An Open Label, Phase 2 Study to Assess the Efficacy and Safety of Tenalisib (RP6530), a PI3K δ/γ and SIK3 Inhibitor, in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Introduction: Despite high response rates to initial treatment, relapse is common in CLL. Although newer agents are approved for treatment recently, CLL remains an incurable disease. Tenalisib (RP6530) is a highly specific and orally available PI3K δ/γ+SIK3 inhibitor. In in-vitro studies, Tenalisib was highly effective (62nM) in demonstrating a cytotoxic effect in patient derived CLL cells and showed very good synergism in combination with fludarabine and ibrutinib at very low concentrations in patient derived primary CLL cells. Tenalisib has demonstrated good clinical activity in patients with T cell lymphomas. Previously, a pooled safety analysis of 93 patients treated with tenalisib monotherapy demonstrated a differentiated safety profile which is largely devoid of immune mediated toxicities (Iyer, ASH 2018).

Methods: This trial is a Phase II, open label, multi-center, Simon's two stage study design to evaluate the efficacy and safety of Tenalisib in patients with CLL who have relapsed or are refractory after at least one prior therapy. In stage 1, 20 patients were to be enrolled and an additional 41 patients to be enrolled in stage 2 based efficacy results of stage 1 (>8 responders needed to proceed to stage 2).

Patients with previously treated CLL with adequate bone marrow, liver, and renal function, ECOG ≤2, and measurable disease are eligible. Patients with prior exposure to drug that specifically inhibits PI3K were excluded. The primary objective was to assess the anti-tumor activity. The secondary objectives were to assess safety and tolerability, and progression free survival (PFS). The responses were assessed using iwCLL criteria (Hallek 2018).

Results: A total of 21 CLL patients predominantly male (86%) with median age was 66 years (range 44-79) were enrolled between Dec 2019 and March 2020 in Stage 1 of the study. 67% of patients had an ECOG score of 1, and 43% had Rai Stage III/IV disease with 67% having spleno/hepatomegaly. Patients had a median of 2 (range: 1-3) prior treatment regimens and 16 (76%) were refractory to last therapy. High risk patients included 15% del 17p, 10% del 11q, 5% ZAP and 5% TP53 mutations.

In all 21 evaluable pts with a median follow-up of 4.9 months, 7 patients showed partial response (33%) while the remaining 14 patients showed stable disease (67%). 19 patients (90%) were still continuing therapy while 2 patients discontinued due to disease progression after showing a stable response. There was a median reduction in nodal disease to the extent of 54% in responding patients. The data readouts at C8D1 for all patients is currently awaited.

The most common AEs which were mild-moderate in severity included transaminitis (19%), GGT elevation (5%) and neutropenia (5%). There was a related Grade 3 AE of neutropenia (5%). None of the related AEs led to study discontinuation. There were no events of diarrhoea/colitis or pneumonitis in patients who were on therapy for more than 6 months.

Conclusions: Tenalisib showed promising single agent anti-tumor activity in patients with CLL with a favourable safety profile. Further data is awaited to estimate the response rates and the decision to move to Stage 2 of the study.