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

• Sponsor: Clovis Oncology, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02202746
• Collaborator: (none)
• Enrollment: 178
• Locations: 33
• Arms: 3
• Actual Duration (Months): 28.3
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Metastatic Breast Cancer; MBC; HER2 Positive; HER2; Estrogen Receptor Positive; ER; Triple Negative	Drug: Lucitanib	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 178 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Open-label, Multicenter, Safety and Efficacy Study of Oral Lucitanib in Patients With FGF Aberrant Metastatic Breast Cancer
• Actual Study Start Date: Sep 9, 2014
• Actual Primary Completion Date: Jan 17, 2017
• Actual Study Completion Date: Jan 18, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A: Lucitanib (CO-3810) 10 mg daily 10 mg of lucitanib daily in patients with FGFR1-amplified or 11q-amplified metastatic breast cancer.	Drug: Lucitanib; 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); Other Names: CO-3810
Experimental: Cohort B: Lucitanib (CO-3810) 15 mg daily 15 mg of lucitanib daily in patients with FGFR1-amplified and 11q-amplified metastatic breast cancer.	Drug: Lucitanib; 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); Other Names: CO-3810
Experimental: Cohort C: Lucitanib (CO-3810) 10 mg daily 10 mg of lucitanib daily in patients with FGFR1 non-amplified and 11q non-amplified metastatic breast cancer.	Drug: Lucitanib; 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); Other Names: CO-3810

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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

6. 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)

7. 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

8. 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.

9. 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.

10. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Oncology Associates	Sedona	Arizona	United States	86336
2	Comprehensive Blood and Cancer Center	Bakersfield	California	United States	93309
3	Saint Jude Heritage Medical Center	Fullerton	California	United States	92835
4	Moores UCSD Cancer Center	La Jolla	California	United States	92093
5	University of Southern California	Los Angeles	California	United States	90033
6	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
7	University of California, Los Angeles	Los Angeles	California	United States	90095
8	Cancer Care Associates Medical Group, Inc.	Redondo Beach	California	United States	90277
9	University of California San Francisco	San Francisco	California	United States	94115
10	Central Coast Medical Oncology Group	Santa Maria	California	United States	93454
11	Yale University	New Haven	Connecticut	United States	06519
12	University of Miami	Deerfield Beach	Florida	United States	33442
13	Memorial West Cancer Center	Hollywood	Florida	United States	33021
14	Northwestern University, Robert H. Lurie Comprehensive Cancer Center	Chicago	Illinois	United States	60611
15	University of Chicago Medical Center	Chicago	Illinois	United States	60637
16	Indiana University Simon Cancer Center	Indianapolis	Indiana	United States	46202
17	Horizon Oncology Center	Lafayette	Indiana	United States	47905
18	The Sidney Kimmel Comprehensive Cancer Center at John Hopkins	Baltimore	Maryland	United States	21231
19	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
20	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89169
21	Cooper University Hospital	Voorhees	New Jersey	United States	08043
22	Sciode Medical Associates, PLLC	Bronx	New York	United States	10469
23	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
24	Weill Cornell Breast Center	New York	New York	United States	10065
25	University Hospitals Case Medical Center	Cleveland	Ohio	United States	44106
26	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
27	Sarah Cannon Cancer Center	Nashville	Tennessee	United States	37203
28	Vanderbilt Ingram Cancer Center	Nashville	Tennessee	United States	37232
29	Texas Oncology - Austin Central	Austin	Texas	United States	78731
30	Texas Oncology - Baylor Charles A. Sammons Cancer Center	Dallas	Texas	United States	75246
31	The Center for Cancer and Blood Disorders	Fort Worth	Texas	United States	76104
32	US Oncology	Houston	Texas	United States	77024
33	Virginia Oncology Associates	Norfolk	Virginia	United States	23502

Sponsors and Collaborators

• Clovis Oncology, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jan 27, 2016
• Statistical Analysis Plan - Feb 15, 2017

More Information

Publications

None provided.

• Responsible Party: Clovis Oncology, Inc.
• ClinicalTrials.gov Identifier: NCT02202746
• Other Study ID Numbers: CO-3810-025
• First Posted: Jul 29, 2014
• Last Update Posted: Jun 23, 2020
• Last Verified: Jun 1, 2020

• Keywords provided by Clovis Oncology, Inc.: Breast cancer; Metastatic breast cancer; MBC; HER2 positive; HER2+; Estrogen receptor positive; ER+; Triple negative; FGFR1; 11q; FGF aberrant; Biomarker negative; FGF non-aberrant
• Additional relevant MeSH terms: Breast Neoplasms

Study Results

Participant Flow

Recruitment Details	178 patients were recruited from 32 sites in the United States.

Arm/Group Title	Lucitanib (CO-3810) 10 mg QD	Lucitanib (CO-3810) 15 mg QD
Arm/Group Description	10 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons	15 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons
Period Title: Overall Study
STARTED	109	69
COMPLETED	109	69
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Lucitanib (CO-3810) 10 mg QD	Lucitanib (CO-3810) 15 mg QD	Total
Arm/Group Description	10 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons	15 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons	Total of all reporting groups
Overall Participants	109	69	178
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	57.0	53.0	55.0
Sex: Female, Male (Count of Participants)
Female	109 100%	67 97.1%	176 98.9%
Male	0 0%	2 2.9%	2 1.1%
Race/Ethnicity, Customized (Count of Participants)
White	87 79.8%	61 88.4%	148 83.1%
Asian	5 4.6%	3 4.3%	8 4.5%
Black	10 9.2%	1 1.4%	11 6.2%
Not provided	4 3.7%	3 4.3%	7 3.9%
Unknown/Not assessed	2 1.8%	1 1.4%	3 1.7%
Other	1 0.9%	0 0%	1 0.6%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	8 7.3%	6 8.7%	14 7.9%
Not Hispanic or Latino	97 89%	61 88.4%	158 88.8%
Not Provided	4 3.7%	2 2.9%	6 3.4%
Number of Prior Anticancer Therapies (Therapies) [Median (Full Range) ]
Median (Full Range) [Therapies]	6.0	6.0	6.0
Fibroblast Growth Factor (FGF) Status (Count of Participants)
11q	34 31.2%	25 36.2%	59 33.1%
FGFR1	50 45.9%	28 40.6%	78 43.8%
FGFR1 & 11q	18 16.5%	10 14.5%	28 15.7%
Negative	7 6.4%	6 8.7%	13 7.3%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Efficacy population: all patients who have received at least one dose of lucitanib and are confirmed as FGR1-, 11q-amplified, or FGF non-amplified per the central laboratory

Arm/Group Title	Lucitanib (CO-3810) 10 mg QD	Lucitanib (CO-3810) 15 mg QD
Arm/Group Description	10 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons	15 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons
Measure Participants	107	67
Median (95% Confidence Interval) [Days]	93	77

2. Secondary Outcome

Title	Objective Response Rate (ORR) by RECIST v1.1
Description	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.
Time Frame	From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 29 months

Outcome Measure Data

Analysis Population Description

Efficacy population: all patients who have received at least one dose of lucitanib and are confirmed as FGR1-, 11q-amplified, or FGF non-amplified per the central laboratory

Arm/Group Title	Lucitanib (CO-3810) 10 mg QD	Lucitanib (CO-3810) 15 mg QD	All Patients
Arm/Group Description	10 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons	15 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons	The total efficacy population analyzed for response
Measure Participants	106	67	173
Number [percentage of participants]	4.7 4.3%	1.5 2.2%	3.5 2%

3. Secondary Outcome

Title	Duration of Response (DR) by RECIST v1.1
Description	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.
Time Frame	From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 29 months

Outcome Measure Data

Analysis Population Description

Efficacy population for patients who had a confirmed CR or PR

Arm/Group Title	Lucitanib (CO-3810) 10 mg QD	Lucitanib (CO-3810) 15 mg QD
Arm/Group Description	10 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons	15 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons
Measure Participants	5	1
Median (Full Range) [Days]	175	336

4. Secondary Outcome

Title	Disease Control Rate (DCR) by RECIST v1.1
Description	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.
Time Frame	From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 29 months

Outcome Measure Data

Analysis Population Description

Efficacy population only

Arm/Group Title	Lucitanib (CO-3810) 10 mg QD	Lucitanib (CO-3810) 15 mg QD	All Patients
Arm/Group Description	10 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons	15 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons	The total efficacy population analyzed for response
Measure Participants	106	67	173
Number [percentage of patients]	48.1	34.3	42.8

5. Secondary Outcome

Title	Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - Cmax
Description	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.
Time Frame	Study Day -7 to Study Day 1, or approximately 8 days

Outcome Measure Data

Analysis Population Description

PK parameters were assessed in a subset of patients (N=15)

Arm/Group Title	Lucitanib (CO-3810) 10 mg QD	Lucitanib (CO-3810) 15 mg QD
Arm/Group Description	10 mg of lucitanib tablet or capsule given orally	15 mg of lucitanib tablet or capsule given orally
Measure Participants	9	6
Tablet	292 (156)	278 (99.8)
Capsule	265 (137)	285 (121)

6. Secondary Outcome

Title	Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - Tmax
Description	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
Time Frame	Study Day -7 to Study Day 1, or approximately 8 days

Outcome Measure Data

Analysis Population Description

PK parameters were assessed in a subset of patients (N=15)

Arm/Group Title	Lucitanib (CO-3810) 10 mg QD	Lucitanib (CO-3810) 15 mg QD
Arm/Group Description	10 mg of lucitanib tablet or capsule given orally	15 mg of lucitanib tablet or capsule given orally
Measure Participants	9	6
Tablet	1.0	1.0
Capsule	1.5	1.0

7. Secondary Outcome

Title	Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - AUClast
Description	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)
Time Frame	Study Day -7 to Study Day 1, or approximately 8 days

Outcome Measure Data

Analysis Population Description

PK parameters were assessed in a subset of patients (N=15)

Arm/Group Title	Lucitanib (CO-3810) 10 mg QD	Lucitanib (CO-3810) 15 mg QD
Arm/Group Description	10 mg of lucitanib tablet or capsule given orally	15 mg of lucitanib tablet or capsule given orally
Measure Participants	9	6
Tablet	2550 (1150)	2840 (1230)
Capsule	2650 (1380)	2420 (613)

8. Secondary Outcome

Title	Comparative Pharmacokinetics (PK) of the Lucitanib Capsule Formulation vs. Tablet Formulation - AUCinf
Description	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
Time Frame	Study Day -7 to Study Day 1, or approximately 8 days

Outcome Measure Data

Analysis Population Description

PK parameters were assessed in a subset of patients (N=15)

Arm/Group Title	Lucitanib (CO-3810) 10 mg QD	Lucitanib (CO-3810) 15 mg QD
Arm/Group Description	10 mg of lucitanib tablet or capsule given orally	15 mg of lucitanib tablet or capsule given orally
Measure Participants	9	6
Tablet	4780 (2140)	5720 (3760)
Capsule	5680 (2730)	4620 (1620)

9. Secondary Outcome

Title	Relative Bioavailability Analysis for Tablet vs Capsule - Cmax, AUClast, AUCinf
Description	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.
Time Frame	Study Day -7 to Study Day 1, or approximately 8 days

Outcome Measure Data

Analysis Population Description

PK parameters were assessed in a subset of patients (N=15).

Arm/Group Title	Lucitanib (CO-3810) 10 mg QD	Lucitanib (CO-3810) 15 mg QD
Arm/Group Description	10 mg of lucitanib tablet or capsule given orally	15 mg of lucitanib tablet or capsule given orally
Measure Participants	9	6
Cmax Geometric Mean Ratio	111.73	100.56
AUClast Geometric Mean Ratio	97.58	112.2
AUCinf Geometric Mean Ratio	82.9	114.23

10. Secondary Outcome

Title	Overall Survival
Description	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.
Time Frame	Cycle 1 Day 1 to date of death, assessed up to 29 months

Outcome Measure Data

Analysis Population Description

Intent to treat population by initial treatment and overall

Arm/Group Title	Lucitanib (CO-3810) 10 mg QD	Lucitanib (CO-3810) 15 mg QD	All Patients
Arm/Group Description	10 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons	15 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons	The total efficacy population analyzed for response
Measure Participants	109	69	178
Median (95% Confidence Interval) [Months]	15.0	7.7	10.7

11. Secondary Outcome

Title	Change From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) Total Score
Description	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.
Time Frame	From Cycle 1 Day 1 until end of treatment, assessed up to 29 months

Outcome Measure Data

Analysis Population Description

Efficacy Population defined as all patients who have received at least one dose of Lucitanib and have at least one post-baseline Investigator Overall Objective Tumor Assessment. 'Overall Number of Participants Analyzed'=participants who completed both a baseline FACT-B assessment and at least one post-baseline assessment.

Arm/Group Title	Lucitanib (CO-3810) 10 mg QD	Lucitanib (CO-3810) 15 mg QD	All Patients
Arm/Group Description	10 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons	15 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons	The total efficacy population analyzed for response
Measure Participants	80	46	126
Mean (Standard Deviation) [units on a scale]	-2.422 (15.5134)	-7.586 (17.0709)	-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.
Adverse Event Reporting Description	If a patient experiences the same preferred term (system organ class) multiple times, then the patient will be counted only once for that preferred term (system organ class).
Arm/Group Title	Lucitanib (CO-3810) 10 mg QD		Lucitanib (CO-3810) 15 mg QD
Arm/Group Description	10 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons		15 mg of lucitanib daily in continuous 28-day treatment cycles until tumor progression, unacceptable toxicity, or withdrawal for other reasons
All Cause Mortality
	Lucitanib (CO-3810) 10 mg QD		Lucitanib (CO-3810) 15 mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/109 (4.6%)		7/69 (10.1%)
Serious Adverse Events
	Lucitanib (CO-3810) 10 mg QD		Lucitanib (CO-3810) 15 mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/109 (28.4%)		22/69 (31.9%)
Blood and lymphatic system disorders
Anaemia	0/109 (0%)		1/69 (1.4%)
Febrile neutropenia	1/109 (0.9%)		0/69 (0%)
Cardiac disorders
Sinus bradycardia	0/109 (0%)		1/69 (1.4%)
Sinus tachycardia	1/109 (0.9%)		0/69 (0%)
Supraventricular tachycardia	1/109 (0.9%)		0/69 (0%)
Endocrine disorders
Adrenal insufficiency	0/109 (0%)		1/69 (1.4%)
Gastrointestinal disorders
Abdominal pain	0/109 (0%)		1/69 (1.4%)
Abdominal pain upper	0/109 (0%)		1/69 (1.4%)
Diarrhoea	0/109 (0%)		1/69 (1.4%)
Duodenal ulcer	0/109 (0%)		1/69 (1.4%)
Dysphagia	2/109 (1.8%)		0/69 (0%)
Gastrointestinal haemorrhage	1/109 (0.9%)		1/69 (1.4%)
Nausea	1/109 (0.9%)		2/69 (2.9%)
Small intestinal obstruction	0/109 (0%)		1/69 (1.4%)
Tooth impacted	0/109 (0%)		1/69 (1.4%)
Upper gastrointestinal haemorrhage	1/109 (0.9%)		0/69 (0%)
Vomiting	0/109 (0%)		2/69 (2.9%)
General disorders
Mucosal inflammation	0/109 (0%)		1/69 (1.4%)
Pyrexia	1/109 (0.9%)		0/69 (0%)
Hepatobiliary disorders
Bile duct obstruction	1/109 (0.9%)		0/69 (0%)
Infections and infestations
Atypical pneumonia	1/109 (0.9%)		0/69 (0%)
Cellulitis	1/109 (0.9%)		0/69 (0%)
Pneumonia	2/109 (1.8%)		1/69 (1.4%)
Urinary tract infection	1/109 (0.9%)		1/69 (1.4%)
Investigations
Alanine aminotransferase increased	1/109 (0.9%)		0/69 (0%)
Ammonia increased	0/109 (0%)		1/69 (1.4%)
Aspartate aminotransferase increased	1/109 (0.9%)		0/69 (0%)
Blood bilirubin increased	1/109 (0.9%)		0/69 (0%)
Platelet count decreased	0/109 (0%)		1/69 (1.4%)
Metabolism and nutrition disorders
Decreased appetite	1/109 (0.9%)		1/69 (1.4%)
Hypomagnesaemia	1/109 (0.9%)		0/69 (0%)
Hyponatraemia	3/109 (2.8%)		1/69 (1.4%)
Musculoskeletal and connective tissue disorders
Back pain	1/109 (0.9%)		0/69 (0%)
Bone pain	0/109 (0%)		1/69 (1.4%)
Osteoarthritis	1/109 (0.9%)		0/69 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	5/109 (4.6%)		5/69 (7.2%)
Malignant pleural effusion	0/109 (0%)		1/69 (1.4%)
Nervous system disorders
Aphasia	0/109 (0%)		1/69 (1.4%)
Headache	2/109 (1.8%)		0/69 (0%)
Migraine	1/109 (0.9%)		0/69 (0%)
Psychiatric disorders
Mental status changes	1/109 (0.9%)		0/69 (0%)
Renal and urinary disorders
Hydronephrosis	0/109 (0%)		1/69 (1.4%)
Renal tubular acidosis	1/109 (0.9%)		0/69 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/109 (1.8%)		1/69 (1.4%)
Dyspnoea exertional	0/109 (0%)		1/69 (1.4%)
Hypoxia	1/109 (0.9%)		3/69 (4.3%)
Lung infiltration	0/109 (0%)		1/69 (1.4%)
Pleural effusion	2/109 (1.8%)		1/69 (1.4%)
Pulmonary embolism	1/109 (0.9%)		1/69 (1.4%)
Vascular disorders
Hypertension	2/109 (1.8%)		2/69 (2.9%)
Hypertensive crisis	1/109 (0.9%)		0/69 (0%)
Other (Not Including Serious) Adverse Events
	Lucitanib (CO-3810) 10 mg QD		Lucitanib (CO-3810) 15 mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	107/109 (98.2%)		69/69 (100%)
Blood and lymphatic system disorders
Anaemia	5/109 (4.6%)		6/69 (8.7%)
Neutropenia	0/109 (0%)		4/69 (5.8%)
Thrombocytopenia	8/109 (7.3%)		9/69 (13%)
Endocrine disorders
Hypothyroidism	41/109 (37.6%)		34/69 (49.3%)
Eye disorders
Vision blurred	7/109 (6.4%)		3/69 (4.3%)
Gastrointestinal disorders
Abdominal distension	9/109 (8.3%)		6/69 (8.7%)
Abdominal pain	16/109 (14.7%)		9/69 (13%)
Abdominal pain upper	5/109 (4.6%)		6/69 (8.7%)
Constipation	20/109 (18.3%)		12/69 (17.4%)
Diarrhoea	33/109 (30.3%)		19/69 (27.5%)
Dry mouth	11/109 (10.1%)		5/69 (7.2%)
Dyspepsia	10/109 (9.2%)		4/69 (5.8%)
Nausea	53/109 (48.6%)		33/69 (47.8%)
Vomiting	35/109 (32.1%)		24/69 (34.8%)
General disorders
Fatigue	55/109 (50.5%)		37/69 (53.6%)
Mucosal inflammation	3/109 (2.8%)		4/69 (5.8%)
Oedema peripheral	13/109 (11.9%)		4/69 (5.8%)
Pain	7/109 (6.4%)		3/69 (4.3%)
Pyrexia	8/109 (7.3%)		2/69 (2.9%)
Infections and infestations
Sinusitis	6/109 (5.5%)		1/69 (1.4%)
Upper respiratory tract infection	4/109 (3.7%)		4/69 (5.8%)
Urinary tract infection	14/109 (12.8%)		10/69 (14.5%)
Investigations
Alanine aminotransferase increased	9/109 (8.3%)		4/69 (5.8%)
Aspartate aminotransferase increased	10/109 (9.2%)		4/69 (5.8%)
Blood alkaline phosphatase increased	9/109 (8.3%)		3/69 (4.3%)
Blood bilirubin increased	6/109 (5.5%)		4/69 (5.8%)
Blood thyroid stimulating hormone increased	6/109 (5.5%)		2/69 (2.9%)
Ejection fraction decreased	3/109 (2.8%)		5/69 (7.2%)
Platelet count decreased	4/109 (3.7%)		6/69 (8.7%)
Weight decreased	8/109 (7.3%)		5/69 (7.2%)
Metabolism and nutrition disorders
Decreased appetite	36/109 (33%)		21/69 (30.4%)
Dehydration	8/109 (7.3%)		2/69 (2.9%)
Hypokalaemia	9/109 (8.3%)		3/69 (4.3%)
Hyponatraemia	9/109 (8.3%)		9/69 (13%)
Musculoskeletal and connective tissue disorders
Arthralgia	13/109 (11.9%)		12/69 (17.4%)
Back pain	18/109 (16.5%)		9/69 (13%)
Muscular weakness	6/109 (5.5%)		2/69 (2.9%)
Musculoskeletal chest pain	6/109 (5.5%)		5/69 (7.2%)
Musculoskeletal pain	8/109 (7.3%)		2/69 (2.9%)
Myalgia	3/109 (2.8%)		5/69 (7.2%)
Neck pain	7/109 (6.4%)		1/69 (1.4%)
Pain in extremity	5/109 (4.6%)		4/69 (5.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	5/109 (4.6%)		5/69 (7.2%)
Nervous system disorders
Dizziness	15/109 (13.8%)		5/69 (7.2%)
Dysgeusia	5/109 (4.6%)		4/69 (5.8%)
Headache	42/109 (38.5%)		24/69 (34.8%)
Psychiatric disorders
Anxiety	7/109 (6.4%)		6/69 (8.7%)
Depression	8/109 (7.3%)		7/69 (10.1%)
Insomnia	11/109 (10.1%)		6/69 (8.7%)
Renal and urinary disorders
Haematuria	3/109 (2.8%)		6/69 (8.7%)
Proteinuria	22/109 (20.2%)		22/69 (31.9%)
Respiratory, thoracic and mediastinal disorders
Cough	19/109 (17.4%)		7/69 (10.1%)
Dyspnoea	22/109 (20.2%)		14/69 (20.3%)
Pleural effusion	4/109 (3.7%)		4/69 (5.8%)
Skin and subcutaneous tissue disorders
Pruritus	6/109 (5.5%)		8/69 (11.6%)
Rash	5/109 (4.6%)		6/69 (8.7%)
Rash maculo-papular	1/109 (0.9%)		4/69 (5.8%)
Vascular disorders
Hot flush	5/109 (4.6%)		4/69 (5.8%)
Hypertension	85/109 (78%)		50/69 (72.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

All parties agree to submit all manuscripts or abstracts to all other parties 30 days prior to submission. This will enable all parties to protect proprietary information and to provide comments based on information that may not yet be available to other parties. The sponsor may request a delay in publication if there are important intellectual property concerns relating to publication, but does not have the right to suppress publication of the study results indefinitely.