Brief Summary
This was a four-arm (parallel group) randomized, open-label, multicenter Phase 3 study to investigate the use of a combination of Lapatinib and Trastuzumab, a sequence of Trastuzumab followed by Lapatinib, and Lapatinib alone, compared to Trastuzumab alone in the adjuvant treatment of Human Epidermal Growth Factor Receptor 2 (HER2) positive early breast cancer.
Brief Title
ALTTO (Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation) Study; BIG 2-06/N063D
Detailed Description
Treatment allocation was stratified by blocked randomization, with three stratification factors:
* Hormone receptor status: Estrogen Receptor (ER) and/or Progesterone Receptor (PgR) positive versus both negative.
* Axillary lymph node involvement: not assessed because of neoadjuvant chemotherapy versus node negative versus 1-3 positive nodes versus 4 or more positive nodes.
* Timing of adjuvant chemotherapy: concurrently with taxanes and targeted therapy (Design 2) and concurrently with non-anthracycline-based platinum chemotherapy and targeted therapy (Design 2B) versus all other chemotherapy completed before randomization (Design 1). Treatments delivered differed according to the timing and type of adjuvant chemotherapy.
The primary objective of this study was to compare disease-free survival (DFS) in subjects with HER2 overexpressing and/or amplified breast cancer randomized to trastuzumab for one year versus lapatinib for one year versus trastuzumab (12 or 18 weeks, according to assigned design) followed by a six week treatment-free interval followed by lapatinib (28 or 34 weeks, according to assigned design) versus trastuzumab in combination with lapatinib for one year (52 weeks).
Secondary objectives included treatment comparisons with respect to overall survival, time to recurrence, time to distant recurrence, safety and tolerability, and incidence of brain metastasis.
Based on the recommendation of the Independent Data Monitoring Committee (IDMC) at the first interim analysis (18-Aug-2011), the Lapatinib alone arm was discontinued prior to primary analysis due to futility. The IDMC also stated that the other three arms (trastuzumab alone, sequential trastuzumab/lapatinib arm and the combination arm) could continued as planned with no changes.
* Hormone receptor status: Estrogen Receptor (ER) and/or Progesterone Receptor (PgR) positive versus both negative.
* Axillary lymph node involvement: not assessed because of neoadjuvant chemotherapy versus node negative versus 1-3 positive nodes versus 4 or more positive nodes.
* Timing of adjuvant chemotherapy: concurrently with taxanes and targeted therapy (Design 2) and concurrently with non-anthracycline-based platinum chemotherapy and targeted therapy (Design 2B) versus all other chemotherapy completed before randomization (Design 1). Treatments delivered differed according to the timing and type of adjuvant chemotherapy.
The primary objective of this study was to compare disease-free survival (DFS) in subjects with HER2 overexpressing and/or amplified breast cancer randomized to trastuzumab for one year versus lapatinib for one year versus trastuzumab (12 or 18 weeks, according to assigned design) followed by a six week treatment-free interval followed by lapatinib (28 or 34 weeks, according to assigned design) versus trastuzumab in combination with lapatinib for one year (52 weeks).
Secondary objectives included treatment comparisons with respect to overall survival, time to recurrence, time to distant recurrence, safety and tolerability, and incidence of brain metastasis.
Based on the recommendation of the Independent Data Monitoring Committee (IDMC) at the first interim analysis (18-Aug-2011), the Lapatinib alone arm was discontinued prior to primary analysis due to futility. The IDMC also stated that the other three arms (trastuzumab alone, sequential trastuzumab/lapatinib arm and the combination arm) could continued as planned with no changes.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Neoplasms, Breast
Eligibility Criteria
Key Inclusion Criteria:
* Patients \>= 18 years of age with histologically confirmed, non-metastatic, operable and over expression/amplification of HER2 (3+ by IHC and/or FISH positive) primary breast cancer, treated with definitive surgery, with baseline LVEF \>= 50%, known hormone receptor status (ER/PgR or ER alone) and ECOG performance status =\< 1, were included.
* For Designs 1 and 2: Patients must have had received at least four cycles of an approved anthracycline-based (neo-) adjuvant chemotherapy regimen or a protocol specified exception.
* Approved, signed written informed consent obtained prior to any study specific screening procedures.
Key Exclusion Criteria:
* History of any prior (ipsi- and/or contralateral) invasive breast carcinoma, past (less than 10 years) or current history of malignant neoplasms, any clinically staged T4 tumor, or bilateral tumors.
* Concurrent anti-cancer treatment, except hormonal therapy or radiotherapy for the present breast cancer;
* Patients with positive or suspicious internal mammary nodes identified by sentinel node technique, which had not been irradiated or would not be irradiated, or patients with supraclavicular lymph node involvement.
* Any prior anti-HER therapy, which includes agents that target other members of the HER family of receptors, e.g. gefitinib (Iressa)
* (Neo-) or adjuvant chemotherapy using peripheral stem cell or bone marrow stem cell support;
* Serious cardiac illness or medical conditions.
* Any of the following abnormal laboratory tests immediately prior to randomization:
1. Serum total bilirubin \>1.5 x upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (\<2 x ULN) was allowed;
2. Alanine amino transferase (ALT) or aspartate amino transferase (AST) \>2.5 x ULN;
3. Alkaline phosphatase (ALP) \>2.5 x ULN;
4. Serum creatinine \>2.0 x ULN;
5. Total white blood cell count (WBC) \<2.5 x 10\^9/L;
6. Absolute neutrophil count \<1.5 x 10\^9/L;
7. Platelets \<100 x 10\^9/L.
* Women of childbearing potential and male patients with partners of childbearing potential, who are unable or unwilling to use adequate contraceptive measures during study treatment, and pregnant or lactating women.
* Concomitant use of CYP3A4 inhibitors or inducers.
* Patients \>= 18 years of age with histologically confirmed, non-metastatic, operable and over expression/amplification of HER2 (3+ by IHC and/or FISH positive) primary breast cancer, treated with definitive surgery, with baseline LVEF \>= 50%, known hormone receptor status (ER/PgR or ER alone) and ECOG performance status =\< 1, were included.
* For Designs 1 and 2: Patients must have had received at least four cycles of an approved anthracycline-based (neo-) adjuvant chemotherapy regimen or a protocol specified exception.
* Approved, signed written informed consent obtained prior to any study specific screening procedures.
Key Exclusion Criteria:
* History of any prior (ipsi- and/or contralateral) invasive breast carcinoma, past (less than 10 years) or current history of malignant neoplasms, any clinically staged T4 tumor, or bilateral tumors.
* Concurrent anti-cancer treatment, except hormonal therapy or radiotherapy for the present breast cancer;
* Patients with positive or suspicious internal mammary nodes identified by sentinel node technique, which had not been irradiated or would not be irradiated, or patients with supraclavicular lymph node involvement.
* Any prior anti-HER therapy, which includes agents that target other members of the HER family of receptors, e.g. gefitinib (Iressa)
* (Neo-) or adjuvant chemotherapy using peripheral stem cell or bone marrow stem cell support;
* Serious cardiac illness or medical conditions.
* Any of the following abnormal laboratory tests immediately prior to randomization:
1. Serum total bilirubin \>1.5 x upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (\<2 x ULN) was allowed;
2. Alanine amino transferase (ALT) or aspartate amino transferase (AST) \>2.5 x ULN;
3. Alkaline phosphatase (ALP) \>2.5 x ULN;
4. Serum creatinine \>2.0 x ULN;
5. Total white blood cell count (WBC) \<2.5 x 10\^9/L;
6. Absolute neutrophil count \<1.5 x 10\^9/L;
7. Platelets \<100 x 10\^9/L.
* Women of childbearing potential and male patients with partners of childbearing potential, who are unable or unwilling to use adequate contraceptive measures during study treatment, and pregnant or lactating women.
* Concomitant use of CYP3A4 inhibitors or inducers.
Inclusion Criteria
Inclusion Criteria:
* Patients \>= 18 years of age with histologically confirmed, non-metastatic, operable and over expression/amplification of HER2 (3+ by IHC and/or FISH positive) primary breast cancer, treated with definitive surgery, with baseline LVEF \>= 50%, known hormone receptor status (ER/PgR or ER alone) and ECOG performance status =\< 1, were included.
* For Designs 1 and 2: Patients must have had received at least four cycles of an approved anthracycline-based (neo-) adjuvant chemotherapy regimen or a protocol specified exception.
* Approved, signed written informed consent obtained prior to any study specific screening procedures.
* Patients \>= 18 years of age with histologically confirmed, non-metastatic, operable and over expression/amplification of HER2 (3+ by IHC and/or FISH positive) primary breast cancer, treated with definitive surgery, with baseline LVEF \>= 50%, known hormone receptor status (ER/PgR or ER alone) and ECOG performance status =\< 1, were included.
* For Designs 1 and 2: Patients must have had received at least four cycles of an approved anthracycline-based (neo-) adjuvant chemotherapy regimen or a protocol specified exception.
* Approved, signed written informed consent obtained prior to any study specific screening procedures.
Gender
All
Gender Based
false
Keywords
Adjuvant
ErbB2-overexpressing
Early stage breast cancer
HER2/neu gene amplified
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT00490139
Org Class
Industry
Org Full Name
Novartis
Org Study Id
EGF106708
Overall Status
Completed
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Randomised, Multi-centre, Open-label, Phase III Study of Adjuvant Lapatinib, Trastuzumab, Their Sequence and Their Combination in Patients With HER2/ErbB2 Positive Primary Breast Cancer
Primary Outcomes
Outcome Description
Disease-Free Survival (DFS) was defined as the interval between randomization and the date of first occurrence of disease recurrence (local, regional or distant), a contralateral invasive breast cancer, a second primary cancer or death without recurrence. Only deaths occurring in participants whose clinical follow-up was ongoing at the time of death and who had no recurrence, contralateral breast cancer (CBC) or second primary malignancy (SPM) reported prior to death were considered as death without recurrence. DFS was estimated using the Kaplan Meier method. The percentile data values presented here indicate the percentage (95, 90, 85, 80 and 75 percent) of participants who had disease free survival for the indicated years.
Outcome Measure
Disease-Free Survival (DFS) at the Primary Analysis
Outcome Time Frame
From randomization until the date of the first occurrence of disease recurrence, a contralateral invasive breast cancer, a second primary cancer, or death from any cause (median follow-up of 4.5 years)
Secondary Ids
Secondary Id
CLAP016B2301
Secondary Id
2006-000562-36
Secondary Outcomes
Outcome Description
Disease-Free Survival (DFS) was defined as the interval between randomization and the date of first occurrence of disease recurrence (local, regional or distant), a contralateral invasive breast cancer, a second primary cancer or death without recurrence. Only deaths occurring in participants whose clinical follow-up was ongoing at the time of death and who had no recurrence, contralateral breast cancer (CBC) or second primary malignancy (SPM) reported prior to death were considered as death without recurrence. DFS was estimated using the Kaplan Meier method. The percentile data values presented here indicate the percentage (95, 90, 85 and 80 percent) of participants who had disease free survival for the indicated years.
Outcome Time Frame
From randomization until the date of the first occurrence of disease recurrence, a contralateral invasive breast cancer, a second primary cancer, or death from any cause, assessed up to approximately 10 years
Outcome Measure
Disease-Free Survival (DFS) at the 10-Year Follow-Up
Outcome Description
Overall Survival (OS) was defined as the time from randomization until death due to any cause. Participants who had not died were censored at the last date they were known to be alive, or date of withdrawal of consent. OS was calculated in years as (date of death minus the date of randomization +1) divided by 365.25. The percentile data values presented here indicate the percentage (99, 98, 97, 96, 95 and 90 percent) of participants who survived for the indicated years.
Outcome Time Frame
From randomization until death due to any cause (median follow-up of 4.5 years)
Outcome Measure
Overall Survival (OS) at the Primary Analysis
Outcome Description
Overall Survival (OS) was defined as the time from randomization until death due to any cause. Participants who had not died were censored at the last date they were known to be alive, or date of withdrawal of consent. OS was calculated in years as (date of death minus the date of randomization +1) divided by 365.25. The percentile data values presented here indicate the percentage (99, 98, 95 and 90 percent) of participants who survived for the indicated years.
Outcome Time Frame
From randomization until death due to any cause, assessed up to approximately 10 years
Outcome Measure
Overall Survival (OS) at the 10-Year Follow-Up
Outcome Description
Time to Recurrence (TTR) was defined as the the time from randomization to breast cancer recurrence, ignoring second primary cancers (including contralateral breast cancers and non-breast second malignancies) and counting deaths without recurrence as a competing risk.
Outcome Time Frame
From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years
Outcome Measure
Analysis of Time to Recurrence (TTR)
Outcome Description
Time to Distant Recurrence (TTDR) was defined as the the time from randomization to first distant breast cancer recurrence, ignoring locoregional recurrences and second primary cancers, (including contralateral breast cancers and non-breast second malignancies ) and counting deaths without recurrence as a competing risk.
Outcome Time Frame
From randomization until the date of the first occurrence of distant recurrence, assessed up to approximately 10 years
Outcome Measure
Analysis of Time to Distant Recurrence (TTDR)
Outcome Description
Time to Central Nervous System (CNS) recurrence was defined as the time from randomization to first CNS recurrence. Both brain metastasis and meningitis carcinomatosa were considered.
Outcome Time Frame
From randomization until the first central nervous system recurrence, assessed up to approximately 10 years
Outcome Measure
Analysis of Time to Central Nervous System (CNS) Recurrence
Outcome Description
The cumulative incidence of brain metastases as the first site of breast cancer recurrence among treatment arms was assessed using a hierarchy of primary type and location of first DFS event in cases where more than one event was identified simultaneously. Because diagnostic procedures for different types of recurrence could not be performed on exactly the same day, any diagnoses noted within a two month (60 day) period of the first reported event was considered as identified simultaneously for purposes of defining the type of the first event and the date of event was be regarded as the earliest of the relevant events.
Outcome Time Frame
From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years
Outcome Measure
Cumulative Incidence of Brain Metastases
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Della Makower
Investigator Email
DMAKOWER@montefiore.org
Investigator Phone