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

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.

• Lucitanib (Drug), also known as CO-3810: 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)

Primary outcomes

• Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by the Investigator [From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 29 months]: 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.

Secondary outcomes

• Objective Response Rate (ORR) by RECIST v1.1 [From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 29 months]: 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.
• Duration of Response (DR) by RECIST v1.1 [From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 29 months]: 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.
• Disease Control Rate (DCR) by RECIST v1.1 [From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 29 months]: 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.
• Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - Cmax [Study Day -7 to Study Day 1, or approximately 8 days]: 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.
• Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - Tmax [Study Day -7 to Study Day 1, or approximately 8 days]: 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
• Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - AUClast [Study Day -7 to Study Day 1, or approximately 8 days]: 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)
• Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - AUCinf [Study Day -7 to Study Day 1, or approximately 8 days]: 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
• Relative Bioavailability Analysis for Tablet vs Capsule - Cmax, AUClast, AUCinf [Study Day -7 to Study Day 1, or approximately 8 days]: 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.
• Overall Survival [Cycle 1 Day 1 to date of death, assessed up to 29 months]: 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.
• Change From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) Total Score [From Cycle 1 Day 1 until end of treatment, assessed up to 29 months]: 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.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by the Investigator (Primary), Median, Days: Lucitanib (CO-3810) 10 mg QD 93 (78 to 140); Lucitanib (CO-3810) 15 mg QD 77 (50 to 86)
• Objective Response Rate (ORR) by RECIST v1.1 (Secondary), Number, percentage of participants: Lucitanib (CO-3810) 10 mg QD 4.7; Lucitanib (CO-3810) 15 mg QD 1.5; All Patients 3.5
• Duration of Response (DR) by RECIST v1.1 (Secondary), Median, Days: Lucitanib (CO-3810) 10 mg QD 175 (44 to 209); Lucitanib (CO-3810) 15 mg QD 336 (336 to 336)
• Disease Control Rate (DCR) by RECIST v1.1 (Secondary), Number, percentage of patients: Lucitanib (CO-3810) 10 mg QD 48.1; Lucitanib (CO-3810) 15 mg QD 34.3; All Patients 42.8
• Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - Cmax (Secondary), Mean, ng/mL: Lucitanib (CO-3810) 10 mg QD 292 +/- 156; Lucitanib (CO-3810) 15 mg QD 278 +/- 99.8
• Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - Tmax (Secondary), Median, Hours: Lucitanib (CO-3810) 10 mg QD 1.0 (0.5 to 4.0); Lucitanib (CO-3810) 15 mg QD 1.0 (0.5 to 2.5)
• Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - AUClast (Secondary), Mean, h*ng/mL: Lucitanib (CO-3810) 10 mg QD 2550 +/- 1150; Lucitanib (CO-3810) 15 mg QD 2840 +/- 1230
• Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - AUCinf (Secondary), Mean, h*ng/mL: Lucitanib (CO-3810) 10 mg QD 4780 +/- 2140; Lucitanib (CO-3810) 15 mg QD 5720 +/- 3760
• Relative Bioavailability Analysis for Tablet vs Capsule - Cmax, AUClast, AUCinf (Secondary), Number, Percentage (tablet/capsule): Lucitanib (CO-3810) 10 mg QD 111.73 (70.35 to 177.45); Lucitanib (CO-3810) 15 mg QD 100.56 (64.59 to 156.55)
• Overall Survival (Secondary), Median, Months: Lucitanib (CO-3810) 10 mg QD 15.0 (10.7 to 17.3); Lucitanib (CO-3810) 15 mg QD 7.7 (6.1 to 10.3); All Patients 10.7 (8.5 to 13.7)
• Change From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) Total Score (Secondary), Mean, units on a scale: Lucitanib (CO-3810) 10 mg QD -2.422 +/- 15.5134; Lucitanib (CO-3810) 15 mg QD -7.586 +/- 17.0709; All Patients -4.307 +/- 16.2248

Adverse events

Time frame: Adverse events were reported from the time of first dose of lucitanib through 28 days after last dose protocol-specified treatment administration, up to approximately 30 months. In addition, study procedure-related AEs that occur after signing of the informed consent form and before administration of lucitanib were also collected.

Serious adverse events by term

Other adverse events by term

• Results publication: Liao M, Zhou J, Wride K, Lepley D, Cameron T, Sale M, Xiao J. Population Pharmacokinetic Modeling of Lucitanib in Patients with Advanced Cancer. Eur J Drug Metab Pharmacokinet. 2022 Sep;47(5):711-723. doi: 10.1007/s13318-022-00773-w. Epub 2022 Jul 18. PMID 35844029

• Study Protocol (PDF, 2016-01-27)
• Statistical Analysis Plan (PDF, 2017-02-15)