CS7017, a novel thiazolidinedione, is an orally available agonist of peroxisome proliferator-activated receptor gamma (PPAr gamma).
PRODUCT SOURCE
Primary Developer
Daiichi Sankyo
PRODUCT SPECIFICATIONS
Therapeutic Indication
Malignancy
Therapeutic Category
Regulation • Cytostatic
Drug Category
Chemical
Technology Details
CS-7017 is a novel, third generation thiazolidinedione (TZD) that is significantly more potent than the second generation TZD such as rosiglitazone.
Mechanism
Gene transcription activation
Mechanism Details
CS-7017 is an activator (ligand) of peroxisome proliferator-activated receptor gamma (PPArgamma). A positive correlation between PPARgamma activation and inhibition of colony formation of tumor cells has been demonstrated in human tumor xenografts in vivo animal models. The drug inhibits the growth of tumor cells in vitro without killing the cells.
CS-7017, a novel thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, activated PPARgamma-mediated luciferase expression with an EC50 of 0.20 nM, and was also highly selective for PPARgamma amongst other PPAR subfamilies. CS-7017 inhibited the proliferation of the human anaplastic thyroid tumor cell line DRO and the pancreatic tumor cell line AsPC-1 in vitro at concentrations as low as 10 nM. In xenograft studies, CS-7017 inhibited the growth of the human colorectal tumor cell line HT-29 in nude mice as well as DRO in nude rats in a dose-dependent manner. At the same dose, an increase in the levels of adiponectin, a surrogate marker for PPARgamma activation, was also observed. CS-7017 prolonged survival of mice inoculated with murine colorectal tumor Colon 38 with marginal tumor growth inhibition. These preclinical results support the potential use of CS-7017 in a clinical setting (Shimazaki N, etal, Eur J Cancer, Aug. 2008;44(12):1734-43).
solid tumor • thyroid cancer • colorectal cancer • pancreatic cancer
CLINICAL STATUS BY INDICATION
Indication
thyroid cancer, anaplastic, advanced or metastatic, first line or second line
Latest Status
Phase I/II (begin 1/08, ongoing 6/10) USA (combination)
Clinical History
A multicenter (n=10), nonrandomized, open label, phase I/II clinical trial (protocol ID: CS7017-A-U103; NCT00603941) was initiated in January 2008, in the USA, to evaluate the safety and efficacy of CS-7017 in combination with paclitaxel chemotherapy in treating patients with anaplastic thyroid cancer. Eligible patients for phase I may have been previously treated with prior chemotherapy while patients in phase II must be chemotherapy-naïve. The trial’s primary objectives are to determine the phase II dose and overall PFS. Secondary objectives are to evaluate safety, PK, ORR, OS, and median survival time. According to protocol, during phase I, CS-7017 will be tested in combination with paclitaxel at the following dosage levels: 0.15, 0.25, 0.35, and 0.50mg twice daily. During phase II, CS-7017 will be administered at the recommended phase II dose. Commercially available paclitaxel will be administrated as IV infusion over 3 hours once every 3 weeks. Biopsies will be obtained from patients with accessible tumor at baseline, two-weeks after the first CS-7017 dosage (prior to the start of combination therapy) and at the end of the first trial cycle (week 3 of combination therapy), in order to evaluate the effects of the trial drug alone and in combination with the chemotherapy agent on the tumor. Treatment will continue until disease progression or the development of intolerable toxicities. The trial is to enroll about 54 patients.
Indication
solid tumors, advanced, refractory
Latest Status
Phase I (begin 11/06, completed 2/10) USA
Clinical History
According to final results from the phase I clinical trial in patients with advanced malignancies and adequate hepatic and renal function, CS-7017 demonstrated promising evidence of antitumor activity and disease stabilization with acceptable tolerability. In this trial, CS-7017 was administered orally twice daily in a dose escalating fashion starting with 0.1 mg with restaging occurring every 6 weeks. Pharmacodynamic (PD) and PK samples were collected at day 1 and 22. Archived tumor specimens were assayed for relevant biomarkers by IHC. Among 32 enrolled patients, 31 were treated with CS-7017 with doses ranging from 0.10-1.15 mg twice daily. The most common malignancies were colorectal cancer (n=12), liposarcoma (n=5), and leiomyosarcoma (n=2); 27 patients were evaluable for response. There was 1 sustained PR in a patient with myxoid liposarcoma, who remains on CS-7017 after more than 553 days. Disease stabilized in 12 patients, 7 of whom had SD for =81 days (range=81-290 days). CS-7017 was well tolerated. Most patients experienced peripheral edema (17/31), often requiring diuretics. There were 3 DLT, all related to fluid retention, but without clear relation to dose. The protocol-defined MTD was not reached, but 0.50 mg twice daily was selected as the recommended phase II dose based on PK/pharmacodynamic and safety analyses. CS-7017 increased plasma adiponectin levels by 6-14-fold at 4 weeks. The plasma concentrations of CS-7017 appeared dose proportional. According to analysis of pretreatment tumor specimens, biomarkers of drug exposure were consistent with PPARgamma pathway activation; PPARgamma and RXR protein expression was significantly higher in patients with prolonged SD or PR (p=0.0079), suggesting a possible predictive biomarker for response (Pishvaian MJ, etal, ASCO10, Abs. 2526).
An open label, nonrandomized, phase I extended use protocol trial (protocol ID: CS7017-A-U102E; NCT00881569) was initiated in March 2009, in the USA, in patients with solid tumors to provide continued treatment with CS-7017 (0.25 mg), twice daily, designed to allow patients who completed a clinical trial with of CS 7017 without disease progression or unacceptable toxicity to continue treatment with this drug. The trial’s primary outcome measure is to evaluate the safety profile of CS-7017. The secondary outcome measure is to determine the response, response duration and TTP. Estimated enrollment is 10 patients.
A phase I clinical trial (protocol ID: CS-7017-A-U102; NCT00408434) was conducted at Lombardi Comprehensive Cancer Center (Washington, DC) and Dana-Farber Cancer Institute (Boston, MA) with CS-7017 in patients with advanced malignancies. CS-7017 was administered orally twice a day for 6 weeks in successive cohorts of at least 3 patients starting at a dose of 0.1 mg. Patients with stable disease continued treatment without interruption. Pharmacodynamic samples were collected from patients' sera and from peripheral blood monocytes, and PK samples were collected at day 1 and day 22. Among 25 patients treated at doses ranging from 0.1 to 0.75 mg twice daily, the most common malignancy was colorectal cancer (n=10) followed by liposarcoma (N=5), and leiomyosarcoma (n=2). CS-7017 was extremely well tolerated. Most patients (17/25) experienced some peripheral edema, often requiring diuretics. There were 2 DLT, both related to fluid retention, one in cohort 1 at 0.1 mg, and one in cohort 3 at 0.25 mg involving an increase in pleural effusion and peripheral edema, respectively. MTD has not yet been reached. Among 24 evaluable patients for response, there were no CR or PR but disease stabilized in 9 patients with 5 persisting for at least 11 weeks (range=11-42 weeks). Further disease-specific testing and combination trials with cytotoxic and targeted therapies are planned (Pishvaian MJ, etal, EORTC-NCI-AACR08, Abs. 409).
A multicenter (n=2), nonrandomized, open label, phase I clinical trial (protocol ID: CS-7017-A-U102; NCT00408434) was initiated in November 2006, in the USA, to evaluate the safety of oral CS-7017 in treating patients with advanced or metastatic malignancy that is refractory to, not curable with, or not eligible for standard treatment. The trial’s primary objective is to determine the recommended phase II dose. Secondary objectives are to document the safety profile, assess PK, explore potential biomarkers of CS-7017 activity, and to make preliminary assessments of antitumor effects. According to protocol, patients are administered CS-7017 at a dose of 0.05 to 3.2 mg twice daily. The trial, to enroll about 48 patients, was completed in February 2010.
Indication
non-small cell lung cancer (nsclc), Stage IV, metastatic, chemotherapy-naïve
Latest Status
Phase II (begin 12/08, ongoing 6/10) USA, phase II (begin 3/10)
Clinical History
An open label, randomized, phase II clinical trial (protocol ID: CS7017-A-U204; NCT01101334) was initiated in March 2010, in the USA, at the Gabrail Cancer Center (Canton, OH) under PI Nashat Gabrail, MD, to determine what effect adding CS-7017 (0.25 mg) twice daily to erlotinib (150 mg) has on safety and survival in patients with advanced (Stage IIIb) or metastatic (Stage IV) non-small cell lung cancer (nsclc) relapsed of refractory to first line treatment. The trial’s primary outcome measure is to establish the proportion of patients with PFS treated with erlotinib with or without CS-7017. Secondary outcome measures are OS, ORR, plasma concentration of CS-7017, and the rate and prevalence of AE. The trial, to enroll about 90 patients, is to be completed in August 2011.
A randomized, double blind, placebo control, phase II clinical trial (protocol ID: CS7017-A-U202, NSCLC; NCT00806286), was initiated in December 2008, at Rush University Medical Center (Chicago, IL) under PI Philip Bonomi, MD, to evaluate the safety and efficacy of carboplatin and paclitaxel with or without CS-7017 in treating patients with chemotherapy-naïve, metastatic, Stage IV NSCLC with no significant pleural effusion or pleural involvement from the tumor. The trial’s primary objective is to determine the PFS rate. Secondary objectives are to determine the median PFS, objective response rate, median survival, and overall survival. According to protocol, patients in arm I are administered 0.25 mg CS-7017 tablets two times daily for 25 to 30 months. Patients are also administered 175 mg/m² once every 3 weeks for up to 18 weeks. Patients are then treated with carboplatin IV, AUC of 6 once every 3 weeks for up to 18 weeks. Patients in arm II are administered 175 mg/m² paclitaxel IV once every 3 weeks for up to 18 weeks and carboplatin IV, AUC of 6 once every 3 weeks for up to 18 weeks. The trial is to enroll about 131 patients.
Indication
colorectal cancer, metastatic, second line
Latest Status
Phase II (begin 7/09, ongoing 3/10) Europe (Czech Republic, France, Germany, Italy, Poland, Russia, Spain, Ukraine, UK).
Clinical History
A multicenter (n=39) placebo-controlled phase II clinical trial (protocol ID: CS7017-A-E201; NCT00986440) was initiated in July 2009, in Europe (Czech Republic, France, Germany, Italy, Poland, Russia, Spain, Ukraine, UK) with CS-7017 in patients with metastatic colorectal cancer that responded or stabilized during first line chemotherapy with FOLFOX or FOLFIRI. The trial’s primary outcome measure is to compare the PFS rate of patients treated with CS-7017 versus placebo. The secondary outcome measure is to compare overall PFS and OS in patients treated with CS-7017 versus placebo. The trial, to enroll about 170 patients, is to be completed in February 2012.
