Novel Agents IPI-145 and ABT-199 Show Encouraging Results in Phase I CLL Studies
Two novel agents—the small-molecule PI3K inhibitor IPI-145 and the Bcl-2 inhibitor ABT-199—show promising activity in chronic lymphocytic leukemia (CLL), according to two phase I studies presented at the 55th American Society of Hematology (ASH) Annual Meeting and Exposition (Abstracts 677 and 872). Both agents achieved excellent response rates in heavily pretreated relapsed/refractory patients including those with poor-risk cytogenetics.
If these preliminary results are validated in phase III studies, IPI-145 and ABT-199 will be poised to join a host of new therapies that promise to improve outcomes for all patients with CLL patients, including those with poor-risk cytogenetics.
IPI-145
IPI-145, a potent, oral small-molecule inhibitor of PI3K gamma and delta, is being studied in a range of hematologic malignancies. A phase I dose escalation study of 193 patients included a total of 67 patients with CLL: 52 patients with treatment-resistant or relapsed CLL and 15 patients with untreated CLL patients. The median age was 67 years.
Twice-daily treatment with IPI-145 at doses of 8 mg to 75 mg in 28-day cycles showed clinical activity in relapsed or treatment-resistant CLL at all doses studied. Importantly, the drug was active in patients with poor-risk cytogenetics (17p deletion or p53 mutation).
Nodal response was defined as a 50% or greater reduction in lymphadenopathy. Among 43 evaluable patients with relapsed/refractory disease, 42 (98%) had a nodal response on computed tomography assessment, and 24 of 27 patients (89%) dosed at ≤ 25 mg twice daily had a nodal response. Nodal responses were seen in three of six evaluable treatment-naive patients, including two with a p53 mutation.
Overall response rate in 47 evaluable patients with relapsed/refractory CLL was 47%, with one complete response defined by International Workshop on CLL (IWCLL) criteria.
The drug was generally well tolerated without the degree of myelosuppression seen with traditional chemotherapy. The investigators selected the 25 mg twice daily dose for phase III study.
“These data support phase III development. Our study suggests that IPI-145 may lend itself well to long-term therapy of patients with CLL. While it has a tolerability 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,” said lead author Ian Flinn, MD, PhD, of Sarah Cannon Research Institute, Nashville, Tennessee. “Emerging data also support development of this compound in other hematologic malignancies, including indolent non-Hodgkin lymphoma and T-cell malignancies.”
ABT-199
ABT-199 targets the B-cell lymphoma-2 (Bcl-2) protein associated with tumor cell proliferation and survival. The goal of ABT-199 treatment is to inhibit Bcl-2 and induce apoptosis in tumors.
The phase I trial of ABT-199 included 57 evaluable patients with relapsed or treatment-resistant CLL or small lymphocytic leukemia. Patients received doses ranging from 150 to 1,200 mg. Early in the trial, tumor lysis syndrome occurred in some patients, leading to a reduction in initial dose and a slower increase in dose escalation over the first few weeks of treatment. In addition, prophylaxis and monitoring have been instituted. This strategy appears to prevent or reduce the likelihood of tumor lysis syndrome, but one death due to tumor lysis syndrome was reported on the amended dosing protocol.
Patients had a median number of four prior therapies (range, 1–11). Nineteen (37%) had 17p deletion; p53 status was unknown; and 75% had unmutated IGHV.
Fifty of 57 patients (88%) had a nodal response, and the median time to 50% reduction in nodal masses was 6 weeks. Response in the bone marrow infiltrate of at least a 50% reduction at 24 weeks was seen in 89% of patients. Median time to 50% reduction in lymphocyte count was 15 days.
The overall response rate was 84%, with complete response occurring in 13 patients (23%) and partial response in 34 patients (61%). Among patients with 17p deletion, the overall response rate was 82%, with complete response in 2 patients (12%) and partial response in 12 patients (71%).
“We are very encouraged by these early results and, in particular, by the high rate of complete response among patients with treatment-resistant or relapsed CLL. Our ongoing studies will seek to improve the efficacy while carefully monitoring toxicities to deliver the maximum benefit to high-risk patients where conventional chemotherapy has proven inadequate,” said lead author John Seymour, MBBS, PhD, of Peter McCallum Cancer Center, Melbourne, Australia.
For full disclosures of the study authors, view the study abstracts on the ASH website.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
