TH V THL: A Randomized Study of TH Versus THL in First Line Treatment of HER2-positive Metastatic Breast Cancer

Sponsor

Cancer Trials Ireland (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01526369

Collaborator

(none)

Enrollment

Locations

Arms

131

Duration (Months)

2.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The proposed phase III randomised trial will compare the efficacy of trastuzumab and paclitaxel with trastuzumab, paclitaxel and lapatinib in first line treatment of HER2 positive metastatic breast cancer. The investigators will also examine potential predictive biomarkers of response to trastuzumab and lapatinib in pre-treatment biopsy samples and serum samples.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Trastuzumab Drug: Paclitaxel Drug: Lapatinib	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

75 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase III Randomized Study of TH (Paclitaxel and Trastuzumab) Versus THL (Paclitaxel, Trastuzumab and Lapatinib) in First Line Treatment of HER2-positive Metastatic Breast Cancer

Study Start Date :

Jan 1, 2012

Actual Primary Completion Date :

Nov 1, 2015

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Paclitaxel and Trastuzumab Weekly paclitaxel (80mg/m², for 3 weeks of a 4 week cycle) + trastuzumab (8mg/kg loading dose on cycle 1 day 1 and 4mg/kg every 2 weeks) until disease progression, unacceptable toxicity or consent withdrawal.	Drug: Trastuzumab Drug: Paclitaxel
Experimental: Paclitaxel, Trastuzumab and Lapatinib Weekly paclitaxel (80 mg/m², for 3 weeks of a 4 week cycle) + trastuzumab (8 mg/kg loading dose on cycle 1 day 1 and 4 mg/kg every 2 weeks) + lapatinib (1,000 mg daily), until disease progression, unacceptable toxicity or consent withdrawal.	Drug: Trastuzumab Drug: Paclitaxel Drug: Lapatinib

Arm

Intervention/Treatment

Active Comparator: Paclitaxel and Trastuzumab

Weekly paclitaxel (80mg/m², for 3 weeks of a 4 week cycle) + trastuzumab (8mg/kg loading dose on cycle 1 day 1 and 4mg/kg every 2 weeks) until disease progression, unacceptable toxicity or consent withdrawal.

Drug: Trastuzumab

Drug: Paclitaxel

Experimental: Paclitaxel, Trastuzumab and Lapatinib

Weekly paclitaxel (80 mg/m², for 3 weeks of a 4 week cycle) + trastuzumab (8 mg/kg loading dose on cycle 1 day 1 and 4 mg/kg every 2 weeks) + lapatinib (1,000 mg daily), until disease progression, unacceptable toxicity or consent withdrawal.

Drug: Trastuzumab

Drug: Paclitaxel

Drug: Lapatinib

Outcome Measures

Primary Outcome Measures

Progression Free Survival [9 months]

Secondary Outcome Measures

Overall Survival [30 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent obtained prior to any study-related procedures
Female age 18 years or greater.
ECOG Performance Status of 0 or 1.
Histologically or cytologically-confirmed invasive metastatic breast cancer.
Patients must have measurable disease according to RECIST criteria Version 1.1, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral CT scan,MRI, or calipers by clinical exam.
Tumour shows HER2 over-expression (3+ by IHC and/or FISH + ) by testing of the primary tumour and if available the biopsied metastatic lesion
Patients who received prior radiotherapy must have completed it at least 4 weeks before registration and recovered from all treatment-related toxicities.
Cardiac ejection fraction within the institutional range of normal as measured by MUGA or ECHO within 14 days prior to registration. Note that baseline and on treatment scans should be performed using the same modality and preferably at the same institution.
Adequate haematological, hepatic, and renal function.

Haemoglobin ≥ 9g/dL
Neutrophils (ANC/AGC) ≥1500/mm³ (1.5 x 10^9/L)
Platelets ≥ (100 x 10^9/L)
Total bilirubin ≤ 1.5mg/dL (25.65 μmol/L)
Both ALT (SGPT) and AST (SGOT) ≤ 3 x ULN with or without liver Metastasis
Alkaline phosphatase ≤ 2.5 x ULN
Serum creatinine ≤1.5 ULN or calculated creatinine clearance (CrCl) ≥ 30mL/min according to the Cockcroft and Gault formula (Appendix K)

Able to swallow and retain oral medication.
Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation. Female patients of childbearing potential must have pregnancy excluded by urine or serum beta-HCG testing within 7 days prior to registration.
Estimated life expectancy greater than 12 weeks

Exclusion Criteria:

Prior systemic therapy for metastatic disease (except one line of hormonal therapy for metastatic disease without trastuzumab).
Recurrence within 12 months from completion of adjuvant chemotherapy to the development of metastatic disease.
Recurrence within 6 months from completion of adjuvant trastuzumab to the development of metastatic disease.
Prior lapatinib treatment.
Peripheral neuropathy ≥ grade 2
Patients with known CNS metastasis should be excluded from this clinical trial
Prior radiotherapy to more than half of the bony pelvis.
Uncontrolled or symptomatic angina, uncontrolled arrhythmias, congestive heart failure, a documented MI within 6 months prior to registration or any other cardiac disorders, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient .
Immediate or delayed hypersensitivity or untoward reaction to paclitaxel, trastuzumab, or other related compounds, or to drugs chemically related to lapatinib (including other anilinoquinazolines, e.g. gefitinib (Iressa®) and erlotinib (Tarceva®), or other chemically-related compounds).
Pregnant or breastfeeding women are excluded from this study.
Patients should not be receiving any other investigational agents (within 30 days prior to registration) or receiving concurrent anticancer therapy.
Concomitant requirement for medication classified as CYP3A4 inducers or inhibitors (Table 9).
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.
Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis).
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)
Concurrent treatment with ovarian hormone replacement therapy. Prior treatment must be stopped prior to registration.

Contacts and Locations

Locations

	Site	City	State	Country
1	Helsinki University Hopsital	Helsinki		Finland
2	Kuopio University hospital	Kuopio		Finland
3	CRLC Val d'Aurelle	Montpellier		France
4	Interdisziplinäre Onkologische Zentrum München (IOZ München)	Munich		Germany
5	St Vincent's University Hospital	Dublin	Leinster	Ireland
6	Cork University Hospital	Cork		Ireland
7	Beaumont Hospital	Dublin		Ireland
8	Mater Misericordiae University Hospital	Dublin		Ireland
9	Mater Private Hospital	Dublin		Ireland
10	St James's Hospital	Dublin		Ireland
11	University Hospital Galway	Galway		Ireland
12	Midwestern Regional Hospital	Limerick		Ireland
13	Sligo General Hospital	Sligo		Ireland
14	Waterford Regional Hospital	Waterford		Ireland
15	Rabin Medical Center	Petah Tikva		Israel
16	The Chaim Sheba Medical Center	Tel Hashomer		Israel
17	Oslo University Hopsital	Oslo		Norway
18	Hospital Santa Maria	Lisbon		Portugal
19	Centro Oncologico de Galicia	A Coruña		Spain
20	Hospital Nuestra Senora de Sonsoles	Avila		Spain
21	Hospital Infanta Cristina	Badajoz		Spain
22	Hospital Virgen de la Luz	Cuenca		Spain
23	Hospital General de Grannollers	Granollers		Spain
24	Complejo Hospitalario de Jaen	Jaén		Spain
25	Hospital Universitari Arnau de Vilanova de Lleida	Lleida		Spain
26	Complejo Hospitalario Xeral Calde / Hospital Lucus Augusti	Lugo		Spain
27	H. Puerta de Hierro	Madrid		Spain
28	Hospital General Universitario Gregorio Maranon	Madrid		Spain
29	Hospital de Mataro	Mataro		Spain
30	Hospital Infanta Cristina	Parla		Spain
31	Hospital Donostia	San Sebastián		Spain
32	Hospital Universitario de Canarias	Santa Cruz De Tenerife		Spain
33	Hospital General Universitario de Elche	Valencia		Spain
34	Hospital General Universitario de Valencia	Valencia		Spain
35	Hospital Clinico Universitario 'Lozano Blesa'	Zaragoza		Spain