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A clinical study to evaluate the safety, tolerability, and efficacy of INCB001158 in combination with chemotherapy in subjects with advanced or metastatic solid tumors.

ABSTRACT: Primary objectives: • Phase 1: To assess the safety and tolerability and determine the recommended Phase 2 dose (RP2D) of INCB001158 in combination with chemotherapy. • Phase 2: To evaluate the objective response rate (ORR) of INCB001158 in combination with chemotherapy. Primary endpoints: • Phase 1: Safety, tolerability, dose-limiting toxicities (DLTs), and RP2D of INCB001158 in combination with chemotherapy, as assessed by adverse events (AEs), clinical laboratory tests, physical examination results, and 12-lead electrocardiogram (ECG) results. • Phase 2: ORR, defined as the percentage of subjects having a complete response (CR) or partial response (PR), as determined by investigator assessment of radiographic disease as per RECIST v1.1.

DISEASE(S): Endometrial Cancer,Phase 1: Advanced Or Metastatic Solid Tumors phase 2: Advanced/metastatic Microsatellite Stable Colorectal Cancer (mss-crc), Biliary Tract Cancer (btc), Gastroesophageal Cancer (gc), And Endometrial Cancer (ec) And Recurrent Ovarian Cancer (oc),Ovarian Cancer Recurrent,Neoplasm Biliary Tract,Colorectal Cancer,Gastroesophageal Cancer,Phase 1: Advanced Or Metastatic Solid Tumorsphase 2: Advanced/metastatic Microsatellite Stable Colorectal Cancer (mss-crc), Biliary Tract Cancer (btc), Gastroesophageal Cancer (gc), And Endometri...

PROVIDER: 2537194 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to reexpression of genes encoding important therapeutic targets, including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC). Purpose: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to re-expression of genes encoding important therapeutic targets including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine (AZA) and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC). Patients and Methods: Patients received AZA 40 mg/m2 (days 1-5, 8-10) and entinostat 7 mg (days 3,10) of 28 day cycle. Continuation of epigenetic therapy was offered with addition of endocrine therapy at time of progression (optional continuation, OC phase). Primary endpoint was objective response rate (ORR) in each cohort. We hypothesized that ORR would be >20% against null of 5% using Simon two-stage design. At least 1 response was required in 1st of 13 patients per cohort to continue accrual to 27 per cohort. Type I error 4%, power 90%. Results: There was one partial response among 27 women with hormone-resistant disease (ORR=4%, 95% CI=0-19%), and none in 13 women with TNBC. One additional partial response was observed in the OC phase in the hormone-resistant cohort (n=12). Mandatory tumor samples were obtained pre- and post-treatment (58% paired) with either up- or down-regulation of ER observed in approximately 50% of post-treatment biopsies in the hormone-resistant, but not TNBC cohort. Conclusion: Combination epigenetic therapy was well tolerated but our primary endpoint was not met. OC phase results suggest that some women benefit from epigenetic therapy and/or reintroduction of endocrine therapy beyond progression but further study is needed.

Dataset Information

A clinical study to evaluate the safety, tolerability, and efficacy of INCB001158 in combination with chemotherapy in subjects with advanced or metastatic solid tumors.

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