P1, N=6, Terminated, University of California, San Diego | N=32 --> 6 | Trial completion date: Feb 2026 --> Oct 2024 | Recruiting --> Terminated | Trial primary completion date: Feb 2025 --> Oct 2024; Oncternal closing clinical trial operations.

P1/2, N=102, Completed, Oncternal Therapeutics, Inc | Active, not recruiting --> Completed

Among them, Compounds 10, 17, and 20 exhibited significant antiproliferative activities with IC50 values of 1.92-8.82 μM, which are very similar to that of the positive control doxorubicin. Molecular mechanistic studies showed that the antitumour activity of Compound 10 was closely related to regulation of the ROR1 and ErbB3 signalling pathways. This study may provide insight into the discovery and utilization of marine macrocyclic cembranoids as lead compounds for anticancer drugs.

P1, N=29, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Jun 2024 --> Oct 2024 | Trial primary completion date: Jun 2024 --> Oct 2024

P1, N=40, Recruiting, Second Affiliated Hospital of Guangzhou Medical University | Trial primary completion date: Dec 2025 --> Dec 2029

P2, N=90, Not yet recruiting, Shanghai Jiaolian Drug Research and Development Co., Ltd

P1, N=15, Recruiting, Pure Biologics S.A. | Not yet recruiting --> Recruiting

P1, N=22, Completed, Barbara Parker, MD | Active, not recruiting --> Completed | Phase classification: P1b --> P1

P1, N=58, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=180, Recruiting, Numab Therapeutics AG

The combination of zilovertamab and paclitaxel was safe and well tolerated in heavily pre-treated advanced breast cancer patients. Further evaluation of ROR1 targeting in breast cancer patients with zilovertamab is warranted.

P1, N=15, Not yet recruiting, Pure Biologics S.A.

P1, N=29, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Nov 2023 --> Jun 2024 | Trial primary completion date: Nov 2023 --> Jun 2024

Strictinin was further identified as synergistic with docetaxel [combination index (CI) = 0.311] and the combination therapy was found to reduce the IC of strictinin to 38.71 µmol/L in PC3 cells. ROR1 is an emerging molecular target that can be utilized for treating prostate cancer. The data from this study establishes strictinin as a potential therapeutic agent that targets AR-AI prostate cancer with elevated ROR1 expression to reduce the migration, invasion, cell cycle progression, and survival of prostate cancer.

P1, N=32, Recruiting, University of California, San Diego

P1/2, N=40, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd.

P1/2, N=102, Active, not recruiting, Oncternal Therapeutics, Inc | Phase classification: P1b/2 --> P1/2

Co-culture of Jurkat-Lucia cells for 6 hours with the anti-CD20 mAb rituximab and MEC1 or MEC1-ROR1 cells induced Jurkat-Lucia cells to express a luciferase reporter gene under the control of an ISG54 minimal promoter fused to six NFAT response elements; this endowed the Jurkat-Lucia cells with high luminescence activity that was not observed in co-cultures of EC and TC without added mAb. ROR1 + CLL cells harboring del(17p) or mutations in TP53 (del(17p)/m TP53) and/or that were resistant to targeted therapies (e. g. , inhibitors of BTK or BCL2), were as susceptible to GE-zilovertamab-directed ADCC as were CLL cells without del(17p)/m TP53 from patients who had not had prior therapy. These data demonstrate that GE-zilovertamab can direct high-level ADCC lysis of ROR1-expressing neoplastic cells with greater activity than zilovertamab, encouraging development of clinical studies to evaluate GE-zilovertamab for therapy of patients with CLL or other ROR1-positive cancers.

P2, N=5, Active, not recruiting, University of California, San Diego | Recruiting --> Active, not recruiting | N=16 --> 5

P1/2, N=40, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting

P1, N=32, Recruiting, University of California, San Diego | Phase classification: P1b --> P1

Zilo + Ibr is well-tolerated with a safety profile that is comparable to Ibr alone. For pts with CLL, Zilo + Ibr is very active and results in durable remissions. The PFS and OS for the subgroup with TP53 mut/del(17p) are particularly encouraging in reference to other trials of BTK inhibitors, maintaining 100% PFS and OS at ∼42 mos.

We utilized the humanized scFv binding domain of zilovertamab (formerly UC-961 and then cirmtuzumab), which showed high affinity and specificity for human ROR1 and a highly favorable safety profile in Phase-1 clinical evaluation [1]...We conclude that lentivirus encoding this anti-ROR1 CAR construct can generate anti-ROR1 CAR T cells using T cells of healthy donors or patients with CLL that are highly effective in killing ROR1-expressing leukemia cells in vitro or in vivo. Moreover, the anti-ROR1 CAR T cells generated using this construct may provide for selective killing of CLL cells without affecting normal CD19/CD20-expressing B cells of patients with CLL, thereby mitigating the risk for further enhancing immune deficiency, such as observed in patients treated with anti-CD19 CAR T cell therapy.

P1, N=58, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Jun 2023 --> Dec 2023 | Trial primary completion date: Jun 2023 --> Dec 2023

P1/2, N=40, Not yet recruiting, Sichuan Baili Pharmaceutical Co., Ltd.

P1, N=90, Recruiting, NovalGen Ltd. | Phase classification: P1/2 --> P1

Overall, our results highlight that incorporation of a functional αCD38-CAR construct into a suitable NK-cell expansion and activation protocol results in a potent and feasible immunotherapeutic strategy for the treatment of patients with MM.

Collectively, our study indicated that dexamethasone up-regulated ROR1 levels on gastric cancer cells. ROR1 participated in and mediated the role of dexamethasone in promoting gastric tumor growth, and blocking ROR1 can prevent the tumor growth.

P1b, N=22, Active, not recruiting, Barbara Parker, MD | Trial completion date: Jan 2023 --> Jan 2024

P1b/2, N=102, Active, not recruiting, Oncternal Therapeutics, Inc | Recruiting --> Active, not recruiting | Trial completion date: Apr 2027 --> Aug 2024 | Trial primary completion date: Mar 2025 --> Aug 2024

P3, N=365, Ongoing, Oncternal Therapeutics, Inc

P1, N=0, Withdrawn, Sichuan Baili Pharmaceutical Co., Ltd. | N=29 --> 0 | Recruiting --> Withdrawn

In conclusion, ABL102 exhibited potent in vitro and vivo anti-tumor activity and it was well tolerated and safe in the NHP toxicity study. These results strongly suggest that ABL102 is promising therapeutics for ROR1 positive cancer patients.

Clinical studies using ROR1 targeting antibodies (Zilovertamab) to treat hematologic malignancies did not reveal relevant clinical toxicity, encouraging the initiation of clinical trials to assess the safety and efficacy of ROR1-CAR-T therapy... With this novel protocol, we aim to obtain the first manufacturing license for CAR-T in Europe that integrates our optimized approach with SB100X mRNA and MC for CAR gene-transfer on the MaxCyte transfection platform. The quality of the drug product supports the developement of a clinical trial with ROR1-CAR-T, and will serve as a blueprint for other CAR-T products.

Finally, results of tumor challenge in immunized mice showed that immunization with TT-mROR1-Fc fusion proteins completely inhibited ROR1+ tumor cells growth in two different syngeneic tumor models until day 120 post tumor challenge. Our preclinical findings, for the first time, showed that our fusion proteins could be considered as a potential candidate vaccine for active immunotherapy of ROR1-expressing malignancies.

We have generated a first in class ROR1 targeting half-life extended TCE that maintains the functional and biophysical properties of the clinically promising NVG-111. Our systematic evaluation suggests that careful selection of HLE format is critical for the development of a molecule with good yield, biophysical characteristics and potency. The selected ROR1 HLE-TCE supports weekly administration whilst maintaining potency at sub-nanomolar concentrations, properties which differentiate it from other TCEs in development.