Phase I Study of RO4929097, a Gamma Secretase Inhibitor of Notch Signaling, in Patients With Refractory Metastatic or Locally Advanced Solid Tumors

Tolcher, Anthony W.; Messersmith, Wells A.; Mikulski, Stanislaw M.; Papadopoulos, Kyriakos P.; Kwak, Eunice L.; Gibbon, Darlene; Patnaik, Amita; Falchook, Gerald S.; Dasari, Arvind; Shapiro, Geoffrey I.; Boylan, John F.; Xu, Zhi Xin; Ka, Wang; Koehler, Astrid; Song, James; Middleton, Steven A.; Deutsch, Jonathan; DeMario, Mark; Kurzrock, Razelle; Wheler, Jennifer J.

doi:10.1200/jco.2011.36.8282

Cited by 225 publications

(198 citation statements)

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“…Because Notch may function as either tumor suppressor or oncogene in certain cancers, it is important to rationally select therapeutic targeting in solid tumors. Therapeutic Notch blockade has been reported with g-secretase inhibitors (GSI) that affect the proteolysis of all four receptors, including those on normal intestinal cells, potentially causing gastrointestinal toxicity (20,21). To date, clinical reports on GSI provide evidence of modest activity in gliomas (20), as well as sarcoma, melanoma, colorectal, and ovarian cancers (21).…”

Section: Discussionmentioning

confidence: 99%

A Phase I First-in-Human Study of Enoticumab (REGN421), a Fully Human Delta-like Ligand 4 (Dll4) Monoclonal Antibody in Patients with Advanced Solid Tumors

Chiorean

LoRusso

Strother

et al. 2015

Clinical Cancer Research

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130

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Purpose: Enoticumab (REGN421) is a fully human IgG 1 monoclonal antibody that binds human Dll4 and disrupts Notch-mediated signaling. The main objectives of this trial were to determine the safety, dose-limiting toxicities (DLT), pharmacokinetics (PK), and recommended phase II dose (RP2D) of enoticumab.Experimental Design: Enoticumab was administered intravenously, with dose escalations from 0.25 to 4 mg/kg every 3 weeks (Q3W) and 0.75 to 3 mg/kg every 2 weeks (Q2W).Results: Of 53 enrolled patients, 31 patients were treated Q3W and 22 patients were treated Q2W. Two DLTs occurred: grade 3 nausea (0.5 mg/kg Q3W) and grade 3 abdominal pain (1 mg/kg Q2W). An MTD was not reached on either schedule. The most frequent adverse events (AE) were fatigue, nausea, vomiting, hypertension, headache, and anorexia. Six treatment-related serious AEs were reported in 4 patients: brain natriuretic peptide (BNP) increase (0.25 mg/kg Q3W, Gr1), troponin I increase (4 mg/kg Q3W, Gr3), right ventricular dysfunction and pulmonary hypertension (1.5 mg/kg Q2W, both Gr3), and left ventricular dysfunction and pulmonary hypertension (3 mg/kg Q2W, both Gr3). Enoticumab was characterized by nonlinear, targetmediated PK, and had a terminal half-life of 8 to 9 days. With multiple Q2W or Q3W dosing, accumulation was not observed. Antitumor activity included two partial responses (non-small cell lung cancer bronchoalveolar-type with a b-catenin mutation, and ovarian cancer) and 16 patients with stable disease (3 > 6 months).Conclusions: Enoticumab was tolerated, with RP2D of 4 mg/kg Q3W and 3 mg/kg Q2W based on PK profile and clinical activity. Responses and SD were noted in ovarian cancer and other solid tumors.

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Section: Discussionmentioning

confidence: 99%

A Phase I First-in-Human Study of Enoticumab (REGN421), a Fully Human Delta-like Ligand 4 (Dll4) Monoclonal Antibody in Patients with Advanced Solid Tumors

Chiorean

LoRusso

Strother

et al. 2015

Clinical Cancer Research

Self Cite

130

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“…The identification of prototypical activating mutations in NOTCH1 in chronic lymphocytic leukemia [Di Ianni et al 2009;Fabbri et al 2011;Puente et al 2011] and the association of NOTCH1 mutations with advanced disease and chemotherapy resistance strongly suggest a potentially major role for anti NOTCH1 therapies in this disease. Similarly, rare but recurrent activating mutations in NOTCH1 have been found in lung cancer [Westhoff et al 2009] and a pathogenic role for NOTCH signaling has been proposed other solid tumors [Roy et al 2007;Shih Ie and Wang, 2007], with recent phase I clinical trials showing relevant results on the safety and potential therapeutic activity of GSIs in nonhematologic malignancies [Krop et al 2012;Tolcher et al 2012].…”

Section: Closing Remarksmentioning

confidence: 99%

The NOTCH signaling pathway: role in the pathogenesis of T-cell acute lymphoblastic leukemia and implication for therapy

Tosello

Ferrando

2013

Therapeutic Advances in Hematology

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T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is characterized by aberrant activation of NOTCH1 in over 60% of T-ALL cases. The high prevalence of activating NOTCH1 mutations highlights the critical role of NOTCH signaling in the pathogenesis of this disease and has prompted the development of therapeutic approaches targeting the NOTCH signaling pathway. Small molecule gamma secretase inhibitors (GSIs) can effectively inhibit oncogenic NOTCH1 and are in clinical testing for the treatment of T-ALL. Treatment with GSIs and glucocorticoids are strongly synergistic and may overcome the gastrointestinal toxicity associated with systemic inhibition of the NOTCH pathway. In addition, emerging new anti-NOTCH1 therapies include selective inhibition of NOTCH1 with anti-NOTCH1 antibodies and stapled peptides targeting the NOTCH transcriptional complex in the nucleus.

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“…LY900009 is cleared by oxidation and amide hydrolysis, and its renal clearance is low, while semagacestat, an analogue of LY900009, mostly depends on renal clearance (89,90). RO4929097 is cleared by autoinduction of cytochrome P450 family 3 subfamily A polypeptide 4 (CYP3A4), indicating that combination RO4929097 therapy with antitumor agents metabolized by CYP3A4 might show limit clinical utility (91) Supplementary Figs. S1-S4).…”

Section: G-secretase Inhibitorsmentioning

confidence: 99%

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

Liu

Sanders

Liang

et al. 2017

Molecular Cancer Therapeutics

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Hairy and Enhancer-of-split related with YRPW motif (Hey) transcription factors are important regulators of stem cell embryogenesis. Clinical relevance shows that they are also highly expressed in malignant carcinoma. Recent studies have highlighted functions for the Hey factors in tumor metastasis, the maintenance of cancer cell self-renewal, as well as proliferation and the promotion of tumor angiogenesis. Pathways that regulate Hey gene expression, such as Notch and TGFb signaling, are frequently aberrant in numerous cancers. In addition, Hey factors control downstream targets via recruitment of histone deacetylases (HDAC). Targeting these signaling pathways or HDACs may reverse tumor progression and provide clinical benefit for cancer patients. Thus, some small molecular inhibitors or monoclonal antibodies of each of these signaling pathways have been studied in clinical trials. This review focuses on the involvement of Hey proteins in malignant carcinoma progression and provides valuable therapeutic information for anticancer treatment.

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Phase I Study of RO4929097, a Gamma Secretase Inhibitor of Notch Signaling, in Patients With Refractory Metastatic or Locally Advanced Solid Tumors

Abstract: RO4929097 was well tolerated at 270 mg on schedule A and at 135 mg on schedule B; the safety of schedule C has not been fully evaluated. Further studies are warranted on the basis of a favorable safety profile and preliminary evidence of clinical antitumor activity.

Cited by 225 publications

References 9 publications

A Phase I First-in-Human Study of Enoticumab (REGN421), a Fully Human Delta-like Ligand 4 (Dll4) Monoclonal Antibody in Patients with Advanced Solid Tumors

A Phase I First-in-Human Study of Enoticumab (REGN421), a Fully Human Delta-like Ligand 4 (Dll4) Monoclonal Antibody in Patients with Advanced Solid Tumors

The NOTCH signaling pathway: role in the pathogenesis of T-cell acute lymphoblastic leukemia and implication for therapy

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

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