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FGFR Inhibitor in FGFR Dysregulated Cancer (FIND)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03827850
Recruitment Status : Recruiting
First Posted : February 4, 2019
Last Update Posted : July 15, 2019
Sponsor:
Information provided by (Responsible Party):
Lung Cancer Group Cologne

Brief Summary:
In the FIND trial, squamous Non Small Cell Lung Carcinoma (sqNSCLC) 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 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.

Condition or disease Intervention/treatment Phase
Lung Cancer NSCLC Pulmonary Neoplasm Squamous Cell Lung Cancer NSCLC Stage IV Drug: ERDAFITINIB Phase 2

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-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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
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)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Cohort 1 FGFR trans
Cohort 1: Activating (high confidence) FGFR translocations (max. 15 patients) under daily Erdaifitinib treatment
Drug: ERDAFITINIB
Daily in a range from 3 mg to 9 mg
Other Names:
  • JNJ -42756493
  • WHO NUMBER 10147

Active Comparator: Cohort 2 FGFR mut
Cohort 2: Activating (high confidence) hotspot FGFR mutations (max. 15 patients) under daily Erdafitinib treatment
Drug: ERDAFITINIB
Daily in a range from 3 mg to 9 mg
Other Names:
  • JNJ -42756493
  • WHO NUMBER 10147

Active Comparator: Cohort 3 FGFR other
Cohort 3: Activating (low confidence) FGFR alteration (max. 20 patients)
Drug: ERDAFITINIB
Daily in a range from 3 mg to 9 mg
Other Names:
  • JNJ -42756493
  • WHO NUMBER 10147




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. number of adverse events per patient [ Time Frame: 3 years ]
    assessment of adverse events according to CTC-AE

  2. time length of progression free survival [ Time Frame: 3 years ]
    assessment of progression free survival

  3. time length of overall survival [ Time Frame: 3 years ]
    assessment of overall survival



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age > 18 years
  • Stage IIIB/IV sqNSCLC patients with activating FGFR alteration after the failure on any prior line of standard treatment, or in the opinion of the investigator no effective standard therapy exists, is appropriate, tolerated or is considered equivalent to study treatment
  • Activating FGFR alteration as approved by FIND Molecular Board
  • Must sign an informed consent form (ICF) (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
  • ECOG performance status score 0, 1, or 2.
  • Clinical laboratory values and cardiovascular measurements at screening as defined in protocol
  • Disease measurable per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for cohort 1 and 2. or evaluable disease.
  • A woman of childbearing potential who is sexually active must have a negative pregnancy test (human chorionic gonadotropin [hCG]) at Screening (urine or serum, minimum sensitivity 25 IU/L or equivalent units of b-HCG) within 24 hours prior to the start of erdafitinib
  • Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP must use appropriate method(s) of contraception with a failure rate of less than 1% per year before study entry, during the study and until 5 months after taking the last dose of study drug. And other Criteria

Exclusion Criteria:

  • Pathogenic somatic mutations/translocations in the following genes: EGFR, ALK, ROS1, BRAF, K-RAS, N-RAS, PIK3CA, PTEN
  • Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to recruitment
  • Treatment with small molecules or chemotherapy within 7 days prior C1D1
  • Treatment with monoclonal antibodies within 28 days prior C1D1 if related to the underlying malignancy
  • Any other history of ongoing malignancy that would potentially interfere with the interpretation of erdafitinib efficacy
  • Symptomatic central nervous system metastases.
  • Received prior FGFR inhibitor treatment or if the patient has known allergies, hypersensitivity, or intolerance to erdafitinib or its excipients
  • Any corneal or retinal abnormality likely to increase the risk of eye toxicity, i.e.:
  • History of or current evidence of CeSR or retinal vascular occlusion (RVO)
  • Active wet, age-related macular degeneration (AMD)
  • Diabetic retinopathy with macular edema (non-proliferative)
  • Uncontrolled glaucoma (per local standard of care)
  • Corneal pathology such as keratitis, keratoconjunctivitis, keratopathy, corneal abrasion, inflammation or ulceration.
  • Has persistent phosphate level >ULN during screening (on 2 consecutive assessments at least 1 week apart, within 14 days prior to Cycle 1 Day 1) and despite medical management
  • Has a history of or current uncontrolled cardiovascular disease as defined in protocol
  • Known human immunodeficiency virus (HIV) infection, testing is mandatory (a-HIV 1/2)
  • Patients with acute or chronic Hepatitis B infection (tests should include assessment of HBsAg and HBc IgG antibody. If one parameter is positive, determine HBV-DNA to confirm acute infection. Patients with positive results for HBsAg and/or HBV-DNA are considered positive for acute or chronic infection.
  • Patients with acute or chronic Hepatitis C infection (determine HCV-RNA. Patients with positive result for HCV-RNA are considered positive for acute or chronic infection).
  • Has not recovered from reversible toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration, Grade 1 neuropathy, Grade 1-2 hearing loss)
  • Has impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions
  • Major surgery within 2 weeks of the first dose, or will not have fully recovered from surgery, or has surgery planned during the time the patient is expected to participate in the study or within 2 weeks after the last dose of study drug administration. (patients with planned surgical procedures to be conducted under local anesthesia may participate).
  • Any serious underlying medical condition, such as:

    • Evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection requiring current systemic treatment
    • Psychiatric conditions (eg, alcohol or drug abuse), dementia, or altered mental status

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03827850


Contacts
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Contact: Antonio Pinto, PhD +4922147898766 antonio.pinto@uk-koeln.de

Locations
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Germany
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    rieke.fischer@uk-koeln.de   
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         
Sponsors and Collaborators
Lung Cancer Group Cologne
Investigators
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Principal Investigator: Lucia Nogova, MD University Clinic Cologne
Publications:
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Responsible Party: Lung Cancer Group Cologne
ClinicalTrials.gov Identifier: NCT03827850    
Other Study ID Numbers: Uni-Koeln-3254
2018-000399-13 ( EudraCT Number )
First Posted: February 4, 2019    Key Record Dates
Last Update Posted: July 15, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Lung Cancer Group Cologne:
sqNSCLC
FGFR Mutations
Additional relevant MeSH terms:
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Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases