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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Breast Neoplasms

Intervention / Treatment
-----------------
* Drug: FCN-437c
* Drug: Letrozole 2.5mg


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This study plans to start dose escalating from 50 mg, followed by 100, 200, 300, 450, and 600 mg as tentatively designated escalating dose groups. After the initial dose group, it is allowed to adjust the subsequent dose level according to the test data, but it will not exceed 100% dose increment. After the completion of DLT observation in each group, the next dose group and the number of cases were determined according to the safety, efficacy and PK data of the dose group. The traditional 3+3 method was used in the design of dose escalating stage, and the improved Fibonacci series was used for the dose increasing stage.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation cohort of FCN-437c<br>This study plans to start escalating from 50 mg QD, through 100 mg, 200 mg, 300 mg, 450 mg, to 600 mg. Participants will receive FCN-437c in sequential 28-day cycles which are made up of monotherapy QD for 21 days followed by a 7 day rest period. Participants must be histologically or cytologically diagnosed with ER+/ HER2- advanced breast cancer. | Drug: FCN-437c<br>* - FCN-437c is a selective and potent CDK4/6 dual inhibitor, with broad antitumor activity in preclinical pharmacology models, favorable physical and pharmacokinetic (PK) properties, and acceptable toxicity profile in nonclinical studies.<br>* Other names: Dose-escalation and expansion;|
| Experimental: Dose expansion cohort of FCN-437c + letrozole<br>The dose expansion stage will be initiated after escalating to MTD. Six patients will be treated with FCN-437c combined with letrozole. DLT assessment and PK blood collection will be completed in the first 28-day cycle. If DLT does not occur in the first three patients, 15 additional patients were enrolled to complete the expansion study of MTD group. If one DLT occurs in the first three patients, three additional patients will be enrolled onal patients were enrolled and completed the MTD group. Patients will be evaluated every 8 weeks until disease progression, intolerable toxicity, death, investigator's decision or patient's voluntary withdrawal from the study. | Drug: FCN-437c<br>* - FCN-437c is a selective and potent CDK4/6 dual inhibitor, with broad antitumor activity in preclinical pharmacology models, favorable physical and pharmacokinetic (PK) properties, and acceptable toxicity profile in nonclinical studies.<br>* Other names: Dose-escalation and expansion;Drug: Letrozole 2.5mg<br>* Letrozole is the latest generation of aromatase inhibitor. Letrozole lowers estrogen levels in postmenopausal women, which may slow the growth of certain types of breast tumors that need estrogen to grow in the body. Letrozole is used to treat breast cancer in postmenopausal women. It is often given to women who have been taking tamoxifen (Nolvadex, Soltamox) for 5 years.<br>* Other names: Dose-escalation;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT within 7 days of FCN-437c monotherapy | The incidence of DLT occurred within 7 days of FCN-437c monotherapy | 7 days | 
| DLT within 28 days of FCN-437c monotherapy | The incidence of DLT occurred within 28 days of FCN-437c monotherapy | 28 days | 
| DLT within 28 days of FCN-437c combined therapy | The incidence of DLT occurred within 28 days of the letrozole-combined treatment. | 28 days | 
| Adverse events until the last followup | The types and frequencies of adverse events (AEs) evaluated according to the National Cancer Institute Common Terminology Criteria for adverse events (NCI-CTCAE) version 5.0. | through study completion, assessed up to 24 months | 
| Serious and significant adverse events | Serious adverse events (SAE) and toxic reactions leading to permanent drug withdrawal occurred during the treatment. | through study completion, assessed up to 24 months | 
| Incidence of Deaths | The frequency and causes of deaths during the treatment. | through study completion, assessed up to 24 months | 
| Incidence of abnormal laboratory results | Abnormal laboratory results of safety concerns such as ALT, AST, Cr and BUN, et al according to NCI-CTCAE 5.0 classification. | through study completion, assessed up to 24 months | 
| Changes of ECGs from baselines | Changes of ECGs from baselines, such as QT interval。 | through study completion, assessed up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor efficacy of monotherapy | Objective response rate (ORR) of FCN-437c monotherapy. | through study completion, assessed up to 24 months | 
| Anti-tumor efficacy of combined treatment | Objective response rate (ORR) of FCN-437c and letrozole-combined treatment. | through study completion, assessed up to 24 months | 
| FPS | Progression free survival (PFS) during the treatment. | through study completion, assessed up to 24 months | 
| OS | overall survival (OS) during the treatment. | through study completion, assessed up to 24 months | 
| survival rate | 1-year OS rate during the 1st year of treatment. | through study completion, assessed up to 24 months | 
| DOR | duration of response (DOR) during the treatment. | through study completion, assessed up to 24 months | 
| CBR | clinical benefit response (CBR) during the treatment. | through study completion, assessed up to 24 months | 
| Cmax of FCN-437c in monotherapy | Maximal plasma concentration of FCN-437c in monotherapy. | through study completion, assessed up to 24 months | 
| AUC of FCN-437c in monotherapy | Entire exposure of FCN-437c in monotherapy. | through study completion, assessed up to 24 months | 
| Cmax of FCN-437c in combined treatment | Maximal plasma concentration of FCN-437c combined with letrozole. | through study completion, assessed up to 24 months | 
| AUC of FCN-437c in combined treatment | Entire exposure of FCN-437c combined with letrozole. | through study completion, assessed up to 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ER-Positive, HER2-Negative, Breast Neoplasms