Clinical trial NCT01013740: Lapatinib in Combination With Vinorelbine
Official title: A Phase II, Randomised, Multi-Centre Study Evaluating Lapatinib in Combination With Vinorelbine or Capecitabine in Women With ErbB2 Overexpressing Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cancer
Keywords: Neoplasms, Breast
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2009-11-16
Enrollment: 112
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: After disease progression in the Randomized Phase (in which participants received lapatinib plus vinorelbine), participants were given the option of crossing over to the alternative treatment arm (lapatinib plus capecitabine), and continuing in a post-progression Cross-over Phase.
Primary purpose: TREATMENT

Brief summary: This is a randomized, parallel-arm, open-label, multi-centre, Phase II study to determine the efficacy and safety of lapatinib in combination with vinorelbine or capecitabine in women with ErbB2 overexpressing metastatic breast cancer (MBC) who have received no more than one chemotherapeutic regimen in the metastatic setting.

Detailed description: Approximately 105 subjects will be enrolled in the study and randomized 2:1 to one of the following regimens Arm A (n=70): Lapatinib 1250 mg orally once daily continuously plus Vinorelbine 20mg/m2 intravenously (IV) on day 1 and 8, every third week, or Arm B (n=35): Lapatinib 1250 mg orally once daily (QD) continuously plus Capecitabine 2000 mg/m2/day orally in 2 doses 12 hours apart on days 1-14 every third week. Randomization will be stratified according to the following variables: 1) Prior receipt of therapy for metastatic breast cancer (Yes or No), and 2) Site of metastatic disease (Visceral/Soft tissue or Bone-only). Subjects will receive randomized study treatment until disease progression or discontinuation of study treatment due to unacceptable toxicity, withdrawal of consent, lost to follow up, or death. All subjects who discontinue study treatment without documented progression will continue to be followed for progression according to protocol-schedule until new anti-cancer therapy is initiated and/or progression or death is documented. Survival data will be collected for all subjects to ensure a minimum of 18 months survival data. This study will include a safety run-in phase for approximately the first 30 subjects (20 randomized to lapatinib and vinorelbine; 10 to lapatinib and capecitabine).

Eligibility criteria: Inclusion Criteria :

* Signed informed consent prior to registration.
* Considered by the investigator to have a life expectancy of ≥12 weeks.
* Subjects must be female and have histologically - confirmed invasive breast cancer with Stage IV disease at primary diagnosis or at relapse after curative - intent surgery.
* Documented overexpression of ErbB2
* Subjects should have progressive disease following prior therapy which may include anthracyclines, taxanes, and trastuzumab.
* Females aged ≥18 years
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1.
* Subjects must have adequate organ and marrow function
* Subjects must have a cardiac ejection fraction of at least 50% and within the institutional range of normal.
* Radiotherapy prior to initiation of study medication is allowed to a limited area ( e . g . , palliative therapy ) , if it is not the sole site of disease.
* Subjects with stable central nervous system (CNS) metastases are permitted.
* Subject must be free of gastrointestinal diseases or any other conditions that impede swallowing, retaining, and absorption of oral medications.
* Bisphosphonate therapy for bone metastases is allowed; however, treatment must be initiated prior to the first dose of study medication. Prophylactic use of bisphosphonates in subjects without bone disease, except for the treatment of osteoporosis, is not permitted.

Exclusion Criteria:

* Subjects taking prohibited medications are not eligible for the study.
* Therapy with lapatinib, vinorelbine, or capecitabine prior to randomization into this study.
* Prior therapy with more than one chemotherapeutic regimen for metastatic breast cancer.
* Concurrent anticancer or concomitant radiotherapy treatment.
* History of uncontrolled or symptomatic angina; history of arrhythmias requiring medications ; clinically significant myocardial infarction \< 6 months from study entry; uncontrolled or symptomatic congestive heart failure; ejection fraction below the institutional normal limit; or any other cardiac condition, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.
* Have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).
* Use of an investigational drug within 30 days or 5 half - lives, whichever is longer, preceding the first dose of investigational treatment, or, concurrent treatment with an investigational agent or participation in another clinical trial involving investigational agents.
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the agents used in this study or their excipients that in the opinion of the investigator or GSK Medical Monitor contraindicates their participation.
* Known deficiency for the enzyme dihydropyrimidine dehydrogenase (DPD).
* Known history of uncontrolled inter - current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness / social situations that would limit compliance with study requirements.
* Concurrent disease or condition that would make the subject inappropriate for study participation , or any serious medical disorder that would interfere with the subject's safety.
* Pregnant or lactating females at any time during the study (due to the potential teratogenic or abortifacient effects of lapatinib and breastfeeding).
* Subjects with diseases affecting gastrointestinal function resulting in an inability to take oral medication , including ; malabsorption syndrome, disease significantly affecting gastrointestinal function , or resection of the stomach , small bowel , or colon. Subjects with inflammatory bowel disease or ulcerative colitis are also excluded.
* Peripheral neuropathy of Grade 2 or greater.
* Unresolved or unstable, serious toxicity from prior administration of another investigational drug and / or of prior cancer treatment.
* Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.

Primary outcomes:
measure: Progression Free Survival (PFS) in the Randomized Phase
timeFrame: From randomization until disease progression, death, or discontinuation from the study (average of 27 study weeks)
Secondary outcomes:
measure: Number of Participants With Overall Response (OR), as Assessed by the Investigator in the Randomized Phase
timeFrame: From randomization until disease progression, death, or discontinuation from the study (average of 27 study weeks)
measure: Overall Survival (OS)
timeFrame: From the date of randomization until death (average of 55 study weeks)
measure: Duration of Response (DOR) in the Randomized Phase
timeFrame: From the time of the first documented confirmed complete or partial response until disease progression or death, if sooner (average of 27 study weeks)
measure: Time to Response in the Randomized Phase
timeFrame: From randomization until the time of the first documented confirmed CR or PR (average of 27 study weeks)
measure: Number of Participants With Clinical Benefit (CB) in the Randomized Phase
timeFrame: From randomization until disease progression, death, or discontinuation from the study (average of 27 study weeks)
measure: Area Under the Concentration-time Curve Over the Dosing Interval (AUC-tau) for Vinorelbine
timeFrame: Days 1 and 8; 0 to 24 hours post-dose
measure: Maximum Concentration (Cmax) for Vinorelbine
timeFrame: Days 1 and 8; 0 to 24 hours post-dose
measure: Number of Participants With Grade 4 and Grade 5 Adverse Events (AE)
timeFrame: From randomization until disease progression, death, or discontinuation from the study (average of 55 study weeks)
Other outcomes:
Locations:
city: Plovdiv
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Varna
country: Bulgaria
facility: Novartis Investigative Site
city: Santiago
country: Chile
facility: Novartis Investigative Site
state: RegiÃ³n Metro De Santiago
city: Santiago
country: Chile
facility: Novartis Investigative Site
state: RegiÃ³n Metro De Santiago
city: ViÃ±a del Mar
country: Chile
facility: Novartis Investigative Site
state: ValparaÃ-so
city: Bayonne
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: NÃ®mes cedex 9
country: France
facility: Novartis Investigative Site
city: Saint-Cloud
country: France
facility: Novartis Investigative Site
city: Rheinfelden
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Muenchen
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: MÃ¼nchen
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Bad Nauheim
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Frankfurt am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Duesseldorf
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Moenchengladbach
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Velbert
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Mainz
country: Germany
facility: Novartis Investigative Site
state: Rheinland-Pfalz
city: Chemnitz
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Heraklion,Crete
country: Greece
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
city: Genova
country: Italy
facility: Novartis Investigative Site
state: Liguria
city: Brescia
country: Italy
facility: Novartis Investigative Site
state: Lombardia
city: Ancona
country: Italy
facility: Novartis Investigative Site
state: Marche
city: Torino
country: Italy
facility: Novartis Investigative Site
state: Piemonte
city: Brindisi
country: Italy
facility: Novartis Investigative Site
state: Puglia
city: Catania
country: Italy
facility: Novartis Investigative Site
state: Sicilia
city: Catania
country: Italy
facility: Novartis Investigative Site
state: Sicilia
city: Verona
country: Italy
facility: Novartis Investigative Site
state: Veneto
city: Monterrey
country: Mexico
facility: Novartis Investigative Site
state: Nuevo LeÃ³n
city: Oaxaca
country: Mexico
facility: Novartis Investigative Site
city: Gdansk
country: Poland
facility: Novartis Investigative Site
city: Gliwice
country: Poland
facility: Novartis Investigative Site
city: Konin
country: Poland
facility: Novartis Investigative Site
city: Lodz
country: Poland
facility: Novartis Investigative Site
city: Lublin
country: Poland
facility: Novartis Investigative Site
city: Olsztyn
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Belgrad
country: Serbia
facility: Novartis Investigative Site
city: Sremska Kamenica
country: Serbia
facility: Novartis Investigative Site
city: Fuenlabrada (Madrid)
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Marbella
country: Spain
facility: Novartis Investigative Site
city: Pamplona
country: Spain
facility: Novartis Investigative Site
city: Reus
country: Spain
facility: Novartis Investigative Site
city: Segovia
country: Spain
facility: Novartis Investigative Site
city: Vigo (Pontevedra)
country: Spain
facility: Novartis Investigative Site
city: Zamora
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Hoon SN, Lau PK, White AM, Bulsara MK, Banks PD, Redfern AD. Capecitabine for hormone receptor-positive versus hormone receptor-negative breast cancer. Cochrane Database Syst Rev. 2021 May 26;5(5):CD011220. doi: 10.1002/14651858.CD011220.pub2.
citation: Janni W, Sarosiek T, Karaszewska B, Pikiel J, Staroslawska E, Potemski P, Salat C, Brain E, Caglevic C, Briggs K, Mahood K, DeSilvio M, Marini L, Papadimitriou C. Final overall survival analysis of a phase II trial evaluating vinorelbine and lapatinib in women with ErbB2 overexpressing metastatic breast cancer. Breast. 2015 Dec;24(6):769-73. doi: 10.1016/j.breast.2015.08.005. Epub 2015 Sep 16.