Table 3.
Drugs targeting the NOTCH signaling pathway assessed in clinical trials
| Type | Drugs | NCT/Ref. | Year | Phase | Status | Cancer type and patients | Results |
|---|---|---|---|---|---|---|---|
| GSI | PF-03084014 | NCT00878189560 | 2009 | I | Completed | Solid malignancies, N = 64 |
ORR: 13%; 1 CR observed in patients with advanced thyroid cancer, and 5 PRs in patients with desmoid tumors; All-grade AEs: 84.4%, grade ≥ 3 AEs: 35.9%. |
| NCT00878189665 | 2009 | I | Completed | T-ALL and T-LBL, N = 8 | 1 CR in a T-ALL patient with NOTCH1 mutation. | ||
| NCT02299635 | 2015 | II | Terminated | TNBC, N = 19 |
SAEs: 6/19; study terminated prematurely based on project reprioritization by the sponsor. |
||
| NCT01981551571 | 2013 | II | Active | Desmoid tumors (aggressive fibromatosis), N = 17 | 5 (29%) patients experienced a PR for more than 2 years with tolerable toxicity. | ||
| NCT04195399 | 2020 | II | Recruiting | Progressive, surgically unresectable desmoid tumors, N = 35 | - | ||
| RO4929097 | NCT00532090561 | 2007 | I | Completed | Platinum-resistant ovarian cancer, N = 110 |
1 PR in patients with colorectal adenocarcinoma with neuroendocrine features; 1 nearly complete FDG-PET response in a patient with melanoma. |
|
| NCT01119599562 | 2010 | 0/I | Completed | Glioma, N = 21 |
No dose-limiting toxicities were observed in combination with temozolomide; decreased expression of NICD in tumor cells and blood vessels. |
||
| NCT01175343569 | 2010 | II | Completed | Platinum-resistant ovarian cancer, N = 45 | No objective responses were observed. | ||
| NCT01122901666 | 2010 | II | Completed | GBM, N = 47 | Inactive in recurrent GBM patients. | ||
| NCT01120275568 | 2016 | II | Completed | Metastatic melanoma, n = 32 | Tolerated but did not achieve NOTCH target inhibition. | ||
| NCT01116687570 | 2010 | II | Completed | Metastatic colorectal cancer, N = 37 | No radiographic responses were seen, and time to progression was short. | ||
| MK-0752 | NCT00100152 | 2005 | I | Terminated | T-ALL, N = 50 |
1/6 patients showed 45% reduction in mediastinal mass; study was halted for severe diarrhea. |
|
| NCT00106145667 | 2005 | I | Completed | Solid tumors, N = 103 |
1 objective response and 10 cases of SD were observed in patients with high-grade gliomas; weekly dosing was generally well tolerated. |
||
| NCT00572182566 | 2008 | I | Terminated | Brain and central nervous system tumors, N = 33 |
No objective responses were reported in 23 pediatric patients; study terminated by sponsor. |
||
| NCT00645333668 | 2008 | I/II | Completed | Breast cancer, N = 30 | Enhanced the efficacy of docetaxel with manageable toxicity. | ||
| NCT00756717 | 2008 | IV | Completed | Breast cancer, N = 20 |
No serious adverse events; No available efficacy data.. |
||
| LY3039478 | NCT01695005565,669,670 | 2012 | I | Completed | Solid cancers, N = 237 |
Prednisone might reduce gastrointestinal toxicities; PR was observed in 1 patient with breast cancer, 1 patient with leiomyosarcoma and 1 patient with angiosarcoma. |
|
| NCT02518113671 | 2015 | I | Completed | T- ALL/T-LBL, N = 36 |
6 patients (16.7%) experienced DLTs; 1 patient (2.8%) had a confirmed response that lasted 10.51 months. |
||
| NCT02784795672 | 2016 | Ib | Completed | Solid cancer, N = 94 | Combination with other anticancer agents produced disappointing results. | ||
| LY900009 | NCT01158404564 | 2010 | I | Completed | Solid cancer, N = 35 |
No objective response; 5/35 patients had a SD. |
|
| AL101 | NCT04461600 | 2020 | II | recruiting | NOTCH-activated TNBC, N = 67 | - | |
| NCT04973683 | 2021 | I | recruiting | NOTCH-activated ACC, N = 12 | - | ||
| DLL3 | Rovalpituzumab tesirine (Rova-T) | NCT01901653673 | 2013 | I | Completed | SCLC, N = 74 |
11 (18%) patients had an objective response, ten of whom had high DLL3 expression; 28 (38%) suffered serious drug-related adverse events. |
| NCT02819999579 | 2016 | I | Terminated | SCLC, N = 26 | There was no clear efficacy benefit of combining Rova-T with platinum-based chemotherapy. | ||
| NCT03026166589 | 2017 | I/II | Terminated | SCLC, N = 42 |
ORR was 30% in patients treated with combination therapy with Rova-T and ICIs; however, the toxicity was high, suggesting that the combination was not well tolerated; enrollment was stopped because of the DLT. |
||
| NCT02674568586 | 2016 | II | Completed | SCLC, N = 339 |
Median OS was 5.6 months; grade 3-5 AEs were seen in 213 (63%) patients; Demonstrated modest clinical activity in 3L+ SCLC, with associated toxicities. |
||
| NCT03033511587 | 2017 | III | Terminated | SCLC, N = 748 |
Lack of survival benefit of maintenance therapy with rovalpituzumab tesirine after first-line platinum-based chemotherapy; the study did not meet its primary end point and was terminated early. |
||
| NCT03061812588 | 2017 | III | Completed | SCLC, N = 444 | Compared with topotecan, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reactions, and peripheral edema. | ||
| SC-002 | NCT02500914591 | 2015 | I | Terminated | SCLC, N = 35 |
5 (14%) patients achieved a PR; 37% of patients had serious AEs considered to be related to SC-002; no further development is planned because of the systemic toxicity and limited efficacy. |
|
| AM757 | NCT03319940 | 2017 | I | Recruiting | SCLC, N = 332 | - | |
| HPN328 | NCT04471727 | 2020 | I | Recruiting | SCLC, N = 67 | - | |
| DLL4 | Enoticumab (REGN421) | NCT00187159594 | 2015 | I | Completed | Solid tumors, N = 53 |
2 PRs were observed in patients with NSCLC and ovarian cancer; MTD was not reached. |
| Demcizumab (OMP-21M18) | NCT00744563595 | 2014 | I | Completed | Solid tumors, N = 55 | Demonstrated antitumor activity with a low dose. | |
| NCT01189968674 | 2010 | I | Completed | Metastatic nonsquamous NSCLC, N = 40 |
Modulated the expression of genes regulating NOTCH signaling and angiogenesis; increased the risk of cardiovascular disease when combined with pemetrexed and carboplatin. |
||
| NCT01952249596 | 2013 | Ib/II | Phase Ib, completed; phase II, terminated | Platinum-resistant ovarian, primary peritoneal, and fallopian tube cancer, N = 19 |
Researchers are no longer pursuing ovarian cancer as an indication; the phase II portion of the study was terminated. |
||
| NOTCH1 | Brontictuzumab (OMP-52M51) | NCT01778439420 | 2013 | I | Completed | Selected refractory solid tumors, N = 48 |
2 patients achieved PR and 4 patients achieved ≥ 6 months of SD in ACC with NOTCH1 activation; DLTs included diarrhea and fatigue. |
| NOTCH2/3 | Tarextumab (OMP-59R5) | NCT01277146616 | 2011 | I | Completed | Solid tumors, N = 42 |
9 subjects had SD; Lower doses were tolerated. |
| NCT01647828615 | 2012 | II | Completed | Untreated metastatic pancreatic cancer, N = 177 | There were no OS, PFS, or ORR benefits with the addition of tarextumab to nab-paclitaxel and gemcitabine in first-line metastatic PDAC. | ||
| NCT01859741 | 2019 | I/II | Terminated | SCLC, N = 172 | Terminated for unimproved PFS in combination with etoposide and platinum therapy. | ||
| NOTCH3 | PF-06650808 | NCT02129205617 | 2014 | I | Terminated | Breast cancer and other advanced solid tumors, N = 40 |
5 PRs were observed with manageable safety; all of responders had positive NOTCH3 expression; the study was terminated due to a change in sponsor prioritization. |
T-ALL T cell acute lymphoblastic leukemia, T-LBL T cell lymphoblastic lymphoma, TNBC triple-negative breast cancer, SCLC small-cell lung cancer, NSCLC non-small-cell lung cancer, PDAC pancreatic ductal adenocarcinoma, GBM glioblastoma, ORR objective response rate, CR complete response, PR partial response, SD stable disease, PFS progression-free survival, OS overall survival, AE adverse event, SAE serious adverse event, ACC adenoid cystic carcinoma, FDG-PET [18F]-2-fluoro-2-deoxy-D-glucose-positron emission tomography, DLT dose-limiting toxicity, NICD NOTCH intracellular domain, 3L+ more than 3 lines of therapy, MTD maximum tolerated dose