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Ibrutinib lead-in followed by venetoclax in patients with chronic lymphocytic leukemia: phase II CAPTIVATE early safety and efficacy results

The phase II CAPTIVATE study examined if a single-agent ibrutinib (I) lead-in period followed by a combination of ibrutinib and venetoclax (V) in first-line chronic lymphocytic leukemia improved clinical outcomes and lowered tumor lysis syndrome risk. Early study results were presented during EHA 2018, and support the safety, activity, and tumor lysis risk reduction potential of ibrutinib lead-in. The early data show promising activity of an I+V oral regimen with MRD(-) responses in 82% of the CLL patients treated in first-line.

Ibrutinib is approved for treatment of chronic lymphocytic leukemia (CLL), including patients with del(17p). Although single-agent ibrutinib results in improved survival, complete remission (CR) rates are low and continuous therapy is required. Ibrutinib and venetoclax have complementary therapeutic activity, and synergistic anti-tumor activity has been shown in preclinical and clinical studies with these agents. Venetoclax improves CR rates and can lead to minimal residual disease-negative (MRD(-)) responses in CLL, but it increases tumor lysis syndrome (TLS) risk. Tumor debulking by single-agent ibrutinib lead-in followed by a combination of ibrutinib and venetoclax (I+V) may improve clinical outcomes and lower TLS risk.

The phase 2 CAPTIVATE-study is a multicenter study of I+V in first-line CLL. The study is conducted in 2 phases. The first phase evaluates the MRD(-) clinical response rate of I+V, followed by MRD status-guided randomized treatment discontinuation. The overall objective is to evaluate whether achievement of MRD(-) remission after I+V allows for treatment holidays. Patients started with a safety run-in of ibrutinib lead-in (420 mg once daily for 3 cycles), followed by I+V (venetoclax ramp up to 400 mg once daily for 12 cycles).

At time of analysis, a total of 164 patients (median age 57 years) were enrolled. After 3 cycles of ibrutinib lead-in, 90% of patients with high baseline TLS risk shifted to medium or low risk, and 19% of patients with medium baseline TLS risk shifted to low risk. No patients developed clinical TLS. Furthermore, safety profiles of I+V were consistent with adverse event profiles of single-agent ibrutinib or venetoclax.

A pre-specified analysis was shown for the first 30 patients who completed 6 cycles of I+V for MRD evaluation. There were high rates of undetectable MRD (77%) in peripheral blood after 6 cycles of I+V. Additionally, the clinical response was assessed in 11 out of 14 patients who had completed 12 cycles of I+V. Six out of 11 patients (55%) showed CR/CR with incomplete blood count recovery (CRi) and 5 out of 11 patients (45%) showed a (nodular) partial remission. All patients with CR/CRi had confirmed undetectable MRD. In 12 out of 14 patients (86%) there was undetectable MRD in the bone marrow after 12 cycles of I+V.

These early study results support the safety, activity, and TLS risk reduction potential of ibrutinib lead-in. The early data show promising activity of an I+V oral regimen, but the assessment for the full treatment plan and durability of response is needed.

 

Reference

Ghia P, Tam C, Siddiqi T, et al. Ibrutinib lead-in followed by venetoclax in patients with chronic lymphocytic leukemia: phase 2 captivate early safety and efficacy results. Presented during EHA 2018; Abstract S806.

Spreker Paolo Ghia

Ghia

Paolo Ghia, MD, PhD, Università Vita-Salute San Raffaele, Milano, Italy

 

Zie: Keyslides

 

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