Multiple Myeloma
Conditions
Keywords
Multiple myeloma, Hematopoietic stem cell transplant, HSCT, Melphalan, Prednisolone, Bortezomib, JNJ-26866138
Brief summary
The purpose of the study in Phase I is to select the recommended dose of bortezomib in combination with melphalan and prednisolone in Japanese participants. In Phase II, to assess the effectiveness and safety of the recommended dose of bortezomib (selected in the phase I portion).
Detailed description
This is an open-label (both physician and participant know the intervention), non-randomized (participants are not assigned by chance), multi-center study in untreated multiple myeloma participants who were not candidates for hematopoietic stem cell transplant. This study consists of two parts: Phase I and Phase II. In Phase I, a total of 18 participants will be enrolled ie, 6 patients per dose level (0.7, 1.0 and 1.3 mg/m2) to determine the recommended dose of bortezomib. In Phase II, additional 83 participants will be enrolled. Safety evaluations will include assessment of adverse events, clinical laboratory test, specifically hematological toxicities.
Interventions
DRUGJNJ-26866138 0.7 mg/m2
JNJ-26866138 0.7 mg/m2 will be administered intravenously on Days 1, 4, 8, 11, 22, 25, 29 and 32 of 6-week cycle up to 4 cycles.
DRUGJNJ-26866138 1.0 mg/m2
JNJ-26866138 1.0 mg/m2 will be administered intravenously on Days 1, 4, 8, 11, 22, 25, 29 and 32 of 6-week cycle up to 4 cycles
DRUGJNJ-26866138 1.3 mg/m2
Phase I: JNJ-26866138 1.3 mg/m2 will be administered intravenously on Days 1, 4, 8, 11, 22, 25, 29 and 32 of 6-week cycle up to 4 cycles. Phase II: JNJ-26866138 1.3 mg/m2 on Days 1, 8, 22 and 29 of 6-week cycle for 5 to 9 cycles.
DRUGMelphalan
Melphalan 9 mg/m2 will be taken orally (by mouth) on Days 1, 2, 3 and 4 of 6-week cycle up to 9 cycles
DRUGPrednisolone
Prednisolone 60 mg/m2 will be taken orally (by mouth) on Days 1, 2, 3 and 4 of 6-week cycle up to 9 cycles
Sponsors
Janssen Pharmaceutical K.K.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants diagnosed with symptomatic or nonsecretory multiple myeloma * Participants who have not received chemotherapy and are not hematopoietic stem cell transplantation candidates * Participants with a measurable lesion * Life expectancy greater than or equal to 3 months
Exclusion criteria
* Previously received treatment for Multiple Myeloma * Greater than or equal to Grade 2 peripheral neuropathy or neuropathic pain * Myocardial infarction within 6 months prior to enrollment or uncontrolled angina, severe uncontrolled ventricular arrhythmias, or clinically significant conduction system abnormalities * Patient is known to be seropositive for the human immunodeficiency virus (HIV), Hepatitis B surface antigen-positive or active hepatitis C infection * Active prior malignancy diagnosed within the last 5 years * Female participant who is pregnant or breast-feeding * Participant is enrolled in another clinical research study and/or is receiving an investigational agent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicity During the Phase I (Cycle 1) | 6 weeks | Dose limiting toxicity defined as an adverse event or adverse drug reaction experienced by the participants during 6 weeks of treatment Cycle 1 |
| Number of Participants With Overall Response (Complete Response [CR] + Partial Response [PR]) - Phase I and II | 54 weeks | Response is evaluated as per the criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation (Blade et al. 1998). CR: disappearance of the original monoclonal protein from the blood and urine and \<5% plasma cells in the bone marrow on at least 2 determinations for a minimum of 6 weeks; no increase in the size or number of lytic bone lesions; disappearance of soft tissue plasmacytomas for at least 6 weeks. PR: ≥50% reduction in the level of serum monoclonal protein for at least 2 determinations 6 weeks apart; If present, reduction in 24-hour urinary light chain excretion by either ≥90% or to \<200 mg for at least 2 determinations 6 weeks apart; ≥50% reduction in the size of soft tissue plasmacytomas for at least 6 weeks; no increase in size or number of lytic bone lesions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to First Response - Phase II | up to 54 weeks | Time to first response is the duartion of time required to achieve first response to treatment |
| Maximum Observed Plasma Concentration (Cmax) of Melphalan - Phase I | Day 4 of Cycle 2 | Cmax of melphalan at dose of 9 mg/m2 on Cycle 2/Day 4 |
| Maximum Observed Plasma Concentration (Cmax) of Bortezomib (JNJ-26866138 in Combination With Melphalan and Prednisolone) - Phase I | Day 4 of Cycle 2 | Cmax of bortezomib following intravenous administration of JNJ-26866138 at dose of 0.7, 1.0, and 1.3 mg/m2 on Cycle 2/Day 4 (combination with melphalan and prednisolone) |
| Maximum Observed Plasma Concentration (Cmax) of Bortezomib (JNJ-26866138 Alone) - Phase I | Day 25 of Cycle 1 | Cmax of bortezomib following intravenous administration of JNJ-26866138 at dose of 0.7, 1.0, and 1.3 mg/m2 on Cycle 1/Day 25 (JNJ-26866138 alone) |
| Maximum Observed Plasma Concentration (Cmax) of Prednisolone - Phase I | Day 4 of Cycle 2 | Cmax of Prednisolone at dose of 60 mg/m2 on Cycle 2/Day 4 |
Countries
Japan
Participant flow
Recruitment details
Total 101 participants (Phase I: 18 and Phase II: 83) were enrolled at multiple sites in Japan.
Pre-assignment details
18 participants were enrolled and treated in Phase I. Total 89 participants were enrolled in Phase II (including 6 participants receiving 1.3 mg/m2 in the Phase I part). Of the 89 participants, 87 were received at least 1 dose of study medication. 2 participants were not treated.
Participants by arm
| Arm | Count |
|---|---|
| Phase I - JNJ-26866138 0.7 mg/m2 Group JNJ-26866138 0.7 mg/m2 on Days 1, 4, 8, 11, 22, 25, 29 and 32 of 6-week cycle up to 4 cycles. Melphalan 9 mg/m2 and Prednisolone 60 mg/m2 on Days 1, 2, 3 and 4 of 6-week cycle up to 4 cycles | 6 |
| Phase I - JNJ-26866138 1.0 mg/m2 Group JNJ-26866138 1.0 mg/m2 on Days 1, 4, 8, 11, 22, 25, 29 and 32 of 6-week cycle up to 4 cycles. Melphalan 9 mg/m2 and Prednisolone 60 mg/m2 on Days 1, 2, 3 and 4 of 6-week cycle up to 4 cycles | 6 |
| Phase I and II - JNJ-26866138 1.3 mg/m2 Group Phase I: JNJ-26866138 1.3 mg/m2 on Days 1, 4, 8, 11, 22, 25, 29 and 32 of 6-week cycle up to 4 cycles. Melphalan 9 mg/m2 and Prednisolone 60 mg/m2 on Days 1, 2, 3 and 4 of 6-week cycle up to 4 cycles. Phase II: JNJ-26866138 1.3 mg/m2 on Days 1, 8, 22 and 29 of 6-week cycle for 5-9 cycles. Melphalan 9 mg/m2 and Prednisolone 60 mg/m2 on Days 1, 2, 3 and 4 of 6-week cycle up to 9 cycles | 87 |
| Total | 99 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 19 |
| Overall Study | Complete response observed over 2 cycles | 0 | 1 | 4 |
| Overall Study | Other | 0 | 0 | 11 |
| Overall Study | Pneumonitis or pulmonary fibrosis | 2 | 0 | 2 |
| Overall Study | Progressive disease | 1 | 2 | 8 |
| Overall Study | Unrecovered toxicity | 0 | 0 | 7 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 8 |
Baseline characteristics
| Characteristic | Total | Phase I - JNJ-26866138 0.7 mg/m2 Group | Phase I - JNJ-26866138 1.0 mg/m2 Group | Phase I and II - JNJ-26866138 1.3 mg/m2 Group |
|---|---|---|---|---|
| Age Continuous | 70.9 Years STANDARD_DEVIATION 5.94 | 72.7 Years STANDARD_DEVIATION 9.2 | 68.5 Years STANDARD_DEVIATION 6.47 | 70.9 Years STANDARD_DEVIATION 5.68 |
| Age, Customized >= 65 and <= 74 years | 67 Participants | 2 Participants | 5 Participants | 60 Participants |
| Age, Customized <65 years | 5 Participants | 1 Participants | 1 Participants | 3 Participants |
| Age, Customized >=75 years | 27 Participants | 3 Participants | 0 Participants | 24 Participants |
| Sex: Female, Male Female | 57 Participants | 3 Participants | 3 Participants | 51 Participants |
| Sex: Female, Male Male | 42 Participants | 3 Participants | 3 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 6 / 6 | 87 / 87 |
| serious Total, serious adverse events | 2 / 6 | 2 / 6 | 1 / 6 | 29 / 87 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicity During the Phase I (Cycle 1)
Dose limiting toxicity defined as an adverse event or adverse drug reaction experienced by the participants during 6 weeks of treatment Cycle 1
Time frame: 6 weeks
Population: Dose Limiting Toxicity set, Which includes all 18 participants in the Phase I
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - JNJ-26866138 0.7 mg/m2 Group | Number of Participants With Dose Limiting Toxicity During the Phase I (Cycle 1) | 0 Participants |
| Phase I - JNJ-26866138 1.0 mg/m2 Group | Number of Participants With Dose Limiting Toxicity During the Phase I (Cycle 1) | 0 Participants |
| Phase I - JNJ-26866138 1.3 mg/m2 Group | Number of Participants With Dose Limiting Toxicity During the Phase I (Cycle 1) | 1 Participants |
Primary
Number of Participants With Overall Response (Complete Response [CR] + Partial Response [PR]) - Phase I and II
Response is evaluated as per the criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation (Blade et al. 1998). CR: disappearance of the original monoclonal protein from the blood and urine and \<5% plasma cells in the bone marrow on at least 2 determinations for a minimum of 6 weeks; no increase in the size or number of lytic bone lesions; disappearance of soft tissue plasmacytomas for at least 6 weeks. PR: ≥50% reduction in the level of serum monoclonal protein for at least 2 determinations 6 weeks apart; If present, reduction in 24-hour urinary light chain excretion by either ≥90% or to \<200 mg for at least 2 determinations 6 weeks apart; ≥50% reduction in the size of soft tissue plasmacytomas for at least 6 weeks; no increase in size or number of lytic bone lesions
Time frame: 54 weeks
Population: Full analysis set: All participants who received at least one dose of the study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - JNJ-26866138 0.7 mg/m2 Group | Number of Participants With Overall Response (Complete Response [CR] + Partial Response [PR]) - Phase I and II | 6 Participants |
| Phase I - JNJ-26866138 1.0 mg/m2 Group | Number of Participants With Overall Response (Complete Response [CR] + Partial Response [PR]) - Phase I and II | 5 Participants |
| Phase I - JNJ-26866138 1.3 mg/m2 Group | Number of Participants With Overall Response (Complete Response [CR] + Partial Response [PR]) - Phase I and II | 4 Participants |
| Phase II - JNJ-26866138 1.3 mg/m2 Group | Number of Participants With Overall Response (Complete Response [CR] + Partial Response [PR]) - Phase I and II | 60 Participants |
| Total | Number of Participants With Overall Response (Complete Response [CR] + Partial Response [PR]) - Phase I and II | 71 Participants |
p-value: <0.000195% CI: [58.9, 79.2]Binominal test
Secondary
Maximum Observed Plasma Concentration (Cmax) of Bortezomib (JNJ-26866138 Alone) - Phase I
Cmax of bortezomib following intravenous administration of JNJ-26866138 at dose of 0.7, 1.0, and 1.3 mg/m2 on Cycle 1/Day 25 (JNJ-26866138 alone)
Time frame: Day 25 of Cycle 1
Population: Pharmacokinetics-evaluable population: 16 participants were included in pharmacokinetics-evaluable population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I - JNJ-26866138 0.7 mg/m2 Group | Maximum Observed Plasma Concentration (Cmax) of Bortezomib (JNJ-26866138 Alone) - Phase I | 45.43 ng/mL | Standard Deviation 10.087 |
| Phase I - JNJ-26866138 1.0 mg/m2 Group | Maximum Observed Plasma Concentration (Cmax) of Bortezomib (JNJ-26866138 Alone) - Phase I | 59.42 ng/mL | Standard Deviation 18.89 |
| Phase I - JNJ-26866138 1.3 mg/m2 Group | Maximum Observed Plasma Concentration (Cmax) of Bortezomib (JNJ-26866138 Alone) - Phase I | 120.3 ng/mL | Standard Deviation 24.527 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Bortezomib (JNJ-26866138 in Combination With Melphalan and Prednisolone) - Phase I
Cmax of bortezomib following intravenous administration of JNJ-26866138 at dose of 0.7, 1.0, and 1.3 mg/m2 on Cycle 2/Day 4 (combination with melphalan and prednisolone)
Time frame: Day 4 of Cycle 2
Population: Pharmacokinetics-evaluable population: 14 participants were included in pharmacokinetics-evaluable population during Cycle 2
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I - JNJ-26866138 0.7 mg/m2 Group | Maximum Observed Plasma Concentration (Cmax) of Bortezomib (JNJ-26866138 in Combination With Melphalan and Prednisolone) - Phase I | 34.40 ng/mL | Standard Deviation 5.7986 |
| Phase I - JNJ-26866138 1.0 mg/m2 Group | Maximum Observed Plasma Concentration (Cmax) of Bortezomib (JNJ-26866138 in Combination With Melphalan and Prednisolone) - Phase I | 69.50 ng/mL | Standard Deviation 19.455 |
| Phase I - JNJ-26866138 1.3 mg/m2 Group | Maximum Observed Plasma Concentration (Cmax) of Bortezomib (JNJ-26866138 in Combination With Melphalan and Prednisolone) - Phase I | 88.87 ng/mL | Standard Deviation 19.568 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Melphalan - Phase I
Cmax of melphalan at dose of 9 mg/m2 on Cycle 2/Day 4
Time frame: Day 4 of Cycle 2
Population: Pharmacokinetics-evaluable population: 14 participants were included in pharmacokinetics-evaluable population during Cycle 2
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I - JNJ-26866138 0.7 mg/m2 Group | Maximum Observed Plasma Concentration (Cmax) of Melphalan - Phase I | 100.2 ng/mL | Standard Deviation 49.515 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Prednisolone - Phase I
Cmax of Prednisolone at dose of 60 mg/m2 on Cycle 2/Day 4
Time frame: Day 4 of Cycle 2
Population: Pharmacokinetics-evaluable population: 14 participants were included in pharmacokinetics-evaluable population during Cycle 2
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I - JNJ-26866138 0.7 mg/m2 Group | Maximum Observed Plasma Concentration (Cmax) of Prednisolone - Phase I | 1131 ng/mL | Standard Deviation 223.92 |
Secondary
Median Time to First Response - Phase II
Time to first response is the duartion of time required to achieve first response to treatment
Time frame: up to 54 weeks
Population: Full analysis set: All participants who received at least one dose of the study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - JNJ-26866138 0.7 mg/m2 Group | Median Time to First Response - Phase II | 51 Days |