NEW ORLEANS — A number of new targeted therapies are currently in development for chronic lymphocytic leukemia (CLL), and early data on 2 of these compounds indicate that treatment options for this disease could be expanding.
Preliminary results from 2 studies reported here at the American Society of Hematology (ASH) 55th Annual Meeting suggest that IPI-145, under development by Infinity, and ABT-199 (GDC-0199), under development by AbbVie/Genentech, are both highly active in CLL.
"These exciting developments in CLL therapy represent a shift toward treatments that hone in on specific regulators of cancer, ultimately providing a safer and more effective treatment regimen," said Jennifer R. Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute in Boston, who moderated a press briefing where the results were highlighted. "These data give us even more reason to believe that the outlook for CLL patients is bright."
Data on IPI-145
IPI-145 is a potent oral compound designed to block the activity of phosphoinositide 3-kinase (PI3K), which is responsible for CLL cell signaling.
"The compound is currently in phase 1 trials for patients with a wide range of hematologic malignancies, including CLL," said lead author Ian Flinn, MD, PhD, from the Sarah Cannon Research Institute in Nashville, Tennessee. "There has been broad activity seen in other lymphoid malignancies."
Dr. Flinn and colleagues investigated the safety and efficacy of IPI-145 in a dose-escalation trial that involved 193 patients (median age, 67 years). In this group of CLL patients, 52 had relapsed or refractory disease and 15 were treatment-naïve.
Of the patients with relapsed or refractory disease, 53% had 17p deletions or p53 mutations; of the treatment-naïve patients, 7 patient had the mutation.
IPI-145 was administered in doses ranging from 8 mg twice daily to 100 mg twice daily. The maximum tolerated dose was determined to be 75 mg.
The cohort was divided then into 3 groups: relapsed or refractory patients who received less than 25 mg twice daily; relapsed or refractory patients who received 75 mg twice daily; and treatment-naïve patients who received 25 mg twice daily.
The median time on the study drug for treatment-naïve patients was only 2.7 months, because they had just entered the trial, Dr. Flinn explained. For the other group, it was more than 5 months. "More than 50% of patients in the relapsed/refractory group remain on treatment," he said.
There was a fairly "overwhelming" nodal response, Dr. Flinn noted. Virtually all patients (98%) had a reduction in adenopathy on CT assessment, and 89% treated with 25 mg had a nodal response greater than 50%.
Of the 47 evaluable patients with relapsed or refractory CLL, 1 had a complete response, 21 had a partial response, 24 had stable disease, and 1 had disease progression. The overall response rate was 47%.
Of the 19 patients with 17p deletions or p53 mutations, the overall response rate was 42%. No patients had a complete response, 8 had a partial response, 10 had stable disease, and 1 had progressive disease.
"We were pleased that we saw 1 patient with a complete response, which is notable in this refractory population," said Dr. Flinn.
He added that the vast majority of adverse events were asymptomatic and reversible, and pointed out that more than 40% of patients in the expansion phase had greater than grade 3 cytopenias at baseline.
Data on ABT-199
In the second trial, John Seymour, MBBS, PhD, from the Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues evaluated ABT-199 (GDC-0199) in a phase 1 dose-escalation study of patients with relapsed/refractory CLL or relapsed/refractory small lymphocytic lymphoma. ABT-199 is an inhibitor of Bcl-2, which has been recognized for more than 2 decades as being critical to the pathogenesis of many hematologic malignancies, and is overexpressed in CLL, Dr. Seymour noted. It is a very attractive treatment target but it has been difficult to select for it until now, he added.
Dr. Seymour noted that the compound has shown preliminary antitumor activity, including complete remission in high‐risk CLL and SLL.
He explained that modifications were made to the dose-escalation scheme, and tumor lysis syndrome (TLS) prophylaxis was added to the monitoring schedule after TLS was observed in some patients.
As of September 30, there were 67 patients enrolled in the study; 43 remain on treatment. Patients were treated with varying doses of the drug, ranging from 150 to 1200 mg. The median time on the study drug was 10.9 months.
Study participants were heavily pretreated, Dr. Seymour pointed out. The median number of previous therapies was 4, although some patients had received as many as 11. Sixty patients (90%) received fludarabine and 35 (52%) were refractory to it.
In addition, 19 patients (37%) had 17p deletions, and 13 of 30 patients (43%) had beta-2 microglobulin levels above 3 mg/L.
The results to date show an overall response rate of 47%, a response rate in patients with 17p deletions of 14%, and a response rate in patients refractory to fludarabine of 14%. There were 13 complete responses (23%) in the entire cohort, there were 2 (12%) in patients with 17p deletions, and there were 6 (22%) in patients refractory to fludarabine
Serious adverse events included febrile neutropenia, TLS (in 1 case related to sudden death), and infection. There were 3 cases of TLS, but Dr. Seymour explained that those occurred prior to making the trial modification, and there have not been any since.
Other studies with the novel agent in CLL are underway, including a phase 2 monotherapy study in patients with relapsed CLL and 17p deletions and combination studies with rituximab or obinutuzumab (GA101) in patients with relapsed CLL.
Dr. Flinn reports consultancy and research funding from Infinity. Dr. Seymour reports consultancy for Genentech.
American Society of Hematology (ASH) 55th Annual Meeting: Abstract 677 presented on December 9, 2013; Abstract 872 presented on December 10, 2013.
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