Phase 1/2 Study of Zilovertamab and Ibrutinib in Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL), or Marginal Zone Lymphoma (MZL).

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Hematological Oncology


Background: Zilovertamab (Zilo) is a humanized monoclonal antibody that inhibits the tumor promoting activity of the cancer stem cell receptor, ROR1, which is highly expressed in many hematologic malignancies but not on normal adult tissues. Methods: Patients (Pts) with relapsed or refractory (RR) MCL or MZL or treatment-naïve (TN) or RR CLL were enrolled. Part 1 (Dose Escalation in CLL & MCL) evaluated multiple doses up to Zilo 600 mg IV q4wks + Ibr 420 mg (CLL) or 560 mg (MCL) daily which was selected for Part 2 (Dose Expansion in CLL, MCL & MZL) and Part 3 (CLL only; pts randomized 2:1 to Zilo+Ibr vs. Ibr alone). Results: To date, 33 MCL, 62 CLL & 4 MZL (99) pts were treated in Parts 1, 2 & 3. In Parts 1&2, 28 RR MCL and 34 CLL (12 TN and 22 RR) on zilo+ibr were efficacy evaluable (MZL not yet evaluable). In Part 3, 23 CLL pts on Zilo+Ibr (16) or Ibr (7) were evaluable. Safety & efficacy results were as of 11 October 2022. Safety in MCL and CLL: The most frequent (≥30%) treatment emergent adverse events (TEAEs) for all MCL & CLL pts on Zilo+Ibr (n = 85) were diarrhea & fatigue (45.9%), contusion (38.8%) and cough (30.6%). The most frequent (≥5%) grade ≥3 TEAEs were hypertension (10.6%), pneumonia (8.2%), atrial fibrillation (AF) & neutropenia (7.1%), and fatigue (5.9%). For all MCL & CLL pts on zilo+ibr, grade ≥3 hematologic lab abnormalities were decreases in neutrophils (11.8%), platelets (4.7%), and hemoglobin (3.5%). Efficacy in MCL: The ORR was 89.3% (42.9% CR); 18% had achieved CR at 3 mos which suggests rapid response; median duration of response (mDOR) was 34.1 mos. Median PFS (mPFS) was not reached (NR) (95% CI: 33.2, NE) with median follow-up (mf/u) of 19.5 mos. Pts with 1 prior line of therapy (LOT) and >1 prior LOT had mPFS of 33.2 mos and NR, respectively. In pts with poor prognostic factors, 7 pts with TP53 mutation had ORR of 85.7% with mPFS NR and 14 pts with Ki-67 ≥30% had ORR of 85.7% with mPFS 33.2 mos. Overall, median OS was NR (95% CI: 22.46, NE). Efficacy in CLL: In parts 1–3, mPFS was NR with mf/u of 40 mos for parts 1&2 and ∼30 mos in part 3. In pooled analysis of all parts, mPFS in 10 pts (5 TN, 5 R/R) with TP53/del(17p) was NR and landmark PFS and OS were 100% at 42 & 40 mos, respectively. Conclusions: Zilo+Ibr is well-tolerated with a safety profile that is comparable to Ibr alone. AF (all grades) occurred in 9.4% of all pts treated which appears lower than rate in Ibr alone studies. The combination is very promising in pts with RR MCL (ORR 89.3%, CR 42.9%, mPFS NR). For CLL pts with TP53 mut/del(17p), Zilo+Ibr is also very active, maintaining 100% PFS and OS at ∼42 mos. This Zilo+ Ibr data after >3 years of f/u is very encouraging in reference to the ALPINE results which reported estimated PFS at 36 mos of ∼55% for Zanubrutinib and ∼42% for Ibr in RR CLL pts with TP53 mutation. The study is currently enrolling MZL pts and has provided a strong rationale for conducting a Phase 3 pivotal study in RR MCL (ZILO-301). The research was funded by: California Institute for Regenerative Medicine and Oncternal Therapeutics, Inc. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Chronic Lymphocytic Leukemia (CLL), Molecular Targeted Therapies

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