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.
Brief Title
A Study of Bemarituzumab Monotherapy and Combination With Other Anti-cancer Therapy in SqNSCLC With FGFR2b Overexpression (FORTITUDE-201)
Categories
Completion Date
Completion Date Type
Actual
Conditions
Squamous-Cell Non-Small-Cell Lung Cancer
Eligibility Criteria
Inclusion Criteria:
* 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
Exclusion Criteria:
* 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
* 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
Exclusion Criteria:
* 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
Inclusion Criteria
Inclusion Criteria:
* 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
* 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
Gender
All
Gender Based
false
Keywords
Squamous-Cell Non-Small-Cell Lung Cancer
FGFR2b-positive Squamous-Cell Non-Small-Cell Lung Cancer
SqNSCLC
Bemarituzumab
Docetaxel
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
99 Years
Minimum Age
18 Years
NCT Id
NCT05267470
Org Class
Industry
Org Full Name
Amgen
Org Study Id
20210102
Overall Status
Terminated
Phases
Phase 1
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Bemarituzumab Monotherapy and Combination With Other Anti-Cancer Therapy in Subjects With Squamous-Cell Non-Small-Cell Lung Cancer (FORTITUDE-201)
Primary Outcomes
Outcome Description
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.
Outcome Measure
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT): Parts 1 and 4
Outcome Time Frame
Day 1 to Day 21 of Cycle 1 (each cycle was 21 days)
Outcome Description
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.
Outcome Measure
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Outcome Time Frame
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.
Secondary Ids
Secondary Id
2021-004058-47
Secondary Id
2023-505456-22
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
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
Outcome Measure
Area Under the Serum Drug Concentration-time Curve From Time 0 to End of Dosing Interval (AUCtau) of Bemarituzumab
Outcome Description
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.
Outcome Time Frame
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
Outcome Measure
Maximum Observed Serum Concentration (Cmax) of Bemarituzumab
Outcome Description
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.
Outcome Time Frame
Pre-dose Cycle 2 Day 1 and Cycle 3 day 1
Outcome Measure
Observed Concentration at the End of a Dose Interval (Ctrough) of Bemarituzumab
Outcome Description
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.
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.
Outcome Time Frame
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)
Outcome Measure
Percentage of Participants Who Achieved an Objective Response (OR)
Outcome Description
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).
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).
Outcome Time Frame
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)
Outcome Measure
Duration of Response (DOR)
Outcome Description
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.
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.
Outcome Time Frame
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)
Outcome Measure
Disease Control Rate (DCR)
Outcome Description
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.
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.
Outcome Time Frame
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
Outcome Measure
Progression-free Survival (PFS)
Outcome Description
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.
Outcome Time Frame
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
Outcome Measure
Overall Survival (OS)
See Also Links
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
99
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Balazs Halmos
Investigator Email
bahalmos@montefiore.org
MeSH Terms
BEMARITUZUMAB
DOCETAXEL
PEMBROLIZUMAB
CARBOPLATIN
PACLITAXEL
130-NM ALBUMIN-BOUND PACLITAXEL
TAXOIDS
CYCLODECANES
CYCLOPARAFFINS
HYDROCARBONS, ALICYCLIC
HYDROCARBONS, CYCLIC
HYDROCARBONS
ORGANIC CHEMICALS
DITERPENES
TERPENES
COORDINATION COMPLEXES