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Millennium Starts Pivotal Trial of Its Aurora Kinase Drug MLN8237 in PTCL

bwt03072012 Millennium

By Catherine Shaffer
Staff Writer

Millennium, a unit of Takeda Pharmaceutical Co. Ltd., may soon be able to add peripheral T-cell lymphoma (PTCL) to its list of cancers that can be treated with its investigational Aurora A kinase inhibitor, MLN8237 (alisertib).

The drug already is under investigation for a broad range of cancers, including B-cell and T-cell non-Hodgkin lymphoma and solid tumors. Now the firm has begun a randomized, open-label Phase III trial testing MLN8237 or investigator's choice single agent in patients with relapsed or refractory PTCL. Millennium will be looking at overall response rate and progression-free survival as primary trial endpoints.

"Currently we're investigating the drug clinically in a broad cancer population from solid to hematological malignancy. We expect it to help a lot of patients," Liviu Niculescu, senior medical director for Millennium, told BioWorld Today.

Aurora kinase inhibition is a new mechanism of action. It helps to create the structure that separates chromosomes in cells, an essential role in cellular multiplication. Millennium said it believes that inhibition of Aurora kinase causes anomalies to occur during cell division, leading to apoptosis.

There are no approved Aurora kinases on the market; however, there are others in development, including AT9283 from Cancer Research UK, and CYC116 from Cyclacel Pharmaceuticals Inc.

The drug development office of Cancer Research UK began its first trial of AT9283 in childhood leukemia. The goal of the trial will be to establish a correct dosage and evaluate treatment potential in children and adolescents with leukemia.

CYC116 has been evaluated in Phase I in patients with advanced solid tumors.

Like most Aurora kinases, those compounds don't distinguish between the A and B forms. According to Niculescu, MLN8237's specificity for Aurora A kinase and its oral dosing form are key differentiators for the drug.

Cambridge, Mass.-based Millennium will face more direct competition from EntreMed Inc., of Rockville, Md., with its Aurora A/angiogenic kinase inhibitor ENMD-2076. In a Phase I trial, it was well tolerated in relapsed/refractory multiple myeloma and showed reductions in bone marrow blast counts in a separate study in relapsed and refractory leukemia.

Niculescu said MLN8237 has been given to a cumulative total of 800 patients in previous clinical studies. Millennium reported Phase II results in B-cell and T-cell non-Hodgkin's lymphoma at the 2011 meeting of the American Society of Hematology. In that trial in 48 patients, the drug was well tolerated, with responses observed in heavily pretreated patients with aggressive forms of the cancer.

In patients with PTCL, the response rate was 57 percent.

"If you compare it with available therapies," Niculescu said, "it's a pretty good response."

And, for patients with relapsed and refractory forms of the disease, those available therapies are not very exciting. First-line treatment is cyclophosphamide, hydroxydaunorubicin, oconvin and prednisone, also known as CHOP therapy.

However, there is no settled standard of care for the relapsed and refractory population. Folotyn (pralatrextate, Allos Therapeutics Inc.) and Istodax (romidepsin, Celgene Corp.) are common choices, but according to Niculescu, solid science supporting one therapy or another in that patient population is lacking.

That was an important factor in Millennium's choice to move forward with a Phase III in PTCL first, among all of the cancer indications it is investigating. "When we choose to research something, we go where the biggest need is for the patient," Niculescu noted. "There is definitely a big unmet need for patients suffering from PTCL."

Although the trial is open label, Niculescu emphasized Millennium's commitment to providing high-quality research to support treatment options for the patient population. The trial is designed with a planned interim analysis by an independent data safety monitoring committee.

It will enroll up to 350 patients, although it could be less than that number if the endpoint is met early. PTCL is a relatively rare cancer, affecting about 3,000 new patients annually. Because of that, Millennium expects that it could take a while to fully enroll. "We can't estimate how the enrollment is going to be and how many patients we're going to have," Niculescu said.

Millennium has enjoyed great success with its drug Velcade (bortezomib), which was the first proteasome inhibitor tested in humans. It was approved in 2003 in multiple myeloma.

It also has compounds in late-stage trials for Hodgkin lymphoma, castration-resistant prostate cancer, nonsquamous non-small-cell lung cancer, ovarian cancer and metastatic pancreatic cancer.