NEW ORLEANS—Preliminary results from an ongoing phase 1 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) show the PI3K-δ,γ inhibitor IPI-145 to be clinically active, according to a results presented at the 55th American Society of Hematology Annual Meeting and Exposition.

Clinical activity has been observed in patients with relapsed/refractory CLL at all doses of IPI-145 studied, from 8 mg to 75 mg twice daily, as well as in those with relapsed/refractory high-risk disease (TP53 mut/17pdel), said Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute, Nashville, TN.

“Our study results suggest that IPI-145 may lend itself well to long-term therapy of patients with CLL,” said Dr. Flinn. “While it has a well-tolerated profile similar to other drugs in its class, it may actually be more potent, which could contribute to its value for patients with relapsed or refractory disease in particular.”

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In the dose-escalation phase, sequential cohorts of patients with hematologic malignancies were enrolled and received IPI-145 twice daily in 28-day cycles, with 75 mg twice daily being identified as the maximum tolerated dose.

Two expansion cohorts of patients with relapsed/refractory CLL are ongoing. One is examining the 75 mg twice daily dose and the other, 25 mg twice daily, which was selected based on pharmacokinetics/pharmacodynamics (PK/PD) showing complete suppression of PI3K-δ (> IC90) and inhibition of PI3K-γ (≥ IC50) at steady state, Dr. Flinn said.

Patients with CLL with pancytopenia and/or prior exposure to PI3K- or BTK-inhibitors are allowed in these expansion cohorts. In addition, an expansion cohort in high-risk, treatment-naïve patients with CLL is also ongoing at the IPI-145 25 mg twice daily dose.

Dr. Flinn presented data of preliminary outcomes in CLL in the three expansion cohorts, which included 52 patients with relapsed/refractory disease—61% of whom were less than 6 months from their prior therapy and 53% of whom had 17p(del) or p53 mutations—and 15 patients who were treatment naïve, all of whom were 65 years of age or older or had one of the mutations.

 Median time on treatment is 5.3 months (range, 1-23 months) in the relapsed/refractory CLL group receiving less than 25 mg twice daily (n = 28) and 5.1 months (range, 2-8 months) the relapsed/refractory CLL group receiving 75 mg twice daily (n = 24); in the treatment-naïve group receiving 25 mg twice daily (n = 15), it was 2.7 months (range, 1-5 months).

To date, 50% of the patients in the two relapsed/refractory CLL groups remain on treatment; half have discontinued primarily due to adverse events (AEs; 29%) and disease progression (14%), Dr. Flinn said. Two patients (8%) have died in the 75 mg group. A total of 93% of patients in the treatment-naïve group remain on treatment.

In the overall relapsed/refractory CLL groups, of the 47 evaluable patients, there is one complete response and 21 partial responses, for an overall response rate (ORR) of 47%, he said. Similar ORRs were observed between the patients in the two dose groups; 48% in the group receiving less than or equal to 25 mg twice daily (with a 50% ORR among patients with 17p[del] or p53 mutation) and 45% in the 75 mg twice daily group (29% among those with a mutation). Median time to response was less than 2 months.

Of the 27 patients with relapsed/refractory CLL dosed at 25 mg twice daily, 24 (89%) had a nodal response, defined as a 50% or greater reduction in adenopathy. Among those who were treatment naïve, nodal responses occurred in three of six patients, including two patients with a p53 mutation.

The PK/PD and clinical activity of IPI-145, currently in development for the treatment of hematologic malignancies, suggest 25 mg twice daily is a biologically active dose; therefore, this dose has been selected for an upcoming randomized phase 3 trial in the relapsed/refractory CLL population, Dr. Flinn reported.

At the phase 3 recommended 25 mg twice daily dose, systemic grade 3 or higher AEs included rash, diarrhea, fatigue, ALT/AST elevations, febrile neutropenia, INR increases, pneumonitis, and stomatitis in the relapsed/refractory CLL group and ALT/AST elevations, appendicitis, and fatigue in the treatment-naïve arm. Hematologic AEs included neutropenia, anemia, and thrombocytopenia in the relapsed/refractory patients and neutropenia in the treatment-naïve group. Infections occurred in both groups.

These evolving efficacy data suggest IPI-145 is highly active in relapsed/refractory CLL, Dr. Flinn said, with the safety profile also supporting further development. Most systemic and infectious AEs were low in grade and all were reversible. Hematologic AEs were generally transient, with evolving AE management paradigms enabling continued treatment. Early trends suggest a higher rate of ALT/AST elevations and a lower rate of neutropenia in non-Hodgkin lymphoma than in CLL.

“Emerging data also support development in other hematologic malignancies, including indolent NHL and T-cell malignancies,” he concluded.


  1. Flinn I et al. Abstract #677. Presented at: American Society of Hematology Meeting 2013. Dec. 7-10, 2013; New Orleans.