On December 10, 2022 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported updated interim clinical data from ongoing Phase 1/2 Study CIRM-0001 in an oral presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2022 Annual Meeting (Press release, Oncternal Therapeutics, DEC 10, 2022, View Source [SID1234625027]). In the study, zilovertamab, an investigational anti-ROR1 monoclonal antibody, is being evaluated in combination with ibrutinib in patients with mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and in a recently opened cohort for patients with marginal zone lymphoma (MZL). The clinical trial is being conducted in collaboration with the University of California San Diego (UC San Diego) and has been partially funded by the California Institute for Regenerative Medicine (CIRM).

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"The data presented in today’s oral session further strengthens our confidence in the significant clinical benefit the combination of zilovertamab and ibrutinib can provide to patients with MCL and CLL. The rapid onset of deep responses in patients with MCL supports our recently initiated randomized global registrational Phase 3 Study ZILO-301 of the combination of zilovertamab plus ibrutinib," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. "The robust response rates and prolonged PFS seen for MCL and CLL patients expressing the p53 mutation/del(17p), who are underserved by current standard of care treatments, is especially exciting. We continue to believe that the inhibition of ROR1 with zilovertamab can play a key role in addressing important unmet medical needs in difficult-to-treat patients across various hematological malignancies."

The updated interim data presented during an oral presentation at the ASH (Free ASH Whitepaper) 2022 meeting include 33 patients with relapsed/refractory (R/R) MCL enrolled in the dose-finding and dose-expansion cohorts of Study CIRM-0001 (Part 1 + Part 2), of whom 28 were evaluable for efficacy as of the October 11, 2022 data cut-off date.

Patients had high-risk factors and were heavily pre-treated at study entry, with 52% having a high Ki-67 proliferative index (≥30%), 47% with p53 mutations or deletions in chromosome 17p (del(17p)), and 46% having an intermediate or high sMIPI prognostic score.
The objective response rate (ORR) was 89% (25 of 28 evaluable patients) and includes recently enrolled patients.
The complete response (CR) rate was 43% (12 of 28 evaluable patients) at 26 months and was already 18% (5 of 28 evaluable patients) at 3 months.
Historical data published for single agent ibrutinib for 370 patients with R/R MCL from three clinical trials showed an ORR of 66%, CR rate of 20% and median PFS of 12.8 months (Rule 2017, British Journal of Haematology).
The partial response (PR) rate was 46% (13 of 28 evaluable patients), and the stable disease (SD) rate was 4% (1 of 28 evaluable patients), for a total clinical benefit rate (CR, PR and SD) of 93%.
The median PFS has not been reached after a median follow-up of 19.5 months (95% CI: 19.4, 28.5), regardless of the number of prior systemic therapies.
Median PFS was also favorable in patients with high-risk features associated with disease difficult-to-treat with BTK inhibitors:
P53 mutation/del(17p): median PFS not reached (95% CI: 2.85, NE). Historical data for single agent ibrutinib in 20 patients with p53 mutation showed a median PFS of 4.0 months (Rule 2019, Haematologica).
Ki-67 ≥30%: median PFS 33.2 months (95% CI: 2.85, NE).
>1 prior systemic therapy: median PFS not reached (95% CI: 4.33, NE).
Thirty-four patients with CLL in the dose-finding and dose-confirming cohorts of this clinical trial (Part 1 & Part 2) as of the October 11, 2022 data cut-off date were all evaluable for efficacy. Patients had high-risk factors, and most were heavily pre-treated at study entry, with a median of two systemic prior therapies (range 1-9).

Landmark PFS was 100% at 42 months in patients with R/R CLL expressing p53 mutation/del(17p) treated with the combination of zilovertamab plus ibrutinib. The most recent data update from the ALPINE study in patients with R/R CLL expressing p53 mutation/del(17p) showed a landmark PFS of 77.6% at 24 months for zanubrutinib monotherapy and 55.7% at 24 months for ibrutinib monotherapy (Brown 2022, ASH (Free ASH Whitepaper)).
Landmark PFS was 95% at 24 months in all patients with R/R CLL treated with the combination of zilovertamab plus ibrutinib. The most recent data update from the ALPINE study in R/R CLL patients showed a landmark PFS at 24 months of 79.5% for zanubrutinib and 67.3% for ibrutinib monotherapy (Brown 2022, ASH (Free ASH Whitepaper)).
The median overall survival (OS) was not reached at 40 months for patients with CLL with p53 mutation/del(17p).
Thirty-one patients with CLL have also been enrolled in the randomized efficacy cohort of this clinical trial (Part 3), of which 23 were evaluable for efficacy. Data from this cohort are maturing. The median PFS had not been reached for either group as of the October 11, 2022 cut-off date after a median follow up of 29 months.

The combination of zilovertamab plus ibrutinib has been well tolerated as of the October 11, 2022 cut-off date, with treatment emergent adverse events consistent with or slightly improved compared to those reported for ibrutinib alone. There have been no dose-limiting toxicities and no serious adverse events attributed to zilovertamab alone. Atrial fibrillation was observed in only 9.4% of the patients and febrile neutropenia in 1.2% of patients.

About the CIRM-0001 Study
The CIRM-0001 Study is a Phase 1/2 trial evaluating zilovertamab in combination with ibrutinib in separate groups of patients with CLL, MCL or MZL. Enrollment of the dose-finding cohorts in CLL and MCL, dose-expansion cohort in CLL and MCL and randomized Phase 2 cohort in CLL has been completed. An additional dose-expansion cohort of up to 10 patients with MZL has started enrolling patients. Additional information about the CIRM-0001 clinical trial and other clinical trials of zilovertamab may be accessed at ClinicalTrials.gov.

About Zilovertamab
Zilovertamab is an investigational, humanized, potentially first-in-class monoclonal antibody targeting Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1). A Phase 3 registrational trial evaluating zilovertamab plus ibrutinib versus ibrutinib plus placebo in relapsed or refractory Mantle Cell Lymphoma (MCL) has been initiated (NCT05431179). Zilovertamab is also being studied in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of patients with MCL, chronic lymphocytic leukemia (CLL) or marginal zone lymphoma (MZL), in a collaboration with the University of California San Diego (UC San Diego) School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, Oncternal is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine, a Phase 1b clinical trial for patients with metastatic castration-resistant prostate cancer (mCRPC), and a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, for patients with relapsed/refractory CLL. Both are open for enrollment.

ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen, not usually expressed on adult cells, but its expression confers a survival and fitness advantage when reactivated and expressed by tumor cells. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to specifically inhibiting ROR1-expressing tumors. This led to the development of zilovertamab which binds this critical epitope of ROR1, highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when zilovertamab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. The FDA has granted Orphan Drug Designations to zilovertamab for the treatment of patients with MCL and CLL/small lymphocytic lymphoma. Zilovertamab is in clinical development and has not been approved by the FDA for any indication.