A Study of Bemarituzumab Monotherapy and Combination With Other Anti-cancer Therapy in SqNSCLC With FGFR2b Overexpression (FORTITUDE-201)

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Squamous-Cell Non-Small-Cell Lung Cancer

Intervention / Treatment
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* Drug: Bemarituzumab
* Drug: Docetaxel
* Drug: Pembrolizumab
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Nab-paclitaxel


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Combination Dose Exploration<br>Participants with SqNSCLC will receive escalating doses of bemarituzumab in combination with docetaxel. | Drug: Bemarituzumab<br>* Intravenous (IV) infusion<br>* Other names: AMG 552;Drug: Docetaxel<br>* IV infusion<br>|
| Experimental: Part 2: Combination Dose Expansion<br>Participants with SqNSCLC and FGFR2b overexpression will receive the dose of bemarituzumab in combination with docetaxel identified as safe during Part 1. | Drug: Bemarituzumab<br>* Intravenous (IV) infusion<br>* Other names: AMG 552;Drug: Docetaxel<br>* IV infusion<br>|
| Experimental: Part 3: Bemarituzumab Monotherapy<br>Participants with SqNSCLC and FGFR2b overexpression will receive bemarituzumab monotherapy. | Drug: Bemarituzumab<br>* Intravenous (IV) infusion<br>* Other names: AMG 552;|
| Experimental: Part 4: Combination Immuno-chemotherapy<br>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. | Drug: Bemarituzumab<br>* Intravenous (IV) infusion<br>* Other names: AMG 552;Drug: Pembrolizumab<br>* IV infusion<br>Drug: Carboplatin<br>* IV infusion<br>Drug: Paclitaxel<br>* IV infusion<br>Drug: Nab-paclitaxel<br>* IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and 4: Number of Participants Who Experience a Dose Limiting Toxicity (DLT) |  | Cycle 1 Day 1 to Cycle 1 Day 21 (cycle is 21 days) | 
| Parts 1, 2, 3 and 4: Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE) | Adverse events (AEs) are defined as any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. TEAEs are any event that occurs after the participant has received study treatment. Any clinically significant changes in vital signs, physical examinations, clinical laboratory tests, and visual acuity that occur after study treatment administration will be recorded as TEAEs. | Cycle 1 Day 1 to 28 days after last dose (approximately 5 months; cycle is 21 days in Parts 1 and 2, cycle is 14 days in Part 3) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1, 2, 3 and 4: Area Under the Concentration Time Curve (AUC) of Bemarituzumab |  | Part 1/2/4: Day 1 cycles 1-3, Day 1 every odd numbered cycle thereafter, and 28 days after last dose (cycle=21 days). Part 3: Day 1 and 8 cycle 1, Day 1 cycles 2-3, Day 1 of every odd numbered cycle thereafter, and 28 days after last dose (cycle=14 days) | 
| Parts 1, 2, 3 and 4: Maximum Observed Concentration (Cmax) of Bemarituzumab |  | Part 1/2/4: Day 1 cycles 1-3, Day 1 every odd numbered cycle thereafter, and 28 days after last dose (cycle=21 days). Part 3: Day 1 and 8 cycle 1, Day 1 cycles 2-3, Day 1 of every odd numbered cycle thereafter, and 28 days after last dose (cycle=14 days) | 
| Parts 1, 2, 3 and 4: Observed Concentration at the End of a Dose Interval (Ctrough) of Bemarituzumab |  | Part 1/2/4: Day 1 cycles 1-3, Day 1 every odd numbered cycle thereafter, and 28 days after last dose (cycle=21 days). Part 3: Day 1 and 8 cycle 1, Day 1 cycles 2-3, Day 1 of every odd numbered cycle thereafter, and 28 days after last dose (cycle=14 days) | 
| Parts 1, 2, 3 and 4: Objective Response Rate |  | Up to approximately 2 years | 
| Parts 1, 2, 3 and 4: Duration of Response |  | Up to approximately 2 years | 
| Parts 1, 2, 3 and 4: Disease Control Rate |  | Up to approximately 2 years | 
| Parts 1, 2, 3 and 4: Progression Free Survival |  | Up to approximately 2 years | 
| Parts 1, 2, 3 and 4: Overall Survival |  | Up to approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Squamous-Cell Non-Small-Cell Lung Cancer, FGFR2b-positive Squamous-Cell Non-Small-Cell Lung Cancer, SqNSCLC, Bemarituzumab, Docetaxel