A Study of Bemarituzumab Monotherapy and Combination With Other Anti-cancer Therapy in SqNSCLC With FGFR2b Overexpression (FORTITUDE-201)
- Conditions
- Squamous-Cell Non-Small-Cell Lung Cancer
- Interventions
- Registration Number
- NCT05267470
- Lead Sponsor
- Amgen
- Brief Summary
The primary objectives of this study are to evaluate the safety and tolerability of bemarituzumab monotherapy and combination with other anti-cancer therapies, and to determine the recommended phase 3 dose of bemarituzumab in combination with other anti-cancer therapies.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 74
- Participant has provided informed consent/assent prior to initiation of any study specific activities/procedures
- Age ≥ 18 years old (or legal adult within country, whichever is older) at the time that the Informed Consent Form (ICF) is signed
- Pathologically confirmed squamous cell lung carcinoma
- Disease that is unresectable, locally advanced or metastatic (not amenable to curative therapy)
- Participants must have archived tumor tissue sample (formalin fixed, paraffin embedded [FFPE] sample [FFPE of excisional, or core needle]) taken within last 5 years or be willing to undergo pre-treatment tumor biopsy (excisional, or core needle) for tissue prior to enrollment
- Participant must have progressed on, or recurred after at least 1 prior systemic therapy (Part 1 and 2 only) or at least 2 prior systemic therapies (Part 3 only) for locally advanced and unresectable or metastatic disease. Prior treatment must include a platinum-based doublet chemotherapy and checkpoint inhibitor for advanced or metastatic disease, either given as one line of therapy or as individual lines of therapy, unless the participant has a medical contraindication to one of the required therapies (which must be documented in the electronic case report form [eCRF]). Additionally, if the participant's tumor was previously identified as having a driver mutation (according to local standard of care or guidelines, e.g., Kirsten rat sarcoma [KRAS] G12C, neurotrophic tyrosine receptor kinase [NTRK]), which has an approved therapy for which the participant is eligible and available, the participant must have received the approved therapy in a prior line of treatment.
- For Part 4, participants may not have received prior systemic therapy for their locally advanced and unresectable or metastatic disease. For Part 4, participants who received peri-operative systemic therapy are eligible if that adjuvant/neoadjuvant therapy was completed at least 12 months prior to diagnosis of locally advanced and unresectable or metastatic disease.
- Measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Adequate organ function as determined per protocol
- Part 2, 3 and 4 only: FGFR2b overexpression as determined by centrally performed immunohistochemistry (IHC) testing
- Mixed small-cell lung cancer or mixed non-small cell lung cancer (NSCLC) histology
- Untreated or symptomatic central nervous system (CNS) metastases or leptomeningeal disease
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures at a frequency greater than monthly
- Impaired cardiac function or clinically significant cardiac disease including: unstable angina within 6 months prior to first dose of study treatment, acute myocardial infarction < 6 months prior to first dose of study treatment, New York Heart Association (NYHA) class II-IV congestive heart failure, uncontrolled hypertension (defined as an average systolic blood pressure >160 mmHg or diastolic >100 mm Hg despite optimal treatment (measured following European Society for Hypertension/European Society of Cardiology [ESH/ESC] 2013 guidelines; Section 11.11), uncontrolled cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin, active coronary artery disease, Fridericia's correction formula (QTc) ≥ 470
- Evidence of any ongoing ophthalmologic abnormalities or symptoms that are acute (within 4 weeks) or actively progressing
- Recent (within 6 months) corneal surgery or ophthalmic laser treatment or recent (within 6 months) history of, or evidence of, corneal defects, corneal ulcerations, keratitis, or keratoconus, or other known abnormalities of the cornea that may pose an increased risk of developing a corneal ulcer
- Part 1 and Part 2: participants that experienced toxicity or hypersensitivity requiring discontinuation of prior docetaxel treatment
- Part 1 only: participants that had disease progression on prior therapy with docetaxel
- Part 2 only: participants have received prior docetaxel in unresectable or metastatic setting (including participants who received prior docetaxel in first line for metastatic disease, but not including participants who received prior docetaxel neoadjuvantly or adjuvantly and did not progress within 6 months of end of therapy)
- Prior treatment with any selective inhibitor of the fibroblast growth factor-fibroblast growth factor receptor (FGF-FGFR) pathway
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 1: Combination Dose Exploration Bemarituzumab Participants with SqNSCLC will receive escalating doses of bemarituzumab in combination with docetaxel. Part 4: Combination Immuno-chemotherapy Bemarituzumab Participants with FGFR2b overexpression will receive the dose of bemarituzumab identified as safe during Part 1 in combination with pembrolizumab, carboplatin and either paclitaxel or nab-paclitaxel. Part 4: Combination Immuno-chemotherapy Nab-paclitaxel Participants with FGFR2b overexpression will receive the dose of bemarituzumab identified as safe during Part 1 in combination with pembrolizumab, carboplatin and either paclitaxel or nab-paclitaxel. Part 1: Combination Dose Exploration Docetaxel Participants with SqNSCLC will receive escalating doses of bemarituzumab in combination with docetaxel. Part 2: Combination Dose Expansion Docetaxel Participants with SqNSCLC and FGFR2b overexpression will receive the dose of bemarituzumab in combination with docetaxel identified as safe during Part 1. Part 4: Combination Immuno-chemotherapy Pembrolizumab Participants with FGFR2b overexpression will receive the dose of bemarituzumab identified as safe during Part 1 in combination with pembrolizumab, carboplatin and either paclitaxel or nab-paclitaxel. Part 4: Combination Immuno-chemotherapy Paclitaxel Participants with FGFR2b overexpression will receive the dose of bemarituzumab identified as safe during Part 1 in combination with pembrolizumab, carboplatin and either paclitaxel or nab-paclitaxel. Part 4: Combination Immuno-chemotherapy Carboplatin Participants with FGFR2b overexpression will receive the dose of bemarituzumab identified as safe during Part 1 in combination with pembrolizumab, carboplatin and either paclitaxel or nab-paclitaxel. Part 2: Combination Dose Expansion Bemarituzumab Participants with SqNSCLC and FGFR2b overexpression will receive the dose of bemarituzumab in combination with docetaxel identified as safe during Part 1. Part 3: Bemarituzumab Monotherapy Bemarituzumab Participants with SqNSCLC and FGFR2b overexpression will receive bemarituzumab monotherapy.
- Primary Outcome Measures
Name Time Method Number of Participants Who Experienced a Dose Limiting Toxicity (DLT): Parts 1 and 4 Day 1 to Day 21 of Cycle 1 (each cycle was 21 days) DLTs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and included the below if considered by the investigator to be related to study drug, excluding toxicities related to disease progression or intercurrent illness: Grade 3 thrombocytopenia for \> 7 days or with Grade \> 2 bleeding, vomiting/diarrhea for \> 3 days, fatigue; Grade ≥ 3 febrile neutropenia, nausea for \> 3 days; Grade 4 neutropenia, thrombocytopenia, anemia, ophthalmologic AE, laboratory value, vomiting/diarrhea; Grade 5 toxicity (death not due to disease progression). CTCAE Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, and Grade 5 results in death.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Day 1 of cycle 1 to 100 days after the last dose of study treatment or end of study date, whichever occurred earlier (Parts 1, 2, and 4 cycle length = 21 days; Part 3 cycle length = 14 days). Median treatment duration was 6.2 weeks. An AE was defined as any untoward medical occurrence in a clinical trial participants. TEAEs were any AE that started on or after receiving the first dose of investigational product and up to 28 days after the last dose of investigational product or the end of study date, whichever is earlier. Treatment-related TEAEs were those considered possibly related to study treatment by the investigator. Any clinically significant changes in electrocardiograms, vital signs, physical examination with a neurological assessment, clinical laboratory tests, and visual acuity were recorded as TEAEs. A serious TEAE resulted in death, was immediately life threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or another medically important serious event. AEs of special interest (AESIs) were ocular events of any CTCAE grade or seriousness occurring up to 100 days after the last dose of bemarituzumab.
- Secondary Outcome Measures
Name Time Method Area Under the Serum Drug Concentration-time Curve From Time 0 to End of Dosing Interval (AUCtau) of Bemarituzumab Parts 1, 2, 3, and 4: Cycles 1 and 2 pre-dose, 0.25, 3, 6, 24, 72, 168, 336, 504 (except Part 3) hours post-dose Bemarituzumab serum concentrations with values below the limit of quantification were set to zero for analysis. Pharmacokinetic (PK) parameters were determined from the time concentration profile using noncompartmental analysis.
Maximum Observed Serum Concentration (Cmax) of Bemarituzumab Parts 1, 2, 3, and 4: Cycles 1 and 2 pre-dose, 0.25, 3, 6, 24, 72, 168, 336, 504 (except Part 3) hours post-dose Bemarituzumab serum concentrations with values below the limit of quantification were set to zero for analysis. PK parameters were determined from the time concentration profile using noncompartmental analysis.
Observed Concentration at the End of a Dose Interval (Ctrough) of Bemarituzumab Pre-dose Cycle 2 Day 1 and Cycle 3 day 1 Bemarituzumab serum concentrations with values below the limit of quantification were set to zero for analysis. PK parameters were determined from the time concentration profile using noncompartmental analysis.
Percentage of Participants Who Achieved an Objective Response (OR) Every 6 (+/- 1) weeks from the first dose of bemarituzumab (cycle 1 day 1) up to week 54, then every 12 (+/- 2 weeks), up to the end of the long term follow-up (LTFU) period (median time on study was approximately 21 weeks) OR was defined as the best overall response of confirmed complete response (CR) or confirmed partial response (PR) as defined by the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1).
CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \<10 mm. All lymph nodes must have been non-pathological in size (\< 10 mm).
PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.Duration of Response (DOR) Every 6 (+/- 1) weeks from the first dose of bemarituzumab (cycle 1 day 1) up to week 54, then every 12 (+/- 2 weeks), up to the end of the LTFU period (median time on study was approximately 21 weeks) DOR was defined as the time from the first documentation of OR (determined by the investigator per RECIST v1.1) until first documentation of disease progression or death due to any cause, whichever occurred first.
DOR was censored at the last evaluable post-baseline tumor assessment prior to subsequent anticancer therapy; otherwise, at date of first documentation of OR (i.e., assigned a one-day interval).Disease Control Rate (DCR) Every 6 (+/- 1) weeks from the first dose of bemarituzumab (cycle 1 day 1) up to week 54, then every 12 (+/- 2 weeks), up to the end of the LTFU period (median time on study was approximately 21 weeks) DCR was defined as the percentage of participants documented to have a CR, PR or stable disease (SD) per RECIST v1.1.
CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \<10 mm. All lymph nodes must have been non-pathological in size (\< 10 mm).
PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD).
PD: at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5 mm. Unequivocal progression of existing non-target lesions.Progression-free Survival (PFS) Participants completed the LTFU for survival every 3 months ± 1 month after the safety follow-up visit (at 28 days after the last dose of bemarituzumab), up to the end of the study. Median time on study was approximately 21 weeks PFS was defined as the time from date of first dose of investigational product until the first documentation of radiologic disease progression or death due to any cause, whichever occurred first, in the absence of subsequent anticancer therapy.
PFS was censored at the last evaluable post-baseline tumor assessment prior to subsequent anticancer therapy; otherwise, at first dose of investigational product. Progression was based on RECIST v1.1 criteria.
PD: at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5 mm. Unequivocal progression of existing non-target lesions.Overall Survival (OS) Participants completed the LTFU for survival every 3 months ± 1 month after the safety follow-up visit (at 28 days after the last dose of bemarituzumab), up to the end of the study. Median time on study was approximately 21 weeks OS was defined as the time from the date of first dose of investigational product until event of death due to any cause through the analysis cutoff date. Participants still alive were censored at the date last known to be alive through the analysis cutoff date.
Trial Locations
- Locations (39)
Taipei Veterans General Hospital
🇨🇳Taipei, Taiwan
Linkou Chang Gung Memorial Hospital of Chang Gung Medical Foundation
🇨🇳Taoyuan, Taiwan
Montefiore Einstein Center for Cancer Care
🇺🇸Bronx, New York, United States
University of California Irvine
🇺🇸Orange, California, United States
University of Pittsburgh, Cancer Institute
🇺🇸Pittsburgh, Pennsylvania, United States
Cliniques Universitaires Saint Luc
🇧🇪Bruxelles, Belgium
Jessa Ziekenhuis - Campus Virga Jesse
🇧🇪Hasselt, Belgium
Institut Bergonie
🇫🇷Bordeaux, France
CHU de Lyon - Hopital Louis Pradel
🇫🇷Bron Cedex, France
Hôpital Tenon
🇫🇷Paris Cedex 20, France
Centre Hospitalier Universitaire de Poitiers - Hopital la Miletrie
🇫🇷Poitiers, France
Centre Hospitalier Universitaire de Rennes - Hopital Pontchaillou
🇫🇷Rennes, France
Institut Gustave Roussy
🇫🇷Villejuif, France
Seoul National University Bundang Hospital
🇰🇷Seongnam-si, Gyeonggi-do, Korea, Republic of
Krakowskie Centrum Medyczne Sp zoo
🇵🇱Krakow, Poland
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Severance Hospital Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Przychodnia Lekarska Komed Roman Karaszewski
🇵🇱Konin, Poland
Pratia Mcm Krakow
🇵🇱Krakow, Poland
Instytut Centrum Zdrowia Matki Polki
🇵🇱Lodz, Poland
Instytut Genetyki i Immunologii GENIM Spzoo
🇵🇱Lublin, Poland
Mazowieckie centrum leczenia
🇵🇱Otwock, Poland
Centrum Medyczne Hope Clinic Sebastian Szklener
🇵🇱Lublin, Poland
Hospital Regional Universitario de Malaga
🇪🇸Malaga, Andalucía, Spain
Hospital Universitario Virgen del Rocio
🇪🇸Sevilla, Andalucía, Spain
Hospital Universitari Vall d Hebron
🇪🇸Barcelona, Cataluña, Spain
Hospital Clinic i Provincial de Barcelona
🇪🇸Barcelona, Cataluña, Spain
Complexo Hospitalario Universitario A Coruña Hospital Teresa Herrera
🇪🇸A Coruña, Galicia, Spain
Institut Catala d Oncologia Hospitalet. Hospital Duran i Reynals
🇪🇸Hospitalet de Llobregat, Cataluña, Spain
Hospital Universitario Puerta de Hierro Majadahonda
🇪🇸Majadahonda, Madrid, Spain
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
National Cheng Kung University Hospital
🇨🇳Tainan, Taiwan
Universitair Ziekenhuis Gent
🇧🇪Gent, Belgium
National Cancer Center Hospital East
🇯🇵Kashiwa-shi, Chiba, Japan
Shizuoka Cancer Center
🇯🇵Sunto-gun, Shizuoka, Japan
Wakayama Medical University Hospital
🇯🇵Wakayama-shi, Wakayama, Japan
Universitair Ziekenhuis Antwerpen
🇧🇪Edegem, Belgium
Morristown Medical Center
🇺🇸Morristown, New Jersey, United States