Non-Hodgkin's Lymphoma
Conditions
Keywords
B-cell Non-Hodgkin's Lymphoma
Brief summary
The purpose of this study is to determine if the combination of VELCADE and rituximab improves progression free survival relative to rituximab alone in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (B-NHL) who never received rituximab or who have previously responded to rituximab. This is an international study being conducted in the United States and in many countries around the world. A complete list of study locations is listed below.
Interventions
VELCADE for Injection will be administered weekly on Days 1,8,15, and 22 of a 35-day cycle in combination with 4 doses of rituximab once a week on Days 1,8,15, and 22 of Cycle 1 and in combination with a single dose of rituximab on Day 1 of Cycles 2 to 5.
DRUGRituximab
rituximab once a week on Days 1,8,15, and 22 of Cycle 1, and as a single dose on Day 1 of Cycles 2 to 5 (for a total of 8 doses).
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Millennium Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects must satisfy the following criteria to be enrolled in the study: * Man or woman and age 18 years or older * Diagnosis of follicular B-NHL of the following subtypes (World Health Organization \[WHO\] classification 1997): follicular lymphoma (FL) (Grades 1 and 2). * Documented relapse or progression following prior antineoplastic treatment. New lesions or objective evidence of progression of existing lesions must document relapse or progression following the previous therapy. If any prior regimen included rituximab, the subject must have responded (complete response \[CR\], unconfirmed complete response \[CRu\], partial response \[PR\]), and the time to progression (TTP) from the first dose of rituximab must have been 6 months or more. * At least 1 measurable tumor mass (greater than 1.5 cm in the longest dimension and greater than 1.0 cm in the short axis) that has not been previously irradiated, or has grown since previous irradiation * In the opinion of the investigator the decision to initiate treatment is justified to manage the subject's lymphoma * No active central nervous system lymphoma * Eastern Cooperative Oncology Group \[ECOG\] status ≤ 2 * Female subjects must be postmenopausal (for at least 6 months), surgically sterile, abstinent, or, if sexually active, be practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) before entry and throughout the study; and have a negative serum beta-human chorionic gonadotropin (β-hCG) pregnancy test at screening. * Subjects (or their legally acceptable representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study. * In countries where health authorities have approved the pharmacogenomic testing, subjects or their legally acceptable representatives must have signed a separate informed consent that they agree to participate in the genetic part and protein testing part of the study; participation in the genetic and protein testing component is mandatory for pharmacogenomics testing, but optional for serum protein testing and future testing.
Exclusion criteria
Potential subjects who meet any of the following criteria will be excluded from participating in the study: * Diagnosed or treated for a malignancy other than NHL within 1 year of randomization, or who were previously diagnosed with a malignancy other than NHL and have any radiographic or biochemical marker evidence of malignancy. Subjects with completely resected basal cell carcinoma, squamous cell carcinoma of the skin, or in situ malignancy are not excluded. * Clinical evidence of a transformation from indolent NHL to a more aggressive form of NHL. * History of disallowed therapies: * Prior treatment with VELCADE * Antineoplastic (including unconjugated therapeutic antibodies), experimental, or radiation therapy within 3 weeks before randomization * Nitrosoureas within 6 weeks before randomization * Radioimmunoconjugates or toxin immunoconjugates within 10 weeks before randomization * Stem cell transplant within 6 months before randomization * Major surgery within 2 weeks before randomization * Residual toxic effects of previous therapy or surgery of Grade 3 or worse * Peripheral neuropathy or neuropathic pain of Grade 2 or worse * Have received an experimental drug or used an experimental medical device within 21 days before the planned start of treatment. * History of allergic reaction attributable to compounds containing boron or mannitol * Known anaphylaxis or immunoglobulin E (IgE)-mediated hypersensitivity to murine proteins or to any component of rituximab including polysorbate 80 and sodium citrate dihydrate * Concurrent treatment with another investigational agent * Female subject who is pregnant or breast-feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Subjects are followed until progressive disease/death or the end of the study. The median follow up time is 33.9 months. | Progression free survival is defined as time from randomization to progressive disease or death due to any cause, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Subjects are followed until progressive disease/death or the end of the study. The median follow up time is 33.9 months. | Overall response rate is defined as Complete Response (CR) + Complete Response Unconfirmed (CRu) + Partial Response (PR) using International Working Group Criteria (IWGC) and Independent Radiographic Review results and clinical results. The IWGC CR requires complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms, and normalization of lactic dehydrogenase and bone marrow involvement. CRu requires more than 75% reduction in sum of product of nodes (SPD). PR requires moer than 50% reduction in SPD. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, China, Cyprus, Czechia, Finland, France, Germany, Greece, Hungary, India, Israel, Italy, Mexico, New Zealand, Poland, Portugal, Puerto Rico, Romania, Russia, Slovakia, South Africa, South Korea, Spain, Sweden, Thailand, Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bortezomib + Rituximab 1.6 mg/m\^2 VELCADE for Injection administered weekly on Days 1, 8, 15, and 22 of a 35-day cycle in combination with 4 doses of 375 mg/m\^2 rituximab once weekly on Days 1, 8, 15, and 22 of Cycle 1 and a single dose of 375 mg/m\^2 rituximab on Day 1 of Cycles 2 through 5 (for a total of 8 doses of rituximab). | 336 |
| Rituximab 375 mg/m\^2 rituximab once weekly on Days 1, 8, 15, and 22 of Cycle 1, and as a single dose of 375 mg/m\^2 on Day 1 of Cycles 2 through 5 (for a total of 8 doses). | 340 |
| Total | 676 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 19 | 5 |
| Overall Study | Death | 2 | 2 |
| Overall Study | Disease Progression | 56 | 77 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Other | 6 | 5 |
| Overall Study | Withdrawal by Subject | 14 | 6 |
Baseline characteristics
| Characteristic | Bortezomib + Rituximab | Total | Rituximab |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 93 Participants | 191 Participants | 98 Participants |
| Age, Categorical Between 18 and 65 years | 243 Participants | 485 Participants | 242 Participants |
| Age Continuous | 56.8 years STANDARD_DEVIATION 11.12 | 57 years STANDARD_DEVIATION 11.56 | 57.3 years STANDARD_DEVIATION 12 |
| Region of Enrollment Argentina | 2 participants | 7 participants | 5 participants |
| Region of Enrollment Australia | 5 participants | 8 participants | 3 participants |
| Region of Enrollment Belgium | 18 participants | 37 participants | 19 participants |
| Region of Enrollment Brazil | 18 participants | 39 participants | 21 participants |
| Region of Enrollment Canada | 9 participants | 19 participants | 10 participants |
| Region of Enrollment China | 46 participants | 86 participants | 40 participants |
| Region of Enrollment Czech Republic | 18 participants | 35 participants | 17 participants |
| Region of Enrollment Finland | 1 participants | 3 participants | 2 participants |
| Region of Enrollment France | 13 participants | 23 participants | 10 participants |
| Region of Enrollment Germany | 0 participants | 3 participants | 3 participants |
| Region of Enrollment Greece | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Hungary | 3 participants | 9 participants | 6 participants |
| Region of Enrollment India | 17 participants | 41 participants | 24 participants |
| Region of Enrollment Israel | 7 participants | 14 participants | 7 participants |
| Region of Enrollment Italy | 14 participants | 29 participants | 15 participants |
| Region of Enrollment Korea, Republic of | 4 participants | 7 participants | 3 participants |
| Region of Enrollment Mexico | 9 participants | 17 participants | 8 participants |
| Region of Enrollment Poland | 24 participants | 45 participants | 21 participants |
| Region of Enrollment Portugal | 11 participants | 23 participants | 12 participants |
| Region of Enrollment Romania | 6 participants | 8 participants | 2 participants |
| Region of Enrollment Russian Federation | 52 participants | 107 participants | 55 participants |
| Region of Enrollment Slovakia | 7 participants | 15 participants | 8 participants |
| Region of Enrollment South Africa | 2 participants | 4 participants | 2 participants |
| Region of Enrollment Spain | 9 participants | 14 participants | 5 participants |
| Region of Enrollment Sweden | 2 participants | 5 participants | 3 participants |
| Region of Enrollment Thailand | 2 participants | 3 participants | 1 participants |
| Region of Enrollment Ukraine | 13 participants | 24 participants | 11 participants |
| Region of Enrollment United Kingdom | 9 participants | 19 participants | 10 participants |
| Region of Enrollment United States | 14 participants | 30 participants | 16 participants |
| Sex: Female, Male Female | 164 Participants | 367 Participants | 203 Participants |
| Sex: Female, Male Male | 172 Participants | 309 Participants | 137 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 288 / 334 | 232 / 339 |
| serious Total, serious adverse events | 59 / 334 | 37 / 339 |
Outcome results
Primary
Progression Free Survival
Progression free survival is defined as time from randomization to progressive disease or death due to any cause, whichever occurs first.
Time frame: Subjects are followed until progressive disease/death or the end of the study. The median follow up time is 33.9 months.
Population: Intention to treat (ITT) population is defined as all patients randomized to the trial.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bortezomib + Rituximab | Progression Free Survival | 389 days |
| Rituximab | Progression Free Survival | 334 days |
p-value: 0.039Log Rank
Secondary
Overall Response Rate
Overall response rate is defined as Complete Response (CR) + Complete Response Unconfirmed (CRu) + Partial Response (PR) using International Working Group Criteria (IWGC) and Independent Radiographic Review results and clinical results. The IWGC CR requires complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms, and normalization of lactic dehydrogenase and bone marrow involvement. CRu requires more than 75% reduction in sum of product of nodes (SPD). PR requires moer than 50% reduction in SPD.
Time frame: Subjects are followed until progressive disease/death or the end of the study. The median follow up time is 33.9 months.
Population: The response-evaluable population was defined as all subjects in the ITT population who received at least 1 dose of VELCADE or rituximab, had at least 1 measurable tumor mass (\>1.5 cm in the longest dimension and \>1.0 cm in the short axis) at baseline, and had at least 1 post-baseline disease assessment by independent radiology reviewers/IRC.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bortezomib + Rituximab | Overall Response Rate | 199 participants |
| Rituximab | Overall Response Rate | 160 participants |
p-value: <0.001Cochran-Mantel-Haenszel