Lapatinib in Combination With Weekly Paclitaxel in Patients With ErbB2 Amplified Advanced Gastric Cancer

GlaxoSmithKline273 enrolled

Overview

EGF104578 is two-part study (Pilot part/Randomized part).Pilot part is designed to find the optimal (best) doses of lapatinib and paclitaxel when given together,Randomized part is designed to evaluate the overall survival in patients receiving lapatinib and paclitaxel compared to patients receiving only paclitaxel.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

273

Conditions

Neoplasms, Gastrointestinal Tract

Interventions

LapatinibDRUG

6 pills at 250 mg each once daily

PaclitaxelDRUG

Infusion at 80 mg/m2 weekly

Eligibility

Sex: ALLMin age: 20 Years

Medical Language ↔ Plain English

Inclusion criteria: Specific Information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the investigational product that may impact subject eligibility is provided in the Investigator's Brochure (IB) Pilot Part Subjects eligible for enrollment in the Pilot Part of the study must meet all of the following criteria: * Signed informed consent * Male or female; ≥ 20 years (at the time of giving consent) * Any histologically or cytologically confirmed gastric carcinoma independent of tumor ErbB2 status * Subjects who have received one prior regimen for gastric carcinoma and developed disease progression or recurrence. The regimen must have contained 5-fluoropyrimidine and/or cisplatin * Left ventricular ejection fraction (LVEF) within institutional range of normal as measured by echocardiogram (ECHO). Multigated acquisition (MUGA) scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive (LVEF of ≥50% required if normal range of LVEF is not provided by institution) * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 * Able to swallow and retain oral medication * Women and men with potential to have children must be willing to practice acceptable methods of birth control during the study * Washout period from the prior last therapy as follows; Chemotherapy (except for agents below) 4 weeks (I.V) Chemotherapy (except for agents below) 2 weeks (P.O) Trastuzumab, Bevacizumab 4 weeks Mitomycin-C, nitrosourea 6 weeks Radiotherapy, Immunotherapy, Biologic therapy and Surgery (except for minor surgical procedure) 2 weeks * Willing to complete all screening assessments as outlined in the protocol * Adequate organ function as defined in Table 2 Baseline Laboratory Values * Able to be hospitalized for PK analysis during cycle 1 * Life expectancy of at least 12 weeks from the first dose of study treatment) Randomized Part Subjects eligible for enrollment in the Randomized Part of the study must meet all of the following criteria: * Signed informed consent * Male or female; ≥ 20 years (at the time of giving consent) * Histologically or cytologically confirmed gastric carcinoma with documented amplification of ErbB2 by fluorescence in situ hybridization (FISH) in primary or metastatic tumor tissue * Subjects who received one prior regimen for gastric carcinoma and defined as progression disease. The regimen must be containing 5-fluoropyrimidine and/or cisplatin * Measurable lesion(s) according to RECIST (Response Evaluation Criteria in Solid Tumors) * Left ventricular ejection fraction (LVEF) within institutional range of normal as measured by echocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive (LVEF of ≥50% required if normal range of LVEF is not provided by institution) * ECOG Performance Status of 0 to 1 * Able to swallow and retain oral medication * Archived (or Biopsy ) tumor tissue available for FISH testing \[Wolff, 2007\] in central laboratory * Women and men with potential to have children must be willing to practice acceptable methods of birth control during the study * Washout period from the prior last therapy as follows; Chemotherapy (except for agents below) 4 weeks (IV) Chemotherapy (except for agents below) 2 weeks (P.O) Trastuzumab, Bevacizumab 4 weeks Mitomycin-C, nitrosourea 6 weeks Radiotherapy, Immunotherapy, Biologic therapy and Surgery (except for minor surgical procedure) 2 weeks * Willing to complete all screening assessments as outlined in the protocol * Adequate organ function as defined in Table 2 * Gastrectomy status depending on the result in the Pilot Part * Life expectancy of at least 12 weeks from the first dose of study treatment Table 2 Baseline Laboratory Values SYSTEM LABORATORY (VALUES) Hematologic: ANC (absolute neutrophil count) Hemoglobin: Platelets (≥ 2.0 × 10\^9/L) (≥ 9 g/dL) (≥ 100 × 10\^9/L) Hepatic Albumin Serum bilirubin AST and ALT (≥ 2.5 g/dL) (≤ 1.25 x ULN) (≤ 2.5 × ULN without liver metastases) (≤ 5 × ULN if documented liver metastases) Renal Serum Creatinine Calculate Creatinine Clearance (see Section 11.3) (≤ 2.0 mg/dL) \- OR - (≥30 mL/min) Exclusion criteria: Subjects meeting any of the following criteria must not be enrolled in the study: * Pregnant or lactating female at anytime during the study * Planned concurrent anti-cancer therapy (chemotherapy, radiotherapy, immunotherapy, biologic therapy, hormonal therapy) while taking investigational treatment * Unresolved or unstable, serious toxicity from prior cancer treatment (any toxicities greater than grade 2) * Peripheral neuropathy of Grade 2 or greater * Malabsorption syndrome, disease significantly affecting gastrointestinal function. Subjects with ulcerative colitis and Crohn's disease are also excluded * History of other malignancy. However, 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 * Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety * Life threatening infection * Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent * Known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure * Known history or clinical evidence of central nervous system (CNS) metastasis * Concurrent treatment with prohibited medications, including herbal remedies and Chinese traditional medicines * Concurrent treatment with an investigational agent within 28 days prior to the administration of paclitaxel and/or lapatinib * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to paclitaxel, including polyethoxylated castor oil, alcohol, or lapatinib or their excipients * Anamnesis or diagnosis of pulmonary disorder, such as interstitial pneumonia, pulmonary fibrosis or serious hypoxia * Gastrectomy surgery if Pilot Part of the study determines that partial gastrectomy (pylorus spared) or total/partial gastrectomy (pylorus removed) has a significant negative impact upon lapatinib PK and safety profile * Known history of use of any EGFR agent (except Trastuzumab) * Prior gastric cancer treatment which included a taxane.

Locations (17)

GSK Investigational Site

Guangzhou, Guangdong, China

GSK Investigational Site

Beijing, China

GSK Investigational Site

Outcomes

Primary Outcomes

Number of Participants With Dose Limiting Toxicities (DLTs) in the Pilot Part of the Study

DLTs consisted of only drug-related toxicities (neurologic and non-neurologic DLTs). A neurologic DLT was defined as grade 3/4 clinically significant peripheral motor and/or sensitive neuropathy. Non-neurologic DLTs mainly included the following: grade 3/4 clinically significant non-hematological toxicity (except nausea), grade 4 neutropenia lasting \>=7 days, thrombocytopenia (\<=25000 cells per cubic millimeter), inability to begin next treatment within 2 weeks of scheduled dosing due to unresolved toxicity, treatment delay (due to toxicity) of \>5 days, for Days 8 or 15 of weekly paclitaxel.

Time frame: 28 days

Overall Survival (OS) in the Randomized Part of the Study

OS was defined as the time from randomization until death due to any cause. For participants who did not die, time to death was censored at the time of last contact. For censored participants, time to death was defined as the time from randomization to the time of last contact.

Time frame: From randomization until death due to any cause (up to 42.58 months)

Secondary Outcomes

Maximum Plasma Concentration (Cmax) of Lapatinib in the Pilot Part of the Study

Pharmacokinetic (PK) samples were collected at pre-dose and at 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose on Days 8 and 14.

Time frame: Days 8 and 14

Time to Cmax (Tmax) of Lapatinib in the Pilot Part of the Study

PK samples were collected at pre-dose and at 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose on Days 8 and 14.

Time frame: Days 8 and 14

Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Lapatinib in the Pilot Part of the Study

PK samples were collected at pre-dose and at 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose on Days 8 and 14. AUC is defined as the area under the lapatinib concentration-time curve as a measure of drug exposure. AUC(0-24) is area under the plasma concentration-time curve from time 0 to 24 hours after oral adminisation.

Data from ClinicalTrials.gov

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GSK Investigational Site

Shanghai, China

GSK Investigational Site

Tokyo, Japan

GSK Investigational Site

Hwasun, South Korea

GSK Investigational Site

Seongnam-si Gyeonggi-do, South Korea

GSK Investigational Site

Seoul, South Korea

GSK Investigational Site

Seoul, South Korea

GSK Investigational Site

Seoul, South Korea

...and 7 more locations

Time frame: Days 8 and 14

Cmax of Paclitaxel in the Pilot Part of the Study

PK samples were collected just before the start of infusion and 0.5, 1.0 (immediately before terminating the infusion), 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose on Days 1 and 8.

Time frame: Days 1 and 8

Tmax of Paclitaxel in the Pilot Part of the Study

PK samples were collected just before the start of infusion and 0.5, 1.0 (immediately before terminating the infusion), 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose on Days 1 and 8.

Time frame: Days 1 and 8

AUC(0-24) of Paclitaxel in the Pilot Part of the Study

PK samples were collected just before the start of infusion and 0.5, 1.0 (immediately before terminating the infusion), 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose on Days 1 and 8. AUC is defined as the area under the paclitaxel concentration-time curve as a measure of drug exposure. AUC(0-24) is area under the plasma concentration-time curve from the start of infusion (time 0) to 24 hours after the start of the infusion.

Time frame: Days 1 and 8

Area Under the Concentration-time Curve From Time Zero to Infinity (AUC[0-inf]) of Paclitaxel in the Pilot Part of the Study

PK samples were collected just before the start of infusion and 0.5, 1.0 (immediately before terminating the infusion), 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose on Days 1 and 8. AUC is defined as the area under the paclitaxel concentration-time curve as a measure of drug exposure. AUC(0-inf) is area under the plasma concentration-time curve from the start of infusion (time 0) extrapolated to infinity.

Time frame: Days 1 and 8

Half-life of Paclitaxel in the Pilot Part of the Study

PK samples were collected just before the start of infusion and 0.5, 1.0 (immediately before terminating the infusion), 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose on Days 1 and 8. Half-life is defined as the time required for the amount of the drug in the plasma to decrease by half.

Time frame: Days 1 and 8

Clearance of Paclitaxel in the Pilot Part of the Study

PK samples were collected just before the start of infusion and 0.5, 1.0 (immediately before terminating the infusion), 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose on Days 1 and 8. Clearance is defined as the clearance of drug from plasma, which is defined as the volume of plasma from which drug is removed per unit time.

Time frame: Days 1 and 8

Distribution Volume at Steady State (Vss) of Paclitaxel in the Pilot Part of the Study

PK samples were collected just before the start of infusion and 0.5, 1.0 (immediately before terminating the infusion), 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose on Days 1 and 8. Vss is the volume of distribution at steady state of paclitaxel.

Time frame: Days 1 and 8

Progression-free Survival (PFS) in the Randomized Part of the Study

PFS was defined as the time from randomization until the earliest date of disease progression (PD) or death due to any cause. Per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions.

Time frame: From randomization until disease progression or death due to any cause (up to 42.35 months)

Time to Progression in the Randomized Part of the Study

Time to progression was defined as the time from randomization until the earliest date of disease progression or death due to disease. Per RECIST, version 1.0, PD is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions.

Time frame: From randomization until disease progression or death due to disease (up to 42.35 months )

Percentage of Participants With Overall Response in the Randomized Part of the Study

Overall response was defined as the percentage of participants achieving either complete response (CR) or partial response (PR). Per RECIST, version 1.0, CR was defined as the disappearance of all target lesions, and PR was defined as a greater than 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD.

Time frame: From randomization up to 5.62 months

Number of Participants With the Indicated Time to Response in the Randomized Part of the Study

Time to response was defined as the time from randomization to CR (the disappearance of all target lesions) or PR (a greater than 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD). For participants who did not achieve a CR or PR, time to response was censored at the last assessment prior to other cancer therapies. For censored participants, time to response was defined as the time from randomization to the time of the last assessment prior to the administation of other cancer therapies.

Time frame: up to 5.62 months

Duration of Response in the Randomized Part of the Study

Duration of response was defined as the time from the first documented evidence of CR (the disappearance of all target lesions) or PR (a greater than 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD) until the first documented sign of disease progression (at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions) or death due to any cause, if sooner.

Time frame: up to 18.27 months

Number of Participants With the Indicated Grade 3 and Grade 4 Adverse Events (AEs) for Which All Grades of the AE Were Reported in >=10% of Participants, Regardless of Causality in the Randomized Part of the Study

The Common Terminology Criteria for Advere Events (CTCAE) is a descriptive terminology that can be used for AE reporting. Grade (G) refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade (G) refers to the severity of the AE: G 1, mild AE; G 2, moderate AE; G 3, severe AE; G 4, life-threatening/disabling AE; G 5, death related to the AE.

Time frame: From the first dose of investigational product to 30 days after the last dose (up to 110.3 weeks in the Randomized part)

Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life (QOL) Questionnaire (EORTC QLQ-C30) Global Health Status (GHS)/QOL Score at the End of Therapy in the Randomized Part of the Study

The EORTC QLQ-C30 is a 30-item, self-reporting questionnaire assessing 15 domains (5 functional scales \[physical/role/emotional/cognitive/social\]; 9 symptom scales \[fatigue/nausea and vomiting/pain/dyspnea/insomnia/appetite loss/constipation/diarrhea/financial difficulties\]; GHS/QOL scale). Participants assessed most statements on a 4-point scale (1, not at all; 4, very much); two questions used a 7-item scale (1, poor; 7, excellent). Scores were averaged and transformed to a 0-100 scale. A high score indicates both a high/healthy level of functioning and a high level of symptoms/problems.