Novel PI3K Inhibitor IPI-145 Shows Promise in CLL

Ian Flinn, MD, PhD

According to preliminary results of a phase I clinical trial, nearly half of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) attained objective responses when treated with IPI-145, an oral inhibitor of phosphoinositide-3-kinase-delta (PI3K-delta) and -gamma.

Overall, 47% of patients had objective responses, including one complete response, to the investigational agent IPI-145. Additionally, 98% of patients with refractory disease had nodal responses, which did not differ between patients with or without the 17p deletion (del) or p53 mutation, a researcher reported during the 55th Annual Meeting of the American Society of Hematology.

The therapy was generally well tolerated, as most systemic and infectious adverse events were low-grade and hematologic adverse events were transient in most cases, reported the researcher, Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute in Nashville, Tennessee.

“The efficacy and safety support phase III development of IPI-145 as monotherapy for CLL,” Flinn said. “Evolving data suggest IPI-145 is highly active in relapsed and refractory CLL. Emerging data also support developing [the drug] in other hematologic malignancies, including indolent non-Hodgkin’s lymphoma and T-cell malignancies.”

PI3K-delta and PI3K-gamma both support the growth and survival of B-cell and T-cell malignancies. Both isoforms are involved in cell differentiation, proliferation, survival, and activation, Flinn said.

Flinn presented data for a subset of 52 study participants with relapsed/refractory CLL. Most of the patients (61%) were less than 6 months removed from prior therapy, and 53% had the 17p(del) or p53 mutation. Additionally, investigators treated 15 patients with newly diagnosed CLL.

The group of patients with relapsed/refractory CLL comprised two cohorts: 28 patients who received IPI-145 doses ≤25 mg BID and 24 patients who received the maximum tolerated dose of 75 mg BID. The previously untreated patients received 25 mg BID.

The two groups with relapsed/refractory disease have received IPI-145 for a median duration of 5 to 6 months, and median treatment duration in the newly diagnosed patients is 2.7 months thus far. Half of the patients with relapsed/refractory disease remain on treatment, along with 14 of the 15 patients with newly diagnosed CLL.

In the previously treated cohorts, patients who discontinued did so most often because of adverse events (13 of 52), followed by disease progression (8), physician decision (2), and patient withdrawal (1). Two patients died.

Among the previously untreated patients, the one patient who discontinued treatment withdrew consent.

Flinn said that 42 of 43 evaluable patients with relapsed/refractory disease (98%) had a reduction in adenopathy by CT assessment. In the subgroup that received doses ≤25 mg BID, 24 of 27 (89%) patients had nodal responses, defined as ≥50% reduction in adenopathy. In the group that received IPI-145 as first-line therapy, three of six evaluable patients had nodal responses, including two patients with p53 mutations.

Similar clinical response rates were seen in patients with or without the 17p(del) or p53 mutation. In the relapsed/refractory group, patients treated with ≤25 mg BID had an overall response rate of 48%, including six of 12 patients with the 17p(del) or p53 mutation. Among patients who received the maximum tolerated dose, nine of 20 (45%) had objective responses, including two of seven patients with 17p(del) or p53 mutation.

The most common grade ≥3 nonhematologic adverse events were febrile neutropenia and increased international normalized ratio (INR), which occurred in about 10% of patients. Rash, diarrhea, fatigue, increased liver enzymes, pneumonitis, and stomatitis each occurred in fewer than 10% of patients. Of the 15 patients with untreated CLL, liver enzyme increases, appendicitis, and fatigue occurred in fewer than 10% of patients.

Among hematologic toxicities, grade ≥4 neutropenia occurred in about 40% of patients with relapsed/refractory CLL, anemia 15-20%, and thrombocytopenia in about 10%. In patients with untreated disease, neutropenia affected fewer than 10% of patients.

Infections occurred in about 15% of the relapsed/refractory group and fewer than 10% of previously untreated patients.

“Most systemic and infectious adverse events were low-grade,” Flinn said. “Hematologic adverse events were generally transient. Evolving adverse-event management paradigms enable continued treatment. The emerging IPI-145 safety profile across hematologic malignancies is generally consistent.”

Flinn I, Patel M, Kahl B, et al. Preliminary Safety and Efficacy of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-δ,γ in Patients with Chronic Lymphocytic Leukemia. Presented at: The 55^thAnnual ASH Meeting; Dec. 7-10, 2013; New Orleans, LA. Abstract 677.

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