Delving into the Latest Updates on CEP-11981 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

2,5,6,11,12,13-Hexahydro-2-methyl-11-(2-methylpropyl)-8-(2-pyrimidinylamino)-4H-indazolo[5,4-c]pyrrolo[3,4-c]carbazol-4-one mono(4-methylbenzenesulfonate)

+ [4]

Target

Tie-2 x VEGFR2

Mechanism

Tie-2 antagonists(TEK receptor tyrosine kinase antagonists), VEGFR2 antagonists(Vascular endothelial growth factor receptor 2 antagonists)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [2]

Active Indication

Adenosquamous CarcinomaGastro-Enteropancreatic Neuroendocrine TumorNeuroendocrine neoplasm of gastrointestinal tract+ [6]

Inactive Indication

Metastatic Renal Cell Carcinoma

Originator Organization

Sanofi

Active Organization

Rogel Cancer Center: University of Michigan

SanofiEsanik Therapeutics, Inc.

+ [1]

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC28H27N7O

InChIKeyAEULIVPVIDOLIN-UHFFFAOYSA-N

CAS Registry856691-93-5

This protocol will enroll patients with pancreatic adenocarcinoma and adenosquamous carcinoma (Cohort 1), gastrointestinal/pancreatic neuroendocrine neoplasms with Ki-67 > 20% (Cohort 2) and neuroendocrine prostate carcinoma (Cohort 3)). Each cohort will have its own interim analysis after enrollment of 10 patients.
Subjects will be given a one-month (28 day) supply of study drug (ESK981). Subjects will be instructed to take 4 capsules, with or without food, once per day for 5 consecutive calendar days, then take a drug holiday for 2 consecutive days before repeating the 5 days on-2 days off cycle in sets of 4 weeks or 28 calendar days. Subjects will be asked to keep a pill diary noting the date they take their study drug.

Start Date19 Apr 2024

Sponsor / Collaborator

Rogel Cancer Center: University of Michigan

NCT04159896 / TerminatedPhase 2IIT

Phase II Multi-Center Trial of ESK981 in Combination With Nivolumab in Patients With Metastatic Castrate Resistant Prostate Cancer

This phase II trial studies the side effects of ESK981 and nivolumab and to see how well they work for the treatment of castration resistant prostate cancer that has spread to other places in the body (metastatic). ESK981 is an investigational drug that targets several important pathways that are believed to play a role in the spread of cancer. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This study is being done to see if giving ESK981 and nivolumab together works better in treating metastatic castration resistant prostate cancer compared to usual treatments.

Start Date13 Nov 2019

Sponsor / Collaborator

Barbara Ann Karmanos Cancer Institute

[+1]

NCT03562507 / TerminatedPhase 2IIT

ERICA: Phase 2 Multi-center Trial of ESK981 in Combination With Nivolumab in Patients With Metastatic Renal Cell Carcinoma

The objective of the trial is to determine the clinical efficacy of ESK981 in combination with nivolumab therapy in patients with metastatic renal cell carcinoma (RCC).

Start Date11 Apr 2019

Sponsor / Collaborator

Rogel Cancer Center: University of Michigan

100 Clinical Results associated with CEP-11981

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100 Translational Medicine associated with CEP-11981

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100 Patents (Medical) associated with CEP-11981

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19

Literatures (Medical) associated with CEP-11981

01 Apr 2020·Journal of Nuclear MedicineQ1 · MEDICINE

PET Imaging of Pancreatic Dopamine D₂ and D₃ Receptor Density with ¹¹C-(+)-PHNO in Type 1 Diabetes

Q1 · MEDICINE

Article

Author: Sanchez-Rangel, Elizabeth ; Bini, Jason ; Matuskey, David ; Huang, Yiyun ; Harris, Paul E ; Cline, Gary W ; Nabulsi, Nabeel ; Gallezot, Jean-Dominique ; Ropchan, Jim ; Najafzadeh, Soheila ; Naganawa, Mika ; Lim, Keunpoong ; Sherwin, Robert S ; Shirali, Anupama ; Carson, Richard E ; Herold, Kevan C

Type 1 diabetes mellitus (T1DM) has traditionally been characterized by a complete destruction of β-cell mass (BCM); however, there is growing evidence of possible residual BCM present in T1DM. Given the absence of in vivo tools to measure BCM, routine clinical measures of β-cell function (e.g., C-peptide release) may not reflect BCM. We previously demonstrated the potential utility of PET imaging with the dopamine D₂ and D₃ receptor agonist 3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol (¹¹C-(+)-PHNO) to differentiate between healthy control (HC) and T1DM individuals. Methods: Sixteen individuals participated (10 men, 6 women; 9 HCs, 7 T1DMs). The average duration of diabetes was 18 ± 6 y (range, 14-30 y). Individuals underwent PET/CT scanning with a 120-min dynamic PET scan centered on the pancreas. One- and 2-tissue-compartment models were used to estimate pancreas and spleen distribution volume. Reference region approaches (spleen as reference) were also investigated. Quantitative PET measures were correlated with clinical outcome measures. Immunohistochemistry was performed to examine colocalization of dopamine receptors with endocrine hormones in HC and T1DM pancreatic tissue. Results: C-peptide release was not detectable in any T1DM individuals, whereas proinsulin was detectable in 3 of 5 T1DM individuals. Pancreas SUV ratio minus 1 (SUVR-1) (20-30 min; spleen as reference region) demonstrated a statistically significant reduction (-36.2%) in radioligand binding (HCs, 5.6; T1DMs, 3.6; P = 0.03). Age at diagnosis correlated significantly with pancreas SUVR-1 (20-30 min) (R ² = 0.67, P = 0.025). Duration of diabetes did not significantly correlate with pancreas SUVR-1 (20-30 min) (R ² = 0.36, P = 0.16). Mean acute C-peptide response to arginine at maximal glycemic potentiation did not significantly correlate with SUVR-1 (20-30 min) (R ² = 0.57, P = 0.05), nor did mean baseline proinsulin (R ² = 0.45, P = 0.10). Immunohistochemistry demonstrated colocalization of dopamine D₃ receptor and dopamine D₂ receptor in HCs. No colocalization of the dopamine D₃ receptor or dopamine D₂ receptor was seen with somatostatin, glucagon, or polypeptide Y. In a separate T1DM individual, no immunostaining was seen with dopamine D₃ receptor, dopamine D₂ receptor, or insulin antibodies, suggesting that loss of endocrine dopamine D₃ receptor and dopamine D₂ receptor expression accompanies loss of β-cell functional insulin secretory capacity. Conclusion: Thirty-minute scan durations and SUVR-1 provide quantitative outcome measures for ¹¹C-(+)-PHNO, a dopamine D₃ receptor-preferring agonist PET radioligand, to differentiate BCM in T1DM and HCs.

19 Dec 2018·ACS Chemical NeuroscienceQ3 · MEDICINE

Deuterium Kinetic Isotope Effect Studies of a Potential in Vivo Metabolic Trapping Agent for Monoamine Oxidase B

Q3 · MEDICINE

Article

Author: Koeppe, Robert A. ; Brooks, Allen F. ; Kilbourn, Michael R. ; Pham, Jonathan M. ; Mufarreh, Anthony J. ; Shao, Xia ; Scott, Peter J. H. ; Drake, Lindsey R.

Visualizing the in vivo activity of monoamine oxidase B (MAO-B) is a valuable tool in the ongoing investigation of astrogliosis in neurodegeneration. Existing strategies for imaging changes in MAO enzyme expression or activity have utilized the irreversible suicide inhibitors or high-affinity reversibly binding inhibitors as positron emission tomography (PET) ligands. As an alternative approach, we developed 4-methyl-7-[(1-[¹¹C]methyl-1,2,3,6-tetrahydropyridin-4-yl)oxy]-2 H-chromen-2-one ([¹¹C]Cou) as a metabolic trapping agent for MAO-B. Trapping of [¹¹C]Cou in rhesus monkey brain demonstrated MAO-B selectivity. In this work, we have attempted to improve on the in vivo pharmacokinetics of [¹¹C]Cou by using the deuterium kinetic isotope effect (KIE) to slow the MAO-B-mediated oxidation step and thus reduce the rate of trapping in brain tissues. However, in vitro assays of enzyme kinetics and in vivo PET imaging of pharmacokinetics in primate brain showed no effects of deuterium substitution on the tetrahydropyridine ring of [¹¹C]Cou. The results are possibly due to masking of the KIE by a second step in the overall metabolism of the new imaging agent.

01 Dec 2014·Investigational New DrugsQ3 · MEDICINE

An open-label study to determine the maximum tolerated dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer

Q3 · MEDICINE

Article

Author: Michael Carducci ; Peter Brown ; Roberto Pili ; Herbert Hurwitz

SummaryBackground This phase I study evaluated the pharmacokinetics and pharmacodynamics of CEP-11981, an oral vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, in patients with advanced, relapsed, or refractory solid tumors. Methods Oral CEP-11981 dose escalations followed a modified Fibonacci sequence (from 3.0 to 4.2, 5.9, 11.8, 19.7, 29.6, 41.4, 55.0, 73.0, 97.4, and 126.6 mg/m2). The maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), tumor response, and safety were evaluated. Results CEP-11981 was tolerated at doses between 3.0 and 97.4 mg/m2. The MTD of CEP-11981 was determined to be 97.4 mg/m2, with DLTs observed at the 126.6 mg/m2 dose. The DLTs were grade 4 neutropenia in 1 patient and grade 3 T-wave inversion with chest heaviness and fatigue in 1 patient. All 3 events resolved on stopping CEP-11981. The most frequently reported adverse events of any grade were fatigue, nausea, diarrhea, decreased appetite, abdominal pain, back pain, vomiting, constipation, headache, dizziness, and dyspnea. Treatment-related grade 3/4 neutropenia was observed in the highest-dose cohorts (2 patients at 97.4 mg/m2 and 1 patient at 126.6 mg/m2), indicating some off-target inhibition. VEGF inhibition was greatest in the higher-dose groups. Although no patient experienced complete or partial response, 44 % patients achieved stable disease when measured at ≥ 6 weeks, which occurred more frequently in cohorts receiving ≥ 73.0 mg/m2. Conclusions In patients with recurrent or refractory solid tumors, disease stabilization was achieved. Despite acceptable tolerability of CEP-11981 at the MTD, further development by the sponsor has ceased.

100 Deals associated with CEP-11981

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Adenosquamous Carcinoma	Phase 2	US	Rogel Cancer Center: University of Michigan	19 Apr 2024
Gastro-Enteropancreatic Neuroendocrine Tumor	Phase 2	US	Rogel Cancer Center: University of Michigan	19 Apr 2024
Neuroendocrine neoplasm of gastrointestinal tract	Phase 2	US	Rogel Cancer Center: University of Michigan	19 Apr 2024
Neuroendocrine tumor of pancreas	Phase 2	US	Rogel Cancer Center: University of Michigan	19 Apr 2024
Pancreatic adenocarcinoma	Phase 2	US	Rogel Cancer Center: University of Michigan	19 Apr 2024
Prostate Neuroendocrine Carcinoma	Phase 2	US	Rogel Cancer Center: University of Michigan	19 Apr 2024
Well Differentiated Pancreatic Endocrine Tumor	Phase 2	US	Rogel Cancer Center: University of Michigan	19 Apr 2024
Prostatic Cancer	Phase 2	-	Sanofi	-
Prostatic Cancer	Phase 2	-	Teva Pharmaceutical Industries Ltd.	-
Metastatic Renal Cell Carcinoma	Phase 1	US	Rogel Cancer Center: University of Michigan	11 Apr 2019

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04159896 (Phase II trial of multi-tyrosine kinase inhibitor ESK981 in combination with PD-1 inhibitor nivolumab, Pubmed \| Invest New Drugs)	Phase 2	Metastatic castration-resistant prostate cancer prostate-specific antigen \| AR amplification	10	ESK981	(rfxtgocffn) = qbskindzgz ophsympftp (jgnxdgcpey, 1.8 - 22.4) View more	Negative	06 Nov 2024
NCT03456804 (Pubmed \| Invest New Drugs) Manual	Phase 2	Castration-Resistant Prostatic Cancer androgen receptor-positive (AR +)	13	ESK981 160 mg	(jwkjwvbznw) = sbymxcuuss ygdqqijiqy (lurtkxadtv, 0.4 - 33.3) View more	Negative	03 Sep 2024
NCT04159896 (Phase II trial of multi-tyrosine kinase inhibitor ESK981 in combination with PD-1 inhibitor nivolumab, CTgov)	Phase 2	Castration-Resistant Prostatic Cancer \| Metastatic Prostate Carcinoma \| Metastatic castration-resistant prostate cancer	10	Nivolumab+Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981	wksivcmkek(oolxgdueio) = ixnotjellm welbjonwoq (hqgzfjhpbi, kgjxnkdgzt - lhcfoxrbsh) View more	-	16 Jul 2024
NCT03456804 (Phase II trial of multi-kinase inhibitor ESK981, CTgov)	Phase 2	Salivary Gland Adenoma, Pleomorphic \| Castration-Resistant Prostatic Cancer \| Metastatic Prostate Carcinoma	13	ESK981	cavghuaqtk(fyewsbwhui) = kkzmktnohb ybbiqtjmgz (ekrugjccnv, iiwzjrdiag - zchplzpfwn) View more	-	14 Jul 2023