Table 2.
Clinical trials with monoclonal antibodies against Notch receptors and ligands in combination with chemotherapeutic drugs registered at clinicaltrials.gov.
| Agent | CT Identifier | Phase/Type | Cancer Type | Drug Combination | Results Description (as of 1 August 2021) |
|---|---|---|---|---|---|
| Tarextumab (OMP-59R5) | NCT01859741 | I/II | Stage IV SCLC | Etoposide and Cisplatin/Carboplatin | Phase I (n = 3, 5, 6 in different dose regimens): MTD was not reached, the recommended phase II determined as 15 mg/kg every 21-day cycle. PR or SD in 80–100% of participants in different OMP dose regimens. OMP-59R5 (15 mg/kg) + ETO + CIS: 83.3% PR, 16.7% PD; OMP-59R5 + ETO + CARB: 66.7% PR, 16.7% SD, 16.7% PD. Phase II (n = 72 in placebo + CIS/CARB, n = 73 in OMP-59R5 + ETO + CIS/CARB): during 1 year observation period, the frequency of disease progression or death in the group of placebo and OMP + ETO was 77.8% and 69.9%, respectively. The frequency of CR was 2.8% and 1.4%, PR 68.1% and 67.1%, SD—13.9% and 12.3% in the groups of placebo and OMP-59R5 + ETO, respectively. The frequency of serious adverse effects was 42.65% (placebo) and 53.62% (OMP-59R5 + ETO), among them: febrile neutropenia, diarrhea, pancytopenia, and cardiac disorders (available at clinicaltrials.gov, accessed on 29 July 2021) |
| NCT01647828 | I/II | Untreated Stage IV Pancreatic Cancer | Gemcitabine and Nab-Paclitaxel | (n = 177) Median OS was 6.4 months in tarextumab group vs. 7.9 months in the placebo group (HR 1.34, p = 0.0985). No difference in OS in the Notch3 gene expression subgroups. PFS in the tarextumab-treated group (3.7 months) was significantly shorter compared with placebo (5.5 months). No difference in ORR. Adverse effects in tarextumab group: diarrhea (72%), fatigue (52%), thrombocytopenia (49%), nausea (41%) [208] | |
| Brontictuzumab (OMP-52M51) | NCT03031691 | I | Metastatic Colorectal Cancer | Trifluridine/Tipiracil | No |
| Demcizumab (OMP-21M18) | NCT01952249 | Ib/II | Platinum Resistant Ovarian Cancer | Paclitaxel | (n = 19), MTD not reached, established dose 3.5 mg/kg, overall response rate 21%, 79% of patients had PD, clinical benefit rate was 42% (PR in 4 patients (21%) and SD in 4 patients (21%), no DLT. Common adverse effects: 68%—diarrhea, 38%—fatigue, 53% peripheral edema, 53% nausea, 16% pulmonary hypertension [225] |
| NCT01189968 | I | Untreated Metastatic Non-Squamous NSCLC | Carboplatin and Pemetrexed | (n = 46), truncated dose regimen and phase II dose 5 mg/kg weekly were recommended. 20 out of 40 (50%) evaluable patients had OR. CR in 1 patient (3%), PR in 19 patients (48%), SD in 15 patients (38%), PD in 5 patients (13%). Clinical benefit rate was 88%/PFS and OS in truncated regimen groups were 5.8 and 11.5 months, respectively. Adverse effects: 80%—fatigue, 67%—vomiting, 54%—constipation, 48% - anemia, 48% - dyspnea, 46% - hypertension, 41% - diarrhea, 37% - headache, 35% - thrombocytopenia or neutropenia. Compared with the baseline, blood expression levels of Notch1, Notch2, MAML2, and MAML3 decreased, and LEF1 and SFRP2 (regulators of blood vessel branching) were increased [226] | |
| NCT01189929 | I | Locally Advanced or Metastatic Pancreatic Cancer | Gemcitabine ± Abraxane | No | |
| NCT02289898 | II | Metastatic Pancreatic Ductal Adenocarcinoma | Gemcitabine, Abraxane | (n = 204), demcizumab did not improve PFS compared to placebo (HR 0.93, p = 0.7158, Kaplan-Meier-based estimation). Frequent adverse effects in demcizumab treatment arms: anemia, diarrhea, vomiting, fatigue, peripheral edema (available at clinicaltrials.gov, accessed on 1 August 2021) | |
| NCT02259582 | II | Non-Squamous NSCLC | Carboplatin and Pemetrexed | (n = 82), PR and SD frequency in placebo and two demcizumab arms of trial, respectively: 52% and 40%, 35.7% and 50.0%, 20.7% and 51.7%. Frequency of serious adverse events: 24.0% in placebo group and 39.29 and 51.72% in two demcizumab arms. Common adverse effects in two demcizumab treatment arms: nausea (64.29% and 48.28%), fatigue (57.14% and 41.38%), vomiting (28.57% and 37.93%), diarrhea (21.43% and 44.83%), decreased appetite (39.29% and 3.03%), hypertension (50.00% and 41.38%), elevated BNP (28.57% and 20.69%) (available at clinicaltrials.gov, accessed on 29 July 2021) | |
| NCT01189942 | I | Metastatic Colorectal Cancer | FOLFIRI | No | |
| Navixizumab (OMP-305B83) | NCT03030287 | Ib | Ovarian, Peritoneal or Fallopian Tube Cancer | Paclitaxel | No |
| NCT03035253 | I | Metastatic Colorectal Cancer | FOLFIRI or FOLFOX | No | |
| ABT-165 | NCT03368859 | II | Metastatic Colorectal Cancer Previously Treated with Fluoropyrimidine, Oxaliplatin and Bevacizumab | FOLFIRI | (n = 70) PFS was 3.78 months and 7.36 months, and ORR was 5.6% and 14.7% in ABT-165 + FOLFIRI and bevacizumab + FOLFIRI groups, respectively. All-cause mortality and frequency of serious adverse events was higher in ABT-165 group compared to bevacizumab (35.29% vs. 18.75% and 50.00% vs. 25.00%, respectively). Common adverse effects in ABT-165 group: 52.94%—diarrhea, 52.94%—nausea, 41.18%—neutropenia, 29.41%—hypertension (available at clinicaltrials.gov, accessed on 27 July 2021) |
| NCT01946074 | I | Solid Tumors | Alone or FOLFIRI or Paclitaxel with and without ABBV-181 | No | |
| Rovalpituzumab tesirine (Rova-T) | NCT02819999 | I | Extensive Stage SCLC | Cisplatin and Etoposide | (n = 26), 4 cohorts evaluating Rova-T alone and in different sequential combinations of Rova-T and cisplatin + etoposide (CE). Combination of Rova-T and CE did not add benefit to median OS and ORR of CE alone. Median OS in Rova-T + CE was 10.3 months, median PFS was 5.2 months, ORR was 50% (in other studies, ES alone produced ORR 60–70%, and median OS around 10 months). Cohort of lower dose of Rova-T + CE showed lower frequency of Rova-T-related adverse events such as pleural effusion (0 vs. 33%), pericardial effusion (0 vs. 17%), ascites (0 vs. 8%), peripheral edema (36% vs. 42%), generalized edema (0 vs. 8%), pneumonia (7% vs. 25%), and hypoalbuminemia (0 vs. 17%) [246] |
| NCT03033511 | III | Advanced SCLC | Rova-T or placebo following platinum-based chemotherapy (+etoposide or irinotecan) 3–9 weeks after achieving CR/PR/SD | (n = 748), no benefit for OS in both low- and high-DLL3-expressing subsets, PFS better in Rova-T group (4.0 vs. 1.4 months in Rova-T group and placebo, respectively). Rova-T-associated adverse effects: 27%—pleural effusion, 27%—decreased appetite, 26%—peripheral edema, 25%—photosensitivity reaction, 25%—fatigue, 22%—nausea, 21%—dyspnea [241] | |
| NCT03061812 | III | Advanced or Metastatic DLL3-high SCLC | Rova-T or topotecan in patients with first disease progression following platinum-based chemotherapy | (n = 444), Rova-T exhibited lower OS (6.3 months) compared to topotecan (8.6 months) and lower PFS (3.0 and 4.3 months in Rova-T and topotecan groups, respectively). ORR was 15% in the Rova-T arm and 21% in the topotecan arm. One CR in the Rova-T group, no CR in the topotecan group. 14% of PR in the Rova-T arm, 21% of PR in the topotecan arm. Rova-T-associated adverse events: pleural effusion (29%), decreased appetite (25%), dyspnea (25%), fatigue (25%), nausea (23%), and pericardial effusion (20%) [240] |