ALTTO (Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation) Study; BIG 2-06/N063D

Phase 3

Completed

Conditions: Neoplasms, Breast

Interventions: Drug: Lapatinib
Biological: Trastuzumab

Registration Number: NCT00490139

Lead Sponsor: Novartis Pharmaceuticals

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 8381

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Lapatinib plus Trastuzumab	Lapatinib	Design 1: Oral lapatinib 1000 mg daily concurrent with trastuzumab 8 mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks (52 weeks total). Design 2: Trastuzumab (4mg/kg loading dose followed by 2mg/kg IV weekly) concurrent with oral lapatinib 750 mg daily and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles (12 weeks). After completion of chemotherapy, the dose of lapatinib will be increased to 1000mg daily concurrently with trastuzumab every 3 weeks (6mg/kg without loading dose) for an additional 40 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concurrently with oral lapatinib 750mg plus weekly trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV. After the completion of chemotherapy, trastuzumab will be administered every 3 weeks (6mg/kg without loading dose) concurrent with lapatinib 1000mg daily for an additional 40 weeks (52 weeks total).
Lapatinib plus Trastuzumab	Trastuzumab	Design 1: Oral lapatinib 1000 mg daily concurrent with trastuzumab 8 mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks (52 weeks total). Design 2: Trastuzumab (4mg/kg loading dose followed by 2mg/kg IV weekly) concurrent with oral lapatinib 750 mg daily and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles (12 weeks). After completion of chemotherapy, the dose of lapatinib will be increased to 1000mg daily concurrently with trastuzumab every 3 weeks (6mg/kg without loading dose) for an additional 40 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concurrently with oral lapatinib 750mg plus weekly trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV. After the completion of chemotherapy, trastuzumab will be administered every 3 weeks (6mg/kg without loading dose) concurrent with lapatinib 1000mg daily for an additional 40 weeks (52 weeks total).
Trastuzumab followed by Lapatinib	Lapatinib	Design 1: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total). Design 2: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks administered concomitantly and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles; followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) followed by a 6 week treatment-free interval followed by oral lapatinib 1500 mg daily for 28 weeks (52 weeks total).
Trastuzumab followed by Lapatinib	Trastuzumab	Design 1: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total). Design 2: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks administered concomitantly and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles; followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) followed by a 6 week treatment-free interval followed by oral lapatinib 1500 mg daily for 28 weeks (52 weeks total).
Lapatinib	Lapatinib	Design 1: Lapatinib 1500mg oral daily for a total of 52 weeks. Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with oral lapatinib at 750mg daily. After completion of chemotherapy, oral lapatinib administered at 1500mg daily for an additional 40 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with oral lapatinib at 750mg daily. After completion of chemotherapy, the dose of lapatinib will be increased to 1500mg oral daily for an additional 40 weeks (52 weeks total).
Trastuzumab	Trastuzumab	Design 1: Trastuzumab 8mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks for a total of 52 weeks. Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly. After completion of chemotherapy, trastuzumab administered every 3 weeks (6mg/kg IV without loading dose) for an additional 40 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly. After completion of chemotherapy, trastuzumab (6mg/kg without loading dose) every 3 weeks for an additional 40 weeks (52 weeks total).

Primary Outcome Measures

Name	Time	Method
Disease-Free Survival (DFS) at the Primary Analysis	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)	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.

Secondary Outcome Measures

Name	Time	Method
Disease-Free Survival (DFS) at the 10-Year Follow-Up	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	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.
Overall Survival (OS) at the Primary Analysis	From randomization until death due to any cause (median follow-up of 4.5 years)	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.
Overall Survival (OS) at the 10-Year Follow-Up	From randomization until death due to any cause, assessed up to approximately 10 years	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.
Analysis of Time to Recurrence (TTR)	From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years	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.
Analysis of Time to Distant Recurrence (TTDR)	From randomization until the date of the first occurrence of distant recurrence, assessed up to approximately 10 years	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.
Analysis of Time to Central Nervous System (CNS) Recurrence	From randomization until the first central nervous system recurrence, assessed up to approximately 10 years	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.
Cumulative Incidence of Brain Metastases	From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years	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.