Advanced Breast Cancer Estrogen Receptor-Positive HER2-Negative Advanced Breast Cancer
Conditions
Interventions
The starting dose is 200 mg G1T48, taken orally once daily. Subsequent dose
levels will be determined by the SMC.
Sponsors
G1 Therapeutics Inc.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: For a patient to be eligible for participation in this study, all of the following criteria must apply. A full list of inclusion criteria are provided in Section 7.1.1 of the study protocol. • Age 18 years or older females (postmenopausal only in Part 1 and any menopausal status in Parts 2 and 3; pre- and peri-menopausal women in Parts 2 and 3 must be chemically or surgically postmenopausal) • Histological or cytological confirmation of adenocarcinoma of the breast with evidence of metastatic or locally advanced disease, which is not amenable to surgical resection ± radiation therapy with curative intent • Documented ER-positive tumor, defined as >= 1% positive stained cells utilizing an assay consistent with local standards. The tumor may be progesterone receptor positive or negative. • Documented HER2-negative tumor per 2017 College of American Pathologists (CAP) criteria • Not eligible for standard therapy that would confer clinical benefit to the patient • For Parts 1 and 2 of the study, objective evidence of either progression after an AI for metastatic/locally advanced disease OR recurrence while on or within 12 months of the end of adjuvant treatment with an AI • For Part 3, patients must meet at least ONE of the following: - Received >= 24 months of endocrine therapy in the adjuvant setting prior to recurrence or progression - Received >= 6 months of endocrine therapy in the advanced/metastatic setting prior to progression • Not eligible for standard therapy that would confer clinical benefit to the patient • For Part 1 of the study, evaluable or measurable disease as defined by RECIST, Version 1.1 • For Parts 2 and 3 of the study, approximately 75% of enrolled patients must have measurable disease as defined by RECIST, Version 1.1 • Exposure to the following: - Part 1: = 5-week interval since the last use of tamoxifen (or other selective estrogen receptor modulators [SERMs]) or fulvestrant (or other SERDs) • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 • Life expectancy > 12 weeks • Adequate bone marrow reserve and organ function as demonstrated by the following laboratory values: - Hemoglobin >= 9 g/dL - Absolute neutrophil count (ANC) >= 1.5 × 109/L - Platelet count >= 100 × 109/L - Estimated glomerular filtration rate >= 50 mL/minute/1.73 m2 - Total bilirubin
Exclusion criteria
Exclusion criteria: A patient will not be eligible for participation in this study if any of the following criteria apply. A full list of exclusion criteria are provided in Section 7.1.2 of the study Protocol. • Patients with immediately life-threatening or rapidly progressive disease or those who experience rapid visceral recurrence during adjuvant endocrine therapy • Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated (eg, radiotherapy, stereotactic surgery) and clinically stable (including patients with residual CNS symptoms/deficits) off enzyme-inducing anticonvulsants and steroids for at least 28 days prior to the first dose of study drug (patients may continue to receive non-enzyme-inducing anticonvulsants throughout the study if needed) • Major surgery, chemotherapy, radiotherapy, or other anticancer therapy within 14 days of first dose of study drug • Prior hematopoietic stem cell or bone marrow transplantation • Blood transfusions or hematopoietic growth factor therapy within 14 days prior to the first dose of study drug • Concurrent use of prohibited medications • Any unresolved toxicities from prior surgeries or therapies > Grade 1 (Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0) at the time of starting study drug with the exception of alopecia (any grade) and Grade 2 peripheral neuropathy • Cardiac criteria as outlined in Section 7.1.2 of the study protocol • Known clinically significant history of liver disease (excluding metastases to the liver) • Unexplained symptomatic endometrial disorders • Any evidence of severe or uncontrolled systemic diseases, which in the investigator opinion makes it undesirable for the patient to participate in the study or that would jeopardize compliance with the protocol • Known chronic, active infection • Refractory nausea and vomiting, chronic gastrointestinal (GI) disease, GI ulcer, GI bleeding, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of study drug • History of other malignancies, except for the following: (1) adequately treated basal or squamous cell carcinoma of the skin; (2) curatively treated a) in situ carcinoma of the uterine cervix, b) superficial bladder cancer; or (3) other curatively treated solid tumor with no evidence of disease for >= 3 years • For Part 3 of the study, prior CDK4/6 inhibitor therapy, oral SERDs, or selective estrogen receptor covalent antagonists (SERCAs) in any setting
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary: 1) AEs, SAEs, and other safety measures (ECGs, physical examinations, vital signs, and laboratory parameters) 2) Safety, tolerability and DLTs | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary: 1) See Table 10.6 of the study protocol 2) See Section 10.7.1 of the study protocol (Part 3) 3) Cmax and AUC ratios 4) PFS, OS, ORR, BOR, and DoR according to RECIST, Version 1.1; CBR (including CR, PR, and SD lasting >= 24 weeks) Exploratory: 1) Correlation between response endpoints and the following cfDNA endpoints: baseline ESR1 mutational status, quantity of cfDNA, mutational changes in cfDNA (including ESR1 and PI3K), and quantification of genetic changes in cfDNA 2) % change in SUV, parameters of kinetic modelling (ie, K1, VT) 3) Enumeration and proportion of ER positive CTCs 4) Evaluate estrogen receptors and downstream effectors 5) Correlation between PK endpoints and response endpoints, including RECIST assessment, FES PET (Parts 1 and 2 only) and fresh tumor tissue (Parts 2 and 3 only). 6) Biomarker status, including ESR1, Ki67, and others in archival tumor tissue, fresh tumor tissue (Parts 2 and 3 only) and correlations with response or resistance | — |
Countries
Netherlands
Outcome results
None listed