Ignite Creation Date:
2024-05-06 @ 12:40 PM
Last Modification Date:
2024-10-26 @ 1:03 PM
Study NCT ID:
NCT03827850
Status:
TERMINATED
Last Update Posted:
2023-06-09
First Post:
2019-01-22
Brief Title:
FGFR Inhibitor in FGFR Dysregulated Cancer
Sponsor:
Lung Cancer Group Cologne
Organization:
Lung Cancer Group Cologne
Study Overview
Official Title:
A Phase II Trial to Evaluate Efficacy and Safety of Erdafitinib in Patients With Advanced Non Small Cell Lung Carcinoma NSCLC Harboring Fibroblast Growth Factor Receptor FGFR Genetic Alterations After Relapse of Standard Therapy
Status:
TERMINATED
Status Verified Date:
2023-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Study-related difficulties faced with patient enrolment no safety-related reasons
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
FIND
Brief Summary:
In the FIND trial Non Small Cell Lung Carcinoma NSCLC patients with Fibroblast Growth Factor Receptor FGFR genetic alteration will be treated with the selective FGFR1-4 inhibitor erdafitinib Archival samples fresh frozen tumor samples and blood for circulating tumor DNA ctDNA will be collected before treatment Patients will be treated until disease progression or unacceptable toxicity In case of progression fresh frozen tumor biopsies and ctDNA analyses will be performed to assess resistance mechanisms The primary objective of the trial is to analyze the efficacy of erdafitinib in NSCLC patients with FGFR genetic alterations NSCLC patient number will be based on a statistical hypothesis aiming at increasing the response rate comparing to chemotherapyimmunotherapy after standard treatment
Detailed Description:
Downstream signaling of fibroblast growth factor receptors 1-4 FGFR 1-4 regulates cell proliferation migration differentiation and survival in healthy cells Genetic alterations amplifications point-mutations and translocations in FGFR1-4 genes cause altered signaling and oncogenic transformation FGFR-alterations with sensitivity to kinase inhibition have been identified in a variety of tumors such as breast- bladder- and endometrial-cancer squamous cell lung and head and neck cancer cholangiocarcinoma and glioblastoma
First-in-manphase-I clinical trials with erdafitinib and BGJ398 - both selective FGFR inhibitors - enrolled patients with any genetic alterations in FGFR The trials showed clinical responses with differences according to the type of FGFR alterations and histological subtypes In the BGJ398 trial the partial response rate was 11 436 in patients with FGFR1 amplified squamous NSCLC sqNSCLC and 38 38 in patients with FGFR3-mutant bladder cancer No PR was observed in patients with FGFR12 amplified n25 and FGFR3 mutant n1 breast cancer All patients with FGFR2-translocated n2 and FGFR2-mutated cholangiocarcinoma n1 showed reduced tumor burden of 20 and 10 respectively In the erdafitinib trial 5 partial responses were seen in FGFR translocated tumors 38 375 patients with urothelial carcinoma 13 33 patients with glioblastoma and 1 patient with endometrial cancer reached PR Summing up the results of the phase-I trials the inhibition of FGFR downstream pathways in FGFR translocated and mutated solid tumors exerted clinical activity Thus focusing treatment with FGFR inhibitors on FGFR mutated and translocated solid tumors may increase response rates progression free and overall survival in these tumors with otherwise adverse prognosis
In NSCLC patients without druggable alterations in genes as EGFR ALK or ROS1 and without high PD-L1 Programmed cell death 1 ligand 1 expression prognosis remains adverse with a median survival time of about 18 months Particularly in sqNSCLC only few driver mutations have been identified yet Of these solely mutations of the KRAS gene although observed at low frequency in sqNSCLC were explored in large clinical studies targeting KRAS downstream signaling with no survival benefit comparing to chemotherapy Immunotherapy with PD-1 antibodies such as nivolumab and pembrolizumab showed benefit in patients with high PD-L1 expression mainly
The frequency of somatic FGFR1-3 mutations in lung cancer is about 4 Helsten et al 2016 Translocations occur with a similar frequency of about 4 in lung cancer Multiple of these FGFR alterations are shown to have oncogenic potential as demonstrated in multiple in vitro in vivo and first-in-man studies
Preclinical models in NSCLC cell lines and xenografts showed oncogenic activity of FGFR23 mutations with consecutive sensitivity to FGFR inhibitors Similarly FGFR3-TACC translocation exerted kinase activation in sqNSCLC cell lines and other tumor types Furthermore patient derived FGFR3-fusion lung xenograft model showed responses to FGFR targeted treatment
In summary on the basis of genetically and phenotypically validated cell-line panels in vivo and particularly on the basis of clinical data there is strong evidence for a clinical benefit from FGFR inhibition for patients with FGFR altered NSCLC
The primary objective of the trial is to analyze the efficacy of erdafitinib in NSCLC patients with FGFR genetic alterations NSCLC patient number will be based on a statistical hypothesis aiming at increasing the response rate comparing to chemotherapyimmunotherapy after standard treatment
First-in-manphase-I clinical trials with erdafitinib and BGJ398 - both selective FGFR inhibitors - enrolled patients with any genetic alterations in FGFR The trials showed clinical responses with differences according to the type of FGFR alterations and histological subtypes In the BGJ398 trial the partial response rate was 11 436 in patients with FGFR1 amplified squamous NSCLC sqNSCLC and 38 38 in patients with FGFR3-mutant bladder cancer No PR was observed in patients with FGFR12 amplified n25 and FGFR3 mutant n1 breast cancer All patients with FGFR2-translocated n2 and FGFR2-mutated cholangiocarcinoma n1 showed reduced tumor burden of 20 and 10 respectively In the erdafitinib trial 5 partial responses were seen in FGFR translocated tumors 38 375 patients with urothelial carcinoma 13 33 patients with glioblastoma and 1 patient with endometrial cancer reached PR Summing up the results of the phase-I trials the inhibition of FGFR downstream pathways in FGFR translocated and mutated solid tumors exerted clinical activity Thus focusing treatment with FGFR inhibitors on FGFR mutated and translocated solid tumors may increase response rates progression free and overall survival in these tumors with otherwise adverse prognosis
In NSCLC patients without druggable alterations in genes as EGFR ALK or ROS1 and without high PD-L1 Programmed cell death 1 ligand 1 expression prognosis remains adverse with a median survival time of about 18 months Particularly in sqNSCLC only few driver mutations have been identified yet Of these solely mutations of the KRAS gene although observed at low frequency in sqNSCLC were explored in large clinical studies targeting KRAS downstream signaling with no survival benefit comparing to chemotherapy Immunotherapy with PD-1 antibodies such as nivolumab and pembrolizumab showed benefit in patients with high PD-L1 expression mainly
The frequency of somatic FGFR1-3 mutations in lung cancer is about 4 Helsten et al 2016 Translocations occur with a similar frequency of about 4 in lung cancer Multiple of these FGFR alterations are shown to have oncogenic potential as demonstrated in multiple in vitro in vivo and first-in-man studies
Preclinical models in NSCLC cell lines and xenografts showed oncogenic activity of FGFR23 mutations with consecutive sensitivity to FGFR inhibitors Similarly FGFR3-TACC translocation exerted kinase activation in sqNSCLC cell lines and other tumor types Furthermore patient derived FGFR3-fusion lung xenograft model showed responses to FGFR targeted treatment
In summary on the basis of genetically and phenotypically validated cell-line panels in vivo and particularly on the basis of clinical data there is strong evidence for a clinical benefit from FGFR inhibition for patients with FGFR altered NSCLC
The primary objective of the trial is to analyze the efficacy of erdafitinib in NSCLC patients with FGFR genetic alterations NSCLC patient number will be based on a statistical hypothesis aiming at increasing the response rate comparing to chemotherapyimmunotherapy after standard treatment
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2018-000399-13 | EUDRACT_NUMBER | None | None |