Millennium reports results from two MLN9708 ongoing Phase I studies on multiple myeloma

Millennium: The Takeda Oncology Company with its parent company Takeda Pharmaceutical Company Limited (TSE:4502) today reported results from two ongoing Phase I studies with MLN9708, the first oral proteasome inhibitor being studied in patients with relapsed and/or refractory multiple myeloma (MM). Results were also reported from a Phase I study with first-in-class investigational drug MLN4924 in patients with acute myeloid leukemia (AML) or high-grade myelodysplastic syndromes (MDS). The two compounds included in these studies are part of Millennium's protein homeostasis pipeline. These data were presented at the 16^th Congress of the European Hematology Association, held June 9 - 12 in London.

"We are excited to see continued progress and promising results from both MLN9708 and MLN4924," said Nancy Simonian, M.D., Chief Medical Officer, Millennium. "These two compounds illustrate our commitment to develop best-in-class and first-in-class cancer therapeutics in the field of protein homeostasis."

Evaluation of twice-weekly and weekly dosing of the investigational agent MLN9708, an oral proteasome inhibitor, in patients with relapsed and/or refractory multiple myeloma: Phase 1 dose-escalation studies

Results from the ongoing Phase I studies, one with weekly dosing and one with twice weekly dosing, were reported in 61 patients with relapsed and/or refractory multiple myeloma. The primary endpoints were to determine the safety profile, tolerability, and maximum tolerated dose (MTD) of MLN9708 administered orally using either a twice-weekly (TW) or weekly (W) dosing schedule. The secondary endpoints were to characterize the pharmacokinetics (PK) on each schedule, to determine the overall response rate (ORR) and, at the MTD, determine the ORR in patients with relapsed and refractory MM, patients who are proteasome inhibitor-naïve, those who have relapsed after bortezomib treatment, and those who have received prior carfilzomib treatment. The results were presented by Ruben Niesvizky, M.D., Weill Cornell Medical College and showed:

In the TW dosing schedule, MLN9708 was administered orally to 35 patients for up to 12 cycles with dosing on days 1, 4, 8, and 11 of 21-day cycles. Forty-nine percent of patients in the TW study were VELCADE-refractory. In the W dosing schedule, 26 patients were administered treatment on days 1, 8, and 15 of 28-day cycles. Once the MTD was established, patients were enrolled into expansion cohorts at the MTD to further characterize safety, tolerability, and efficacy. No grade ≥3 peripheral neuropathy has been reported with oral TW or W MLN9708. Dose escalation on both schedules proceeded from 0.24 mg/m². Response evaluation and combination trials guided by these data are ongoing.

MLN4924, a novel, investigational NEDD8-activating enzyme (NAE) inhibitor, in adult patients with acute myeloid leukemia (AML) or high-grade myelodysplastic syndromes (MDS): Results from a phase 1 study

MLN4924 is a small molecule inhibitor of the NEDD8-Activating Enzyme (NAE), a key component of the protein homeostasis pathway. It is the first inhibitor of this class of enzyme to be studied clinically, and is currently being examined in Phase I clinical trials.

The primary endpoints of this open-label, multicenter, Phase I dose-escalation study were to evaluate safety and tolerability, maximum tolerated dose (MTD), and to determine the recommended Phase II dose in patients with AML and high-grade MDS. Secondary endpoints included preliminary assessment of efficacy and analysis of pharmacokinetics (PK) and pharmacodynamics (PD). The results were presented by Harry P. Erba, M.D., Ph.D., University of Michigan, and showed:

• MTD has been determined as 59 mg/m² on this schedule (days 1, 3, 5 of 21-day cycles)
• One DLT, of unrelated grade 3 dyspnea, was reported at the 44 mg/m² dose level
• Two DLTs were reported at the 78 mg/m² dose level:
  • One patient with multi-organ failure
  • One patient with reversible MLN4924-related grade 3 elevation of alanine aminotransferase
• Patients received a median of 2 (range 1-19) treatment cycles
  • 17 patients received 1-2 cycles; 3 patients received 4-5 cycles; 7 patients received 6-19 cycles
• The most common AEs of any grade included:
  • 44% diarrhea; 41% each nausea and pyrexia
• Grade ≥3 AEs have been reported in 78% of patients including:
  • 33% febrile neutropenia; 19% elevated alanine aminotransferase; 11% each anemia, hypoxia, and pneumonia
• Four patients achieved complete responses (CR)
  • Duration of CR ranged from 2.7 months to 11.2 months

Twenty-seven patients were administered MLN4924 as a 60-minute IV infusion on days 1, 3, and 5 of a 21-day cycle for ≤ 12 months or until documented disease progression.