Phase III Study of Vinflunine Plus Capecitabine Versus Capecitabine Alone in Patients With Advanced Breast Cancer

• Sponsor: Pierre Fabre Medicament (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01953003
• Collaborator: (none)
• Enrollment: 112
• Locations: 18
• Arms: 2
• Actual Duration (Months): 46
• Patients Per Site: 6.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Options for the treatment of patients who have progressed after an anthracycline and a taxane are limited. Capecitabine currently has a role in this setting, yet as many as 80% of patients do not respond to this treatment and those who respond eventually develop clinical resistance.

The antitumour activity of vinflunine has been demonstrated in patients with breast cancer after exposure to anthracycline and to taxane.

Vinflunine plus capecitabine has been shown to be a feasible combination for patients previously treated with an anthracycline and a taxane. Each drug in combination can be administered at efficacious doses.

This population has few therapeutic options with established clinical benefit. The development of a new regimen and potential new standard of care for this group is important.

• Primary objective:

• to compare in patients with advanced breast cancer pretreated with anthracycline and taxane the efficacy of the combination of vinflunine and capecitabine with capecitabine alone, in terms of progression-free survival.

• Secondary objectives:

• to evaluate the response rate, the time to response and the duration of response in both arms

• to compare the disease control rate between arms

• to evaluate the duration of disease control in both arms

• to evaluate the overall survival in both arms

• to evaluate safety

Methodology This multicentre, open-label, randomised, Phase III study will enrol a total of 334 patients with advanced breast cancer who have previously been treated with an anthracycline and a taxane. Patients will be randomised in a 1:1 ratio to receive VFL plus capecitabine (Arm A) or capecitabine alone (Arm B).

Condition or Disease	Intervention/Treatment	Phase
Malignant Neoplasm of Breast	Drug: vinflunine; Drug: Capecitabine	Phase 3

Detailed Description

RECIST 1.1 will be used for tumor assessment CTC - CAE version 3.0 will be used for safety assessment

Study Design

• Study Type: Interventional
• Actual Enrollment: 112 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomised, Phase III Study of Vinflunine Plus Capecitabine Versus Capecitabine Alone in Patients With Advanced Breast Cancer Previously
• Actual Study Start Date: Sep 1, 2013
• Actual Primary Completion Date: Jul 1, 2017
• Actual Study Completion Date: Jul 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A : iv vinflunine plus Capecitabine Vinflunine dose 280 mg/m² on day 1 of each cycle every 3 weeks, Capecitabine 825 mg/m² twice daily orally for 14 consecutive days beginning on day 1 of each cycle followed by 1 week of rest.	Drug: vinflunine; intravenous administration day 1 once every 3 weeks, 280 mg/m²; Other Names: Javlor ; Drug: Capecitabine; Arm A : 1650 mg/m² Arm B : 2500 mg/m²; Other Names: xeloda from day 1 to day 14
Active Comparator: capecitabineArm B : capecitabine 1250 mg/m² twice daily orally for 14 consecutive days beginning on day 1 of each cycle followed by 1 week of rest	Drug: Capecitabine; Arm A : 1650 mg/m² Arm B : 2500 mg/m²; Other Names: xeloda from day 1 to day 14

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [progression date will be assessed evey 6 weeks starting from the randomization date until first documented progression or date of death from any cause whichever came first assessed up to 3 years]

   The primary endpoint for the trial is progression-free survival calculated from the date of randomisation until the date of progression or the date of death whatever the cause of death. Patient who does not progressed will be censored at the date of last tumour assessment or the date of last contact of a follow-up showing no progression.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 80 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

INCLUSION CRITERIA:

1. Written informed consent

2. Histologically or cytologically confirmed Her-2 negative carcinoma of the breast

3. Documented locally recurrent or metastatic disease not amenable to curative surgery or radiotherapy

4. One, two or three prior chemotherapy regimens including those administered in the neoadjuvant or adjuvant setting. At least one of the regimens must have been given for the treatment of advanced disease.

5. Prior treatment must have included both an anthracycline and a taxane. minimum cumulative dose of 180 mg/m² of doxorubicin or of 300 mg/m² of epirubicin

6. Documented progression on or within 12 months of the most recent chemotherapy.

7. Prior hormone therapy is allowed

8. Prior radiation therapy is allowed to less than 30% of the bone marrow

9. LMeasurable or non measurable disease defined according to RECIST V1.1

10. Adequate recovery from recent surgery

11. Estimated life expectancy superior or equal of 12 weeks

12. KPS equal or superior to 70%

13. Age equal or superior to 21 years and < 80 years

14. ANC) equal or superior to 1.5 x 109/L, platelet count equal or superior to 100 x109/L and haemoglobin > 10 g/dL.

15. Bilirubin inferior or equal to 1.5 x upper limit of normal (ULN), AST and ALT inferior or equal to 2.5 x ULN or inferior or equal to 5 x ULN in the case of liver metastases, alkaline phosphatase inferior or equal to 5 x ULN.

16. Calculated creatinine clearance superior or equal to 50 mL/min

17. Normal ECG

18. Patients on coumadin or warfarin must be on stable doses and INR inferior or equal to 3

19. Women of childbearing potential must be using a medically accepted method of contraception. Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to first treatment administration.

20. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed with the patient before registration in the trial.

EXCLUSION CRITERIA

1. Known or with clinical evidence of brain metastasis or leptomeningeal involvement.

2. Pulmonary lymphangitis or symptomatic pleural effusion (grade > 2) that results in pulmonary dysfunction requiring active treatment.

3. Patients having received any other experimental drug or chemotherapy within 30 days

4. History of second primary malignancy, except: bilateral breast carcinoma, in situ carcinoma of the cervix, adequately treated non melanomatous carcinoma of the skin, and other malignancy treated at least 5 years previously with no evidence of recurrence

5. Pre-existing motor/sensory peripheral neuropathy of CTCAE version 3.0 grade >1

6. Patients having received > 3 regimens of chemotherapy

7. Prior therapy with capecitabine and/or vinca-alkaloids

8. History of severe hypersensitivity to vinca alkaloids and/or to fluoropyrimidine or any contra indication to any of the study drugs

9. Known or suspected DPD

10. Pregnant or lactating; With positive pregnancy test at inclusion

11. Female of childbearing potential who is unwilling or unable to use a medically accepted method to avoid pregnancy during the 2 months preceding the start of study treatment, throughout the study period and at least 3 months following the last dose of study treatment

12. Known history of HIV infection

13. Inability to take and/or absorb oral medication

14. Any serious, concurrent uncontrolled medical disorder especially uncontrolled hypercalcaemia, congestive heart failure, uncontrolled high-risk hypertension, arrhythmia, angina pectoris or previous history of myocardial infarction within 6 months prior to randomisation.

15. Prior BMT or autologous stem cell infusion following high-dose chemotherapy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Beijing		China
2		Changchun		China
3		Chengdu		China
4		Dalian		China
5		Fuzhou		China
6		Hangzhou		China
7		Harbin		China
8		Jinan		China
9		Nanjing		China
10		Shanghai		China
11		Shenyang		China
12		Tianjin		China
13		Wuhan		China
14	NUH	Singapore		Singapore	119228
15	Gleneagles Hospital	Singapore		Singapore	258500
16		Kaohsiung		Taiwan
17		Taichung		Taiwan
18		Taipei		Taiwan

Sponsors and Collaborators

• Pierre Fabre Medicament

Investigators

• Study Chair: Binghe XU, MD, Cancer Institute & Hospital. Chinese Academy of Medical Sciences, Beijing

Study Documents (Full-Text)

• Study Protocol - Jul 29, 2016
• Statistical Analysis Plan - Jul 5, 2017

More Information

Publications

None provided.

• Responsible Party: Pierre Fabre Medicament
• ClinicalTrials.gov Identifier: NCT01953003
• Other Study ID Numbers: L00070 IN 311 B0
• First Posted: Sep 30, 2013
• Last Update Posted: May 2, 2019
• Last Verified: Jan 1, 2019

• Additional relevant MeSH terms: Neoplasms; Breast Neoplasms; Capecitabine

Study Results

Participant Flow

Arm/Group Title	Arm A : iv Vinflunine Plus Capecitabine	Arm B : Capecitabine
Arm/Group Description	Vinflunine dose 280 mg/m² on day 1 of each cycle every 3 weeks, Capecitabine 825 mg/m² twice daily orally for 14 consecutive days beginning on day 1 of each cycle followed by 1 week of rest. vinflunine: intraveinous administration day 1 once every 3 weeks, 280 mg/m² Capecitabine: Arm A : 1650 mg/m² Arm B : 2500 mg/m²	1250 mg/m² twice daily orally for 14 consecutive days beginning on day 1 of each cycle followed by 1 week of rest Capecitabine: Arm A : 1650 mg/m² Arm B : 2500 mg/m²
Period Title: Overall Study
STARTED	56	56
COMPLETED	0	1
NOT COMPLETED	56	55

Baseline Characteristics

Arm/Group Title	Arm A : iv Vinflunine Plus Capecitabine	Arm B : Capecitabine	Total
Arm/Group Description	Vinflunine dose 280 mg/m² on day 1 of each cycle every 3 weeks, Capecitabine 825 mg/m² twice daily orally for 14 consecutive days beginning on day 1 of each cycle followed by 1 week of rest. vinflunine: intraveinous administration day 1 once every 3 weeks, 280 mg/m² Capecitabine: Arm A : 1650 mg/m² Arm B : 2500 mg/m²	1250 mg/m² twice daily orally for 14 consecutive days beginning on day 1 of each cycle followed by 1 week of rest Capecitabine: Arm A : 1650 mg/m² Arm B : 2500 mg/m²	Total of all reporting groups
Overall Participants	56	56	112
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	55 98.2%	54 96.4%	109 97.3%
>=65 years	1 1.8%	2 3.6%	3 2.7%
Sex: Female, Male (Count of Participants)
Female	56 100%	56 100%	112 100%
Male	0 0%	0 0%	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Singapore	4 7.1%	5 8.9%	9 8%
China	49 87.5%	46 82.1%	95 84.8%
Taiwan	3 5.4%	5 8.9%	8 7.1%
Menopausal status (Count of Participants)
Menopausal	31 55.4%	29 51.8%	60 53.6%
Non-Menopausal	25 44.6%	27 48.2%	52 46.4%
Tumour site - primary cancer (Count of Participants)
Right Breast	23 41.1%	32 57.1%	55 49.1%
Left Breast	33 58.9%	24 42.9%	57 50.9%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	The primary endpoint for the trial is progression-free survival calculated from the date of randomisation until the date of progression or the date of death whatever the cause of death. Patient who does not progressed will be censored at the date of last tumour assessment or the date of last contact of a follow-up showing no progression.
Time Frame	progression date will be assessed evey 6 weeks starting from the randomization date until first documented progression or date of death from any cause whichever came first assessed up to 3 years

Outcome Measure Data

Analysis Population Description

The ITT population, comprised of all randomised patients

Arm/Group Title	Arm A : iv Vinflunine Plus Capecitabine	Arm B : Capecitabine
Arm/Group Description	Vinflunine dose 280 mg/m² on day 1 of each cycle every 3 weeks, Capecitabine 825 mg/m² twice daily orally for 14 consecutive days beginning on day 1 of each cycle followed by 1 week of rest. vinflunine: intraveinous administration day 1 once every 3 weeks, 280 mg/m² Capecitabine: Arm A : 1650 mg/m² Arm B : 2500 mg/m²	1250 mg/m² twice daily orally for 14 consecutive days beginning on day 1 of each cycle followed by 1 week of rest Capecitabine: Arm A : 1650 mg/m² Arm B : 2500 mg/m²
Measure Participants	56	56
Number of events (Participants)	42 75%	46 82.1%
Number of censored observations (Participants)	14 25%	10 17.9%

Adverse Events

Time Frame	3 years 3 months
Arm/Group Title	Arm A : iv Vinflunine Plus Capecitabine		Arm B : Capecitabine
Arm/Group Description	Vinflunine dose 280 mg/m² on day 1 of each cycle every 3 weeks, Capecitabine 825 mg/m² twice daily orally for 14 consecutive days beginning on day 1 of each cycle followed by 1 week of rest. vinflunine: intraveinous administration day 1 once every 3 weeks, 280 mg/m² Capecitabine: Arm A : 1650 mg/m² Arm B : 2500 mg/m²		1250 mg/m² twice daily orally for 14 consecutive days beginning on day 1 of each cycle followed by 1 week of rest Capecitabine: Arm A : 1650 mg/m² Arm B : 2500 mg/m²
All Cause Mortality
	Arm A : iv Vinflunine Plus Capecitabine		Arm B : Capecitabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/56 (46.4%)		32/55 (58.2%)
Serious Adverse Events
	Arm A : iv Vinflunine Plus Capecitabine		Arm B : Capecitabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/56 (26.8%)		7/55 (12.7%)
Blood and lymphatic system disorders
Febrile neutropenia	2/56 (3.6%)		0/55 (0%)
Leukopenia	1/56 (1.8%)		0/55 (0%)
Neutropenia	1/56 (1.8%)		0/55 (0%)
Thrombocytopenia	1/56 (1.8%)		0/55 (0%)
Anaemia	0/56 (0%)		1/55 (1.8%)
Gastrointestinal disorders
Abdominal Pain	2/56 (3.6%)		0/55 (0%)
Ileus	2/56 (3.6%)		0/55 (0%)
Intestinal obstruction	1/56 (1.8%)		0/55 (0%)
Mouth ulceration	1/56 (1.8%)		0/55 (0%)
General disorders
Fatigue	1/56 (1.8%)		0/55 (0%)
Pain	1/56 (1.8%)		0/55 (0%)
Chest discomfort	0/56 (0%)		1/55 (1.8%)
Death	1/56 (1.8%)		0/55 (0%)
Infections and infestations
Pneumonia	1/56 (1.8%)		0/55 (0%)
Investigations
ALAT increased	0/56 (0%)		1/55 (1.8%)
ASAT increased	0/56 (0%)		1/55 (1.8%)
Neutrophil count decreased	1/56 (1.8%)		0/55 (0%)
Platelet count decreased	1/56 (1.8%)		0/55 (0%)
Musculoskeletal and connective tissue disorders
Bone pain	1/56 (1.8%)		0/55 (0%)
Myalgia	1/56 (1.8%)		0/55 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	0/56 (0%)		1/55 (1.8%)
Malignant pleural effusion	0/56 (0%)		1/55 (1.8%)
Metastases to central nervous system	0/56 (0%)		1/55 (1.8%)
Renal and urinary disorders
Haematuria	1/56 (1.8%)		0/55 (0%)
Other (Not Including Serious) Adverse Events
	Arm A : iv Vinflunine Plus Capecitabine		Arm B : Capecitabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	54/56 (96.4%)		46/55 (83.6%)
Blood and lymphatic system disorders
Neuropenia	11/56 (19.6%)		4/55 (7.3%)
Febrile neutropenia	7/56 (12.5%)		0/55 (0%)
Leukopenia	3/56 (5.4%)		1/55 (1.8%)
Thrombocytopenia	3/56 (5.4%)		1/55 (1.8%)
Gastrointestinal disorders
Nausea	13/56 (23.2%)		12/55 (21.8%)
Constipation	19/56 (33.9%)		3/55 (5.5%)
Abdominal pain	13/56 (23.2%)		3/55 (5.5%)
Vomiting	11/56 (19.6%)		4/55 (7.3%)
Stomatitis	10/56 (17.9%)		3/55 (5.5%)
Diarrhoea	3/56 (5.4%)		7/55 (12.7%)
Abdominal pain upper	8/56 (14.3%)		1/55 (1.8%)
Abdominal distension	7/56 (12.5%)		0/55 (0%)
Mouth ulceration	3/56 (5.4%)		2/55 (3.6%)
Gastroesophagal reflux disease	3/56 (5.4%)		3/55 (5.5%)
Oral pain	3/56 (5.4%)		0/55 (0%)
General disorders
Fatigue	14/56 (25%)		9/55 (16.4%)
Pain	10/56 (17.9%)		1/55 (1.8%)
Oedema pheripheral	1/56 (1.8%)		5/55 (9.1%)
Hepatobiliary disorders
Liver disorder	1/56 (1.8%)		3/55 (5.5%)
Investigations
Weight decreased	14/56 (25%)		9/55 (16.4%)
Weight increased	4/56 (7.1%)		13/55 (23.6%)
Neutrophil count decreased	6/56 (10.7%)		0/55 (0%)
White blodd cell count decreased	3/56 (5.4%)		1/55 (1.8%)
Musculoskeletal and connective tissue disorders
Myalgia	9/56 (16.1%)		3/55 (5.5%)
Bone pain	3/56 (5.4%)		2/55 (3.6%)
Arthralgia	3/56 (5.4%)		0/55 (0%)
Pain in extremity	0/56 (0%)		3/55 (5.5%)
Nervous system disorders
Headache	4/56 (7.1%)		3/55 (5.5%)
Dizziness	4/56 (7.1%)		1/55 (1.8%)
Hypoaesthenia	1/56 (1.8%)		4/55 (7.3%)
Respiratory, thoracic and mediastinal disorders
Cough	6/56 (10.7%)		4/55 (7.3%)
Dyspnoea	1/56 (1.8%)		4/55 (7.3%)
Oesopharyngeal pain	3/56 (5.4%)		0/55 (0%)
Skin and subcutaneous tissue disorders
Palmer-plantar erythrodysaesthesia	5/56 (8.9%)		17/55 (30.9%)
Pigmentation disorder	1/56 (1.8%)		4/55 (7.3%)

Limitations/Caveats

Early termination of the study. Efficacy analyses were reduced to a descriptive summary of the primary efficacy variable (PFS) in the ITT population. This did not demonstrate any additional benefit of supplementing CAPE with VFL. Abbreviated CSR.

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.