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

NCT04488107 | Unknown Phase 1

• 1 other identifier: AH150201
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 1

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.

Conditions

Breast Neoplasms

Keywords

ER-Positive; HER2-Negative; Breast Neoplasms

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (11)

• Anti-tumor efficacy of monotherapy

  through study completion, assessed up to 24 months

• Anti-tumor efficacy of combined treatment

  through study completion, assessed up to 24 months

• FPS

  through study completion, assessed up to 24 months

• OS

  through study completion, assessed up to 24 months

• survival rate

  through study completion, assessed up to 24 months

Study Arms (2)

Dose escalation cohort of FCN-437c

EXPERIMENTAL

* 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

Dose expansion cohort of FCN-437c + letrozole

EXPERIMENTAL

* 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; Drug: Letrozole 2.5mg

Interventions

FCN-437c DRUG

\- 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.

Also known as: Dose-escalation and expansion

Dose escalation cohort of FCN-437c; Dose expansion cohort of FCN-437c + letrozole

Letrozole 2.5mg DRUG

* 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.

Also known as: Dose-escalation

Dose expansion cohort of FCN-437c + letrozole

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Women with breast cancer,
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 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.

You may not qualify if:

• 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;
• 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) ;

Sponsors & Collaborators

• Ahon Pharmaceutical Co., Ltd.: lead
• Fudan University: collaborator
• Zhejiang Cancer Hospital: collaborator
• Sir Run Run Shaw Hospital: collaborator

Study Sites (1)

Fudan University Shanghai Cancer Center

Shanghai, China

RECRUITING

Related Publications (6)

• 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.

  PMID: 27336726 BACKGROUND

• 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.

  PMID: 27542767 BACKGROUND

• 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.

  PMID: 26991823 BACKGROUND

• 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.

  PMID: 19097774 BACKGROUND

• 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.

  PMID: 25278265 BACKGROUND

• 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.

  PMID: 34109484 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

FCN-437c; Letrozole

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Xichun Hu, M.D.

  Fudan University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Xichun Hu, M.D.

CONTACT

13816110335; xchu2009@hotmail.com

Jian Zhang, M.D.

CONTACT

syner2000@163.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: July 13, 2020
• First Posted: July 27, 2020
• Study Start: February 14, 2019
• Primary Completion: December 31, 2021
• Study Completion: June 30, 2022
• Last Updated: July 27, 2020

Record last verified: 2020-07

Locations

CN (1)