Safety, Tolerability, Pharmacokinetics and Antitumor Activity of FCN-437c

A Multicenter, Open, Single Arm Dose-escalation and Dose-expansion Study: to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of FCN-437c Alone or in Combination With Letrozole in ER+/ HER2- Advanced Breast Cancer

This is a multicenter, open, single arm dose escalation and dose expansion clinical study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of FCN-437c alone or in combination with letrozole in women with ER +/ HER2 - advanced breast cancer.

This is a multicenter, open, single arm clinical study to evaluate the safety, tolerability, and antitumor activity of FCN-437c in combination with letrozole in postmenopausal women with ER + / HER2 - advanced breast cancer, and to evaluate the PK characteristics of FCN-437c monotherapy and combined therapy.

The single drug administration period (7 days) . The continuous administration period made up of 21 days of continuous administration, followed by 7 days of withdrawal, which made up of 28 days as a treatment cycle. The evaluation was conducted every 8 weeks until one of the following happened, disease progression, intolerable toxicity, death, the researcher's decision or the patients' voluntary withdrawal from the study. The follow-up visit was conducted 30 days after the last administration. The telephone follow-up was conducted once every 3 months until the end of the study to record the survival period.

In the expansion period, FCN-437c was continuous administration per day for 21 days, followed by 7 days of withdrawal, making a treatment cycle of 28 days during which letrozole was continuously administrated 2.5 mg QD. Evaluation was conducted every 8 weeks until one of the following occurred, disease progression, intolerable toxicity, death, decision of the researcher or patients' voluntary withdrawal of the study. Follow up visit was conducted 30 days after the last administration, followed by the survival period telephone follow-up every 3 months until the end of the study.

End of of the study was defined as the last patient in the dose expansion stage took the treatment for more than one year, or terminated the treatment (depending on which occurred earlier.

At the end of the study, patients with no disease progression were determined to continue taking FCN-437c according to the clinical benefits.

Inclusion Criteria:

• Adult (>= 18 years old) patients diagnosed as ER +/ HER2 - advanced breast cancer, without standard treatment or unable to receive standard treatment;
• The eastern cooperative oncology group (ECOG) score is 0 or 1;
• According to RECIST version 1.1, there was at least one measurable lesion or only bone metastasis;
• The expected survival period is at least 12 weeks;
• Patients have sufficient bone marrow and organ function;
• Patients is willing and able to follow the planned visit, treatment plan, laboratory examination and other test procedures;
• Patients fully understand the study and are willing to sign the informed consent form (ICF);
• The inclusion criteria specific for the dose expansion stage are as follows.
• The postmenopausal patients (>= 18 years old) diagnosed as ER +/ HER2 - breast cancer have evidence of local recurrence or metastasis, and are not suitable for surgical resection or radiotherapy for the purpose of cure;
• There was neither history of systematic treatment nor clinical indication for chemotherapy for patients in the dose expansion stage;
• The patients in the dose expansion stage should neither have received neoadjuvant or adjuvant endocrine therapy previously, nor have progression free survival during or after the neoadjuvant or adjuvant endocrine therapy was shorter than 12 months.

Exclusion Criteria:

• HER2 + breast cancer, either defined as by fluorescence hybridization (FISH) or detected by standard immunohistochemistry (IHC);
• History of previous CDK4 / 6 inhibitors treatment;
• Received anti-tumor chemotherapy, major surgery, radiotherapy, biological drug therapy or other research drug treatment within 28 days before enrollment;
• The toxicity of previous anti-tumor therapy has not recovered (>= grade 2 according to NCI CTCAE version 5.0), except for hair loss; the neurotoxicity of patients who have received chemotherapy before should be restored to grade 2 or below based on NCI CTCAE version 5.0;
• The patient used CYP3A strong inhibitor or CYP3A inducer 14 days before the first dose administration;
• Cardiac dysfunction or disease are consistent with one of the following conditions such as arrhythmia with clinical significance, any risk factors increasing risk of QTc interval prolongation, or congestive heart failure (CHF) with grade ≥ 3 according to NYHA ;
• Dysphagia, active digestive system disease, major gastrointestinal surgery, malabsorption syndrome, or other conditions that may impair the absorption of FCN-437c;
• Known allergy to letrozole, FNC-437c or any other excipients;
• Uncontrolled central system metastasis;
• Active infection, including HBV, HCV, HIV, et al;
• Any other disease or condition of clinical significance (e.g., uncontrolled diabetes, active or uncontrollable infection) that the researchers believe may affect protocol compliance or affect patients' signing of ICF;
• The exclusion criteria specific for the dose expansion stage was as follows.
• Postmenopausal women with advanced breast cancer who have received neoadjuvant / adjuvant endocrine therapy and progressed less than 12 months after treatment;
• Patients with advanced breast cancer who had received systemic anti-tumor therapy including endocrine and chemotherapy (patients with ER + and HER2 - who had received aromatase inhibitors for no more than 14 days were allowed to be enrolled) ;
• Other exclusion criteria are the same as those of the dose escalation stage.