4005 - STop and Restart Acalabrutinib In fRail Patients With Previously Untreated Chronic Lymphocytic Leukemia (STAIR): a randomized phase 2 study from the FILO-CLL group

Abstract Text: Summary
The irreversible Bruton's Tyrosine Kinase inhibitor (BTKi) acalabrutinib (ACA) displays potent clinical activity as a single agent in patients with treatment-naive or refractory/relapsed Chronic Lymphocytic Leukemia (CLL). However, there is growing concern regarding the unlimited administration of such targeted therapies as BTKi. First, long-term treatment expose the patients to an increased risk of adverse events (infections, bleeding or cardiovascular problems). Second, continuous administration could also increase the risk of clonal evolution and therapeutic resistance resulting from genetic alterations, such as BTK or PLCG2 mutations. Discontinuation of therapy after a fixed period is expected to prevent these events. Rapid and deep responses yielded by ACA in elderly, comorbid patients pave the way for investigating a limited 18-months period schedule. The STAIR study aims to investigate 1-year PFS after ACA discontinuation and the efficacy of restarting ACA upon symptomatic relapse.

Design of the trial
This multicenter, non-comparative, randomized phase II trial led in French FILO centers aims at evaluating the impact of a “stop and restart ACA” strategy on the PFS of CLL patients >70-year-old (yo) and/or with coexisting comorbidities (NCT04963946). Patients received continuous ACA at 100 mg bid for 18 months (dose adaptations according to labels). At month 19 day 1, 160 patients (to include assuming a drop-out rate before 18 months of 20%) were planned to be randomized 1:2 in two arms (importantly: regardless of the response assessed by CT scan/minimal residual disease):
• Arm 1 = Control arm (ACA) continuing ACA until disease progression or unacceptable toxicity
• Arm 2 = Experimental arm (watch and monitor) without ACA.
Patients were stratified based on the presence or absence of complex karyotype and del(17p)/TP53 mutations.
Upon progression in the experimental arm, all patients will be re-treated with ACA at the last received dose after central reviewing of iwCLL2018 re-treatment criteria.
Upon progression in the control arm, patients will receive next-line therapy at the discretion of their physicians and according to iwCLL2018 criteria.
Patients will be monitored every three months until M31, then every 6 months until M60 or progression, for both response and toxicity according to CTCAE v.5.

Population
Recruitment began in October 2021 and was completed in June 2023 (10 months ahead of schedule). The first patient was randomized in May 2023. These patients have a median age of 76 yo (range 70-96 yo) and 62% had a CIRS>6 at inclusion. Of note, they are much older than the median of 64yo (33-85 yo) in the single-arm phase 1/2 trial (ACE-CL-001) and the median of 70yo (66-75 yo) in the ELEVATE-TN trial where patients alsor had less comorbidities (11.7% with CIRS>6).
Conclusion
The ongoing STAIR trial is reported here, testing a stop and re-start ACA strategy in elderly and comorbid CLL patients. The trial was designed with the aim to demonstrate the absence of PFS disadvantage and even improvement, with less adverse events, of a fixed duration strategy versus continued administration of a BTKi.

Keywords : unfit
frontline
acalabrutinib

Please indicate how this research was funded. : Promotion: FILO French CLL group
Fully funded by Company

Please indicate the name of the funding organization.: AstraZeneca