Amyloidosis
Conditions
Brief summary
This is a phase 1/2 open-label, dose-escalation study investigating single-agent therapy with VELCADE in patients with previously treated systemic AL-amyloidosis who require further treatment.
Interventions
DRUGVELCADE
Once weekly at: 0.7, 1.0, 1.3 or 1.6 mg/m2 Or Twice-weekly at: 0.7, 1.0, or 1.3 mg/m2
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or Female 18 y/o and older 2. Female patients must be practicing an effective method of birth control 3. Biopsy-proven AL-amyloidosis 4. Must have been previously treated (failed at least 1 previous treatment) and in the opinion of the physician, patient requires further treatment
Exclusion criteria
1. Hypersensitivity to boron or mannitol 2. Prior treatment with VELCADE 3. Patient requires other concomitant chemotherapy, radiotherapy or ancillary therapy considered investigational 4. Uncontrolled infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose | 5 weeks in once weekly (QW) dose cohorts and 3 weeks in twice weekly (BIW) dose cohorts | Maximum Tolerated Dose (MTD) was defined as the highest dose level that has 0/1 out of 6 patients experiences Dose Limited Toxicity (DLT). MTD is defined separately for QW and BIQ dose cohorts. DLT was defined as adverse events occurring during Cycle 1 and: (1) related to VELCADE, (2) Grade 4 thrombocytopenia or neutropenia, (3) Grade 3 or higher nonhematologic toxicity. |
| Subjects With Treatment Emergent Adverse Events | from first study-related procedure to 30 days after last dose of study medication | Treatment emergent adverse events observed during outcome measure time frame |
| Subjects With Serious Treatment Emergent Adverse Events | from first study-related procedure to 30 days after last dose of study medication | Serious treatment emergent adverse events observed during outcome measure time frame |
| Subjects Grade 3/4/5 Treatment Emergent Adverse Events | from first study-related procedure to 30 days after last dose of study medication | Grade 3/4/5 treatment emergent adverse events observed during outcome measure time frame. Grade is determined according to Common Terminology Criteria for Adverse Event (CTCAE) Version 3.0. |
| Subjects With Treatment Emergent Adverse Events Leading to Treatment Termination | from first study-related procedure to 30 days after last dose of study medication | Treatment emergent adverse events observed during outcome measure time frame leading to treatment termination |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Confirmed Hematologic Responders | from first dose of study medication to end of study visit | Hematologic response was determined by the investigator per the response criteria for immunoglobulin light chain amyloidosis by Gertz (2005). It include Complete and Partial Responders (CR+PR). CR requires serum and urine negative for a monoclonal protein by immunofixation and free light chain ratio normal. PR requires: 1. reduction in quantitative serum M-protein by 50% if baseline value is at least 0.5 g/dL, 2. if light chain is detected in the urine (with a consistent peak and \>100 mg/ 24 hours), then 50% reduction is required, 3. if free light chain \>10 mg/dL, reduction by 50% is required. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Single Agent VELCADE Bortezomib 0.7, 1.0, 1.3 and 1.6 mg/m\^2 once weekly (QW) 4 doses in a 5 week cycle, and 0.7, 1.0, 1.3 mg/m\^2 twice weekly (BIW) 4 doses in a 3 week cycle | 70 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 18 |
| Overall Study | Death | 2 |
| Overall Study | Deterioration in KPS and organ function | 1 |
| Overall Study | Other | 4 |
| Overall Study | Progression of amyloid markers | 4 |
| Overall Study | Subjects overall condition deterioration | 4 |
| Overall Study | Treatment ongoing | 4 |
| Overall Study | Withdrawal by Subject | 9 |
Baseline characteristics
| Characteristic | Single Agent VELCADE |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 27 Participants |
| Age, Categorical Between 18 and 65 years | 43 Participants |
| Age Continuous | 61 years STANDARD_DEVIATION 10.1 |
| Region of Enrollment Canada | 8 participants |
| Region of Enrollment France | 3 participants |
| Region of Enrollment Germany | 11 participants |
| Region of Enrollment Italy | 9 participants |
| Region of Enrollment Spain | 4 participants |
| Region of Enrollment United States | 35 participants |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 70 / 70 |
| serious Total, serious adverse events | 25 / 70 |
Outcome results
Primary
Maximum Tolerated Dose
Maximum Tolerated Dose (MTD) was defined as the highest dose level that has 0/1 out of 6 patients experiences Dose Limited Toxicity (DLT). MTD is defined separately for QW and BIQ dose cohorts. DLT was defined as adverse events occurring during Cycle 1 and: (1) related to VELCADE, (2) Grade 4 thrombocytopenia or neutropenia, (3) Grade 3 or higher nonhematologic toxicity.
Time frame: 5 weeks in once weekly (QW) dose cohorts and 3 weeks in twice weekly (BIW) dose cohorts
Population: Phase 1 Safety Population includes all subjects who received at least one dose of VELCADE in phase 1 dose escalation cohorts
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Agent VELCADE | Maximum Tolerated Dose | 2 participants with DLT |
Primary
Subjects Grade 3/4/5 Treatment Emergent Adverse Events
Grade 3/4/5 treatment emergent adverse events observed during outcome measure time frame. Grade is determined according to Common Terminology Criteria for Adverse Event (CTCAE) Version 3.0.
Time frame: from first study-related procedure to 30 days after last dose of study medication
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Agent VELCADE | Subjects Grade 3/4/5 Treatment Emergent Adverse Events | 43 participants |
Primary
Subjects With Serious Treatment Emergent Adverse Events
Serious treatment emergent adverse events observed during outcome measure time frame
Time frame: from first study-related procedure to 30 days after last dose of study medication
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Agent VELCADE | Subjects With Serious Treatment Emergent Adverse Events | 25 participants |
Primary
Subjects With Treatment Emergent Adverse Events
Treatment emergent adverse events observed during outcome measure time frame
Time frame: from first study-related procedure to 30 days after last dose of study medication
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Agent VELCADE | Subjects With Treatment Emergent Adverse Events | 70 participants |
Primary
Subjects With Treatment Emergent Adverse Events Leading to Treatment Termination
Treatment emergent adverse events observed during outcome measure time frame leading to treatment termination
Time frame: from first study-related procedure to 30 days after last dose of study medication
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Agent VELCADE | Subjects With Treatment Emergent Adverse Events Leading to Treatment Termination | 23 participants |
Secondary
Best Confirmed Hematologic Responders
Hematologic response was determined by the investigator per the response criteria for immunoglobulin light chain amyloidosis by Gertz (2005). It include Complete and Partial Responders (CR+PR). CR requires serum and urine negative for a monoclonal protein by immunofixation and free light chain ratio normal. PR requires: 1. reduction in quantitative serum M-protein by 50% if baseline value is at least 0.5 g/dL, 2. if light chain is detected in the urine (with a consistent peak and \>100 mg/ 24 hours), then 50% reduction is required, 3. if free light chain \>10 mg/dL, reduction by 50% is required.
Time frame: from first dose of study medication to end of study visit
Population: Efficacy population included all treated subjects with an evaluable post baseline resposne assessment in the MTD cohorts (1.6 mg/m\^2 QW and 1.3 mg/m\^2 BIW).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Agent VELCADE | Best Confirmed Hematologic Responders | 33 participants responded |