A Study to Assess the Safety and Efficacy of the VEGFR-FGFR-PDGFR Inhibitor, Lucitanib, Given to Patients With Metastatic Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine whether lucitanib is safe and effective in the treatment of patients with FGF aberrant metastatic breast cancer, as well as in the treatment of patients with biomarker negative (FGF non-aberrant) metastatic breast cancer.

Detailed Description
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Lucitanib is a selective, orally available tyrosine kinase inhibitor targeting FGFR1-3, VEGFR1-3, and PDGFRα and β, with activity in relevant cell lines and animal models. The first in human trial of lucitanib demonstrated that daily dosing with lucitanib can provide durable clinical responses in patients with FGFR1- or 11q (FGF3, FGF4, Cyclin D1, or FGF19)-amplified breast cancer. RECIST partial responses (PRs) were also observed in patients not known to have FGF abnormalities. Based on these results, this study is designed to explore the safety and anti-tumor activity of daily lucitanib in breast cancer patients with and without alterations of the FGF pathway.

Official Title
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A Phase 2, Open-label, Multicenter, Safety and Efficacy Study of Oral Lucitanib in Patients With FGF Aberrant Metastatic Breast Cancer

Conditions
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Breast Cancer, Metastatic Breast Cancer, MBC, HER2 Positive, HER2, Estrogen Receptor Positive, ER, Triple Negative

Intervention / Treatment
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* Drug: Lucitanib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed metastatic breast cancer relapsed or refractory to approved standard available treatment Prior treatment with standard first line therapy in the metastatic setting Availability of tumor tissue sufficient for confirmatory testing of FGFR1 and 11q amplification status Demonstrated progression of disease by radiological or clinical assessment (Measurable disease according to RECIST Version 1.1 is NOT required for enrollment) Estimated life expectancy >6 months Exclusion Criteria: Current or recent treatment with biologic anticancer therapies Ongoing AEs from prior anticancer therapies Active central nervous system (CNS) metastases Clinically significant or uncontrolled hypertension or cardiac disease Females who are pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Lucitanib (CO-3810) 10 mg daily<br>10 mg of lucitanib daily in patients with FGFR1-amplified or 11q-amplified metastatic breast cancer. | Drug: Lucitanib<br>* Lucitanib is a potent, orally available selective inhibitor of the tyrosine kinase activity of fibroblast growth factor receptors (FGFR1-3), vascular endothelial growth factor receptors (VEGFR1-3), and platelet-derived growth factor receptors alpha and beta (PDGFR alpha and beta)<br>* Other names: CO-3810;|
| Experimental: Cohort B: Lucitanib (CO-3810) 15 mg daily<br>15 mg of lucitanib daily in patients with FGFR1-amplified and 11q-amplified metastatic breast cancer. | Drug: Lucitanib<br>* Lucitanib is a potent, orally available selective inhibitor of the tyrosine kinase activity of fibroblast growth factor receptors (FGFR1-3), vascular endothelial growth factor receptors (VEGFR1-3), and platelet-derived growth factor receptors alpha and beta (PDGFR alpha and beta)<br>* Other names: CO-3810;|
| Experimental: Cohort C: Lucitanib (CO-3810) 10 mg daily<br>10 mg of lucitanib daily in patients with FGFR1 non-amplified and 11q non-amplified metastatic breast cancer. | Drug: Lucitanib<br>* Lucitanib is a potent, orally available selective inhibitor of the tyrosine kinase activity of fibroblast growth factor receptors (FGFR1-3), vascular endothelial growth factor receptors (VEGFR1-3), and platelet-derived growth factor receptors alpha and beta (PDGFR alpha and beta)<br>* Other names: CO-3810;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by the Investigator | The primary efficacy endpoint of PFS was calculated as 1+ the number of days from the date of first dose of study drug to disease progression or death due to any cause, whichever occurs first. Patients without a documented event of progression were censored on the date of their last adequate tumor assessment (i.e., radiologic assessment), or the date of randomization if no tumor assessments were performed. Progression events were determined by the investigator. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. | From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 29 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) by RECIST v1.1 | ORR is the percentage of patients with a best response of CR or PR according to RECIST v1.1. The best response is recorded from the start of the treatment (Day 1) until disease progression or recurrence. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. | From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 29 months | 
| Duration of Response (DR) by RECIST v1.1 | DR for complete response (CR) and partial response (PR) was measured from the date that any of these best confirmed responses was first recorded until the first date that PD was objectively documented. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. | From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 29 months | 
| Disease Control Rate (DCR) by RECIST v1.1 | The DCR is defined as the percentage of patients with a best response rate of CR, PR, or SD for at least 12 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started. | From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 29 months | 
| Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - Cmax | The comparative PK study was a within-patient comparison of tablet and capsule formulations of lucitanib administered orally. PK sampling was performed at specified time points on each of the following two days: • Day -7: patients received a single administration of 10 mg or 15 mg lucitanib tablet formulation • Day 1: patients received a single administration of 10 mg or 15 mg lucitanib in capsule formulation. Cmax = maximum concentration following administration of lucitanib. | Study Day -7 to Study Day 1, or approximately 8 days | 
| Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - Tmax | The comparative PK study was a within-patient comparison of tablet and capsule formulations of lucitanib administered orally. PK sampling was performed at specified time points on each of the following two days: • Day -7: patients received a single administration of 10 mg or 15 mg lucitanib tablet formulation • Day 1: patients received a single administration of 10 mg or 15 mg lucitanib in capsule formulation. Tmax = time to maximum concentration following administration of lucitanib | Study Day -7 to Study Day 1, or approximately 8 days | 
| Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - AUClast | The comparative PK study was a within-patient comparison of tablet and capsule formulations of lucitanib administered orally. PK sampling was performed at specified time points on each of the following two days: • Day -7: patients received a single administration of 10 mg or 15 mg lucitanib tablet formulation • Day 1: patients received a single administration of 10 mg or 15 mg lucitanib in capsule formulation. AUClast = area under the plasma concentration time curve from time 0 to the last quantifiable time point (24 hour) | Study Day -7 to Study Day 1, or approximately 8 days | 
| Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - AUCinf | The comparative PK study was a within-patient comparison of tablet and capsule formulations of lucitanib administered orally. PK sampling was performed at specified time points on each of the following two days: • Day -7: patients received a single administration of 10 mg or 15 mg lucitanib tablet formulation • Day 1: patients received a single administration of 10 mg or 15 mg lucitanib in capsule formulation. AUCinf = area under the plasma concentration time curve from 0 to infinity | Study Day -7 to Study Day 1, or approximately 8 days | 
| Relative Bioavailability Analysis for Tablet vs Capsule - Cmax, AUClast, AUCinf | Relative bioavailability of lucitanib was evaluated by comparison of (log-transformed) AUClast, Cmax and AUCinf of the tablet formulation to the capsule formulation using an analysis of variance (ANOVA) model with treatment as a fixed effect. The geometric means, ratio of the geometric means and 90% confidence intervals (CI) on the ratio of Tablet to Capsule (T:R) were presented for AUClast, Cmax and AUCinf. The CIs on the ratio of untransformed PK parameters were derived through reverse transformation of the 90% CI of the difference in the log scale to the 90% CI of the ratio in the original scale. | Study Day -7 to Study Day 1, or approximately 8 days | 
| Overall Survival | Overall survival (OS) is defined as the number of days from the date of first dose of study drug to the date of death (due to any cause). Patients without a known date of death will be censored on the date the patient was last known to be alive. | Cycle 1 Day 1 to date of death, assessed up to 29 months | 
| Change From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) Total Score | FACT-B is used for assessment of health-related quality of life (QoL) in participants with breast cancer. It consists of 37 items, summarized to 5 subscales: physical (7 items), functional (7 items), social/family (7 items); all 3 ranged from 0 to 28, emotional (6 items) ranging from 0 to 24, and breast cancer subscale (10 items) ranging from 0 to 40; high subscale score represents a better QoL. All single-item measures range from 0='Not at all' to 4='Very much'. FACT-B Total Score is derived from adding the five subscale scores. Total possible score ranges from 0 to 148. High scale score represents a better QoL. | From Cycle 1 Day 1 until end of treatment, assessed up to 29 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, Metastatic breast cancer, MBC, HER2 positive, HER2+, Estrogen receptor positive, ER+, Triple negative, FGFR1, 11q, FGF aberrant, Biomarker negative, FGF non-aberrant