A multicenter phase 1 study of gamma -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors

Noelle K. LoConte; Albiruni R. A. Razak; Percy Ivy; Amye Tevaarwerk; Rachael Leverence; Jill Kolesar; Lillian Siu; Sam J. Lubner; Daniel L. Mulkerin; William R. Schelman; Dustin A. Deming; Kyle D. Holen; Lakeesha Carmichael; Jens Eickhoff; Glenn Liu

doi:10.1007/s10637-014-0166-6

$A multicenter phase 1 study of gamma -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors$

Journal article

Peer reviewed

A multicenter phase 1 study of gamma -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors

Noelle K. LoConte, Albiruni R. A. Razak, Percy Ivy, Amye Tevaarwerk, Rachael Leverence, Jill Kolesar, Lillian Siu, Sam J. Lubner, Daniel L. Mulkerin, William R. Schelman, …

Investigational new drugs, Vol.33(1), pp.169-176

02/01/2015

DOI: 10.1007/s10637-014-0166-6

PMCID: PMC4297251

PMID: 25318436

Files and links (1)

url

https://www.ncbi.nlm.nih.gov/pmc/articles/4297251View

Open Access

Abstract

Background RO4929097 is an oral inhibitor of gamma -secretase that results in Notch signaling inhibition. Prior work has demonstrated that Notch signaling inhibition enhances chemotherapy sensitivity of cancer cells. This phase I study was conducted to determine maximum tolerated dose (MTD), toxicities and efficacy of RO4929097 and capecitabine in advanced solid tumors. Methods Patients with refractory solid tumors received capecitabine at a fixed dose of 1,000 mg/m(2) twice daily with escalating doses of RO4929097 on a 21-day cycle in a 3 + 3 design. Capecitabine was administered for 14 days and the RO49029097 once daily, 3 days per week, both for a 21 day cycle. Results Thirty patients were treated on six dose levels (20 to 150 mg). The maximally tolerated dose was not reached. One dose limiting toxicity was observed at each level 3 through 6 (hypophosphatemia, fatigue, and nausea/vomiting). Three confirmed partial responses were observed: two patients with fluoropyrimide-refractory colon cancer and one patient with cervical cancer. Autoinduction of RO4929097 was demonstrated with increasing dose levels and duration. Conclusions The recommended phase 2 dose is capecitabine 1,000 mg/m(2) orally twice daily on days 1 through 14 with RO4929097 20 mg orally once daily on days 1-3, 8-10 and 15-17 with a 21 day cycle. Clinical benefit was observed in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. Plasma concentrations of RO4929097 were above those needed for Notch inhibition.

Life Sciences & Biomedicine

Oncology

Pharmacology & Pharmacy

Science & Technology

Details

Title: Subtitle: A multicenter phase 1 study of gamma -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors
Creators: Noelle K. LoConte - University of Wisconsin Carbone Cancer Center
Albiruni R. A. Razak - Princess Margaret Cancer Centre
Percy Ivy - National Cancer Institute
Amye Tevaarwerk - University of Wisconsin Carbone Cancer Center
Rachael Leverence - University of Wisconsin Carbone Cancer Center
Jill Kolesar - University of Wisconsin Carbone Cancer Center
Lillian Siu - Princess Margaret Cancer Centre
Sam J. Lubner - University of Wisconsin Carbone Cancer Center
Daniel L. Mulkerin - University of Wisconsin Carbone Cancer Center
William R. Schelman - University of Wisconsin Carbone Cancer Center
Dustin A. Deming - University of Wisconsin Carbone Cancer Center
Kyle D. Holen - University of Wisconsin Carbone Cancer Center
Lakeesha Carmichael - University of Wisconsin Carbone Cancer Center
Jens Eickhoff - University of Wisconsin–Madison
Glenn Liu - University of Wisconsin Carbone Cancer Center
Resource Type: Journal article
Publication Details: Investigational new drugs, Vol.33(1), pp.169-176
DOI: 10.1007/s10637-014-0166-6
PMID: 25318436
PMCID: PMC4297251
NLM abbreviation: Invest New Drugs
ISSN: 0167-6997
eISSN: 1573-0646
Publisher: Springer Nature
Number of pages: 8
Grant note: U01 CA062491; U01-CA132123 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 9U54TR000021 / National Institutes of Health Clinical and Translational Science Awards program; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA UM1CA186644; U01CA132123; U01CA062491; P30CA014520 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) KL2TR000428; UL1TR000427 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) P30 CA014520 / University of Wisconsin Carbone Cancer Center Princess Margaret Hospital Phase I Consortium UL1RR025011 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR)
Language: English
Date published: 02/01/2015
Academic Unit: Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
Record Identifier: 9984696556702771

Metrics

18 Record Views

35 Times Cited - Web of Science