Clinical trial NCT02238509: Safety and QoL of Trastuzumab With Lapatinib or Chemiotherapy in MBC and HER2+ Patients Refractory to Anti HER2 Therapies
Official title: A Randomised, Multicentre, Open-label Phase II Trial Investigating Activity of Chemotherapy and Lapatinib and Trastuzumab in Patients With HER2-positive Metastatic Breast Cancer (MBC) Refractory to Anti HER2 Therapies
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Keywords: Breast cancer
HER2 Positive
HER2+
MBC
Metastatic
Metastatic breast cancer
Chemotherapy
Lapatinib
Trastuzumab
anti HER2 therapies
Lead sponsor: Consorzio Oncotech
Sponsor class: OTHER
Collaborators: name: Clinical Research Technology S.r.l.
First posted: 2014-09-12
Enrollment: 154
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Recent clinical studies have shown that the combination of lapatinib and trastuzumab has superior antitumor activity compared to either single drug in both neoadjuvant and metastatic setting and is well tolerated. According to this evidence, the combination of lapatinib and trastuzumab today offers a valid chemotherapy-free option, primarily for patients with pre-treated HER2-positive MBC

Detailed description: The present study is designed to determine the efficacy and safety profile of the combination of lapatinib and trastuzumab (plus endocrinetherapy in ER-positive breast cancer) versus trastuzumab and chemotherapy in heavily pretreated patient population with HER2-positive MBC and to investigate the predictive role of cfDNA for detection of HER2 gene amplification on patients' outcome. The presence of circulating free DNA (cfDNA) for detection of HER2 gene amplification was associated with worse prognosis and seems to allow early response evaluation. However, many aspects of the role of cfDNA detection in patients undergoing molecular target agents such as trastuzumab or lapatinib are not well described. With the availability of improved and standardized techniques for cfDNA detection, it should now be possible to examine several of these important questions within a prospective multicenter study and a striking potential of cfDNA for detection of HER2 gene amplification might enable a more individual and optimized antimetastatic therapy inpatients with cancer.

Eligibility criteria: Inclusion Criteria:

* Histological or cytological confirmed and documented adenocarcinoma of the breast with metastatic disease
* The original tumour specimen must be HER2 IHC 3+ positive or, in case of IHC 2+
* Age ≥18
* Life expectancy of \>12 weeks
* ECOG PS 0-1
* Measurable disease as defined by RECIST1.1 criteria
* All patients must have received prior anthracycline-and taxane-based regimens as well as trastuzumab based regimens in either the adjuvant or the metastatic setting. Patients must have been already treated with at least one line of the anti HER2 inhibitor therapy lapatinib for their metastatic breast cancer. A maximum of three previous lines of anti-HER-2 therapies in the metastatic setting are allowed.
* Adequate haematological function as defined by: ANC 1.5 x 109/L, platelet count 100 x 109/L, haemoglobin 10 g/dL.
* Adequate renal function, as defined by: creatinine 1.5 x UNL
* Adequate hepatobiliary function, as defined by the following baseline liver function tests: total serum bilirubin 1.5 upper normal limit (UNL); alanine amino transferase (ALT), aspartate amino transferase (AST) 2.5xUNL; alkaline phosphatase (AP) 2.5xUNL; if total alkaline phosphatase (AP) \> 2.5xUNL, alkaline phosphatase liver fraction must be 2.5xUNL
* Adequate contraception for all fertile patients
* Negative pregnancy test.
* Postmenopausal women fulfilling any of the NCCN criteria may be included.
* Left ventricular ejection fraction (LVEF) ≥50% during a baseline period of 28 days, as determined by either echocardiography (ECHO) or multi gated acquisition (MUGA) scan.
* Signed, written informed consent

Exclusion Criteria:

* History of persistent Grade ≥ 2 hematologic toxicity resulting from previous systemic therapy
* Current peripheral neuropathy of NCI-CTCAE, Version 3.0, Grade ≥ 3 at randomization
* History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or basal cell carcinoma
* Bone-only disease, unless a measurable lesion is evident as determined by RECIST v1.1
* Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure bone lesions. ve
* Blastic bone lesions are non-measurable.
* Uncontrolled hypertension (systolic \>150 mm Hg and/or diastolic \>100 mm Hg) or clinically significant (i.e. active) cardiovascular disease.
* Current dyspnoea at rest due to complications of advanced malignancy, or other diseases that require continuous oxygen therapy.
* Inadequate organ function, evidenced by the following laboratory results within 28 days prior to randomization.
* Current severe, uncontrolled systemic disease
* Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start or anticipation of the need for major surgery during the course of study treatment
* History of receiving any investigational treatment within 28 days of randomization
* Current known infection with HIV, HBV, or HCV
* Receipt of IV antibiotics for infection within 14 days of randomization
* Known hypersensitivity to any of the study drugs
* Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol
* Lack of physical integrity of the upper gastrointestinal tract, clinically significant malabsorption syndrome, or inability to take oral medications
* Concurrent interventional or non-interventional studies

Primary outcomes:
measure: Clinical Benefit Rate
timeFrame: Clinical Benefit Rate is defined as confirmed complete response plus partial response at any time, plus stable disease up to 24 weeks
Secondary outcomes:
measure: Progression free survival
timeFrame: Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 36 months
measure: Overall Survival
timeFrame: Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 36 months
measure: Safety and tolerability
timeFrame: Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 36 months
measure: Quality of life
timeFrame: Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 36 months
Other outcomes:
Locations:
city: Ancona
country: Italy
facility: A.O.U. Ospedali Riuniti Umberto I
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico
city: Bologna
country: Italy
facility: Policlinico S. Orsola Malpighi
city: Bolzano
country: Italy
facility: Ospedale Centrale di Bolzano
city: Brindisi
country: Italy
facility: Presidio Ospedaliero 'Antonio Perrino
city: Catania
country: Italy
facility: A.O.R.N.A.S. Garibaldi Nesima di Catania
city: Catania
country: Italy
facility: Humanitas Centro Catanese di Oncologia
city: Como
country: Italy
facility: Azienda Ospedaliera S. Anna
city: Frosinone
country: Italy
facility: Ospedale 'F. Spaziani'
city: Genova
country: Italy
facility: I.R.C.C.S. A.O.U. San Martino
city: Guastalla
country: Italy
facility: Ospedale Civile di Guastalla
city: Lecce
country: Italy
facility: Ospedale Vito Fazzi
city: Lugo
country: Italy
facility: Ospedale di Lugo - AUSL della Romagna
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
city: Milano
country: Italy
facility: Ospedale Niguarda Ca' Granda
city: Monza
country: Italy
facility: A.O. San Gerardo
city: Naples
country: Italy
facility: AORN "A. Cardarelli"
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori - IRCCS "Fondazione G.Pascale"
city: Napoli
country: Italy
facility: Policlinico SUN
city: Napoli
country: Italy
facility: Università degli Studi di Napoli "Federico II"
city: Palermo
country: Italy
facility: A.R.N.A.S. Ospedale Civico e Benfratelli
city: Perugia
country: Italy
facility: Ospedale S. Maria della Misericordia
city: Pordenone
country: Italy
facility: Azienda Ospedaliera Santa Maria degli Angeli
city: Ravenna
country: Italy
facility: Ospedale di Ravenna
city: Reggio Emilia
country: Italy
facility: Arcispedale S. Maria Nuova Azienda Ospedaliera di Reggio Emilia
city: Rimini
country: Italy
facility: Ospedale Infermi di Rimini
city: Roma
country: Italy
facility: Policlinico Universitario Campus Biomedico
city: Roma
country: Italy
facility: Istituto Regina Elena per lo studio e la cura dei tumori
city: Salerno
country: Italy
facility: Ospedale G. Da Procida
city: Sassari
country: Italy
facility: Ospedale Civile di Sassari SS Annunaziata
city: Sora
country: Italy
facility: Ospedale 'SS. Trinità'
city: Terni
country: Italy
facility: Azienda Ospedaliera S.Maria di Terni
city: Torino
country: Italy
facility: A.O.U. San Giovanni Battista di Torino
city: Udine
country: Italy
facility: A.O.U. Santa Maria della Misericordia di Udine
city: Varese
country: Italy
facility: A.O. Ospedale di Circolo e Fondazione Macchi
city: Verona
country: Italy
facility: Ospedale Sacro Cuore Don Calabria
Study officials:
affiliation: Dipartimento di Medicina Clinica e Chirurgia Oncologia Università degli Studi di Napoli "Federico II"
name: Grazia Arpino, MD
role: PRINCIPAL_INVESTIGATOR
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