall Survival 5 years after transplant | 67 percentage of participants |