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

The parent macrocyclic peptides represented by Compound 1 and Compound 14 displayed nanomolar cell-based binding to ROR1 and relatively good internalization in 786-O and MDA-MB-231 tumor cell lines. However, these peptides were not observed to induce apoptosis in Mia PaCa-2 cells, a model pancreatic tumor cell line with a relatively low level of cell surface expression of ROR1.

P1, N=156, Recruiting, CStone Pharmaceuticals | Trial completion date: Mar 2024 --> Jun 2025

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.

Outlining the discovery and development of a novel ROR1 ADC using a newly designed β-Glu Exatecan linker payload; Providing an overview of the preclinical characterization of STRO-003 anti-tumor efficacy across xenograft and PDX tumor models; Highlighting the pharmacokinetics and attractive safety profile of STRO-003 in non-human primates

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

Follow-up vaccination studies were performed to further explore the significance of STRO-003-induced ICD and protective immunity in vivo. These results demonstrate that tumor cells pre-treated with STRO-003 or SC3386 undergo potent immunogenic cell damage which can, in turn, mount protective immunity in vivo.

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.

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.

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.

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

Since all the components of ADCs, including the antibody, linker and payload, as well as the conjugation method, play critical roles in ADC's efficacy and performance, their choice and combination will determine how far they can be advanced. This review summarizes the design and development of current anti-ROR1 ADCs and highlights an emerging trend to target ROR1 for cancer therapy.

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.

In combination with other clinically relevant targeting drugs as venetoclax a synergistic apoptotic effect was seen. Two other small molecules (ARI-1 and strictinin) bound also to ROR1 and inhibited tumor growth. Development of small molecule ROR1 inhibitors is warranted to include this novel therapeutic approach for cancer therapy.

Options in this setting may depend of treatment availability, patient and physician preference, and patient age and comorbidity status. We discuss the rapid recent development of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in this space as well as the utility of allogenic stem cell transplantation and novel therapies such as non-covalent, reversible BTK inhibitors, ROR1 antibody drug conjugates and bispecific antibodies.

The activity of NM32-2668 has the potential to provide significant benefit to patients with ROR1+ malignancies on a convenient dosing schedule. We intend to rapidly progress NM32-2668 to clinical development.

No abstract available

Lastly, we show that the B-cell lymphoma 2 (BCL2)-dependent cytotoxicity of huXBR1-402-G5-PNU can be leveraged by combined treatment strategies with the BCL2 inhibitor venetoclax. Together, our data present compelling preclinical evidence for the efficacy of huXBR1-402-G5-PNU in treating ROR1+ hematologic malignancies.

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.

AZD5991 is a highly selective BH3-mimetic that demonstrates high in vitro potency in MCL1-dependent cell lines with an IC50 <1 nM.7 We have demonstrated that direct MCL1 inhibition with AZD5991 disrupts survival of neoplastic B-cells in lymph-node mimicking conditions, induces mitochondrial dysfunction and cooperates with BCL2/X inhibitors in vitro and in vivo.8 A phase 1 clinical trial of AZD5991 alone or in combination with venetoclax in hematologic malignancies is ongoing (NCT03218683)...AMG-176 demonstrated synergy with venetoclax in AML models; however, it also caused cytopenias.9 AMG-176 was shown to induce apoptosis of CLL cells independent of prognostic markers and overcame the protective effect of stromal microenvironment.10 However, suppressive effects on hematopoiesis will likely become the dose- limiting factor in clinical trials of MCL1-targeting agents. The effect of MCL1 inhibition on cord blood-derived CD34+ cells was studied using a small-molecule inhibitor, S63845,11 resulting in almost complete depletion of human hematopoietic stem and progenitor cells, while mature blood cells survived normally...We have shown that SYK inhibition with entospletinib leads to downmodulation of MCL1 protein in CLL both in vitro and in the clinic.12,13 Treatment of CLL cells with entospletinib, but not other BCR-signaling inhibitors, led to a disruption of BAFF-BCR cross-talk and downmodulation of MCL1 mRNA and protein, thus implicating SYK in transduction of multiple pro-survival signals emanating from the tumor microenvironment.13 Entospletinib has shown promising clinical activity in CLL.12,14 It is currently being developed in myeloid malignancies.15 A novel dual SYK/BTK inhibitor luxeptinib also was shown to downregulate MCL1 and other pro-survival BCL2 proteins in CLL.16 Transcriptional cyclin-dependent kinases (CDK7/9) regulate activity of RNA polymerase, thereby controlling production of mRNA. Downmodulation of MCL1 has been considered a key mechanistic event accounting for the pro-apoptotic activity of CDK inhibitors in neoplastic B-cells.17,18 Pan-CDK inhibitors (flavopiridol, dinaciclib) demonstrate clinical efficacy in lymphoid malignancies. We and others reported that preclinical efficacy of AZ5576, a selective inhibitor of CDK9, and its clinical congener AZD4573 in lymphoid tumors depended on rapid downmodulation of MCL1, BFL1, and MYC.19–21 CDK9 inhibition can increase efficacy of BH3-mimetics, but safety of this combination will need to be explored.22,23 CDK9 inhibitors in development, in addition to AZD4573, include VIP152, CYC065, and voruciclib...Navitoclax is a small-molecule inhibitor of BCL2, BCLX, and BCL2L2; however, its use in CLL has been plagued by thrombocytopenia.24 AZD4320 is an alternative agent that co-targets BCL2/X...ABBV-155, an antibody-drug conjugate targeting BCLX, where BCLX is being used as a payload to avoid “off-tumor” effects, demonstrated promise in solid tumor models.26 Finally, as many microenvironment-driven pro-survival pathways converge on NFB, leading to induction of chemokines, cell cycle regulators, and BCL2 family proteins themselves, this transcription factor continues to be an attractive target in CLL...When combined with ibrutinib in murine CLL models, VAY-736 produced prolonged survival compared with either therapy alone.28 Alternative targets for therapeutic antibodies include ROR1 (cirmtuzumab), CD19 (tafasitamab), and others.29 As resistance to novel agents is becoming an unmet need in CLL, exploration of novel targets is of paramount importance...Multiple CDK inhibitors are currently being explored and have anti-tumor effects not restricted to MCL1 inhibition. CAR T cells and bi-specific antibodies have exceptional efficacy in lymphoid malignancies and thus are of high relevance in CLL.

Ph 1 dose escalation was initiated on 17 JULY 2020 and is still recruiting in the US . Ph 2 is planned to be initiated in 2022.

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.