A Clinical Pharmacology and Exploratory Study of Bortezomib in Combination With Melphalan and Prednisolone in Previously Untreated Multiple Myeloma Patients

• Phase 1: to make a preliminary evaluation of efficacy (anti-tumor effect) [ Time Frame: After 9 cycles ] [ Designated as safety issue: No ]
• Phase 1: to assess the pharmacokinetics of bortezomib with or without a combination of melphalan and prednisolone [ Time Frame: Day 25 of cycle 1, Day 4 of cycle 2 ] [ Designated as safety issue: No ]
• Phase 2: time to response and duration of response [ Time Frame: After 9 cycles ] [ Designated as safety issue: No ]

This is an open-label (both physician and patient know the treatment will be administered), non-randomized, multi-center study. Bortezomib will be administered in combination with melphalan and prednisolone to multiple myeloma patients up to 9 cycles. The objectives of the Phase 1 portion of this study are to assess the safety and to select the recommended dose of bortezomib in combination with melphalan and prednisolone and to assess the pharmacokinetic parameters (absorption, distribution, elimination, etc.). The objective of the Phase 2 portion is to assess the efficacy and safety of the recommended dose of bortezomib selected in the phase 1 portion.

This is a phase 1/2, open-label (both physician and patient know the treatment will be administered), non-randomized, multi-center study in untreated multiple myeloma. This study consists of two portions, phase 1 portion and phase 2 portion. The objectives of this study is to assess the safety, to establish the recommended dose, to evaluate pharmacokinetic parameters (absorption, distribution, elimination,etc.) of bortezomib in the phase 1 portion, and to assess the efficacy and safety of the recommended dose of bortezomib in the phase 2 portion. Primary outcome measure is response rate (percentage of patients achieved a complete response or a partial response after the treatment) of the combination of bortezomib, melphalan and prednisolone in patients with untreated multiple myeloma. Administration method for bortezomib and combination drugs are as follows: Bortezomib will be administered intravenously on day 1, 4, 8, 11, 22, 25, 29 and 32 followed by a 10-day rest period of 6 weeks. With 6 weeks regarded as one cycle, treatment can be repeated for up to 4 cycles. At the 5th or later cycles, bortezomib will be administered intravenously on day 1, 8, 22, and 29 followed by a 13-day rest period of 6 weeks. With 6 weeks regarded as one cycle, treatment can be repeated for up to 9 cycles. Melphalan and prednisolone will be administered orally on day 1, 2, 3 and 4 followed by a 38-day rest period of 6 weeks. With the 6 weeks regarded as one cycle, treatment can be repeated for up to 9 cycles. Safety evaluation in this study includes adverse event reporting (all through the trial), vital signs examination and laboratory tests (Cycle 1 to 4: day 1, 4, 8, 11, 22, 25, 29, 32 and 42 of 6-week cycle, Cycle 5 to 9: day 1, 4, 8, 22, 29 and 42 of 6-week cycle). Dosage of bortezomib are 0.7, 1.0 and 1.3 mg/m2 in the phase I portion and either of the dose will be selected as recommended dose in the phase 2 portion. Bortezomib will be administered intravenously with 6-week cycle for up to 9 cycles. Melphalan 9mg/m2 and prednisolone 60mg/m2 will be administered orally with 6-week cycle for up to 9 cycles.

• Drug: Bortezomib
  0.7-1.3 mg/m2 on day 1, 4, 8, 11, 22, 25, 29, 32 of 6-week cycle up to 4 cycles
• Drug: Melphalan
  9 mg/m2 on day 1, 2, 3, 4 of 6-week cycle, up to 9 cycles
• Drug: Prednisolone
  60 mg/m2 on day 1, 2, 3, 4 of 6-week cycle, up to 9 cycles
• Drug: Bortezomib
  0.7-1.3 mg/m2 on day 1, 8, 22, 29 of 6-week cycle for 5-9 cycles

Inclusion Criteria:

• Patients diagnosed with symptomatic or nonsecretory multiple myeloma
• Patients who have not received chemotherapy and are not hematopoietic stem cell transplantation candidates
• Patients with a measurable lesion
• Life expectancy >= 3 months

Exclusion Criteria:

• Previously received treatment for Multiple Myeloma
• >=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 subject who is pregnant or breast-feeding
• Patient is enrolled in another clinical research study and/or is receiving an investigational agent