Clinical trials of four investigational compounds in solid tumors presented at ASCO Annual Meeting

Millennium: The Takeda Oncology Company today announced data from clinical trials of four investigational compounds in solid tumors presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO), held in Chicago, Illinois, June 4-8, 2010. These data include an oral presentation on MLN8237, the Company's selective Aurora A kinase inhibitor. First clinical data were presented for MLN9708, Millenium's next proteasome inhibitor, and TAK-701, a hepatocyte growth factor (HGF) antibody. The first Phase II data for TAK-700, a selective 17,20 lyase inhibitor, were also presented.

“We are advancing our pipeline quickly. These preliminary results support further development of our molecules”

"We are advancing our pipeline quickly. These preliminary results support further development of our molecules," said Nancy Simonian, M.D., Chief Medical Officer, Millennium. "Our hope is that our clinical trials will eventually lead to valuable treatment options for patients with cancer."

MLN9708 - Millennium's Next Proteasome Inhibitor

MLN9708 is Millennium's next proteasome inhibitor being studied in both oral and intravenous (IV) formulations and is developed from the Company's groundbreaking research in protein homeostasis. The data reported were on the IV formulation in patients with advanced solid tumors. The Phase I trial, an open-label, multi-center, dose-escalation study, was designed to determine the safety profile of IV MLN9708 as well as establish the maximum tolerated dose (MTD). Eve Rodler, M.D., Seattle Cancer Care Alliance, reported the following results of 23 evaluable patients:

• MTD has been established as 1.76 mg/m²
• DLT was seen in six patients after data cut-off (two Grade 3 rash, three Grade 4 thrombocytopenia, one Grade 3 renal failure)
• The most common AEs were fatigue, nausea and vomiting; Grade 3/4 AEs related to MLN9708 were anorexia, dehydration, fatigue, nausea, vomiting, peripheral sensory neuropathy, macular rash, renal failure and thrombocytopenia

All patients received MLN9708 intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Doses administered ranged from .125 mg/m² up to 2.34 mg/m². This trial will continue to evaluate MLN9708 in patients at MTD in a variety of solid tumors.

MLN8237 - Selective Aurora A kinase Inhibitor

MLN8237 is an oral, selective, Aurora A kinase inhibitor discovered by Millennium scientists. Phase I data on this compound in patients with solid tumors were selected for oral presentation during the Developmental Therapeutics - Experimental Therapeutics session held on June 5. E. Claire Dees, M.D., University of North Carolina, Chapel Hill, presented the following results from 65 eligible patients:

• MTD was reached and the recommended Phase II dose is 50 mg twice daily on days 1-7 of a 21 day cycle; neutropenia and stomatitis defined the MTD
• The most common AEs were nausea, fatigue and diarrhea; Grade 3/4 AEs included neutropenia, febrile neutropenia, diarrhea, thrombocytopenia and anemia
• Twenty-seven (42%) patients achieved stable disease; one patient had a partial response

MLN8237 was evaluated at daily and twice-daily schedules in doses ranging from 5-150 mg with cycle duration ranging from 7-21 days.

An additional study, presented by Andres Certvantes, M.D., University of Valencia, looked at pharmacodynamic (PD) effects of Aurora A kinase inhibition with MLN8237 in human skin and tumor biopsies from two trials, including the one described above. The two trials investigated the administration of MLN8237 across a range of doses and dosing schedules. Dr. Cervantes presented the following analysis of samples from 117 patients:

• Dose/exposure-related pharmacodynamic effects in the skin and tumor provide proof of mechanism
• Steady-state exposure increased approximately dose proportionally over the dosing range of 5-200 mg/day
• Skin mitotic index and skin apoptotic index analyses denoted phenotypes consistent with Aurora A kinase inhibition

TAK-700 - Selective 17,20 Lyase Inhibitor

TAK-700 is an oral, selective, non-steroidal inhibitor of the 17,20 lyase, which is a key enzyme in the production of steroidal hormones. The compound is currently in clinical trials evaluating its use in patients with metastatic castration resistant prostate cancer (mCRPC). Data presented by Robert Dreicer, M.D., Cleveland Clinic, at ASCO are from the Phase II portion of an ongoing Phase I/II trial. Phase I results were presented by Dr. Dreicer at ASCO's Genitourinary Cancers Symposium (ASCO GU) in March 2010. Results from the Phase II portion evaluating 57 patients include:

• Most common AEs were fatigue, nausea and constipation; Grade ≥3 AEs were fatigue, hypokalemia and hypertension
• Of all patients>
• PD analysis demonstrated androgen suppression as shown by reductions in testosterone and DHEA-S

In the Phase II portion of this trial, patients received 300 mg without prednisone, or 400 or 600 mg with prednisone orally twice daily. The Phase II portion is ongoing and planning for Phase III studies is currently underway.

TAK-701 - Selective Hepatocyte Growth Factor Inhibitor

The first clinical data for TAK-701 from a Phase I, multi-center, open-label, dose-escalation study were presented at this year's ASCO. TAK-701 is a humanized monoclonal antibody against HGF. At data cut-off 22 patients with advanced non-hematologic malignancies had enrolled. The following results were reported by Suzanne Jones, PharmD, Sarah Cannon Research Institute:

• There were no DLTs and thus the MTD has not been reached
• The most common AEs were fatigue, constipation and cough; the most serious treatment-related AEs included ileus, muscular weakness, asthenia, urinary tract infection and dehydration
• Preliminary analysis of all dose groups indicate dose-proportional pharmacokinetics
• Pharmacodynamic analysis showed that in five of seven patients free HGF was not detected while being treated with TAK-701

Patients received up to twelve 28-day cycles of TAK-701 at five dose levels (2 mg/kg-30 mg/kg).