Shuquan Chen

Pharmacological effects of CS-0777, a selective sphingosine 1-phosphate receptor-1 modulator: Results from a 12-week, open-label pilot study in multiple sclerosis patients

CS-0777 is a selective sphingosine 1-phosphate receptor-1 modulator under investigation for treatment of multiple sclerosis (MS). We conducted an open-label, pilot study in 25 MS patients to assess the safety, pharmacokinetics, pharmacodynamics and exploratory efficacy of oral CS-0777 (0.1, 0.3 and 0.6 mg), administered once weekly or every other week for 12 weeks. CS-0777 resulted in a pronounced, dose-dependent decrease in lymphocytes and CD4 T cell subsets, which returned to baseline within 4 weeks after the last dose. Overall, CS-0777 was safe and well-tolerated. These results require confirmation in a double-blind, placebo-controlled and adequately powered phase 2 study in MS.

Clinical Translation and Validation of a Predictive Biomarker for Patritumab, an Anti-human Epidermal Growth Factor Receptor 3 (HER3) Monoclonal Antibody, in Patients With Advanced Non-small Cell Lung Cancer.

Background During early clinical development, prospective identification of a predictive biomarker and validation of an assay method may not always be feasible. Dichotomizing a continuous biomarker measure to classify responders also leads to challenges. We present a case study of a prospective–retrospective approach for a continuous biomarker identified after patient enrollment but defined prospectively before the unblinding of data. An analysis of the strengths and weaknesses of this approach and the challenges encountered in its practical application are also provided. Methods HERALD (NCT02134015) was a double-blind, phase 2 study in patients with non-small cell lung cancer (NSCLC) randomized to erlotinib with placebo or with high or low doses of patritumab, a monoclonal antibody targeted against human epidermal growth factor receptor 3 (HER3). While the primary objective was to assess safety and progression-free survival (PFS), a secondary objective was to determine a single predictive biomarker hypothesis to identify subjects most likely to benefit from the addition of patritumab. Although not identified as the primary biomarker in the study protocol, on the basis of preclinical results from 2 independent laboratories, expression levels of the HER3 ligand heregulin (HRG) were prospectively declared the predictive biomarker before data unblinding but after subject enrollment. An assay to measure HRG mRNA was developed and validated. Other biomarkers, such as epidermal growth factor receptor (EGFR) mutation status, were also evaluated in an exploratory fashion. The cutoff value for high vs. low HRG mRNA levels was set at the median delta threshold cycle. A maximum likelihood analysis was performed to evaluate the provisional cutoff. The relationship of HRG values to PFS hazard ratios (HRs) was assessed as a measure of internal validation. Additional NSCLC samples were analyzed to characterize HRG mRNA distribution. Results The subgroup of patients with high HRG mRNA levels (“HRG-high”) demonstrated clinical benefit from patritumab treatment with HRs of 0.37 (P = 0.0283) and 0.29 (P = 0.0027) in the high- and low-dose patritumab arms, respectively. However, only 102 of the 215 randomized patients (47.4%) had sufficient tumor samples for HRG mRNA measurement. Maximum likelihood analysis showed that the provisional cutoff was within the optimal range. In the placebo arm, the HRG-high subgroup demonstrated worse prognosis compared with HRG-low. A continuous relationship was observed between increased HRG mRNA levels and lower HR. Additional NSCLC samples (N = 300) demonstrated a similar unimodal distribution to that observed in this study, suggesting that the defined cutoff may be applicable to future NSCLC studies. Conclusions The prospective–retrospective approach was successful in clinically validating a probable predictive biomarker. Post hoc in vitro studies and statistical analyses permitted further testing of the underlying assumptions. However, limitations of this analysis include the incomplete collection of adequate tumor tissue and a lack of stratification. In a phase 3 study, findings are being confirmed, and the HRG cutoff value is being further refined. ClinicalTrials.gov Number NCT02134015.

An open‐label, phase 1 study to evaluate the effects of hepatic impairment on edoxaban pharmacokinetics and pharmacodynamics

Edoxaban, a once‐daily, oral, direct factor Xa inhibitor, is approved for stroke prevention in nonvalvular atrial fibrillation and venous thromboembolism treatment. This study examined the effects of mild or moderate hepatic impairment on the pharmacokinetics of edoxaban and its metabolite M4. Thirty‐three subjects enrolled in 4 treatment cohorts—mild hepatic impairment (n = 8), moderate hepatic impairment (n = 9), and 2 cohorts of healthy controls matched for age, sex, and weight (each n = 8)—and received a single 15‐mg dose of edoxaban. Plasma pharmacokinetics for edoxaban and M4, prothrombin time (PT), activated partial thromboplastin time (aPTT), and safety data were measured over 72 hours. Edoxaban and M4 exposures were similar in subjects with mild or moderate hepatic impairment compared with matched controls. Higher PT and aPTT values were observed at baseline and after edoxaban dosing in the hepatic impairment groups compared with healthy controls. Edoxaban 15 mg was well tolerated in all cohorts. These results suggest that edoxaban exposure does not significantly increase in patients with mild or moderate hepatic impairment. However, because of the potential for underlying coagulopathy, edoxaban is not recommended for use in patients with moderate or severe hepatic impairment. No dose reduction is recommended for patients with mild hepatic impairment.

Abstract CT311: A randomized, open-label phase 2 study of efatutazone and erlotinib as second- or third-line therapy for non-small cell lung cancer (NSCLC)

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction: Efatutazone is a potent, highly selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist active in preclinical cancer models, including NSCLC. In phase 1 studies, efatutazone showed anticancer activity and a manageable safety profile. An in vitro study combining a PPARγ agonist and an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), similar to erlotinib, showed an increase in the antiproliferative effects of the EGFR-TKI in NSCLC cells (Lee et al. Lung Cancer. 2006). This study evaluated the safety and efficacy of efatutazone added to erlotinib as second- or third-line NSCLC therapy. Methods: Patients from Germany, India, Korea, and the United States with NSCLC that progressed after first-line platinum therapy and no more than 1 additional therapy were stratified by Eastern Cooperative Oncology Group (ECOG) status (0/1 vs 2) and randomized 1:1 to efatutazone + erlotinib (E+E) or erlotinib alone (E). Efatutazone (0.5 mg) was administered orally, twice daily; erlotinib (150 mg) was administered orally, once daily. Treatment was given continuously in the absence of disease progression, withdrawal of consent, or unacceptable toxicity. The primary end point was progression-free survival (PFS) assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Results: Characteristics of the 90 randomized patients for E+E and E treatment groups, respectively, were: median age, 60 vs 61 years; male sex, 75.6% vs 55.6%; never smoker, 31.1% vs 46.7%; ECOG status 0/1, 91.1% vs 91.1%; and partial response (PR) as best response to prior therapy, 15.6% vs 26.7%. PFS was not different between treatments (hazard ratio [HR], 0.93; P = 0.79) with median PFS of 4.1 vs 2.8 months in the E+E vs E arms, respectively. The objective response rate was also similar at 20.5% vs 20.0% for E+E and E, respectively. Overall survival was not statistically different between the E+E vs E arms (median, 7.6 vs 11.4 months; HR, 1.20; P = 0.46). The most frequent adverse events (≥ 25%) or those of special interest for E+E and E, respectively, were anemia (36.4% vs 6.7%), diarrhea (40.9% vs 40.0%), peripheral edema (38.6% vs 2.2%), decreased appetite (40.9% vs 22.2%), dermatitis acneiform (34.1% vs 20.0%), rash (25.0% vs 31.1%), and pleural effusion (22.7% vs 0%).Conclusions: Efatutazone did not improve the efficacy of erlotinib as second- or third-line therapy for NSCLC. Adverse events associated with efatutazone in combination with erlotinib were related to anemia and fluid retention as expected with this drug class. Citation Format: Ana B. Oton, Byoung Chul Cho, Myung-Ju Ahn, Sang-We Kim, Kirushnakumar Subramanian, Chirag Desai, Dale Shuster, Terri Goldberg, Hamim Zahir, Dipen Dutta, Shuquan Chen, Richard Von Roemeling, Joachim von Pawel. A randomized, open-label phase 2 study of efatutazone and erlotinib as second- or third-line therapy for non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT311. doi:10.1158/1538-7445.AM2014-CT311