Clinical trial NCT01160211: 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
Official title: A Phase III Trial to Compare the Safety and Efficacy of Lapatinib Plus Trastuzumab Plus an Aromatase Inhibitor (AI) vs. Trastuzumab Plus an AI vs. Lapatinib Plus an AI as 1st- or 2nd- Line Therapy in Postmenopausal Subjects With Hormone Receptor+, HER2-positive Metastatic Breast Cancer (MBC) Who Received Prior Trastuzumab and Endocrine Therapies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neoplasms, Breast
Keywords: 1st line MBC
MBC
hormone receptor positive
lapatinib
trastuzumab
HER2 positive
aromatase inhibitor
Lead sponsor: Novartis
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2010-07-12
Enrollment: 369
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: 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.

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.

Primary outcomes:
measure: Progression Free Survival (PFS) Events in Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) vs. Trastuzumab + Aromatase Inhibitor (AI)
timeFrame: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 5 years
measure: Median Kaplan Meier Estimates for PFS in Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) vs. Trastuzumab + Aromatase Inhibitor (AI)
timeFrame: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 5 years
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 11 years
measure: Overall Survival (OS)
timeFrame: From date of randomization until date of death from any cause, assessed up approximately 11 years
measure: Overall Response Rate (ORR)
timeFrame: Up approximately 11 years
measure: Clinical Benefit Rate (CBR)
timeFrame: Up approximately 11 years
measure: Time to Response
timeFrame: From date of randomization until the earliest date of Complete Response (CR) or Partial Response (PR), assessed up approximately 11 years
measure: Duration of Response (DoR)
timeFrame: From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up approximately 11 years
measure: Mean Change in the Quality of Life (QoL) Status Relative to Baseline FACT-B Overall and Subscale Scores at Last On Treatment Assessment
timeFrame: Day 1 (pre-dose), up approximately 11 years
Other outcomes:
Locations:
city: Hollywood
country: United States
facility: Novartis Investigative Site
state: Florida
city: Augusta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Germantown
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Tacoma
country: United States
facility: Novartis Investigative Site
state: Washington
city: Berazategui
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Capital Federal
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: La Plata
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Viedma
country: Argentina
facility: Novartis Investigative Site
state: Río Negro
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: La Rioja
country: Argentina
facility: Novartis Investigative Site
city: Quilmes
country: Argentina
facility: Novartis Investigative Site
city: San Miguel de Tucuman
country: Argentina
facility: Novartis Investigative Site
city: Albury
country: Australia
facility: Novartis Investigative Site
city: Douglas
country: Australia
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Namur
country: Belgium
facility: Novartis Investigative Site
city: Goiania
country: Brazil
facility: Novartis Investigative Site
state: Goiás
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: Rio Grande Do Sul
city: Barretos
country: Brazil
facility: Novartis Investigative Site
state: São Paulo
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: São Paulo
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: São Paulo
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: São Paulo
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
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: Fuzhou
country: China
facility: Novartis Investigative Site
state: Fujian
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Changchun
country: China
facility: Novartis Investigative Site
state: Jilin
city: Harbin
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Osijek
country: Croatia
facility: Novartis Investigative Site
city: Zagreb
country: Croatia
facility: Novartis Investigative Site
city: Besancon
country: France
facility: Novartis Investigative Site
city: Montpellier Cedex 5
country: France
facility: Novartis Investigative Site
city: Paris Cedex 20
country: France
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Furstenwalde
country: Germany
facility: Novartis Investigative Site
state: Brandenburg
city: Goslar
country: Germany
facility: Novartis Investigative Site
state: Niedersachsen
city: Troisdorf
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Velbert
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Alexandroupolis
country: Greece
facility: Novartis Investigative Site
city: Chania
country: Greece
facility: Novartis Investigative Site
city: Heraklion
country: Greece
facility: Novartis Investigative Site
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: Kowloon
country: Hong Kong
facility: Novartis Investigative Site
city: Tuen Mun
country: Hong Kong
facility: Novartis Investigative Site
city: Gyor
country: Hungary
facility: Novartis Investigative Site
city: Gyula
country: Hungary
facility: Novartis Investigative Site
city: Kaposvar
country: Hungary
facility: Novartis Investigative Site
city: Miskolc
country: Hungary
facility: Novartis Investigative Site
city: Nyiregyhaza
country: Hungary
facility: Novartis Investigative Site
city: Pecs
country: Hungary
facility: Novartis Investigative Site
city: Szeged
country: Hungary
facility: Novartis Investigative Site
city: Zalaegerszeg
country: Hungary
facility: Novartis Investigative Site
city: Nagpur
country: India
facility: Novartis Investigative Site
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Haifa
country: Israel
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Ramat Gan
country: Israel
facility: Novartis Investigative Site
city: Rozzano (MI)
country: Italy
facility: Novartis Investigative Site
state: Lombardia
city: Aichi
country: Japan
facility: Novartis Investigative Site
city: Chiba
country: Japan
facility: Novartis Investigative Site
city: Ehime
country: Japan
facility: Novartis Investigative Site
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Saitama
country: Japan
facility: Novartis Investigative Site
city: Tokyo
country: Japan
facility: Novartis Investigative Site
city: Gyeonggi-do
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Arequipa
country: Peru
facility: Novartis Investigative Site
city: Lima
country: Peru
facility: Novartis Investigative Site
city: Konin
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Lisbon
country: Portugal
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Arkhangelsk
country: Russian Federation
facility: Novartis Investigative Site
city: Kazan
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Ryazan
country: Russian Federation
facility: Novartis Investigative Site
city: St. Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St. Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Belgrade
country: Serbia
facility: Novartis Investigative Site
city: Sremska Kamenica
country: Serbia
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Castellon
country: Spain
facility: Novartis Investigative Site
city: La Coruna
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Changhua
country: Taiwan
facility: Novartis Investigative Site
city: Kaohsiung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei City
country: Taiwan
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Chernivtsi
country: Ukraine
facility: Novartis Investigative Site
city: Kharkiv
country: Ukraine
facility: Novartis Investigative Site
city: Lyutizh
country: Ukraine
facility: Novartis Investigative Site
city: Sumy
country: Ukraine
facility: Novartis Investigative Site
city: Uzhgorod
country: Ukraine
facility: Novartis Investigative Site
city: Vinnitsia
country: Ukraine
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Maidstone
country: United Kingdom
facility: Novartis Investigative Site
city: Peterborough
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.