Breast Neoplasms
Conditions
Keywords
ER-Positive, HER2-Negative, Breast Neoplasms
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.
Interventions
DRUGFCN-437c
\- 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.
DRUGLetrozole 2.5mg
* 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.
Sponsors
Fudan University
Zhejiang Cancer Hospital
Sir Run Run Shaw Hospital
Ahon Pharmaceutical Co., Ltd.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DLT within 7 days of FCN-437c monotherapy | 7 days | The incidence of DLT occurred within 7 days of FCN-437c monotherapy |
| DLT within 28 days of FCN-437c monotherapy | 28 days | The incidence of DLT occurred within 28 days of FCN-437c monotherapy |
| DLT within 28 days of FCN-437c combined therapy | 28 days | The incidence of DLT occurred within 28 days of the letrozole-combined treatment. |
| Adverse events until the last followup | through study completion, assessed up to 24 months | 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. |
| Serious and significant adverse events | through study completion, assessed up to 24 months | Serious adverse events (SAE) and toxic reactions leading to permanent drug withdrawal occurred during the treatment. |
| Incidence of Deaths | through study completion, assessed up to 24 months | The frequency and causes of deaths during the treatment. |
| Incidence of abnormal laboratory results | through study completion, assessed up to 24 months | Abnormal laboratory results of safety concerns such as ALT, AST, Cr and BUN, et al according to NCI-CTCAE 5.0 classification. |
| Changes of ECGs from baselines | through study completion, assessed up to 24 months | Changes of ECGs from baselines, such as QT interval。 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC of FCN-437c in monotherapy | through study completion, assessed up to 24 months | Entire exposure of FCN-437c in monotherapy. |
| Anti-tumor efficacy of monotherapy | through study completion, assessed up to 24 months | Objective response rate (ORR) of FCN-437c monotherapy. |
| AUC of FCN-437c in combined treatment | through study completion, assessed up to 24 months | Entire exposure of FCN-437c combined with letrozole. |
| Cmax of FCN-437c in combined treatment | through study completion, assessed up to 24 months | Maximal plasma concentration of FCN-437c combined with letrozole. |
| Anti-tumor efficacy of combined treatment | through study completion, assessed up to 24 months | Objective response rate (ORR) of FCN-437c and letrozole-combined treatment. |
| FPS | through study completion, assessed up to 24 months | Progression free survival (PFS) during the treatment. |
| OS | through study completion, assessed up to 24 months | overall survival (OS) during the treatment. |
| survival rate | through study completion, assessed up to 24 months | 1-year OS rate during the 1st year of treatment. |
| DOR | through study completion, assessed up to 24 months | duration of response (DOR) during the treatment. |
| CBR | through study completion, assessed up to 24 months | clinical benefit response (CBR) during the treatment. |
| Cmax of FCN-437c in monotherapy | through study completion, assessed up to 24 months | Maximal plasma concentration of FCN-437c in monotherapy. |
Countries
China
Contacts
Primary ContactXichun Hu, M.D.
Backup ContactJian Zhang, M.D.
Outcome results
None listed