Infigratinib in Subjects With GC or GEJ With FGFR2 Amplification or Other Solid Tumors With Other FGFR Alterations

Gastric Cancer Clinical Trial

— FGFR  

Official title:

A Phase IIa of Infigratinib in Subjects With Locally Advanced or Metastatic Gastric Cancer or Gastroesophageal Junction Adenocarcinoma With FGFR2 Amplification or Other Advanced Solid Tumors With Other FGFR Alterations

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05019794
• Other study ID #: LB1001-201
• Status: Recruiting
• Phase: Phase 2
• Start date: May 13, 2020
• Est. completion date: December 30, 2023

Study information

• Verified date: June 2022
• Source: LianBio LLC
• Contact: Lei Mu, Master
• Phone: 86 21 61329798
• Email: Lei.mu[@]lianbio.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Infigratinib is an oral drug which selectively binds to fibroblast growth factor receptor (FGFR) 1-3. This is a multicenter, open-label, single arm phase IIa study to evaluate the efficacy and safety of Infigratinib in subjects with locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma with FGFR2 genetic amplification or other advanced solid tumors with other FGFR genetic alternations who have failed in 2nd line or above treatment. This trial includes 2 cohorts (i.e., baskets) with above mentioned indications.

Description:

The subject will go through 4 periods, including Pre-screen period, screening period, treatment period and follow up period.

Pre-screening period (up to 28 days) For cohort 1, subject sign pre-screening ICF( Inform consent ), subject will do tumor biopsy or provide FFPE samples before prescreening for FGFR2-amp detection by FISH from the central laboratory. If the result is positive, subjects can go through the main screening stage, otherwise participants will be considered a prescreen failure. subjects can go through the main screening stage, otherwise participants will be considered a prescreen failure.

Screening period ( All cohorts; up to 28 days): Subjects who had positive genetic result could sign main ICF for all the screening examinations and establish study baseline documents. Only the eligible participants could enter the next treatment period.

Treatment period: Eligible subjects will be orally administered Infigratinib (125mg, QD) for 3 weeks on, 1-week off in each 28-day cycle until the occurrence of unacceptable toxicity, disease progression, withdrawing informed consent, death, contact lost, starting a new anticancer therapy, etc (whichever occurs first). During this period, subjects will be routinely assessed efficacy status by radiographic check at W9/W17/W25/W33 . After that, subjects will be evaluated every 12 weeks until disease progression. The safety assessment will be performed at cycle 1- 4;

Follow up period: Once a treatment discontinuation happens, subjects should return to the hospital within 30 days to receive a complete safety examination. Subjects with treatment discontinuation or disease progression should directly enter the follow-up period, visit approximately every 3 months for survival status reporting until withdrawing informed consent, death, contact lost, starting a new anti-cancer therapy, etc. (whichever occurs first).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: December 30, 2023
• Est. primary completion date: December 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Cohort 1 : 1) histologically or cytologically confirmed locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. 2) failed 2nd line or above therapy with locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. 3) willing to do tumor biopsy for FGFR2 gene amplification via FISH test at central lab

2. Cohort 2: 1) Histologically or cytologically confirmed locally advanced or metastatic solid tumors other than CHOL and UC. 2) Subjects must have failed established standard medical anti-cancer therapies for a diagnosed tumor or have been intolerant to such therapy, or no standard therapy, or in the opinion of the Investigator have been considered ineligible for a particular form of standard therapy on medical grounds.(3) Previous documented proof of FGFR1, FGFR2 ,or FGFR3 fusions/rearrangements and activating mutations (FISH/NGS/PCR results could be accepted) presented by local laboratory or central laboratory. [Except Cohort 1GC, or GEJ patients with FGFR2 amplification]

3. Measurable disease by RECIST v1.1.

4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

Exclusion Criteria:

To be eligible for the study, subjects must not meet any of the following criteria:

1. History of other primary malignancies within 3 years except adequately treated in situ carcinoma of the cervix or nonmelanoma carcinoma of the skin or any other curatively treated malignancy that is not expected to require treatment for recurrence during the course of the study.

2. Previous or current treatment of a mitogen-activated protein kinase (MAPK-MEK) or selective FGFR inhibitor.

3. Any known hypersensitivity to Infigratinib or its excipients.

4. Subjects with symptomatic central nervous system metastasis.

5. History and/or current evidence of extensive tissue calcification.

6. Amylase or lipase >2.0 × ULN.

7. Abnormal calcium or phosphorus, or calcium-phosphorus product =55 mg2/dL2.

8. Current evidence of endocrine alterations of calcium/phosphate homeostasis.

9. Current evidence of corneal or retinal disorder/keratopathy.

10. Currently receiving or planning to receive treatment with agents or foods that are known strong inducers or inhibitors of CYP3A4 and medications which increase serum phosphorus and/or calcium concentration during this study. Subjects are not permitted to receive enzyme-inducing anti-epileptic drugs.

Related Conditions & MeSH terms

• Adenocarcinoma
• Esophageal Neoplasms
• Gastric Cancer
• Gastroesophageal Junction Adenocarcinoma
• Solid Tumor
• Stomach Neoplasms

Intervention

Drug:
• Infigratinib
Infigratinib (BGJ398) 125 mg orally daily, 3 weeks on, 1 week off.

Locations

Country	Name	City	State
China	Affiliated Hospital of Hebei University	Baoding	Hebei
China	Beijing Cancer Hospital	Beijing	Beijing
China	Beijing Cancer Hospital ( Department of Thoracic Oncology )	Beijing	Beijing
China	Beijing Cancer Hospital (Department of Gynecological Oncology)	Beijing	Beijing
China	The First People's Hospital of Changzhou	Changzhou	Jiangsu
China	Fujian Cancer Hospital	Fuzhou	Fujian
China	Fujian Medical University Union Hospital	Fuzhou	Fujian
China	The Sixth Affiliated Hospital, Sun Yat-sen University	Guangzhou	Guangdong
China	Sir Run Run Shaw hospital, Zhejiang University school of Medicine	Hangzhou	Zhejiang
China	The First Affiliated Hospital Zhejiang University School of Medicine	Hangzhou	Zhejiang
China	Harbin Medical University Cancer Hospital	Harbin	Heilongjiang
China	Henan Cancer Hospital	Henan	Zhengzhou
China	Nanjing Drum Tower Hospital	Nanjing	Jiangsu
China	Zhongshan Hospital Fudan University	Shanghai	Shanghai
China	Liaoning Cancer Hospital & Institute	Shenyang	Liaoning
China	Shanxi Provincial Cancer Hospital	Taiyuan	Shanxi
China	Hubei Cancer Hospital	Wuan	Hubei

Sponsors (1)

Lead Sponsor	Collaborator
LianBio LLC

Country where clinical trial is conducted

China, 

References & Publications (6)

Dienstmann R, Rodon J, Prat A, Perez-Garcia J, Adamo B, Felip E, Cortes J, Iafrate AJ, Nuciforo P, Tabernero J. Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors. Ann Oncol. 2014 Mar;25(3):552-563. doi: 10.1093/annonc/mdt419. Epub 2013 Nov 20. Review. — View Citation

Hierro C, Alsina M, Sánchez M, Serra V, Rodon J, Tabernero J. Targeting the fibroblast growth factor receptor 2 in gastric cancer: promise or pitfall? Ann Oncol. 2017 Jun 1;28(6):1207-1216. doi: 10.1093/annonc/mdx081. Review. Erratum in: Ann Oncol. 2018 Jul 1;29(7):1605. — View Citation

Nogova L, Sequist LV, Perez Garcia JM, Andre F, Delord JP, Hidalgo M, Schellens JH, Cassier PA, Camidge DR, Schuler M, Vaishampayan U, Burris H, Tian GG, Campone M, Wainberg ZA, Lim WT, LoRusso P, Shapiro GI, Parker K, Chen X, Choudhury S, Ringeisen F, Graus-Porta D, Porter D, Isaacs R, Buettner R, Wolf J. Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study. J Clin Oncol. 2017 Jan 10;35(2):157-165. Epub 2016 Nov 21. Erratum in: J Clin Oncol. 2017 Mar 10;35(8):926. J Clin Oncol. 2019 Feb 1;37(4):358. — View Citation

Su X, Zhan P, Gavine PR, Morgan S, Womack C, Ni X, Shen D, Bang YJ, Im SA, Ho Kim W, Jung EJ, Grabsch HI, Kilgour E. FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study. Br J Cancer. 2014 Feb 18;110(4):967-75. doi: 10.1038/bjc.2013.802. Epub 2014 Jan 23. — View Citation

Xue WJ, Li MT, Chen L, Sun LP, Li YY. Recent developments and advances of FGFR as a potential target in cancer. Future Med Chem. 2018 Sep 1;10(17):2109-2126. doi: 10.4155/fmc-2018-0103. Epub 2018 Aug 1. Review. — View Citation

Zhang J, Tang PMK, Zhou Y, Cheng ASL, Yu J, Kang W, To KF. Targeting the Oncogenic FGF-FGFR Axis in Gastric Carcinogenesis. Cells. 2019 Jun 25;8(6). pii: E637. doi: 10.3390/cells8060637. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR)	Defined as the proportion of subjects with confirmed responses of CR or PR; Tumor response status will be assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	Approximately 12 months after dosed
Secondary	Duration of response (DOR)	Defined as from the first evaluation as CR or PR to the first evaluation as PD or death of any cause (percent of subjects with =6 months, =9 months, and =12 months DOR will be reported).	Approximately 12 months after dosed
Secondary	Disease Control Rate (DCR)	Defined as the proportion of subjects whose best overall response is confirmed to be CR or PR or SD (RECIST v1.1).	Approximately 12 months after dosed
Secondary	Best Overall Response (BOR)	Defined as best response recorded from the start of the study treatment until the disease progression/recurrence	Approximately 12 months after dosed
Secondary	Progression-free survival (PFS)	Defined as the time from the first date of treatment to the date of progression determined by investigator or death due to any cause.	Approximately 12 months after dosed
Secondary	Overall Survival (OS)	Defined as the time from the first date of treatment until date of death.	Approximately 24 months after dosed
Secondary	Incidence of Adverse Events	The incidence of adverse events is defined as the proportion of the patients, who have adverse event(s) since the time of main informed consent.	Approximately 24 months
Secondary	Incidence of Serious Adverse Events	The incidence of serious adverse events is defined as the proportion of the patients, who have serious adverse event(s) since the time of main informed consent.	Approximately 24 months
Secondary	Incidence of Laboratory Abnormalities	Incidence of abnormal laboratory is defined as the proportion of patients who have abnormal laboratory value since the time of main informed consent.	Approximately 24 months
Secondary	Maximum plasma concentration (Cmax)	To characterize the pharmacokinetic parameter Maximum plasma concentration (Cmax) of Infigratinib following oral administration of Infigratinib in patients	Approximately 5 months.
Secondary	Area under the plasma concentration versus time curve (AUC)	To characterize the pharmacokinetic parameter Area under the plasma concentration versus time curve (AUC) of Infigratinib following oral administration of Infigratinib in patients.	Approximately 5 months.
Secondary	Apparent total plasma clearance (CL/F)	To characterize the pharmacokinetic parameter Apparent total plasma clearance (CL/F) of Infigratinib following oral administration of Infigratinib in patients.	Approximately 5 months.
Secondary	Terminal elimination half-life (t1/2)	To characterize the pharmacokinetic parameter Terminal elimination half-life (t1/2) of Infigratinib following oral administration of Infigratinib in patients.	Approximately 5 months.
Secondary	Accumulation ratio (Racc)	To characterize the pharmacokinetic parameter Accumulation ratio (Racc) of Infigratinib following oral administration of Infigratinib in patients.	Approximately 5 months.

External Links

•   A similar incidence of FGFR2 amplification was found in Asian and UK GCs and was associated with lymphatic invasion and poor prognosis.
•   Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I Stu
•   Strengthening the role of FGFR signaling in cancer biology and providing more possibilities for the therapeutic application of FGFR inhibitors
•   The pathogenic mechanisms of FGF-FGFR signaling in gastric adenocarcinoma together with the current targeted strategies in aberrant FGF-FGFR activated GC cases.
•   To describe the basic knowledge regarding FGF/FGFR signaling and categorize the clinical FGFR inhibitors. The mechanisms of resistance to FGFR inhibitors and corresponding strategies of overcoming drug resistance will also be discussed.
•   To describe the FGFR2 plays a key role in gastric cancer pathogenesis. FGFR inhibitors have been tested in FGFR-aberrant GC patients. Efforts should be done to identify reliant predictive biomarkers for selecting patients most likely to benefit.