Study of Oral MLN9708 in Combination With Melphalan and Prednisone in Patients With Newly Diagnosed Multiple Myeloma

• Maximum Tolerated Dose and Recommended phase 2 dose of MLN9708 (phase 1) [ Time Frame: Dose Limiting Toxicities determined in Cycle 1 and adverse events monitored throughout the study will inform the recommended phase 2 dose, approximately 2 years ] [ Designated as safety issue: Yes ]
  Based on toxicity and efficacy outcomes
• Number of patients with a complete response and very good partial response (phase 2) [ Time Frame: During the induction period, approximately 1 year ] [ Designated as safety issue: No ]
  Combined response rate

• Maximum Tolerated Dose and Recommended phase 2 dose of MLN9708 (phase 1) [ Time Frame: Dose Limiting Toxcities determined in Cycle 1 and adverse events monitored throughout the study will inform the recommended phase 2 dose, approximately 2 years ] [ Designated as safety issue: Yes ]
  Based on toxicity and efficacy outcomes
• Number of patients with a complete response and very good partial response (phase 2) [ Time Frame: During the induction period, approximately 1 year ] [ Designated as safety issue: No ]
  Combined response rate

• Maximum inhibition (Emax) and time of occurrence of Emax (TEmax) (phase 1) [ Time Frame: At multiple time points during cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study ] [ Designated as safety issue: No ]
  Whole blood 20S proteasome inhibition parameters
• Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and area under the plasma concentration-time curve (AUC) (phase 1) [ Time Frame: At multiple time points during cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study ] [ Designated as safety issue: No ]
  Single and multiple dose plasma pharmacokinetics
• Number of patients with response, including Complete Response, Very Good Partial Response and Partial Response (phase 1 and 2) [ Time Frame: Duration of treatment and then every 12 weeks thereafter until disease progression or initiation of subsequent antineoplastic therapy, expected duration approximately 4 years ] [ Designated as safety issue: No ]
  Overall reponse rate
• Time to response (phase 2) [ Time Frame: From the date of enrollment to the date of the first documented response during the induction period, expected average of up to 1 year ] [ Designated as safety issue: No ]
• Duration of response (phase 2) [ Time Frame: From the date of first response to the date of disease progression, approximately 4 years ] [ Designated as safety issue: No ]
• Time to progression (phase 2) [ Time Frame: From date of enrollment to the date of first documented disease progression, approximately 4 years ] [ Designated as safety issue: No ]
• Time to next therapy (phase 2) [ Time Frame: From the date of enrollment to the date of subsequent antineoplastic therapy, approximately 4 years ] [ Designated as safety issue: No ]
• Number of patients with progression free survival (phase 2) [ Time Frame: From the date of enrollment to the date of first documented disease progression or death, approximately 4 years ] [ Designated as safety issue: No ]
• Number of patients with overall survival (phase 2) [ Time Frame: From date of enrollment to date of death, approximately 4 years ] [ Designated as safety issue: No ]
• Number of all adverse events (phase 2) [ Time Frame: From first dose of study drug through 30 days after last dose of study drug or until the start of subsequent antineoplastic therapy, approximately 2 years and 30 days ] [ Designated as safety issue: Yes ]
• Assessments of Quality of Life (phase 2) [ Time Frame: At screening, Day 1 of each treatment cycle, and Days 1 and 15 of each maintenance cycle, approximately 2 years ] [ Designated as safety issue: No ]

• Maximum inhibition (Emax) and time of occurrence of Emax (TEmax) (phase 1) [ Time Frame: At mulitple time points during cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study ] [ Designated as safety issue: No ]
  Whole blood 20S proteasome inhibition parameters
• Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and area under the plasma concentration-time curve (AUC) (phase 1) [ Time Frame: At mulitple time points during cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 daus depending on the arm of the study ] [ Designated as safety issue: No ]
  Single and multiple dose plasma pharmacokinetics
• Number of patients with response, including Complete Response, Very Good Partial Response and Partial Response (phase 1 and 2) [ Time Frame: Duration of treatment and then every 12 weeks thereafter until disease progression or initiation of subsequent antineoplastic therapy, expected duration approximately 4 years ] [ Designated as safety issue: No ]
  Overall reponse rate
• Time to response (phase 2) [ Time Frame: From the date of enrollment to the date of the first documented response during the induction period, expected average of up tp 1 year ] [ Designated as safety issue: No ]
• Duration of response (phase 2) [ Time Frame: From the date of first response to the date of disease progression, approximately 4 years ] [ Designated as safety issue: No ]
• Time to progression (phase 2) [ Time Frame: From date of enrollment to the date of first documented disease progression, approximately 4 years ] [ Designated as safety issue: No ]
• Time to next therapy (phase 2) [ Time Frame: From the date of enrollment to the date of subsequent antineoplastic therapy, approximately 4 years ] [ Designated as safety issue: No ]
• Number of patients with progression free survival (phase 2) [ Time Frame: From the date of enrollment to the date of first documented disease progression or death, approximately 4 years ] [ Designated as safety issue: No ]
• Number of patients with overall survival (phase 2) [ Time Frame: From date of enrollment to date of death, approximately 4 years ] [ Designated as safety issue: No ]
• Number of all adverse events (phase 2) [ Time Frame: From first dose of study drug through 30 days after last dose of study drug or until the start of subsequent antineoplastic therapy, approximately 2 years and 30 days ] [ Designated as safety issue: Yes ]
• Assessments of Quality of Life (phase 2) [ Time Frame: At screening, Day 1 of each treatment cycle, and Days 1 and 15 of each maintenance cycle, approximately 2 years ] [ Designated as safety issue: No ]

This will be a phase 1/2, multicenter, 2-arm, open-label study using the oral formulation of MLN9708 when added to standard melphalan and prednisone (MP) treatment. Both phases of the study will include patients who have newly diagnosed multiple myeloma and are ineligible for high-dose therapy plus stem cell transplantation because of age (≥65 years of age) or coexisting conditions and for whom standard MP treatment is indicated.

Note: Phase 2 of the trial will be randomized.

• Drug: MLN9708 plus Melphalan and Prednisone

  Ph 1: Patients will receive escalating doses of MLN9708 on Days 1,4,8,11,22,25,29,&32 of a 42-day cycle & fixed doses of melphalan (9mg/m2) & prednisone (60mg/m2) on Days 1-4 of every cycle. Treatment repeats every 42 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or disease responding to treatment with an acceptable toxicity profile will continue treatment in the maintenance therapy portion of the study.

  Ph 2: Patients will receive MLN9708 at the maximum tolerated dose or recommended phase 2 dose on Days 1,4,8,11,22,25,29,&32 of a 42-day cycle & melphalan (9mg/m2) & prednisone (60mg/m2) on Days 1-4 of every cycle. Treatment repeats every 42 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or disease responding to treatment with an acceptable toxicity profile will continue treatment in the maintenance therapy portion of the study.

• Drug: MLN9708 plus Melphalan and Prednisone

  Ph 1: Patients will receive escalating doses of MLN9708 on Days 1, 8, and 15 and fixed doses of melphalan (6mg/m2) and prednisone (60mg/m2) on Days 1-4 of a 28-day cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or disease responding to treatment with an acceptable toxicity profile will continue treatment in the maintenance therapy portion of the study.

  Ph 2: Patients will receive MLN9708 at the maximum tolerated dose or recommended phase 2 dose on Days 1, 8, and 15 and melphalan (6mg/m2) and prednisone (60mg/m2) on Days 1 through 4 of a 28-day cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or disease responding to treatment with an acceptable toxicity profile will continue treatment in the maintenance therapy portion of the study.

• Experimental: Arm A
  MLN9708 Twice Weekly plus Melphalan and Prednisone every 42 days for up to 9 cycles followed by maintenance therapy with MLN9708 once weekly
  Intervention: Drug: MLN9708 plus Melphalan and Prednisone
• Experimental: Arm B
  MLN9708 Once Weekly plus Melphalan and Prednisone every 28 days for up to 12 cycles followed by maintenance therapy with MLN9708 once weekly
  Intervention: Drug: MLN9708 plus Melphalan and Prednisone

Inclusion Criteria:

• Male or female patient for whom standard melphalan prednisone (MP) treatment is indicated and who is not a candidate for high-dose therapy plus stem cell transplantation (HDT-SCT) for 1 of the following reasons: the patient is 65 years of age or older OR the patient is less than 65 years of age but has significant comorbid condition(s) that are likely to have a negative impact on tolerability of HDT-SCT
• Symptomatic multiple myeloma or asymptomatic myeloma with myeloma-related organ damage diagnosed according to standard criteria
• Measurable disease as specified in study protocol
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• Must have adequate hematologic, liver, and renal function
• Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse
• Male patients who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse
• Voluntary written consent

Exclusion Criteria

• Peripheral neuropathy that is greater or equal to Grade 2
• Female patients who are lactating or pregnant
• Major surgery or radiotherapy within 14 days before the first dose of study drug
• Uncontrolled infection requiring systematic antibiotics
• Diarrhea (> Grade 1)
• Prior systemic therapy for multiple myeloma, including investigational drugs (prior treatment with corticosteroids or localized radiation therapy dose not disqualify the patient)
• Central nervous system involvement
• Cardiac status as described in protocol
• Known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption of tolerance of MLN9708
• Diagnosis of smoldering multiple myeloma, Waldenstrom's macroglobulinemia, POEMS syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome
• Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
• Diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease with the exception of nonmelanoma skin cancer or any completely resected carcinoma in situ
• Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol