LOGiC - Lapatinib Optimization Study in ErbB2 (HER2) Positive Gastric Cancer: A Phase III Global, Blinded Study Designed to Evaluate Clinical Endpoints and Safety of Chemotherapy Plus Lapatinib

Novartis Pharmaceuticals545 enrolled

Overview

This was an international multi-center trial that enrolled patients with locally advanced, unresectable, or metastatic gastric, esophageal, or gastro-esophageal junction cancer whose tumors had amplification of the ErbB2 (HER2) gene. The trial investigated whether lapatinib, when added to the chemotherapy regimen, capecitabine plus oxaliplatin (CapeOx), extended the time to progression and overall survival. Tumor ErbB2 (HER2) status had to be known before trial entry. CapeOx was administered to all patients, and patients were randomly assigned to receive either lapatinib or placebo.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

545

Conditions

Neoplasms, Gastrointestinal Tract

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Key inclusion criteria: * Histologically confirmed gastric adenocarcinoma or adenocarcinoma of the esophagus or gastro-esophageal junction. * Gastric cancer that is unresectable due to locally advanced (defined as stage IV: T4N1-3 or TanyN3), metastatic, or locally recurrent disease; Esophageal cancer that is unresectable due to locally advanced (T3N1 or T4Nany), metastatic or locally recurrent disease. * Measurable or non-measurable, but radiologically evaluable disease, according to RECIST. * HER2 amplification by FISH assessed by the local or designated central laboratory; Subjects with unknown HER2 status were not eligible. * Adequate organ function, as defined in the study protocol, assessed within 14 days prior randomization. * Cardiac ejection fraction within institutional range of normal as measured by echocardiogram (ECHO). * Prior/Concurrent Therapy: * At least 3 weeks following major surgery, such as gastrectomy, and were recovered from any related toxicity More than 5 years since prior chemotherapy for malignancy other than GC. At least 4 weeks since prior radiotherapy * More than 5 years since prior biologic or hormonal therapy or immunotherapy for malignancy other than gastric carcinoma. Key exclusion criteria: * Pregnant or lactating females at any time during the study. * Known history of active CNS disease. * Uncontrolled ascites. * Concurrent anti-cancer therapy (chemotherapy, radiation therapy other than for pain relief, immunotherapy, biologic therapy, hormonal therapy or surgery) while taking investigational treatment. * Gastric carcinoid, epidermoid, sarcomas, or squamous cell carcinoma. * Prior palliative chemotherapy for the treatment of gastric cancer. * Prior treatment with oxaliplatin-based neoadjuvant or adjuvant chemotherapy completed \<12 months. * Malabsorption syndrome or uncontrolled inflammatory gastrointestinal disease (such as Crohn's disease or ulcerative colitis). * Known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure. * Uncontrolled infection. * History of other malignancy. However, subjects who were disease-free for 5 years, or subjects with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma, were eligible.

Locations (183)

Novartis Investigative Site

Alhambra, California, United States

Novartis Investigative Site

Fullerton, California, United States

Novartis Investigative Site

La Verne, California, United States

Novartis Investigative Site

Northridge, California, United States

Novartis Investigative Site

Oxnard, California, United States

Outcomes

Primary Outcomes

Overall Survival at the Time of Primary Analysis

Overall Survival was defined as the time from randomization to death from any cause. Participants who had not died were censored at their follow-up visit, either because follow-up had ended or was still ongoing.

Time frame: From date of randomization till death due to any cause, assessed up the cut-off date for Primary Analysis (24-Sep-2012) (average of 4 years)

Overall Survival in All Randomized Participants at the Time of Primary Analysis

Time frame: From date of randomization till death due to any cause, assessed up the cut-off date for Primary Analysis (24-Sep-2012) (average of 4 years)

Secondary Outcomes

Overall Survival at the Time of Final Analysis

Time frame: From date of randomization till death due to any cause, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Progression Free Survival (PFS)

Progression-Free Survival (PFS) was defined as the time from randomization to the earliest occurrence of disease progression or death from any cause. Per RECIST v1.0, progression was defined as at least a 20% increase in the sum of diameters of target lesions from the smallest recorded sum or the appearance of one or more new lesions. Participants with symptomatic progression, even without radiological confirmation, were also counted. Those who had neither progressed nor died were censored at their follow-up visit, either because follow-up had ended or was ongoing. Participants who received non-study anti-cancer therapies before progression were also censored.

Time frame: From date of randomization till the earliest date of disease progression or death due to any cause, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Percentage of Participants With a Confirmed Complete Response (CR) or a Partial Response (PR)

A participant was considered a responder if they had achieved either a complete response (CR), defined as the disappearance of all target and non-target lesions, or a partial response (PR), defined as at least a 30% reduction in the sum of the longest diameters of target lesions from baseline, as assessed by the investigator and confirmed by radiographic imaging within four weeks of the initial observation.

Time frame: From date of randomization till the date of the first documented response of CR or PR, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Percentage of Participants With Clinical Benefit (CB)

Clinical Benefit (CB) was defined as evidence of a complete response (CR), partial response (PR), or stable disease (SD). CR referred to the disappearance of all target and non-target lesions, PR to at least a 30% reduction in the sum of the longest diameters of target lesions from baseline, and SD to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progression, based on the smallest sum of diameters recorded since treatment initiation. All assessments were made by the investigator.

Time frame: From date of randomization till date of disease progression (PD) or death due to any cause, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Time to Response (TTR)

Time to Response (TTR) was defined as the duration from randomization to the first documented evidence of either a complete response (CR) (the disappearance of all target and non-target lesions) or a partial response (PR) (at least a 30% reduction in the sum of the longest diameters of target lesions from baseline) as assessed by the investigator.

Time frame: From date of randomization till the first documented evidence of confirmed CR or PR, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Duration of Response (DOR)

Duration of Response (DOR) was defined as the time from the first documented evidence of a complete response (CR) or partial response (PR) until the first recorded sign of disease progression or death from any cause. According to RECIST, progression was defined as at least a 20% increase in the sum of diameters of target lesions from the smallest recorded sum or the appearance of one or more new lesions. Participants who had neither progressed nor died were censored at their follow-up visit, either because follow-up had ended or was ongoing. Those who received non-study anti-cancer therapies before progression were also censored.

Time frame: From the time of the first documented evidence of a confirmed CR or PR until the earliest date of disease progression or death due to any cause, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Percentage of Participants With Any On-therapy Adverse Event (AE) and Serious Adverse Event (SAE)

An Adverse Event (AE) was defined as any untoward medical occurrence in a participant that was temporally associated with the use of a medicinal product, regardless of its causal relationship. This included any unfavorable or unintended sign (such as abnormal lab findings), symptom, or disease, whether new or worsened. A Serious Adverse Event (SAE) was defined as any such occurrence that, at any dose, resulted in death, was life-threatening, required hospitalization or its prolongation, caused disability or incapacity, led to a congenital anomaly or birth defect, or was a potential case of drug-induced liver injury.

Time frame: From the first dose of study medication until 30 days after the last dose, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Percentage of Participants With On-therapy Adverse Event (AE) by Maximum Grade

An Adverse Event (AE) was defined as any untoward medical occurrence in a participant that was temporally associated with the use of a medicinal product, regardless of its relationship to the product. This included any unfavorable or unintended sign (such as abnormal lab results), symptom, or disease, whether new or worsened. The severity of AEs was graded according to NCI CTCAE version 3.0: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), and Grade 5 (death related to toxicity).

Time frame: From the first dose of study medication until 30 days after the last dose, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Percentage of Participants With On-therapy Serious Adverse Event (SAE) by Maximum Grade

A Serious Adverse Event (SAE) was defined as any such occurrence that resulted in death, was life-threatening, required hospitalization or its prolongation, caused disability or incapacity, led to a congenital anomaly or birth defect, or was a potential case of drug-induced liver injury. The severity of SAEs was graded according to NCI CTCAE version 3.0: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), and Grade 5 (death related to toxicity).

Time frame: From the first dose of study medication until 30 days after the last dose, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores

The EORTC QLQ-C30 is a comprehensive questionnaire developed for assessing the quality of life of cancer patients across different aspects including function scales namely physical, role, cognitive, emotional and social; symptom scales such as fatigue, pain, nausea and vomiting; and a global scale pronouncing overall health status. Its scoring method involves a 4-point Likert scale (ranging from 1 'Not at all' to 4 'Very Much'). Domain scores are calculated by averaging the items within the respective domain and then linearly transforming the score to fit within a 0-100 scale to finalize the scores. In terms of interpretation, a high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.

Time frame: From Baseline up to disease progression (PD), assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Mean Change From Baseline in the EORTC Quality of Life (QOL) Questionnaire of Stomach 22 (QLQ-STO22) Scales/Items Score Scale

The QLQ-STO22 consists of 22 items divided into five subscales: dysphagia, pain, reflux, eating restrictions and anxiety, as well as single items addressing dry mouth, body image, taste, and hair loss. Each item is answered on a 4-point scale, ranging from 1 (not at all) to 4 (very much). Raw scores for each subscale or single item are calculated by averaging the scores of the individual items that make up the scale. These scores are then linearly transformed to range from 0 to 100. In terms of interpretation, a higher score indicates a worse quality of life concerning the specific symptoms assessed.

Time frame: From Baseline up to disease progression (PD), assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Mean Change From Baseline in Utility Score (Health Utility Index) in the EuroQoL-5 Dimensions (EQ-5D) Questionnaire

The EQ-5D is a standardized instrument developed by the EuroQoL Group to measure health-related quality of life. It includes a descriptive system covering five dimensions and a Visual Analogue Scale (VAS), often referred to as the Thermometer Score. The Utility Score (Health Utility Index) is derived from the five dimensions of the EQ-5D descriptive system (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has levels indicating severity (e.g., 1 = no problems, 2 = some problems, 3 = extreme problems). These combinations form a health state, which is then converted into a single index value using a country-specific value set. In the UK-based value set, the possible EQ-5D index utility values range from -0.594 to 1.0, where: 1.0 = perfect health, 0 = death and \< 0 = health states considered worse than death.

Time frame: From Baseline up to disease progression (PD), assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Mean Change From Baseline in Thermometer Score (EQ VAS) in the EuroQoL-5 Dimensions (EQ-5D) Questionnaire

The EQ-5D is a standardized instrument developed by the EuroQol Group to measure health-related quality of life. It includes a descriptive system covering five dimensions and a Visual Analogue Scale (VAS), often referred to as the Thermometer Score. The Thermometer Score is a self-rated health score using a vertical visual analogue scale , where respondents rate their overall health on a scale from 0 (worst imaginable health) to 100 (best imaginable health).

Time frame: From Baseline up to disease progression (PD), assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Percentage of Participants With Worst-case On-therapy Chemistry Toxicities

The severity of chemistry parameters was graded according to NCI CTCAE version 3.0: Grade 0 (No adverse event or within normal limits), Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (life-threatening). Chemistry data included: Alanine aminotransferase (ALT), Albumin, Alkaline phosphatases (ALP), Aspartate aminotransferase (AST), Calcium (hypercalcemia), Calcium (hypocalcemia), Creatine Kinase (CK), Creatine, Glucose (hyperglycemia), Glucose (hypoglycemia), Magnesium (hypermagnesemia), Magnesium (hypomagnesemia), Potassium (hyperkalemia), Potassium (hypokalemia), Sodium (hypernatremia), Sodium (hyponatremia) and Total Bilirubin.

Time frame: From the first dose of study medication until 30 days after the last dose, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Percentage of Participants With Worst-case On-therapy Hematologic Toxicities

The severity of hematologic parameters was graded according to NCI CTCAE version 3.0: Grade 0 (No adverse event or within normal limits), Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (life-threatening). Hematology data included: Hemoglobin, Platelet count, Total Neutrophils (Total ANC - Total Absolute Neutrophil Count) and White Blood Cell count.

Time frame: From the first dose of study medication until 30 days after the last dose, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)