zilovertamab vedotin (MK-2140)

P3, N=1046, Not yet recruiting, Merck Sharp & Dohme LLC

P2/3, N=290, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Jun 2027 --> Sep 2027 | Trial primary completion date: Jun 2027 --> Sep 2027

The total mAb, acMMAE, and free MMAE model showed a good fit to the data. The pediatric population can match the acMMAE adult exposure at the same weight-based dose regimen without concerns that the toxic MMAE concentration will reach higher levels than found in adults.

P2, N=60, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting | Trial completion date: Jan 2026 --> Apr 2029 | Trial primary completion date: Jan 2026 --> Apr 2029

P2, N=102, Terminated, VelosBio Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Completed --> Terminated; Business reasons

P1/2, N=90, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P1/2, N=90, Not yet recruiting, Merck Sharp & Dohme LLC

P2/3, N=260, Recruiting, Merck Sharp & Dohme LLC | N=420 --> 260 | Trial completion date: Dec 2025 --> Jun 2027 | Trial primary completion date: Dec 2025 --> Jun 2027

P1, N=91, Completed, VelosBio Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Active, not recruiting --> Completed | N=330 --> 91

P2, N=140, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

P1, N=330, Active, not recruiting, VelosBio Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Trial primary completion date: Sep 2023 --> Dec 2023

Zilovertamab vedotin showed preliminary evidence of efficacy and no evidence of on-target off-tumor toxicity in patients with advanced B cell malignancies (Wang 2022)...Subjects will receive a conditioning regimen of intravenous (IV) cyclophosphamide and fludarabine, followed by ONCT-808 IV infusion...The trial is currently active and patients have been treated in the phase 1 dose escalation. Clinical Trial Identifier: NCT05588440

In this updated analysis of waveLINE-004, zilovertamab vedotin continued to demonstrate clinically meaningful antitumor activity in pts with R/R DLBCL who had progressed after or were ineligible for ASCT and/or CAR T-cell therapy. The safety profile of zilovertamab vedotin was manageable, and consistent with the known profile of MMAE-containing agents.

P1/2, N=40, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

P2, N=102, Completed, VelosBio Inc. | Active, not recruiting --> Completed | N=210 --> 102

At the data cutoff (Nov 16, 2022), 40 pts had been enrolled and had received ≥1 dose of zilovertamab vedotin; 23 (58%) pts had discontinued treatmentand 17 (43%) were ongoing.The median age was 68.0 years, 29 pts (73%) were male, 37 pts (93%) had an ECOG PS of 0 or 1,and 24 pts (60%) had received ≥3 prior lines of therapy. Theseearly results from waveLINE-004 show that zilovertamab vedotin had clinically meaningful antitumor activity and a manageablesafety profilethat was consistent with other monomethyl auristatin E–containing agents in pts with R/R DLBCL who had progressed after or wereineligiblefor ASCTand CAR-Tcell therapy.

The results of this updated analysis support prior findings from waveLINE-001 showing ZV had a tolerable safetyprofile and promising antitumor activity in pts with heavily pretreated DLBCL, MCL, and RT, including those who had received prior CAR-T/CAR-NK therapy.

P2, N=210, Active, not recruiting, VelosBio Inc. | Recruiting --> Active, not recruiting | Trial completion date: Nov 2024 --> Aug 2023 | Trial primary completion date: May 2024 --> Jul 2023

P2, N=210, Recruiting, VelosBio Inc. | Trial completion date: Mar 2024 --> Nov 2024 | Trial primary completion date: Sep 2023 --> May 2024

Updated results from WAVELINE-001 support prior analyses showing ZV had a tolerable safety profile and promising response rates, and favorable PFS and OS among heavily pre-treated pts with DLBCL, MCL, and RT, including pts who had received prior CAR-T/CAR-NK therapy.

Large gains were made in the first decade of the new century when clinical trials established the importance of high-dose therapy and autologous stem-cell rescue and high-dose cytarabine in younger patients and the benefits of maintenance rituximab and bendamustine in older patients...In newly diagnosed patients with MCL ineligible for intensive therapy and ASCT, the standardof-care has generally been R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by rituximab, maintenance. In recent years, bendamustinebased therapy has been increasingly adopted for older MCL patients and more recently, vincristine has been replaced by bortezomib in the R-CHOP combination as VR-CAP for previously untreated patients...In particular, agents recently approved by the Food and Drug Administration include the proteasome inhibitor bortezomib, immunomodulator lenalidomide, and Bruton's tyrosine kinase inhibitor ibrutinib...Acalabrutinib, originally referred to as ACP-196, is a novel, irreversible BTK inhibitor that was designed to be more kinase-selective than ibrutinib. Orelabrutinib is an orally administered, potent, irreversible and highly selective BTK-inhibitor being developed the treatment of B cell malignancies and autoimmune diseases. Tirabrutinib irreversibly and covalently binds to BTK in B cells and inhibits aberrant B cell receptor signalling in B cell-related cancers and autoimmune diseases. Zanubrutinib received accelerated approval in the USA on 14 November 2019 for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy, based on overall response rate (ORR) seen in phase II and I/II clinical trials. Palbociclib is a specific, potent, oral inhibitor of CDK4/6 capable of inducing a complete, prolonged G1 cell cycle arrest (pG1) in Rb+ MCL cells. Zilovertamab vedotin is an antibodydrug conjugate, which binds specifically to receptor tyrosine kinase-like orphan receptor-1 (ROR-1), an oncoprotein that is pathologically expressed in mantle cell lymphoma and other malignancies. The development of anti-CD19 CAR T-cell therapy represents a major advance in the treatment of patients with chemorefractory B-cell malignancies.

PFS, disease control rate by BICR, overall survival, ORR per investigator review, pharmacokinetic profile, biomarker analysis (including correlation of outcomes and ROR1 expression on tumor cells), and health-related quality of life are exploratory end points. ORR with 95% CI will be estimated by the Clopper-Pearson method.

In the part 1 dose confirmation phase, 30 patients from cohort A will receive ZV at increasing doses of 1.75, 2.0, 2.25, and 2.5 mg/kg; starting at 1.75 mg/kg plus gemcitabine-oxaliplatin + rituximab (R-GemOx) to establish the recommended phase 2 dose using the mTPI design...The safety run-in phase of part 2 will include 30 patients from cohort B who will receive ZV + bendamustine and rituximab (BR)...Key secondary end points in the dose expansion phase of part 2 for both cohorts include objective response rate (complete response and partial response) and duration of response, both by BICR per Lugano 2014 criteria, and overall survival. Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

P2, N=60, Ongoing, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc

Given their excellent activity in the relapsed/refractory setting, increasingly, biologically targeted therapeutics-such as covalent Bruton tyrosine kinase inhibitors, lenalidomide, and venetoclax-are being incorporated into "chemotherapy-free" regimens and in combination with established chemoimmunotherapy backbones for treatment-naïve mantle cell lymphoma. After Bruton tyrosine kinase inhibitor failure, many promising standard or investigational therapies exist, including CAR T-cell therapy (including brexucabtagene autoleucel and lisocabtagene maraleucel), bispecific antibody therapy targeting CD20-CD3, zilovertamab vedotin (an antibody-drug conjugate that targets ROR1), and the noncovalent Bruton tyrosine kinase inhibitor pirtobrutinib. These new therapies show promising efficacy, even among high-risk patients, and will likely translate to improvements in survival outcomes for patients with progressive mantle cell lymphoma following treatment with a Bruton tyrosine kinase inhibitor.

For pts who received prior CAR-T/CAR-NK, the ORR was 40.0% (95% CI, 16.3%-67.6%); 2 pts had a CR and 4 had a PR. Conclusion Targeting the ROR1 pathway with zilovertamab vedotin is associated with a tolerable safety profile and promising antitumor activity in pts with relapsed/refractory NHL.

P2, N=210, Recruiting, VelosBio Inc. | N=90 --> 210

These data suggest that targeting the ROR1 pathway with zilovertamab vedotin is associated with a tolerable safety profile and promising antitumor activity in patients with relapsed/refractory NHL.

Brexucabtagene autoleucel, the first and only FDA approved chimeric antigen receptor (CAR) T product in MCL, demonstrated unprecedented efficacy in overcoming resistance to Bruton's tyrosine kinase inhibitors...Importantly, VLS-101 safely induced tumor regression in PDX models resistant to CAR T-cell therapy, ibrutinib and/or venetoclax...These data also provide strong evidence for future enrollment of post-CD19 CAR T-cell relapsed MCL patients in a first in-human phase 1b VLS-101 trial. The upcoming testing in a clinical setting will provide important insights on this new therapeutic development aiming to overcome the CAR T resistance via targeting ROR1, which is a rising unmet clinical need in MCL.

There are currently three FDA-approved irreversible BTKifor the treatment of R/R MCL, including ibrutinib, the first approved BTKi, and the more selective BTKi, acalabrutinib and zanubrutinib...A phase 3 trial in R/R MCL randomizing patients to the investigator’s choice of approved covalent BTKiversus pirtobrutinib is planned...A large phase 3 study (NCT03112174) comparing single-agent ibrutinib to the combination of ibrutinib and venetoclax has completed accrual but has yet to be reported...The selective PI3K inhibitor parsaclisib has activity in patients with BTKi-naïve and BTKipreviously treated MCL...VLS-101, an anti-ROR1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE), has shown early promising activity in R/R MCL...Chimeric Antigen Receptor T-Cells Brexucabtagene autoleucel was the first autologous CD19-directed cellular therapy approved by the FDA in R/R MCL, based on results of the pivotal phase 2 trial that reported on 60 patients evaluable for response, with an ORR of 93%, including 67% CR.11 With a median follow-up of 12 months, the 1-year PFS and OS were 61% and 83%, respectively...Lisocabtagene maraleucel is a second autologous CD19-directed cellular therapy being evaluated in R/R MCL with preliminary results of 32 patients treated in the phase 1 trial reporting an ORR of 84% and a CR rate of 66%; with a median follow-up of 6 months, the median PFS and OS were not reached.12 Any grade CRS was reported to be 59%, and any grade neurotoxicity 34%, suggesting an improved toxicity profile...However, almost all patients will progress on BTKitherapy, resulting in the need to both improve outcomes using BTKi-based combinations and the need for effective therapies at progression, which will become even more critical as BTKiare moved into upfront treatment approaches. The recent approval of a CAR-T cell product has provided an effective therapy option for such patients after progression on BTKitherapies, and the sequencing of this earlier in the treatment of patients with high-risk disease features is attractive.

ROR1 is also involved in mediating drug resistance (for example to chemotherapies as well as to the targeted therapy T-DM1), activation of YAP/TAZ signalling and up-regulation of BMI-1...This has been fuelled by recent Phase I clinical data for the ROR1 ADC, VLS-101, in patients with advanced MCL and DLBCL and the potential of ROR1-targeting drug conjugates for the treatment of ROR1+ solid tumour indications...As the lead Candidate progresses toward clinical development, we anticipate that this excellent pre-clinical profile will translate to a highly differentiated product for the treatment of both solid tumor and haematological cancer indications. In addition, the flexible formatting accessible using our drug discovery platform has allowed us to readily access ROR1-targeting bi-paratopic and bi-specific therapeutic formats.

UC-961 (cirmtuzumab), a humanized IgG1 monoclonal antibody, binds with high affinity to a specific extracellular epitope of human ROR1 and rapidly internalizes and traffics to lysosomes. VLS-101 and VLS-211 showed expression-level dependent activity against ALL and EWS models. These results support ROR1 as a relevant immuno-oncology target for the subset of B-ALL and Ewing sarcoma cases with elevated ROR1 expression. Further research is required to identify the optimal payload for ROR1 ADCs for use against pediatric cancers.

Our results confirm ROR1 as a target in RS and demonstrate the therapeutic potential of using an ADC directed toward ROR1 for the treatment of hematological cancers. A Phase 1 clinical trial of VLS‑101 (NCT03833180) is ongoing in patients with RS and other hematological malignancies.

VLS-101, utilizes the UC-961 anti-ROR1 antibody which is conjugated to monomethyl auristatin E (MMAE) via a cleavable linker...VLS-101 treatment of ibrutinib-venetoclax dual-resistant ROR1+ PDX model resulted in significant regressions of the tumor bearing spleens and livers when compared to vehicle controls (p=0.0001 and p=0.002 respectively)...Importantly, our study revealed that even the heavyly pretreated tumors in the clinical setting may express targetable levels of ROR1 and that targeting ROR1 using ADC is a promising approach for the treatment of MCL. Building on these types of results, a Phase 1 clinical trial on VLS-101 (NCT03833180) is ongoing in patients with lymphoid cancers.

VLS‑101 is an antibody-drug conjugate (ADC) comprising a rapidly internalizing, humanized monoclonal antibody (UC-961) that recognizes extracellular ROR1, a cleavable linker, and the anti-microtubule cytotoxin, monomethyl auristatin E (MMAE). In heavily pretreated patients, VLS-101 infusions were well tolerated and demonstrated a predictable safety profile consistent with an MMAE-containing ADC. Tumor selectivity was confirmed, with no evidence of ROR1-mediated toxicities or non-MMAE toxicities that would suggest normal tissue binding. Considering all data, the VLS‑101 RDR was 2.5 mg/kg every 3 wk.