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

Novartis

Status and phase: Completed; Phase 3

Conditions: Neoplasms, Breast

Treatments: Biological: Trastuzumab; Drug: Lapatinib

Study type: Interventional

Funder types: Other; NETWORK; Industry; NIH

Identifiers

NCT00490139

CLAP016B2301 (Other Identifier)

EGF106708

2006-000562-36 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 8,381 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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8,381 participants in 4 patient groups

Lapatinib plus Trastuzumab

Experimental group

Description:

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).

Treatment:

Drug: Lapatinib

Biological: Trastuzumab

Trastuzumab followed by Lapatinib

Experimental group

Description:

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).

Treatment:

Drug: Lapatinib

Biological: Trastuzumab

Lapatinib

Experimental group

Description:

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).

Treatment:

Drug: Lapatinib

Trastuzumab

Active Comparator group

Description:

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).

Treatment:

Biological: Trastuzumab