Table 1.
A current summary of cancer clinical trials involving Notch antagonists.
| Drug Class | Drug Name | CT Identifier | Study Name | Phase | Primary Endpoint | Status | Clinical Outputs Met? | Published Results |
|---|---|---|---|---|---|---|---|---|
|
Gamma Secretase Inhibitor
(GSI) |
RO4929097
(R4733) |
NCT00532090 | A Multiple Ascending Dose Study of R4733 in Patients with Advanced Solid Tumours | I | AE | Completed | Yes | No results published |
| NCT01070927 | An Exploratory Study of RO4929097 in Patients with Recurrent or Refractory Non-Small Cell Lung Cancer | II | PD | Completed | Yes | No results published | ||
| NCT01071564 | RO4929097 and Vismodegib in Treating Patients with Breast Cancer That is Metastatic or Cannot Be Removed By Surgery | I | MTD, AE, DLT | Terminated early (drug development and manufacturing ceased) | No results published | |||
| NCT01088763 | Gamma-Secretase Inhibitor RO4929097 in Treating Young Patients with Relapsed or Refractory Solid Tumours, CNS Tumours, Lymphoma, or T-Cell Leukemia | I | MTD, DLT | Terminated | No results published | |||
| NCT01096355 | Gamma-Secretase Inhibitor RO4929097 in Treating Patients with Metastatic or Unresectable Solid Malignancies | I | DLT | Completed | Yes | No results published | ||
| NCT01116687 | RO4929097 in Treating Patients with Metastatic Colorectal Cancer | II | ORR | Completed | No | [162] | ||
| NCT01119599 | RO4929097, Temozolomide, and Radiation Therapy in Treating Patients with Newly Diagnosed Malignant Glioma | I | MTD | Completed | Yes | www.clinicaltrials.gov | ||
| NCT01120275 | Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients with Stage IV Melanoma | II | PFS, OS | Terminated early (drug development and manufacturing ceased) | [163] | |||
| NCT01122901 | Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients with Recurrent or Progressive Glioblastoma | II | PFS, PD | Terminated early (drug development and manufacturing ceased) | [164] | |||
| NCT01131234 | Gamma-Secretase Inhibitor RO4929097 and Cediranib Maleate in Treating Patients with Advanced Solid Tumours | I | MTD | Completed | Yes | [165] | ||
| NCT01141569 | A Study of RO4929097 in Patients with Advanced Renal Cell Carcinoma That Have Failed Vascular Endothelial Growth Factor (VEGF)/Vascular Endothelial Growth Factor Receptor (VEGFR) Therapy | II | ORR | Completed | No | www.clinicaltrials.gov | ||
| NCT01145456 | Gamma-Secretase Inhibitor RO4929097 and Gemcitabine Hydrochloride in Treating Patients with Advanced Solid Tumours | I | DLT | Completed | Yes | [166] | ||
| NCT01149356 | RO4929097 And Exemestane in Treating Pre- and Postmenopausal Patients with Advanced or Metastatic Breast Cancer | I | AE, Time to relapse | Terminated early (drug development and manufacturing ceased) | [167] | |||
| NCT01151449 | Gamma-secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients with Advanced, Metastatic, or Recurrent Triple Negative Invasive Breast Cancer | II | ORR, PFS | Terminated (Administratively Completed) | www.clinicaltrials.gov | |||
| NCT01154452 | Vismodegib and Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients with Advanced or Metastatic Sarcoma | I/II | I: MTD II: PFS |
Completed | I: Yes II: No |
I: [153] II: www.clinicaltrials.gov |
||
| NCT01158274 | RO4929097 and Capecitabine in Treating Patients with Refractory Solid Tumours | I | MTD, AE | Completed | Yes | [168] | ||
| NCT01175343 | A Phase II Study of RO4929097 in Advanced Platinum Resistant Ovarian Cancer | II | PFS, PD -CA125 progression | Completed | No | [169] | ||
| NCT01189240 | RO4929097and Bevacizumab in Treating Patients with Progressive or Recurrent Malignant Glioma | I/II | MTD | Terminated early (drug development and manufacturing ceased) | [170] | |||
| NCT01193868 | RO4929097 in Treating Patients with Advanced Non-Small Cell Lung Cancer Who Have Recently Completed Treatment With Front-Line Chemotherapy | II | ORR | Completed | N/A | No results published | ||
| NCT01208441 | RO4929097 and Letrozole in Treating Post-Menopausal Women with Hormone Receptor-Positive Stage II or Stage III Breast Cancer | Ib | MTD | Terminated early (drug development and manufacturing ceased) | No results published | |||
| NCT01200810 | Bicalutamide and RO4929097 in Treating Patients with Previously Treated Prostate Cancer | II | PD - PSA Progression | Terminated early (drug development and manufacturing ceased) | [171] | |||
| NCT01198535 | Phase I Study of Cetuximab With RO4929097 in Metastatic Colorectal Cancer | I | MTD | Terminated early | No results published | |||
| NCT01198184 | Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 and Temsirolimus in Treating Patients with Advanced Solid Tumours | I | DLT, AE | Completed | Yes | [172] | ||
| NCT01196416 | Gamma-secretase/Notch Signalling Pathway Inhibitor RO4929097 in Combination with Cisplatin, Vinblastine, and Temozolomide in Treating Patients With Recurrent or Metastatic Melanoma | I/II | ORR, MTD, OS | Completed | No | [163] | ||
| NCT01193881 | RO4929097 and Erlotinib Hydrochloride in Treating Patients with Stage IV or Recurrent Non-small Cell Lung Cancer | I | AE, MTD, PD | Terminated early (drug development and manufacturing ceased) | No results published | |||
| NCT01192763 | RO4929097 Before Surgery in Treating Patients with Pancreatic Cancer NCT01192763 | I | PD, AE | Terminated early (drug development and manufacturing ceased) | www.clinicaltrials.gov | |||
| NCT01217411 | RO4929097 and Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients with Brain Metastases From Breast Cancer | I | MTD, ORR | Terminated (slow patient enrolloment and drug development ceased) | N/A—study too small | |||
| NCT01216787 | RO4929097 in Treating Patients with Stage IIIB, Stage IIIC, or Stage IV Melanoma That Can Be Removed by Surgery | II | PD | Withdrawn (drug development and manufacturing ceased) | N/A | |||
| NCT01218620 | Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients with Advanced Solid Tumours | I | PD | Completed | N/A | No results published | ||
| NCT01232829 | Gamma Secretase Inhibitor RO4929097 in Previously Treated Metastatic Pancreas Cancer | II | OS | Completed | No | [173] | ||
| NCT01236586 | RO4929097 in Children with Relapsed/Refractory Solid or CNS Tumours, Lymphoma, or T-Cell Leukemia | I/II | I: MTD, AE II: Efficacy |
Withdrawn (drug development and manufacturing ceased) | N/A | |||
| NCT01238133 | Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097, Paclitaxel, and Carboplatin Before Surgery in Treating Patients with Stage II or Stage III Triple-Negative Breast Cancer | I | DLT, MTD | Terminated early (drug development and manufacturing ceased) | [174] | |||
| NCT01251172 | RO4929097 After Autologous Stem Cell Transplant in Treating Patients with Multiple Myeloma | II | ORR | Withdrawn (drug development ceased) | N/A | |||
| NCT01270438 | Combination Chemotherapy and Bevacizumab with or Without RO4929097 in Treating Patients With Metastatic Colorectal Cancer | II | PFS | Withdrawn (drug development ceased) | N/A | |||
| NCT01189240 | RO4929097 and Bevacizumab in Treating Patients with Progressive or Recurrent Malignant Glioma | I | DLT, MTD | Terminated early (drug development ceased) | [170] | |||
|
LY3039478
(JSMD194) |
NCT01695005 | A Study of LY3039478 in Participants with Advanced Cancer | I | DLT, ORR | Completed | Yes | [175] | |
| NCT02518113 | A Study of LY3039478 in Combination with Dexamethasone in Participants With T-ALL/T-LBL | I | DLT, AE, ORR | Completed | No | www.clinicaltrials.gov | ||
| NCT02784795 | A Phase 1b Study of LY3039478 in Combination with Other Anticancer Agents in Patients With Advanced or Metastatic Solid Tumours | I | MTD | Completed | Yes | No results published | ||
| NCT03502577 | BCMA-Specific CAR T-Cells Combined with a Gamma Secretase Inhibitor (JSMD194) to Treat Relapsed or Persistent Multiple Myeloma | I | MTD, AE | Ongoing | N/A | |||
|
Nirogacestat
(PF-03084014) |
NCT00878189 | A Phase I trial of PF-03084014 in patients with advanced solid tumour malignancy and T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma | I | DLT | Completed | Yes | [176] [177] |
|
| NCT01876251 | A Study Evaluating The PF-03084014 In Combination with Docetaxel In Patients With Advanced Breast Cancer | I | DLT, PFS | Discontinued (change in development strategy) | [178] | |||
| NCT02299635 | Study of PF-03084014 In Combination with Gemcitabine And Nab-Paclitaxel In Patients With Metastatic Pancreatic Adenocarcinoma Not Previously Treated With Anticancer Therapies | II | ORR | Discontinued (change in development strategy) | Data on primary endpoint not collected | |||
| NCT02109445 | Study of PF-03084014 In Combination with Gemcitabine And Nab-Paclitaxel In Patients With Metastatic Pancreatic Adenocarcinoma Not Previously Treated With Anticancer Therapies | I/II | I: DLT II: OS |
Discontinued (change in development strategy) | Data on primary endpoint not collected. Phase II not initiated | |||
| NCT01981551 | Phase II Trial of the Gamma-Secretase Inhibitor PF-03084014 in Adults with Desmoid Tumours/Aggressive Fibromatosis | II | ORR | Active | [179] | |||
| NCT03785964 | A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Nirogacestat Versus Placebo in Adult Patients with Progressing Desmoid Tumours/Aggressive Fibromatosis (DeFi) | III | PFS | Recruiting | N/A | |||
| NCT04195399 | A Safety, Pharmacokinetic and Efficacy Study of a y-Secretase Inhibitor, Nirogacestat (PF-03084014), in Children and Adolescents with Progressive, Surgically Unresectable Desmoid Tumours | II | PFS, DLT, PD | Recruiting 2020 | N/A | |||
|
AL101
(BMS-906024) |
NCT01292655 | Study to Evaluate the Safety and Tolerability of IV Doses of BMS-906024 in Subjects with Advanced or Metastatic Solid Tumours | I | AE, DLT | Completed | Yes | [180] | |
| NCT01363817 | Study to Evaluate the Safety and Tolerability of Weekly Intravenous (IV) Doses of BMS-906024 in Subjects with Acute T-cell Lymphoblastic Leukemia or T-cell Lymphoblastic Lymphoma | I | AE, DLT | Completed | Yes | [181] | ||
| NCT01653470 | Study to Evaluate Safety & Tolerability of BMS-906024 in Combination With Chemotherapy & to Define DLTs & MTD of BMS-906024 in Combination With One of the Following Chemotherapy Regimens; Weekly Paclitaxel, 5FU+Irinotecan or Carboplatin+Paclitaxel in Subjects With Advanced / Metastatic Solid Tumours | Ib | AE, DLT | Completed | Yes | No results published | ||
| NCT03691207 | A Study Of AL101 In Patients With Adenoid Cystic Carcinoma (ACC) Bearing Activating Notch Mutations (ACCURACY) | II | ORR | Ongoing | [182] | |||
|
AL102
(BMS-986115) |
NCT01986218 | Phase I Ascending Multiple-Dose Study of BMS-986115 in Subjects with Advanced Solid Tumours | I | DLT, AE | Completed | Yes | [183] | |
| DLL-4 Antibody | MEDI0639 | NCT01577745 | A Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI0639 in Advanced Solid Tumours | I | DLT, MTD | Completed | Yes | [184] |
| Enoticumab (REGN421) | NCT00871559 | A Multiple-Ascending-Dose Study of the Safety and Tolerability of REGN421 (SAR153192) in Patients with Advanced Solid Malignancies | I | DLT | Completed | Yes | [185] | |
| Demcizumab | NCT01189929 | A Study of Gemcitabine and Demcizumab (OMP-21M18) With or Without Abraxane® as 1st-line Treatment in Subjects with Locally Advanced or Metastatic Pancreatic Cancer | Ib | MTD | Completed | Yes | [186] | |
| NCT01189968 | A Study of Carboplatin and Pemetrexed Plus Demcizumab (OMP-21M18) in Subjects with Non-Squamous Non-Small Cell Lung Cancer | Ib | MTD | Completed | Yes | [187] | ||
| NCT01952249 | A Study of Demcizumab Plus Paclitaxel in Subjects with Platinum Resistant Ovarian (SIERRA) | Ib | DLT, MTD | Completed (Phase II portion planned but not initiated) |
Yes | [188] | ||
| NCT02259582 | A Study of Carboplatin, Pemetrexed Plus Placebo vs Carboplatin, Pemetrexed Plus 1 or 2 Truncated Courses of Demcizumab in Subjects with Non-Squamous Non-Small Cell Lung Cancer (DENALI) | II | ORR | Completed | No | [189] | ||
| NCT02289898 | Study of Gemcitabine, Abraxane® Plus Placebo Versus Gemcitabine, Abraxane® Plus 1 or 2 Truncated Courses of Demcizumab in Subjects With 1st-Line Metastatic Pancreatic Ductal Adenocarcinoma (YOSEMITE) | II | PFS | Completed | No | [190] | ||
| NCT02722954 | A Phase 1b Study of Demcizumab Plus Pembrolizumab in Locally Advanced or Metastatic Solid Tumours | Ib | DLT | Completed | Yes | [191] | ||
| Notch receptor Antibody |
Brontictuzumab
(OMP-52M51) |
NCT01703572 | A Dose Escalation Study of OMP-52M51 in Subjects with Lymphoid Malignancies | I | DLT | Completed | Yes | [192] |
| NCT01778439 | A Dose Escalation Study of OMP-52M51 in Subjects with Solid Tumours | I | DLT | Completed | Yes | [193] | ||
| NCT02662608 | Compassionate Use of Brontictuzumab for Adenoid Cystic Carcinoma (ACC) | N/A | PFS | Completed | No | [194] | ||
| NCT03031691 | A Study of Brontictuzumab with Chemotherapy for Subjects with Previously Treated Metastatic Colorectal Cancer | Ib | AE, DLT, immuno-genicity | Terminated early | [Press release] [195] | |||
| Tarextumab (OMP-59R5) | NCT01277146 | A Dose Escalation Study of OMP-59R5 in Subjects with Solid Tumours | I | AE, DLT | Completed | Yes | [196] | |
| NCT01647828 | A Phase 1b/2 Study of OMP-59R5 in Combination with Nab-Paclitaxel and Gemcitabine in Subjects With Previously Untreated Stage IV Pancreatic Cancer (ALPINE) | I/II | I: DLT, II: PFS |
Completed | I: Yes II: No |
I: [197] II: [198] |
||
| NCT01859741 | A Phase 1b/2 Study of OMP-59R5 (Tarextumab) in Combination with Etoposide and Platinum Therapy (PINNACLE) | I/II | I: MTD, ORR II: PFS |
Terminated early | I: [199] II: [195] |
|||
|
Notch Transcription
Complex Inhibitor |
CB-103 | NCT03422679 | Study of CB-103 in Adult Patients with Advanced or Metastatic Solid Tumours and Haematological Malignancies | I/II | I: DLT, II: Efficacy |
Ongoing | [200] | |
| NCT03422679 | Study of CB-103 in Adult Patients with Advanced or Metastatic Solid Tumours and Haematological Malignancies | I/II | I: DLT, II: Efficacy |
Ongoing | [200] |
AE: Adverse Effects, DLT: Dose-Limiting Toxicities, MTD: Maximum Tolerated Dose, ORR: Objective/Overall Response Rate, OS: Overall Survival, PD: Drug Pharmacodynamics Measurements, PFS: Progression-Free Survival, N/A: Not Applicable; No Data published.