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.

Study Overview

• Status: Unknown
• Conditions: Breast Neoplasms
• Intervention / Treatment: Drug: FCN-437c; Drug: Letrozole 2.5mg

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.

• Study Type: Interventional
• Enrollment (Anticipated): 78
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Shanghai, China
    • Recruiting
    • Fudan University Shanghai Cancer Center
    • Contact: Xichun Hu, M.D.; Phone Number: 13816110335; Email: xchu2009@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose escalation cohort of FCN-437c; 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; - 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.; Other Names: Dose-escalation and expansion
Experimental: Dose expansion cohort of FCN-437c + letrozole; 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; - 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.; Other Names: Dose-escalation and expansion; Drug: 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.; 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
OS	overall survival (OS) during the 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
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
survival rate	1-year OS rate during the 1st year of 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

Collaborators and Investigators

• Sponsor: Ahon Pharmaceutical Co., Ltd.
• Collaborators: Zhejiang Cancer Hospital; Fudan University; Sir Run Run Shaw Hospital

Publications and helpful links

General Publications

• 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.
• Curigliano G, Gomez Pardo P, Meric-Bernstam F, Conte P, Lolkema MP, Beck JT, Bardia A, Martinez Garcia 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.
• 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. doi: 10.1158/1078-0432.CCR-16-1248. Epub 2016 Aug 19.
• 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.
• Elsasser 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.
• Zhang J, Wang X, Wang X, Hui A, Wu Z, Tian L, Xu C, Yang Y, Zhang W, Hu X. Phase 1a study of the CDK4/6 inhibitor, FCN-437c, in Chinese patients with HR + /HER2- advanced breast cancer. Invest New Drugs. 2021 Dec;39(6):1549-1558. doi: 10.1007/s10637-021-01133-2. Epub 2021 Jun 9.

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2019
• Primary Completion (Anticipated): December 31, 2021
• Study Completion (Anticipated): June 30, 2022

Study Registration Dates

• First Submitted: July 13, 2020
• First Submitted That Met QC Criteria: July 23, 2020
• First Posted (Actual): July 27, 2020

Study Record Updates

• Last Update Posted (Actual): July 27, 2020
• Last Update Submitted That Met QC Criteria: July 23, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Breast Neoplasms; HER2-Negative; ER-Positive
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole
• Other Study ID Numbers: AH150201

Plan for Individual participant data (IPD)

Study Data/Documents

1. ICH topic S9 - nonclinical evaluation for anticancer pharmaceuticals. 2009
   Information identifier: ICH topic S9
2. label for IBRANCE® (palbociclib) capsules
   Information identifier: IBRANCE® (palbociclib) capsule
3. label for IBRANCE® (palbociclib) tablets,
   Information identifier: IBRANCE® (palbociclib) tablets
4. Label for KISQALI® (ribociclib) tablets
   Information identifier: KISQALI® (ribociclib) tablets
5. ICH Topic E6 (R1) Guideline for Good Clinical Practice
   Information identifier: ICH Topic E6 (R1)
6. ICH Topic E9 Statistical Principles for Clinical Trials
   Information identifier: ICH Topic E9

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No