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Press Release

ASCO Presentations Highlight Preliminary Results of Studies with MLN9708, First Oral Proteasome Inhibitor in Clinical Trials in Multiple Myeloma

Millennium: The Takeda Oncology Company
Posted on: 03 Jun 12

Millennium: The Takeda Oncology Company with its parent company Takeda Pharmaceutical Company Limited (TSE:4502) today reported phase 1 and phase 1/2 preliminary results from three studies evaluating the safety, tolerability, dosing and response of MLN9708, the first oral proteasome inhibitor in clinical trials. The studies evaluated once or twice weekly oral dosing of MLN9708, alone or in combination, in patients with relapsed and/or refractory or previously untreated multiple myeloma (MM). These data were announced during the annual meeting of the American Society of Clinical Oncology (ASCO), held June 1-5 in Chicago, Illinois.

The results of these early studies of MLN9708, in patients with both heavily pre-treated relapsed/refractory and previously untreated multiple myeloma, showed high response rates, and we are particularly encouraged by the responses observed after one or two cycles of treatment,” said Karen Ferrante, M.D., Chief Medical Officer, Millennium. “Informed by the data from these studies, we will be initiating phase 3 trials in the next few months, which will investigate a fixed oral weekly dose of MLN9708.”

Oral weekly MLN9708, an investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: a phase 1/2 study (Abstract #8033)

The trial evaluated 65 patients with previously untreated MM in a phase 1/2 study. The primary objectives of the phase 1 portion of this study were to determine the safety, tolerability and maximum tolerated dose (MTD) of weekly oral MLN9708 in combination with standard dose lenalidomide and dexamethasone. The primary objectives of the phase 2 portion were to determine complete response (CR) and very good partial response (VGPR) rates. Secondary objectives included duration of response, progression-free survival (PFS) and overall survival (OS). Results from both portions of the study, which were presented by Paul G. Richardson, M.D., Dana-Farber Cancer Institute, included:

  • MTD has been determined as 2.97 mg/m2 for the weekly dosing schedule used in this trial
  • Phase 2 dose was determined to be 2.23/m2, and translated to a fixed dose of 4 mg based on population PK results
  • The most common drug-related adverse events of any grade were rash (35 percent), fatigue (32 percent) and nausea (31 percent)
  • The most common drug-related adverse events of grade 3 or higher were rash (11 percent); vomiting and nausea (5 percent each)
  • No severe (= grade 3) peripheral neuropathy (PN) was observed at or below the MTD
  • One case of grade 3 PN was reported at almost twice the recommended phase 2 dose
  • Of 64 patients who received at least one cycle of treatment and a median of four cycles, the overall response rate (ORR) was 91 percent
  • Of the 46 patients who completed = 4 cycles of therapy (median 5 cycles), the ORR was 98 percent; 26 percent achieved a CR with 46 percent of patients achieved a VGPR or greater
  • There was one on-study death due to RSV pneumonia
  • Median PFS and OS have not been reached at a follow up as of April 30th, 2012

Patients with previously untreated MM, aged 18 years or olderwith measurable disease received MLN9708 (phase 1: 1.68–3.95 mg/m2) days 1, 8, and 15; lenalidomide 25 mg days 1–21; and dexamethasone 40 mg days 1, 8, 15, and 22, for up to twelve 28-day cycles.

Phase 1 study of twice-weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients with relapsed and/or refractory multiple myeloma (Abstract #8017)

This study evaluated MLN9708 in 58 patients who had received two or more prior therapies. The primary objectives of this ongoing study were to determine the safety, tolerability and MTD of twice weekly MLN9708. Results from the dose-escalation and expansion cohorts of the phase 1 dose-escalation study, which were presented by Sagar Lonial, M.D., Emory University, included:

  • The MTD has been determined at 2.0 mg/m2 for the twice weekly dosing schedule in this patient population
  • The most common drug-related adverse events of any grade were fatigue (45 percent), thrombocytopenia (41 percent) and nausea (36 percent)
  • The most common drug-related adverse events of grade 3 or higher were thrombocytopenia (55 percent), neutropenia (16 percent) and fatigue (9 percent)
  • Grade 1 PN was reported in 3 patients and grade 2 PN in three patients
  • No grade 3 or higher peripheral neuropathy was reported,
  • Of 53 evaluable patients, after a median of four cycles, six patients achieved a partial response (PR) or better, including one stringent CR, one near-CR, one VGPR and three PR
  • 20 patients achieved stable disease at the MTD, including 11 in the relapsed/refractory cohort, five in the bortezomib-relapsed cohort, three in the proteasome inhibitor-naïve cohort and one in the carfilzomib pre-treated cohort
  • Duration of disease control was up to 21.1+ months as of March 27, 2012

Patients aged 18 years or older with measurable MM received MLN9708 on days 1, 4, 8, and 11 of 21-day cycles. In the dose-escalation phase, patients had received =2 prior therapies (including bortezomib, thalidomide/lenalidomide, and corticosteroids). 90 percent of patients had prior bortezomib exposure and 26 percent were bortezomib refractory, 88 percent had previous lenalidomide exposure, 62 percent had prior thalidomide exposure and 12 percent had prior carfilzomib/marizomib exposure. At the MTD (2.0 mg/m2), pts were enrolled to relapsed and refractory [RR], bortezomib-relapsed [VR], proteasome-inhibitor [PI] naïve, and carfilzomib [CZ] expansion cohorts.

Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients with relapsed/refractory multiple myeloma (MM): a phase 1 study (Abstract #8034)

This study evaluated MLN9708 in 52 patients who had received two or more prior therapies. The primary objectives of this ongoing study were to determine the safety, tolerability and MTD of weekly MLN9708. Results from the dose-escalation and expansion cohorts of the phase 1 dose-escalation study, presented by Shaji Kumar, M.D., included:

  • The MTD has been determined at 2.97 mg/m2 on a weekly dosing schedule
  • DLTs included grade 3 rash, grade 3 nausea, vomiting and diarrhea
  • The most common drug-related adverse events of any grade were thrombocytopenia (44 percent), diarrhea (37 percent) and fatigue (35 percent)
  • The most common drug-related adverse events of grade 3 or higher were thrombocytopenia (31 percent), diarrhea (15 percent) and fatigue (10 percent).
  • A total of six patients reported PN, with three reporting grade 1 PN after 1 – 4 cycles of treatment, and three with grade 1 at onset of the study worsening to grade 2
  • No grade 3 or higher peripheral neuropathy was reported
  • Of the 52 evaluable patients, after a median number of 2 cycles of MLN9708 , one patient achieved a VGPR, three achieved PR and another 12 achieved stable disease which was durable up to 9.5 months

Patients aged 18 years or older received MLN9708 on days 1, 8, and 15 of 28-day cycles. In the dose-escalation phase, patients required =2 prior therapies (including bortezomib, thalidomide/lenalidomide, and corticosteroids). 85 percent of patients had prior bortezomib exposure and18 percent were bortezomib refractory, 92 percent had previous lenalidomide exposure, 48 percent had prior thalidomide exposure and 12 percent had prior carfilzomib exposure. At the MTD, patients were to be enrolled to relapsed and refractory (RR), bortezomib-relapsed (VR), proteasome inhibitor (PI) naïve, and carfilzomib (CZ) expansion cohorts.

About MLN9708

MLN 9708 is an oral, potent, specific proteasome inhibitor, which is being studied in multiple myeloma and other hematologic malignancies and solid tumors. It is the first oral proteasome inhibitor to enter clinical trials in patients.

Editor’s Note: This press release is also available under the Media section of the Company’s website at: www.millennium.com/InTheNews.aspx.

About Millennium

Millennium: The Takeda Oncology Company, a leading biopharmaceutical company based in Cambridge, Mass., markets VELCADE, a first-in-class proteasome inhibitor, and has a robust clinical development pipeline of product candidates. Millennium Pharmaceuticals, Inc. was acquired by Takeda Pharmaceutical Company Ltd. in May, 2008. The Company’s research, development and commercialization activities are focused in oncology. Additional information about Millennium is available through its website, www.millennium.com.

About Takeda

Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for patients worldwide through leading innovation in medicine. Additional information about Takeda is available through its corporate website, www.takeda.com.

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Last updated on: 03/06/2012

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