An Open-Label Study to Assess the Effect of CYP3A4 Induction on the Pharmacokinetics of VELCADE (Bortezomib)

Study Overview
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Brief Summary
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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.

Official Title
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An Open-Label Study to Assess the Effect of CYP3A4 Induction on the Pharmacokinetics of VELCADE (Bortezomib)

Conditions
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Multiple Myeloma, Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: bortezomib
* Drug: bortezomib, rifampicin
* Drug: bortezomib, dexamethasone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VELCADE<br>Control arm, bortezomib 1.3 mg/m^2 on days 1, 4, 8, 11 over a 21-day treatment cycle. | Drug: bortezomib<br>* 1.3 mg/m^3 on days 1, 4, 8, 11 over a 21-day treatment cycle<br>* Other names: VELCADE;|
| Experimental: VELCADE + rifampicin<br>Treatment Arm, 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. | Drug: bortezomib, rifampicin<br>* 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<br>* Other names: rifampicin;|
| Experimental: VELCADE + dexamethasone<br>Treatment arm, 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. | Drug: bortezomib, dexamethasone<br>* 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<br>* Other names: dexamethasone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-time Curve (AUC) 0-72 Hours |  | Cycle 3 day 14 (72 hours post last dose) |