The purpose of this study is to characterize the clinical pharmacokinetic and pharmacodynamic profiles of the 2 doses of VELCADE (bortezomib) for Injection. Patients who volunteer to participate in the pharmacogenetic portion of the study, an additional blood sample will be collected before the Cycle 1 Day 1 dose of bortezomib to assess the genotype of drug metabolizing enzymes.

Condition	Treatment or Intervention	Phase
Multiple Myeloma	Drug: Bortezomib	Phase I

Further Study Details: 

Expected Total Enrollment:  40

This is a prospective, multicenter, open-label, randomized, single- and multiple-dose, clinical pharmacokinetic and pharmacodynamic study in which approximately 40 adult patients with relapsed multiple myeloma will be enrolled (to obtain 12 evaluable patients at each of 2 doses). Eligible patients will be randomized to 1 of 2 bortezomib doses: 1.0 mg/m2 (Treatment arm A) or 1.3 mg/m2 (Treatment arm B). Bortezomib dosing will occur on Days 1, 4, 8, and 11 followed by a 10-day rest period (21 day cycle). Pharmacokinetic and pharmacodynamic assessments will be completed during the first 3 cycles. Blood samples will be obtained at 0 (predose), 5, 15, and 30 minutes, and then 1, 2, 4, 6, 8, 12, 24, and 48 hours following the Day 1 and Day 11 doses of Cycles 1 and 3 to characterize the single- and multiple-dose plasma pharmacokinetics of bortezomib and to determine the extent and time course of 20S proteasome inhibition. A blood sample also will be obtained just before the dose on Days 4 and 8 (trough concentrations) during Cycles 1 and 3; on Days 15, 17, and 19 during the rest period of Cycles 1 and 3; and at predose on Day 1 of Cycles 2 and 4. Upon completion of the PK/PD assessment portion of the study (Cycles 1 through 3), the patient may continue treatment with bortezomib at the discretion of the investigator during Cycles 4 through 8. The duration of treatment in this study is a maximum of 8 cycles. Patients randomized to Treatment arm A (1.0 mg/m2) but not responding to therapy after 3 cycles can have the dose of bortezomib increased to 1.3 mg/m2 if no prohibitive toxicity occurred at the lower dose. The focus of this study is to characterize the clinical pharmacokinetic and pharmacodynamic profiles of the 2 doses of bortezomib. Only limited efficacy data (investigator’s assessment of response and quantitation of serum and urine M-protein, including immunofixation) will be collected. For patients who volunteer to participate in the pharmacogenetic portion of the study, an additional blood sample will be collected before the Cycle 1 Day 1 dose of bortezomib to assess the genotype of drug metabolizing enzymes. Patients will remain at the study site for 4 days (Days 1, 2, 11, and 12) of Cycles 1 and 3 for the intensive sampling, and will return as outpatients for the other days of dosing and sampling.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• Must be male and female patients 18 years old or older.
• Must have relapsed multiple myeloma (diagnosed using standard criteria) following at least one line of prior chemotherapy and who require additional treatment.
• Must have life expectancy equal or greater then 3 months.
• Resolution of toxicities considered related to prior antineoplastic therapy.
• Must have KPS equal or greater than 70%.
• The following laboratory values at Screening must be: Aspartate transaminase (AST) equal or less than x upper limit of normal range (ULN); Alanine transaminase (ALT) equal or less than 2 x ULN; Total bilirubin equal or less than 1.5 x ULN; Hemoglobin equal or greater than 10 g/dL; (transfusion allowed to meet this criterion); Platelets equal or greater than 50 x 109/L; Absolute neutrophil count (ANC) equal or greater than 1000/uL; Calculated creatinine clearance equal or greater than 50 mL/min; Normal serum calcium (serum calcium, corrected for serum albumin, equal or less than ULN; 8.6-10.3 mg/dL or 2.15-2.58 mmol/L).
• Female patient must be either postmenopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.
• Male patient must agree to use an acceptable method for contraception for the duration of the study.
• Must have voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
• Patients must be willing to remain in the hospital for PK/PD assessments.

Exclusion Criteria:

• Patient must not have a history of allergic reaction attributable to compounds containing boron or mannitol.
• Patient can not have an active systemic infection requiring treatment.
• Female patient can not be pregnant or breast-feeding. Confirmation that the patient is not pregnant must be established by a negative serum b-human chorionic gonadotropin (b-hCG) pregnancy test result obtained during Screening. Pregnancy testing is not required for postmenopausal or surgically sterilized women.
• Significant cardiac disease, including a myocardial infarction within the previous 6 months.
• Neuropathy is equal or greater then Grade 2. Transfusion-dependence (red blood cells and/or platelets). Patients who receive one transfusion before Cycle 1 Day 1 but are not transfusion-dependent may be enrolled. Transfusion-dependent is the term applied to patients who, on average, have received 4 to 6 transfusions of red cells and/or platelets within 6 months of the first dose of the planned study (i.e., equal or greater then 1 transfusion/month).
• Receipt of extensive radiation therapy, systemic chemotherapy, or other antineoplastic therapy within 4 weeks of enrollment.
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
• Must not have active hepatitis, HIV disease, secondary malignancy, POEMS syndrome, or plasma cell leukemia.
• Can not have concurrent treatment with another investigational agent within 4 weeks of enrollment. Concurrent participation in non-treatment studies is allowed, if such participation will not interfere with participation in this study.

Elizabeth Trehu, M.D.      1-866-VELCADE    elizabeth.trehu@mpi.com

Florida
      H. Lee Moffitt Cancer Center, Tampa,  Florida,  33612,  United States; Recruiting
Pennsylvania
      University of Pittsburgh Medical Center, Pittsburgh,  Pennsylvania,  15232,  United States; Recruiting
Tennessee
      The Sarah Cannon Cancer Center, Nashville,  Tennessee,  37203,  United States; Recruiting
Canada, Ontario
      Princess Margaret Hospital/Toronto Research Inst., Toronto,  Ontario,  M5G2M9,  Canada; Recruiting
Canada, Quebec
      Royal Victoria Hospital, Montreal,  Quebec,  H2W 1S6,  Canada; Recruiting

Study ID Numbers:  M34103-058
Record last reviewed:  July 2004
Last Updated:  October 13, 2004
Record first received:  March 30, 2004
ClinicalTrials.gov Identifier:  NCT00080405
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-04-08