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

Breast Neoplasms Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04488107
• Other study ID #: AH150201
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: February 14, 2019
• Est. completion date: June 30, 2022

Study information

• Verified date: July 2020
• Source: Ahon Pharmaceutical Co., Ltd.
• Contact: Xichun Hu, M.D.
• Phone: 13816110335
• Email: xchu2009[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 78
• Est. completion date: June 30, 2022
• Est. primary completion date: December 31, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Neoplasms

Intervention

Drug:
• FCN-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.
• Letrozole 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.

Locations

Country	Name	City	State
China	Fudan University Shanghai Cancer Center	Shanghai

Sponsors (4)

Lead Sponsor	Collaborator
Ahon Pharmaceutical Co., Ltd.	Fudan University, Sir Run Run Shaw Hospital, Zhejiang Cancer Hospital

Country where clinical trial is conducted

China, 

References & Publications (5)

Curigliano G, Gómez Pardo P, Meric-Bernstam F, Conte P, Lolkema MP, Beck JT, Bardia A, Martínez García M, Penault-Llorca F, Dhuria S, Tang Z, Solovieff N, Miller M, Di Tomaso E, Hurvitz SA. Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study. Breast. 2016 Aug;28:191-8. doi: 10.1016/j.breast.2016.06.008. Epub 2016 Jun 20. — View Citation

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026. — View Citation

Elsäßer A, Regnstrom J, Vetter T, Koenig F, Hemmings RJ, Greco M, Papaluca-Amati M, Posch M. Adaptive clinical trial designs for European marketing authorization: a survey of scientific advice letters from the European Medicines Agency. Trials. 2014 Oct 2;15:383. doi: 10.1186/1745-6215-15-383. Review. — View Citation

Infante JR, Cassier PA, Gerecitano JF, Witteveen PO, Chugh R, Ribrag V, Chakraborty A, Matano A, Dobson JR, Crystal AS, Parasuraman S, Shapiro GI. A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas. Clin Cancer Res. 2016 Dec 1;22(23):5696-5705. Epub 2016 Aug 19. — View Citation

Tamura K, Mukai H, Naito Y, Yonemori K, Kodaira M, Tanabe Y, Yamamoto N, Osera S, Sasaki M, Mori Y, Hashigaki S, Nagasawa T, Umeyama Y, Yoshino T. Phase I study of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in Japanese patients. Cancer Sci. 2016 Jun;107(6):755-63. doi: 10.1111/cas.12932. Epub 2016 May 11. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	DLT within 7 days of FCN-437c monotherapy	The incidence of DLT occurred within 7 days of FCN-437c monotherapy	7 days
Primary	DLT within 28 days of FCN-437c monotherapy	The incidence of DLT occurred within 28 days of FCN-437c monotherapy	28 days
Primary	DLT within 28 days of FCN-437c combined therapy	The incidence of DLT occurred within 28 days of the letrozole-combined treatment.	28 days
Primary	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
Primary	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
Primary	Incidence of Deaths	The frequency and causes of deaths during the treatment.	through study completion, assessed up to 24 months
Primary	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
Primary	Changes of ECGs from baselines	Changes of ECGs from baselines, such as QT interval?	through study completion, assessed up to 24 months
Secondary	Anti-tumor efficacy of monotherapy	Objective response rate (ORR) of FCN-437c monotherapy.	through study completion, assessed up to 24 months
Secondary	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
Secondary	FPS	Progression free survival (PFS) during the treatment.	through study completion, assessed up to 24 months
Secondary	OS	overall survival (OS) during the treatment.	through study completion, assessed up to 24 months
Secondary	survival rate	1-year OS rate during the 1st year of treatment.	through study completion, assessed up to 24 months
Secondary	DOR	duration of response (DOR) during the treatment.	through study completion, assessed up to 24 months
Secondary	CBR	clinical benefit response (CBR) during the treatment.	through study completion, assessed up to 24 months
Secondary	Cmax of FCN-437c in monotherapy	Maximal plasma concentration of FCN-437c in monotherapy.	through study completion, assessed up to 24 months
Secondary	AUC of FCN-437c in monotherapy	Entire exposure of FCN-437c in monotherapy.	through study completion, assessed up to 24 months
Secondary	Cmax of FCN-437c in combined treatment	Maximal plasma concentration of FCN-437c combined with letrozole.	through study completion, assessed up to 24 months
Secondary	AUC of FCN-437c in combined treatment	Entire exposure of FCN-437c combined with letrozole.	through study completion, assessed up to 24 months