A Study to Compare the Safety and Efficacy of an Aromatase Inhibitor in Combination With Lapatinib, Trastuzumab or Both for the Treatment of Hormone Receptor Positive, HER2+ Metastatic Breast Cancer

NCT ID: NCT01160211

Last Updated: 2025-03-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 369 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-05-05
• Study Completion Date: 2022-06-06

Brief Summary

A study to compare the safety and efficacy of an aromatase inhibitor in combination with lapatinib, trastuzumab or both for the treatment of hormone receptor positive, HER2+ metastatic breast cancer (MBC).

Detailed Description

This Phase III, multicenter, open-label study randomized subjects to one of the three treatment arms:

1. Treatment group A: lapatinib 1000 mg PO once daily + trastuzumab (loading dose of 8 mg/kg) followed by the maintenance dose of 6 mg/kg IV q3weeks + an AI (either letrozole, anastrozole, or exemestane) of Investigator's choice PO once daily.

2. Treatment group B: trastuzumab (loading dose of 8 mg/kg) followed by maintenance dose of 6 mg/kg IV q3weeks + an AI (either letrozole, anastrozole, or exemestane) of Investigator's choice PO once daily.

3. Treatment group C: lapatinib 1500 mg PO once daily + an AI (either letrozole, anastrozole, or exemestane) of Investigator's choice PO once daily.

Treatment continued until disease progression, death, or unacceptable toxicities, whichever came first.

Subjects who discontinued study treatment for reasons other than disease progression were followed-up every 12 weeks until disease progression or death, until the start of post-study treatment anti-cancer therapy (including radiotherapy and surgery), withdrawal of consent, or lost to follow-up, whichever came first.

Conditions

Neoplasms, Breast

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment group A

Lapatinib 1000 mg PO once daily + Trastuzumab (loading dose of 8 mg/kg) followed by the maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks) + an Aromatase Inhibitor (AI) of Investigator's choice PO once daily.

Group Type: EXPERIMENTAL

Lapatinib

Intervention Type: DRUG

1000 mg by mouth once a day

Trastuzumab

Intervention Type: DRUG

Loading dose of 8 mg/kg IV followed by the maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks)

Aromatase Inhibitor

Intervention Type: DRUG

Aromatase inhibitor (either letrozole, anastrozole, or exemestane) of investigator's choice given by mouth once daily

Treatment group B

Trastuzumab (loading dose of 8 mg/kg) followed by maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks) + an Aromatase Inhibitor (AI) of Investigator's choice PO once daily.

Group Type: ACTIVE_COMPARATOR

Trastuzumab

Intervention Type: DRUG

Loading dose of 8 mg/kg IV followed by the maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks)

Aromatase Inhibitor

Intervention Type: DRUG

Aromatase inhibitor (either letrozole, anastrozole, or exemestane) of investigator's choice given by mouth once daily

Treatment Group C

Lapatinib 1500 mg PO once daily + an Aromatase Inhibitor (AI) of Investigator's choice PO once daily.

Group Type: ACTIVE_COMPARATOR

Aromatase Inhibitor

Intervention Type: DRUG

Aromatase inhibitor (either letrozole, anastrozole, or exemestane) of investigator's choice given by mouth once daily

Lapatinib

Intervention Type: DRUG

1500 mg by mouth once daily

Interventions

Lapatinib

1000 mg by mouth once a day

Intervention Type: DRUG

Trastuzumab

Loading dose of 8 mg/kg IV followed by the maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks)

Intervention Type: DRUG

Aromatase Inhibitor

Aromatase inhibitor (either letrozole, anastrozole, or exemestane) of investigator's choice given by mouth once daily

Intervention Type: DRUG

Lapatinib

1500 mg by mouth once daily

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Subjects eligible for enrollment in the study must meet all of the following criteria:

1. Signed written informed consent. In Korea and Japan, subjects between >=18 and <20 years of age must also have a legal representative sign the written informed consent.

2. Post-menopausal female subjects >=18 years of age. Post-menopausal as defined by any of the following:

• Subjects at least 60 years of age.
• Subjects under 60 years of age and amenorrhic for at least 12 consecutive months AND follicle-stimulating hormone (FSH) and estradiol levels in postmenopausal range (utilizing ranges from the local laboratory facility).
• Prior bilateral oophorectomy.
• Prior radiation castration with amenorrhea for at least 6 months

3. Subjects must have a history of histologically confirmed breast cancer, with a clinically confirmed diagnosis of metastatic disease [confirmed by histology, cytology or other clinical means (e.g. CT, MRI)]. Subjects may have either measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

4. Tumors that are ER+ and/or PgR+ by local laboratory

5. Documentation of HER2 overexpression or gene amplification, in the invasive component of either the primary tumor or metastatic disease site as defined as:

• 3+ by Immunohistochemistry (IHC) and/or
• HER2/neu gene amplification by fluorescence, chromogenic or silver in situ hybridization [FISH, CISH or SISH; >6 HER2/neu gene copies per nucleus or a FISH, CISH or SISH test ratio (HER2 gene copies to chromosome 17 signals) of ≥2.0]

6. Subject must have received at least one prior regimen containing trastuzumab in combination with chemotherapy for breast cancer:.

• Subject has ONLY received prior trastuzumab in combination with chemotherapy as neoadjuvant and/or adjuvant treatment. OR
• Subject has received ONE prior trastuzumab-containing regimen for metastatic disease (and has progressed), and may or may not have received prior trastuzumab in combination with chemotherapy as neoadjuvant and/or adjuvant treatment.

7. Subject must have received prior endocrine therapy (such as aromatase inhibitors or selective estrogen receptor modulators). 8. Subjects who have a life expectancy of > 6 months as assessed by the treating investigator

9. Subjects must have baseline Left Ventricular Ejection Fraction (LVEF) ≥50% measured by echocardiography (ECHO) or multi-gated acquisition scan (MUGA) 10. Subject must have an ECOG performance status of 0-1 11. All prior treatment related toxicities must be CTCAE (Version 4.0) ≤ Grade 1 at the time of randomization 12. Completion of screening assessments 13. Adequate baseline organ function. 14. Subjects must meet all of the following criteria:

• QTc <450msec or
• QTc <480msec for subjects with bundle branch block The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB) or to Fridericia's formula (QTcF), machine or manual over read, for males and females. The specific formula that will be used in a protocol should be determined prior to initiation of the study, and the formula used to determine inclusion and discontinuation should be the same throughout the study. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period

Exclusion Criteria

1. History of another malignancy. Exception: Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.

2. Subjects with extensive symptomatic visceral disease including hepatic involvement and pulmonary lymphangitic spread of tumor, or the disease is considered by the investigator to be rapidly progressing or life threatening (subjects who are intended for chemotherapy)

3. Serious cardiac illness or medical condition including but not confined to:

• Uncontrolled arrhythmias
• Uncontrolled or symptomatic angina
• History of congestive heart failure (CHF)
• Documented myocardial infarction <6 months from study entry

4. Known history of, or clinical evidence of, central nervous system (CNS) metastases or leptomeningeal carcinomatosis

5. Have acute or currently active/requiring anti-viral therapy hepatic or biliary disease (with the exception of subjects with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)

6. Have a concurrent disease or condition that may interfere with study participation, or any serious medical disorder that would interfere with the subject's safety (for example, active or uncontrolled infection or any psychiatric condition prohibiting understanding or rendering of informed consent)

7. Have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels

8. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the study agents or their excipients that, in the opinion of the Investigator or GSK medical monitor, contraindicates their participation

9. Any prohibited medication.

10. Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: collaborator

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Hollywood, Florida, United States

Novartis Investigative Site

Augusta, Georgia, United States

Novartis Investigative Site

Germantown, Tennessee, United States

Novartis Investigative Site

Tacoma, Washington, United States

Novartis Investigative Site

Berazategui, Buenos Aires, Argentina

Novartis Investigative Site

Capital Federal, Buenos Aires, Argentina

Novartis Investigative Site

Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina

Novartis Investigative Site

Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina

Novartis Investigative Site

La Plata, Buenos Aires, Argentina

Novartis Investigative Site

Viedma, Río Negro Province, Argentina

Novartis Investigative Site

Rosario, Santa Fe Province, Argentina

Novartis Investigative Site

Córdoba, , Argentina

Novartis Investigative Site

La Rioja, , Argentina

Novartis Investigative Site

Quilmes, , Argentina

Novartis Investigative Site

San Miguel de Tucumán, , Argentina

Novartis Investigative Site

Albury, , Australia

Novartis Investigative Site

Douglas, , Australia

Novartis Investigative Site

Leuven, , Belgium

Novartis Investigative Site

Namur, , Belgium

Novartis Investigative Site

Goiânia, Goiás, Brazil

Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, Brazil

Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, Brazil

Novartis Investigative Site

Barretos, São Paulo, Brazil

Novartis Investigative Site

São Paulo, São Paulo, Brazil

Novartis Investigative Site

São Paulo, São Paulo, Brazil

Novartis Investigative Site

São Paulo, São Paulo, Brazil

Novartis Investigative Site

Rio de Janeiro, , Brazil

Novartis Investigative Site

Plovdiv, , Bulgaria

Novartis Investigative Site

Sofia, , Bulgaria

Novartis Investigative Site

Sofia, , Bulgaria

Novartis Investigative Site

Varna, , Bulgaria

Novartis Investigative Site

Fuzhou, Fujian, China

Novartis Investigative Site

Guangzhou, Guangdong, China

Novartis Investigative Site

Changchun, Jilin, China

Novartis Investigative Site

Harbin, , China

Novartis Investigative Site

Shanghai, , China

Novartis Investigative Site

Osijek, , Croatia

Novartis Investigative Site

Zagreb, , Croatia

Novartis Investigative Site

Besançon, , France

Novartis Investigative Site

Montpellier, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Munich, Bavaria, Germany

Novartis Investigative Site

Fürstenwalde, Brandenburg, Germany

Novartis Investigative Site

Goslar, Lower Saxony, Germany

Novartis Investigative Site

Troisdorf, North Rhine-Westphalia, Germany

Novartis Investigative Site

Velbert, North Rhine-Westphalia, Germany

Novartis Investigative Site

Alexandroupoli, , Greece

Novartis Investigative Site

Chania, , Greece

Novartis Investigative Site

Heraklion, , Greece

Novartis Investigative Site

Hong Kong, , Hong Kong

Novartis Investigative Site

Kowloon, , Hong Kong

Novartis Investigative Site

Tuenmen, , Hong Kong

Novartis Investigative Site

Győr, , Hungary

Novartis Investigative Site

Gyula, , Hungary

Novartis Investigative Site

Kaposvár, , Hungary

Novartis Investigative Site

Miskolc, , Hungary

Novartis Investigative Site

Nyíregyháza, , Hungary

Novartis Investigative Site

Pécs, , Hungary

Novartis Investigative Site

Szeged, , Hungary

Novartis Investigative Site

Zalaegerszeg, , Hungary

Novartis Investigative Site

Nagpur, , India

Novartis Investigative Site

New Delhi, , India

Novartis Investigative Site

Haifa, , Israel

Novartis Investigative Site

Jerusalem, , Israel

Novartis Investigative Site

Ramat Gan, , Israel

Novartis Investigative Site

Rozzano (MI), Lombardy, Italy

Novartis Investigative Site

Aichi, , Japan

Novartis Investigative Site

Chiba, , Japan

Novartis Investigative Site

Ehime, , Japan

Novartis Investigative Site

Osaka, , Japan

Novartis Investigative Site

Osaka, , Japan

Novartis Investigative Site

Saitama, , Japan

Novartis Investigative Site

Tokyo, , Japan

Novartis Investigative Site

Arequipa, , Peru

Novartis Investigative Site

Lima, , Peru

Novartis Investigative Site

Konin, , Poland

Novartis Investigative Site

Warsaw, , Poland

Novartis Investigative Site

Lisbon, , Portugal

Novartis Investigative Site

Porto, , Portugal

Novartis Investigative Site

Arkhangelsk, , Russia

Novartis Investigative Site

Kazan', , Russia

Novartis Investigative Site

Moscow, , Russia

Novartis Investigative Site

Ryazan, , Russia

Novartis Investigative Site

Saint Petersburg, , Russia

Novartis Investigative Site

Saint Petersburg, , Russia

Novartis Investigative Site

Belgrade, , Serbia

Novartis Investigative Site

Kamenitz, , Serbia

Novartis Investigative Site

Singapore, , Singapore

Novartis Investigative Site

Gyeonggi-do, , South Korea

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

A Coruña, , Spain

Novartis Investigative Site

Barcelona, , Spain

Novartis Investigative Site

Castellon, , Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Changhua, , Taiwan

Novartis Investigative Site

Kaohsiung City, , Taiwan

Novartis Investigative Site

Taipei, , Taiwan

Novartis Investigative Site

Ankara, , Turkey (Türkiye)

Novartis Investigative Site

Izmir, , Turkey (Türkiye)

Novartis Investigative Site

Chernivtsi, , Ukraine

Novartis Investigative Site

Kharkiv, , Ukraine

Novartis Investigative Site

Liutizh, , Ukraine

Novartis Investigative Site

Sumy, , Ukraine

Novartis Investigative Site

Uzhhorod, , Ukraine

Novartis Investigative Site

Vinnitsia, , Ukraine

Novartis Investigative Site

London, , United Kingdom

Novartis Investigative Site

Maidstone, , United Kingdom

Novartis Investigative Site

Peterborough, , United Kingdom

Countries

United States; Argentina; Australia; Belgium; Brazil; Bulgaria; China; Croatia; France; Germany; Greece; Hong Kong; Hungary; India; Israel; Italy; Japan; Peru; Poland; Portugal; Russia; Serbia; Singapore; South Korea; Spain; Taiwan; Turkey (Türkiye); Ukraine; United Kingdom

References

Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE. J Clin Oncol. 2018 Mar 10;36(8):741-748. doi: 10.1200/JCO.2017.74.7824. Epub 2017 Dec 15.

Reference Type: BACKGROUND

PMID: 29244528 (View on PubMed)

Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. J Clin Oncol. 2021 Jan 1;39(1):79-89. doi: 10.1200/JCO.20.01894. Epub 2020 Aug 21.

Reference Type: DERIVED

PMID: 32822287 (View on PubMed)

Other Identifiers

2010-019577-16

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CLAP016A2307

Identifier Type: OTHER

Identifier Source: secondary_id

114299

Identifier Type: -

Identifier Source: org_study_id