P625: a phase 1b/2 study of navtemadlin combined with acalabrutinib in btk inhibitor naïve patients with relapsed/refractory (r/r) chronic lymphocytic leukemia (cll) or small lymphocytic lymphoma (sll)

Background: CLL/SLL is a B cell malignancy characterized by dysregulated B cell receptor (BCR) signaling and overexpression of Bcl-2 protein (Kapoor 2020). BTK inhibitors (BTKi) have transformed the CLL/SLL treatment landscape by prolonging disease control and significantly improving overall survival. However, inducing complete remissions (CRs) in R/R pts is rare, leading to BTKi resistance and disease progression over time. Navtemadlin (Nvtm), a potent, selective, orally available mouse double minute 2 inhibitor (MDM2i) restores p53 function to activate pro-apoptotic Bcl-2 family proteins and drive apoptosis of TP53 wild-type (TP53WT) B-CLL cells. Separately, inhibition of BTK disrupts pro-proliferative BCR signaling and releases B-CLL cells from their supportive, pro-survival tumor microenvironment into the circulating peripheral blood. Combining BTKi with MDM2i in R/R CLL/SLL pts may potentiate the pro-apoptotic effects of nvtm on malignant B cells, through reduced stromal support and a lowered apoptotic threshold, to induce deeper responses (CRs). Aims: To determine the recommended Phase (Ph) 2 dose (RP2D), and evaluate the safety and efficacy of nvtm combined with BTKi acalabrutinib (acala) in BTKi-naïve R/R CLL/SLL. Methods: This multicenter, global Ph 1b/2 study is enrolling adults with ECOG 0-2, BTKi-naïve, TP53WT R/R CLL/SLL (NCT04502394). The Ph 1b 3 + 3 dose-escalation evaluated three doses of nvtm once-daily (Day 1-7/28-day cycle) added to acala 100 mg twice-daily continuously to determine the RP2D for expansion (n=30). An initial 28-day lead-in of monotherapy acala was tested but closed after the first six pts enrolled. Primary objectives were determine the RP2D (Ph 1b) and the rate of CR/CRi (Ph 2). Key secondary objectives included overall response rate (ORR), duration of response, and safety and tolerability. Results: As of 06 February 2023, 15 pts were enrolled in the Ph 1b portion at 10 sites in six countries with a median age of 64 years, ECOG 0-1, 73% Binet Stage B/C disease. Pts had a median one line of prior therapy, nearly half were IGHV unmutated, 27% had del11q and no pts had del17p (Table 1). There were no dose limiting toxicities, and the RP2D was 240 mg (Day 1-7/28-day-cycle). Response evaluable pts treated at the RP2D ≥6 months (n=7) demonstrated an 86% ORR (≥PR) with two CR/CRi at Week 32 (Table 2). Six pts were dosed with nvtm and acala concurrently from C1D1 and all showed minimal lymphocytosis with rapid reduction in absolute lymphocyte count (Figure 1). All pts experienced a treatment-emergent AE (TEAE) with the most common any grade (Gr) TEAEs (>20%), regardless of causality, nausea (80%), diarrhea (60%), constipation (47%), fatigue (40%), vomiting (40%), headache (40%), thrombocytopenia (33%), cough (27%), dizziness (27%). Gr3/4 TEAEs were reported in 73% of pts; the most common Gr3/4 (>10%) were diarrhea, thrombocytopenia, neutropenia (13% each). There were no Gr5 TEAEs. At the RP2D, TEAEs led to nvtm dose reductions in 3 pts (Gr2 diarrhea, Gr4 neutropenia, Gr2 vomiting), acala in 2 pts (Gr2 diarrhea 1 pt, Gr2 vomiting/headache 1 pt). One pt discontinued study (Gr3 vomiting). Summary/Conclusion: Nvtm combined with acala has an acceptable safety profile with no DLTs in dose escalation and showed encouraging preliminary activity in BTKi-naïve R/R CLL/SLL. Two out of seven pts (29%) reported CR/CRi at ≥6 months follow-up. Ph2 expansion is ongoing.Keywords: TP53, Chronic lymphocytic leukemia, B-CLL, relapsed/refractory