Ixazomib in Treating Patients With Relapsed Multiple Myeloma That Is Not Refractory to Bortezomib

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PRIMARY OBJECTIVES: I. To determine the confirmed overall response rate (>= partial response [PR]) of MLN9708 (ixazomib citrate), used as a single agent in patients with relapsed multiple myeloma, who are proteasome inhibitor naïve (including bortezomib) naive OR have received less than 6 cycles of ...

PRIMARY OBJECTIVES: I. To determine the confirmed overall response rate (>= partial response [PR]) of MLN9708 (ixazomib citrate), used as a single agent in patients with relapsed multiple myeloma, who are proteasome inhibitor naïve (including bortezomib) naive OR have received less than 6 cycles of therapy with bortezomib and had a better than PR with no progression at the time of discontinuation. (Arm A - Permanently closed to accrual as of Addendum 5) II. To determine the confirmed overall response rate (>= PR) of MLN9708 at a 4 mg dose level in combination with dexamethasone in patients with relapsed multiple myeloma, who are proteasome inhibitor naïve (including bortezomib) naïve OR have received less than 6 cycles of therapy with bortezomib and had a better than PR with no progression at the time of discontinuation. (Arm B) III. To determine the confirmed overall response rate (>= PR) of MLN9708 at a 5.5 mg dose level in combination with dexamethasone in patients with relapsed multiple myeloma, who are proteasome inhibitor naïve (including bortezomib) naïve OR have received less than 6 cycles of therapy with bortezomib and had a better than PR with no progression at the time of discontinuation. (Arm C) IV. To determine the confirmed overall response rate (>= PR) of MLN9708 in combination with cyclophosphamide and dexamethasone in patients with relapsed multiple myeloma, who are proteasome inhibitor naive (including bortezomib) naïve OR have received less than 6 cycles of therapy with bortezomib and had a better than PR with no progression at the time of discontinuation. (Arm D) SECONDARY OBJECTIVES: I. To determine the overall response rate of MLN9708 in combination with dexamethasone, when dexamethasone is added to MLN9708 for lack of response or for progression. (Arm A) II. To determine the event free survival and overall survival among patients with relapsed myeloma following treatment with MLN9708 with dexamethasone added for lack of response or progression. (Arm A) III. To determine the event free survival and overall survival among patients with relapsed myeloma following treatment with MLN9708 at two different doses, in combination with dexamethasone. (Arms B and C) IV. To determine the event free survival and overall survival among patients with relapsed myeloma following treatment with MLN9708 in combination with cyclophosphamide and dexamethasone. (Arms D) OUTLINE: Patients are randomized to 1 of 3 treatment arms (Arm A permanently closed to accrual as of Addendum 5). ARM A: Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15. Patients with lack of minor response by the end of the second course or lack of partial response by the end of the fourth course also receive dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive ixazomib citrate PO on days 1, 8 and 15 and dexamethasone PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive higher dose of ixazomib citrate PO on days 1, 8, and 15 and dexamethasone PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM D: Patients receive ixazomib citrate PO on days 1, 8, and 15, cyclophosphamide PO and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM E: Patient receive isazomib citrate PO on days 1,8 and 15, cyclophosphamide PO on days 1,8,15 and 22. Daratumumab IV Days 1, 8, 15, 22 for cycles 1-2; Days 1, 15 for cycles 3-6; and Day 1 for subsequent cycles. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Dexamethasone IV (PO only if IV unavailable) days 1,8,15 and 22. *Dexamethasone is started Day 1 Cycle 1 **Dexamethasone should be given IV (PO only if IV is unavailable), approximately 1 hour or less prior to daratumumab infusion. On days when subjects receive this dose of dexamethasone in the clinic, dexamethasone will not be self-administered at home. On days when daratumumab is not scheduled, PO may be taken at home. After completion of study treatment, patients are followed up every 6 or 12 months for 2 years.

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