No Safety Concerns in Trial of Ibrutinib to Early-Stage CLL

Published: Tuesday, Dec 08, 2015

Dr Petra Langerbeins

Petra Langerbeins, MD

Preliminary data from an ongoing phase III clinical trial suggest ibrutinib has an acceptable safety profile when used to prevent disease progression in patients with asymptomatic, early-stage chronic lymphocytic leukemia (CLL), German investigators reported at the 2015 ASH Annual Meeting.

Among 192 patients randomized thus far to placebo or ibrutinib, 29 serious adverse events (SAEs) have occurred in 19 patients in both treatment groups combined. Investigators have judged that 15 (51.7%) of the SAEs were related to treatment with ibrutinib, according to Petra Langerbeins, MD, a hematologist at the University of Cologne, Germany.

“The serious adverse events are consistent with those previously reported for ibrutinib,” said Langerbeins. “Given the total number of SAEs reported thus far, the risk of ibrutinib is considered acceptable.”

Three of the SAEs were classified as possible unexpected serious adverse reactions: a non-ST elevation myocardial infarction that occurred during the third cycle of therapy in an 82-year old man during the third cycle of therapy; a cerebral seizure secondary to subdural bleeding that occurred during the first cycle of therapy in a 78-year-old man with a high comorbidity score and on concomitant rivaroxaban; and a case of QT-prolongation and ventricular tachycardia in a 66-year-old women during the third cycle of therapy, leading to implantation of a cardioverter-defibrillator.

To minimize bleeding risk, the trial protocol has been amended to exclude patients using novel oral anticoagulants. Additionally, patients on direct factor Xa inhibitors have either stopped treatment or switched to a different anticoagulant.

For patients with asymptomatic, early-stage CLL observation is standard of care, and treatment is reserved until the onset of symptoms. The German CLL12 trial is the first phase III, randomized, double-blind, placebo-controlled trial to evaluate whether a targeted agent can improve event-free survival (EFS) in early stage CLL.

Patients with asymptomatic Binet A-stage CLL are risk-stratified for disease progression by means of a comprehensive prognostic score (Blood. 2014;124:49-62). Low-risk patients are observed. Patients with an intermediate, high, or very high-risk score were randomized 1:1 to placebo or ibrutinib at a dose of 420 mg/day.

The primary endpoint is EFS, defined as the time from randomization until disease progression, initiation of subsequent treatment for CLL, or death. Secondary endpoints include overall survival, progression-free survival, treatment-free survival, time to next CLL treatment, overall response, safety, and quality of life.

As of November 2015, 357 patients had been screened, and 281 underwent risk stratification. On the basis of the prognostic score, 89 patients were classified as having a low risk of progression and were assigned to the observation group. The remaining 192 patients constituted the initial randomized cohort, consisting 142 patients with intermediate-risk scores, 44 with high-risk scores, and six with very high-risk scores.

The safety analysis included 266 patients, who had a median age of 61 and a median comorbidity score of 2. More than half (57.4%) of the patients had more than one comorbid condition. Men accounted for two thirds of the safety population.

As of September 2015, randomized patients had a median treatment duration of 124 days (4.4 cycles), and 51 patients had discontinued treatment. The primary reason for discontinuation was refusal of further treatment (n = 31), followed by toxicity (n = 10), disease progression (n = 5), use of oral anticoagulants (n = 4), and diagnosis of small-cell lung cancer (n = 1).

According to an updated statistical analysis that took into account safety data and discontinuations, the trial would take 8 years to reach primary and secondary endpoints. As a result, investigators have petitioned German regulatory authorities for permission to double the number of randomized patients, Langerbeins said. With the larger patient population, the primary endpoint would be reached in a year and a half, and survival data would be sufficiently mature after an additional one and a half years.


Langerbeins P, Bahlo J, Rhein C, etal. Ibrutinib in Early Stage CLL: Preliminary Safety Results of a Placebo-Controlled Phase III Study. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 2934.

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