Safety and QoL of Trastuzumab With Lapatinib or Chemiotherapy in MBC and HER2+ Patients Refractory to Anti HER2 Therapies

Sponsor

Consorzio Oncotech (Other)

Overall Status

Unknown status

CT.gov ID

NCT02238509

Collaborator

Clinical Research Technology S.r.l. (Industry)

154

Enrollment

Locations

Arms

Duration (Months)

4.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Lapatinib Drug: Trastuzumab	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

154 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Nov 1, 2014

Anticipated Primary Completion Date :

Oct 1, 2017

Anticipated Study Completion Date :

Oct 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: lapatinib and trastuzumab ARM A: Lapatinib and trastuzumab (experimental arm). Patients with hormone receptor (HR) positive breast cancer will also receive endocrine therapy at the physician's discretion (preferred choice with fulvestrant).	Drug: Lapatinib ARM A: oral lapatinib 1,000 mg daily in combination with intravenous trastuzumab 6mg/kg q3wks (after the initial 8 mg/kg loading dose). Other Names: Tyverb Drug: Trastuzumab ARM A: oral lapatinib 1,000 mg daily in combination with intravenous trastuzumab 6mg/kg q3wks (after the initial 8 mg/kg loading dose). Other Names: Herceptin
Experimental: trastuzumab plus chemotherapy ARM B: Trastuzumab plus chemotherapy (control arm). Any type of chemotherapy in combination with trastuzumab will be allowed at the physician's discretion.	Drug: Trastuzumab ARM A: oral lapatinib 1,000 mg daily in combination with intravenous trastuzumab 6mg/kg q3wks (after the initial 8 mg/kg loading dose). Other Names: Herceptin

Arm

Intervention/Treatment

Experimental: lapatinib and trastuzumab

ARM A: Lapatinib and trastuzumab (experimental arm). Patients with hormone receptor (HR) positive breast cancer will also receive endocrine therapy at the physician's discretion (preferred choice with fulvestrant).

Drug: Lapatinib

ARM A: oral lapatinib 1,000 mg daily in combination with intravenous trastuzumab 6mg/kg q3wks (after the initial 8 mg/kg loading dose).

Other Names:

Tyverb

Drug: Trastuzumab

ARM A: oral lapatinib 1,000 mg daily in combination with intravenous trastuzumab 6mg/kg q3wks (after the initial 8 mg/kg loading dose).

Other Names:

Herceptin

Experimental: trastuzumab plus chemotherapy

ARM B: Trastuzumab plus chemotherapy (control arm). Any type of chemotherapy in combination with trastuzumab will be allowed at the physician's discretion.

Drug: Trastuzumab

ARM A: oral lapatinib 1,000 mg daily in combination with intravenous trastuzumab 6mg/kg q3wks (after the initial 8 mg/kg loading dose).

Other Names:

Herceptin

Outcome Measures

Primary Outcome Measures

Clinical Benefit Rate [Clinical Benefit Rate is defined as confirmed complete response plus partial response at any time, plus stable disease up to 24 weeks]
To evaluate clinical benefit rate (CBR) for patients treated with lapatinib and trastuzumab and for patients treated with trastuzumab and chemotherapy. CBR is defined as: confirmed complete response (CR) plus partial response (PR) at any time, plus stable disease (SD) for 24 weeks

Secondary Outcome Measures

Progression free survival [Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 36 months]
Second-line progression-free survival, defined as the time from first dosing to the first documented disease progression or death from any cause, whichever occurs first.
Overall Survival [Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 36 months]
OS is defined as the time from first dosing in second line to death from any cause.
Safety and tolerability [Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 36 months]
Safety of second line treatment will be evaluated by the frequency of AEs and SAEs, cardiac events, clinically significant abnormal laboratory tests, vital signs, and ECOG PS. All patients who received at least one dose of study treatment will be included in the safety analysis.
Quality of life [Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 36 months]
QoL and symptom control will be assessed using the FACT-B questionnaire.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	A.O.U. Ospedali Riuniti Umberto I	Ancona	Italy	60020
2	Centro di Riferimento Oncologico	Aviano	Italy	33081
3	Policlinico S. Orsola Malpighi	Bologna	Italy	MD
4	Ospedale Centrale di Bolzano	Bolzano	Italy	39100
5	Presidio Ospedaliero 'Antonio Perrino	Brindisi	Italy	72100
6	A.O.R.N.A.S. Garibaldi Nesima di Catania	Catania	Italy	95122
7	Humanitas Centro Catanese di Oncologia	Catania	Italy	95126
8	Azienda Ospedaliera S. Anna	Como	Italy	22100
9	Ospedale 'F. Spaziani'	Frosinone	Italy	03100
10	I.R.C.C.S. A.O.U. San Martino	Genova	Italy	16132
11	Ospedale Civile di Guastalla	Guastalla	Italy	42016
12	Ospedale Vito Fazzi	Lecce	Italy	73100
13	Ospedale di Lugo - AUSL della Romagna	Lugo	Italy	48022
14	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola	Italy	47014
15	Ospedale Niguarda Ca' Granda	Milano	Italy	20162
16	A.O. San Gerardo	Monza	Italy	20900
17	AORN "A. Cardarelli"	Naples	Italy	80131
18	Istituto Nazionale Tumori - IRCCS "Fondazione G.Pascale"	Napoli	Italy	8011
19	Policlinico SUN	Napoli	Italy	80131
20	Università degli Studi di Napoli "Federico II"	Napoli	Italy	80131
21	A.R.N.A.S. Ospedale Civico e Benfratelli	Palermo	Italy	90127
22	Ospedale S. Maria della Misericordia	Perugia	Italy	06156
23	Azienda Ospedaliera Santa Maria degli Angeli	Pordenone	Italy	33170
24	Ospedale di Ravenna	Ravenna	Italy	48100
25	Arcispedale S. Maria Nuova Azienda Ospedaliera di Reggio Emilia	Reggio Emilia	Italy	42123
26	Ospedale Infermi di Rimini	Rimini	Italy	47923
27	Policlinico Universitario Campus Biomedico	Roma	Italy	00128
28	Istituto Regina Elena per lo studio e la cura dei tumori	Roma	Italy	00144
29	Ospedale G. Da Procida	Salerno	Italy	84126
30	Ospedale Civile di Sassari SS Annunaziata	Sassari	Italy	07100
31	Ospedale 'SS. Trinità'	Sora	Italy	03039
32	Azienda Ospedaliera S.Maria di Terni	Terni	Italy	05100
33	A.O.U. San Giovanni Battista di Torino	Torino	Italy	10126
34	A.O.U. Santa Maria della Misericordia di Udine	Udine	Italy	33100
35	A.O. Ospedale di Circolo e Fondazione Macchi	Varese	Italy	21100
36	Ospedale Sacro Cuore Don Calabria	Verona	Italy	37024