FGFR Inhibitor in FGFR Dysregulated Cancer (FIND)
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|ClinicalTrials.gov Identifier: NCT03827850|
Recruitment Status : Recruiting
First Posted : February 4, 2019
Last Update Posted : July 15, 2019
|Condition or disease||Intervention/treatment||Phase|
|Lung Cancer NSCLC Pulmonary Neoplasm Squamous Cell Lung Cancer NSCLC Stage IV||Drug: ERDAFITINIB||Phase 2|
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-man/phase-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% (4/36) in patients with FGFR1 amplified squamous cell NSCLC (sqNSCLC) and 38% (3/8) in patients with FGFR3-mutant bladder cancer. No PR was observed in patients with FGFR1/2 amplified (n=25) and FGFR3 mutant (n=1) breast cancer. All patients with FGFR2-translocated (n=2) and FGFR2-mutated cholangiocarcinoma (n=1) showed reduced tumor burden of 20% and 10%, respectively. In the erdafitinib trial, 5 partial responses were seen in FGFR translocated tumors: 3/8 (37.5%) patients with urothelial carcinoma, 1/3 (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 inhibitor 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 FGFR2 and FGFR3 mutations in squamous cell lung cancer is about 3% (Helsten et al., 2016). Translocations occur with a similar frequency of about 3% in squamous cell 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. Of note, FGFR alterations are less frequent in adenocarcinoma and arise mainly in squamous cell lung cancer. However, the exact distribution of mutations and translocations between sqNSCLC and lung adenocarcinoma hasn't been explored yet due to their low frequency.
Preclinical models in sqNSCLC cell lines and xenografts showed oncogenic activity of FGFR2/3 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 sqNSCLC.
The primary objective of the trial is to analyze the efficacy of erdafitinib in sqNSCLC patients with FGFR genetic alterations. NSCLC patient number will be based on a statistical hypothesis aiming at increasing the response rate comparing to chemotherapy/immunotherapy after standard treatment.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||50 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||Patients with sqNSCLC and FGFR alteration with high evidence on oncogenic transformation according to FIND molecular board will be included to cohort 1 (FGFR translocated sqNSCLC patients) and cohort 2 (FGFR mutated patients). Patients with sqNSCLC and FGFR alterations without enough evidence (intermediate / low evidence according to FIND molecular tumor board) for recruitment into cohorts 1 or 2, will be treated in cohort 3. Overall response rate under Erdafitinib treatment will be the primary endpoint|
|Masking:||None (Open Label)|
|Official Title:||A Phase II Trial to Evaluate Efficacy and Safety of Erdafitinib in Patients With Advanced Squamous Non Small Cell Lung Carcinoma (sqNSCLC) Harboring Fibroblast Growth Factor Receptor (FGFR) Genetic Alterations After Relapse of Standard Therapy.|
|Actual Study Start Date :||March 25, 2019|
|Estimated Primary Completion Date :||September 15, 2021|
|Estimated Study Completion Date :||March 15, 2022|
Active Comparator: Cohort 1 FGFR trans
Cohort 1: Activating (high confidence) FGFR translocations (max. 15 patients) under daily Erdaifitinib treatment
Daily in a range from 3 mg to 9 mg
Active Comparator: Cohort 2 FGFR mut
Cohort 2: Activating (high confidence) hotspot FGFR mutations (max. 15 patients) under daily Erdafitinib treatment
Daily in a range from 3 mg to 9 mg
Active Comparator: Cohort 3 FGFR other
Cohort 3: Activating (low confidence) FGFR alteration (max. 20 patients)
Daily in a range from 3 mg to 9 mg
- Overall Response Rate [ Time Frame: 3 years ]Overall response rate (ORR) per RECIST 1.1 under erdafitinib treatment in sqNSCLC with genetic alteration in FGFR
- number of adverse events per patient [ Time Frame: 3 years ]assessment of adverse events according to CTC-AE
- time length of progression free survival [ Time Frame: 3 years ]assessment of progression free survival
- time length of overall survival [ Time Frame: 3 years ]assessment of overall survival
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03827850
|Contact: Antonio Pinto, PhDemail@example.com|
|Uniklinik RWTH Aachen - Klinik für Hämotologie, Onkologie||Not yet recruiting|
|Aachen, NRW, Germany, 52074|
|Contact: Jens Panse, Dr.|
|University Hospital of Cologne||Recruiting|
|Cologne, NRW, Germany, 50937|
|Contact: Antonio Pinto, MSc, PhD +49 221 478 ext 98766 Antonio.Pinto@uk-koeln.de|
|Contact: Rieke Fischer, MD +49 221 478 ext 97904 firstname.lastname@example.org|
|Sub-Investigator: Juergen Wolf, MD, PhD|
|Principal Investigator: Lucia Nogova, MD, PhD|
|Sub-Investigator: Rieke Fischer, MD|
|Sub-Investigator: Diana SY Abdulla, MD, PhD|
|Sub-Investigator: Sebastian Michels, MD, PhD|
|Universitätsklinikum Würzburg Comprehensive Cancer center||Recruiting|
|Würzburg, NRW, Germany, 97080|
|Contact: Jens Kern, Dr.|
|Evangelische Lungenklink Berlin||Recruiting|
|Berlin, Germany, 13125|
|Contact: Christian Grohé, Dr. med|
|Principal Investigator:||Lucia Nogova, MD||University Clinic Cologne|