IPI-145 Shows Promise in CLL Patients Free

Results of a phase I study of Infinity Pharmaceuticals' IPI-145, which inhibits both the δ and γ isoforms of phosphoinositide3-kinase (PI3K), suggest the drug is safe and effective in patients with advanced chronic lymphocytic leukemia (CLL).

In a trial among 155 blood cancer patients, 52 patients had relapsed refractory CLL. Evaluable patients in this group showed a 47% overall response to the drug, with 1 showing a complete response and 21 a partial response; 24 had stable disease and 1 was progressing. High-risk patients with mutations in the TP53 tumor suppressor gene, or loss of gene function caused by 17p deletions, also showed response rates of approximately 50%.

In addition, the study found that in 89% of patients, enlarged lymph nodes shrank by 50% or more. “Almost everyone is responding with reduction in adenopathy and about half are achieving true IWCLL [International Workshop on Chronic Lymphocytic Leukemia] responses,” says Ian Flinn, MD, PhD, director of the Blood Cancer Research Program at Sarah Cannon Research Institute in Nashville, TN. Flinn presented the trial results at the annual meeting of the American Society for Hematology on December 9 in New Orleans, LA.

Lymph node shrinkage can lead to a temporary increase in lymphocytes, a sign of disease progression in other settings, but an expected reaction to all drugs in this setting. That's why the IWCLL set criteria for CLL remission based on nodal responses and lymphocyte count.

“Some of the patients in this study who are showing a nodal response may ultimately convert to remission as defined by the accepted criteria,” says Flinn, who observed similar delayed responses 5 years ago in early trials of the PI3K-δ inhibitor idelalisib (GS-1101; Gilead Sciences).

“From my perspective, the results for IPI-145 have been exciting,” Flinn says.

He adds that IPI-145 is well tolerated. Transient neutropenia was noted, but there was little blood toxicity. Less than 10% of patients had grade 3 or higher increase in liver function tests, and that condition was reversible.

Nearly 16,000 new cases of CLL were predicted in the United States in 2013, with an estimated 4,500 deaths, according to the National Cancer Institute. Approximately 20% of cases are refractory and do not respond well to any treatment.

“This is an exciting time in lymphoma and CLL because there are many new drugs coming forward,” says Flinn. “There's a great need for these new therapies for both relapsing and newly diagnosed CLL patients to move us away from current cytotoxic chemotherapy approaches.”

A phase III trial is planned to compare IPI-145 to the CD20 monoclonal antibody ofatumumab (Arzerra; GlaxoSmithKline and Genmab) in patients with relapsed CLL who are not good candidates for aggressive chemotherapy.

IPI-145 is being tested against multiple hematologic malignancies and has also shown encouraging results in low-grade lymphoma.

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