Multiple Myeloma, Non-Hodgkin's Lymphoma
Conditions
Brief summary
The primary purpose of this Phase I study is to evaluate the effect of the co-administration of CYP3A4 inducers on the pharmacokinetics profile of VELCADE (bortezomib). Rifampicin will be used to assess the effect of a strong CYP3A4 inducer and dexamethasone to assess the effect of a relatively weak inducer. This study is also to evaluate the impact of CYP3A4 inducers on the pharmacodynamics (PD) of VELCADE and the safety profile of VELCADE.
Interventions
DRUGbortezomib
1.3 mg/m\^3 on days 1, 4, 8, 11 over a 21-day treatment cycle
DRUGbortezomib, rifampicin
bortezomib 1.3 mg/m\^2 on days 1, 4, 8, 11 over a 21-day treatment cycle, rifampicin 600 mg once daily days 4 to 10 in cycle 3
DRUGbortezomib, dexamethasone
bortezomib 1.3 mg/m\^2 on days 1, 4, 8, 11 over a 21-day treatment cycle, dexamethasone 40 mg once daily days 1 to 4, and 9 to 12 in cycle 3
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
* Male or female of at least 18 years of age. * Has documented relapsed or refractory multiple myeloma or NHL following prior anti-neoplastic treatment. * Female patients must be post menopausal for at least 1 year (must not have had a natural menses for at least 12 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; have a negative serum β-HCG or a negative urine pregnancy test at screening. (an alternative to oral contraceptives should be used if the patient is randomized to Arm B with rifampicin). * Male patients must agree to use an acceptable method of contraception (for themselves or female partners as listed above) for the duration of the study. * Must be able to swallow capsules/tablets whole (without chewing, crushing, or opening). * Agree to refrain from the use of any methylxanthine-containing products, including caffeine (e.g., chocolate bars or beverages, coffee, teas, or colas), on Day 11 of Cycles 2 and 3. * Agree to refrain from the use of any products containing nicotine, alcohol, quinine, grapefruit juice, or Seville oranges from 7 days before the first administration of VELCADE through completion of the 72-hour PK blood sample collection (post Day 11 VELCADE dose) in Cycle 3.
Exclusion criteria
* Diagnosis or treatment of a malignancy other than multiple myeloma or NHL within 1 year of randomization, or who have previously been diagnosed with a malignancy other than multiple myeloma or NHL and have any radiographic or biochemical marker evidence of malignancy. * History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurological, psychiatric, or metabolic disturbances. * Known or suspected hypersensitivity or intolerance to rifampicin and/or other antibiotics, corticosteroids, boron or mannitol. * Peripheral neuropathy or neuropathic pain Grade 2 or higher. * Preplanned surgery or procedures that would interfere with the conduct of the study or major surgery within 2 weeks before randomization. * History of disallowed therapies: * Prior treatment with VELCADE. * Any drugs or agents that inhibit (e.g., cimetidine, erythromycin, fluoxetine, ketoconazole, paroxetine) or induce (e.g., carbamazepine, glucocorticoids, phenobarbital, phenytoin, St. John's Wort) CYP2C19 or CYP3A4 within 28 days before the first administration of VELCADE. * Any exposure to rifampicin or corticosteroids within 28 days of screening. * Have received an investigational agent or used an investigational medical device within 28 days before the planned start of treatment. Concurrent participation in non-treatment studies is allowed, if it will not interfere with participation in this study. * Female patient who is pregnant or breastfeeding. * Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Area Under the Plasma Concentration-time Curve (AUC) 0-72 Hours | Cycle 3 day 14 (72 hours post last dose) |
Countries
Israel, Italy, Poland, South Africa, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| VELCADE Control arm, bortezomib 1.3 mg/m\^2 IV bolus on days 1, 4, 8, 11 over a 21-day treatment cycle. | 30 |
| VELCADE + Rifampicin Treatment Arm, bortezomib 1.3 mg/m\^2 IV bolus on days 1, 4, 8, 11 over a 21-day treatment cycle, rifampicin 600 mg oral tablet once daily days 4 to 10 in cycle 3. | 13 |
| VELCADE + Dexamethasone Treatment arm, bortezomib 1.3 mg/m\^2 IV bolus on days 1, 4, 8, 11 over a 21-day treatment cycle, dexamethasone 40 mg oral tablet once daily days 1 to 4, and 9 to 12 in cycle 3. | 18 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 0 | 1 |
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Progressive Disease | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 0 | 0 |
Baseline characteristics
| Characteristic | VELCADE | VELCADE + Rifampicin | VELCADE + Dexamethasone | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 16 Participants | 5 Participants | 10 Participants | 31 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 8 Participants | 8 Participants | 30 Participants |
| Age Continuous | 64.7 years STANDARD_DEVIATION 10.86 | 60.2 years STANDARD_DEVIATION 9.97 | 62.3 years STANDARD_DEVIATION 11.72 | 63.0 years STANDARD_DEVIATION 10.91 |
| Sex: Female, Male Female | 15 Participants | 7 Participants | 9 Participants | 31 Participants |
| Sex: Female, Male Male | 15 Participants | 6 Participants | 9 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 28 / 30 | 13 / 13 | 18 / 18 |
| serious Total, serious adverse events | 14 / 30 | 5 / 13 | 7 / 18 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve (AUC) 0-72 Hours
Time frame: Cycle 3 day 14 (72 hours post last dose)
Population: Pharmacokinetic (PK) evaluable population, include all subjects completed 3 cycles of treatment and all PK assessments during the first 3 cycles of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VELCADE + Rifampicin | Area Under the Plasma Concentration-time Curve (AUC) 0-72 Hours | 123 ng*h/mL | Standard Deviation 34.2 |
| VELCADE + Dexamethasone | Area Under the Plasma Concentration-time Curve (AUC) 0-72 Hours | 170 ng*h/mL | Standard Deviation 64.5 |
| VELCADE | Area Under the Plasma Concentration-time Curve (AUC) 0-72 Hours | 215 ng*h/mL | Standard Deviation 58.4 |