Study For Patients With Untreated Gastric Cancer Who Will Receive Capecitabine And Lapatinib

Study Overview
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Brief Summary
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The study will determine if changes in expression of markers involved in the 5-FU pathways are associated with response to treatment with the combination of lapatinib and capecitabine independent of tumor erbB2 status.

Official Title
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An Exploratory, Phase II Trial to Determine the Association of Lapatinib Induced Fluoropyrimidine Gene Changes With Efficacy Parameters of Lapatinib and Capecitabine in First Line Gastric Cancer

Conditions
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Neoplasms, Gastrointestinal Tract

Intervention / Treatment
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* Drug: Lapatinib and Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has signed inform consent Untreated, newly diagnosed, advanced metastatic or unresectable gastric cancer, including the gastro-esophageal junction Tumor accessible to and patient consent for endoscopic biopsy at study start and after 7 days of single agent Lapatinib Measurable disease according to RECIST criteria Male or female > or = 18 years of age Cardiac ejection fraction within the institutional range of normal as measured by echocardiogram must have adequate organ function as defined by baseline laboratory values Exclusion Criteria: Gastric carcinoid, sarcomas, or squamous cell cancer Pregnant or lactating females Intractable nausea, vomiting, or gastro intestinal obstruction requiring decompression and drainage with a gastric tube or nasogastric suction. patients who require continuous enteral feeding Malabsorption syndrome or uncontrolled inflammatory GI disease (Crohn's or ulcerative colitis Known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Lapatinib and Capecitabine|oral lapatinib (1250mg) administered as a monotherapy run-in followed by its combination with capecitabine|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Start of Run-in Period in Biomarker Expression Levels at Day 0 | Participants were analyzed for intratumoral expression levels of genes involved in the 5-fluorouracil (FU) pathway and lapatinib-targeted genes. Change in biomarker expression levels was calculated as the levels measured after the lapatinib Run-in Period (Baseline) of the study minus the levels measured at the start of monotherapy (Day -7). EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor. Data are presented as ratios of the normalized gene expression of the target gene to that of beta actin. | evaluated at baseline and after 7 days of study treatment | 
| Response Rate (Measured as the Percentage of Participants With Response [Complete Response or Partial Response]) | Response is defined as documented evidence of complete response (CR) or partial response (PR). The investigator evaluated response based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response is defined as the disappearance of all target lesions (TLs) and non-TLs and the appearance of no new lesions (NLs). Partial response for TLs is defined as >= a 30% decrease in the sum of the longest diameter (LD) of TLs, taking as a reference the Baseline sum LD. For non-TLs it is defined as the persistence of 1 or more non-TL and no new TLs or non-TLs. | From Baseline (Day 0) until disease progression or death due to any cause evaluated every 6 or 12 weeks (up to approximately 85 weeks) | 
| Percentage of Participants (Par.) With 5-month Progression-free Survival (PFS) | 5-month (mo.) PFS was defined as the percentage of par. who were alive/progression free for 5 months from the time of initial treatment. PFS is defined as the time from the initial treatment until the first observation of disease progression (DP)/death due to any cause; the percentage of par. whose follow-up ended or was ongoing was reported. DP is defined as symptomatic progression or the appearance of >=1 NL and/or unequivocal progression of existing non-TLs, and a >=20% increase in the sum of the LD of TLs, taking as a reference the smallest sum LD recorded since treatment started. | From initial treatment up to 24 weeks (next available assessment after the 5-month assessment for progressive disease) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | PFS is defined as the time from the initial treatment until the first observation of disease progression or death due to any cause. The date of documented disease progression was defined as the earliest date of radiographic disease assessment progression or symptomatic progression, whichever came first. For participants who did not die/progress, survival was censored at the time of the last assessment (or contact). | From Baseline (Day 0) until disease progression or death due to any cause (up to approximately 85 weeks) | 
| Overall Survival (OS) | Overall survival is defined as the time from the initial treatment until death due to any cause. A death occurring during the study is defined as a death occurring during treatment or within 30 days of the last administration of study medication. | From Baseline (Day 0) until death due to any cause evaluated at approximately 12 months (up to approximately 100 weeks) | 
| Time to Progression (All Deaths Are Treated as Competing Risk) | Time to progression is defined as the time from the initial treatment (first dose) until the first documented radiological symptomatic sign of disease progression. Time to progression data are presented as cumulative incidence estimate, which is defined as the time from the initial treatment until crude hazard probability of the occurrence of a particular event is reached to a particular point. All factors that hinder the observation of the event are defined as competing risks. | From Baseline (Day 0) until disease progression or death due to any cause (up to approximately 85 weeks) | 
| Time to Progression (All Deaths Due to Non-PD Are Treated as Competing Risk) | Time to progression is defined as the time from the initial treatment (first dose) until the first documented radiological symptomatic sign of disease progression. Time to progression data are presented as cumulative incidence estimate, which is defined as the time from the initial treatment until crude hazard probability of occurrence of a particular event is reached to a particular point. All factors that hinder the observation of the event are defined as competing risks. | From Baseline (Day 0) until disease progression or death due to any cause (up to approximately 85 weeks) | 
| Time to Response | Time to response is defined as the time from the initial treatment until the first documented evidence of CR (disappearance of all TLs and non-TLs and the appearance of no new lesions) or PR (>= a 30% decrease in the sum of the longest diameter of TLs, taking as reference the Baseline sum longest diameter) (whichever status was recorded first). Time to response data are presented as cumulative incidence estimate, which is defined as the time from the initial treatment until crude hazard probability of the occurrence of a particular event is reached to a particular point. | Baseline (Day 0) until first documented evidence of response (up to approximately 60 weeks) | 
| Duration of Response | Duration of response is defined as the time from the first documented evidence of tumor response (CR or PR) until the first documented sign of disease progression or death due to any cause, whichever came first. | From date of first documented evidence of response until the date of first documented sign of disease progression or death due to any cause (up to approximately 78 weeks) | 
| Number of Participants in the Indicated Categories for Best Overall Response (BOR) | Best overall response was evaluated by the investigator based on RECIST criteria: CR; PR; Stable Disease (SD), defined as no sufficient shrinkage to qualify for PR, no sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started; PD, defined as at least a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of >= 1 new lesions; Unknown, defined as participants who do not have CR, PR, SD, or PD. | From Baseline (Day 0) until disease progression or death due to any cause (up to approximately 85 weeks) | 
| Number of Participants With Change From Baseline (Measured as Any Grade Increase [AGI], Increase to Grade 3 [ItoG3], and Increase to Grade 4 [ItoG4]) in Toxicity Grades for Albumin at the Indicated Time Points | Toxicity was measured in grades (AE severity) per National Cancer Institute Common Toxicity Criteria for Adverse Event (NCI CTCAE) version (v) 3.0, displaying Grades (G) 1-5 with unique clinical descriptions of the severity of each AE. For albumin (per blood samples): G 1 (<lower limit of normal [LLN] to 3 grams per deciliter [g/dL]), mild; G 2 (<3 to 2 g/dL), moderate; G 3 (<2 g/dL), severe; G 4 (value not available), life threatening/disabling; G 5 (death), death related to AE. Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 
| Number of Participants With Change From Baseline (Measured as AGI, ItoG3, and ItoG4) in Toxicity Grades for Alkaline Phosphatase (ALP) at the Indicated Time Points | Toxicity was measured in grades (AE severity) per NCI CTCAE, v3.0, displaying Grades (G) 1-5 with unique clinical descriptions of the severity of each AE. For ALP: G 1 (upper limit of normal [ULN] to 2.5x ULN), mild; G 2 (>2.5 to 5.0x ULN), moderate; G 3 (>5.0 to 20.0x ULN), severe; G 4 (>20.0x ULN), life threatening/disabling; G 5 (value not available), death related to AE. Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 
| Number of Participants With Change From Baseline (Measured as AGI, ItoG3, and ItoG4) in Toxicity Grades for Aspartate Aminotransferase (AST) at the Indicated Time Points | Blood samples were collected for the evaluation of AST. Toxicity was measured in grades (AE severity) per NCI CTCAE, v3.0, displaying Grades (G) 1-5 with unique clinical descriptions of the severity of each AE. For AST: G 1 (>ULN to 2.5x ULN), mild; G 2 (>2.5 to 5.0x ULN), moderate; G 3 (>5.0 to 20.0x ULN), severe; G 4 (>20.0x ULN), life threatening/disabling; G 5 (value not available), death related to AE. Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 
| Number of Participants With Change From Baseline (Measured as AGI, ItoG3, and ItoG4 ) in Toxicity Grades for Alanine Aminotransferase (ALT) at the Indicated Time Points | Blood samples were collected for the evaluation of ALT. Toxicity was measured in grades (AE severity) per NCI CTCAE, v3.0, displaying Grades (G) 1-5 with unique clinical descriptions of the severity of each AE. For ALT: G 1 (>ULN to 2.5x ULN), mild; G 2 (>2.5 to 5.0x ULN), moderate; G 3 (>5.0 to 20.0x ULN), severe; G 4 (>20.0x ULN), life threatening/disabling; G 5 (value not available), death related to AE. Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 
| Number of Participants With Change From Baseline (Measured as AGI, ItoG3, and ItoG4) in Toxicity Grades for Total Bilirubin at the Indicated Time Points | Blood samples were collected for the evaluation of total bilirubin. Toxicity was measured in grades (AE severity) per NCI CTCAE, v3.0, displaying Grades (G) 1-5 with unique clinical descriptions of the severity of each AE. For total bilirubin: G 1 (>ULN to 1.5x ULN), mild; G 2 (>1.5 to 3.0x ULN), moderate; G 3 (>3.0 to 10.0x ULN), severe; G 4 (>10.0x ULN), life threatening/disabling; G 5 (value not available), death related to AE. Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 
| Number of Participants With Change From Baseline (Measured as AGI, ItoG3, and ItoG4) in Toxicity Grades for Calcium at the Indicated Time Points | Blood samples were collected for calcium evaluation. Toxicity was measured in grades (AE severity) per NCI CTCAE, v3.0, displaying Grades (G) 1-5 with unique clinical descriptions of the severity of each AE. For calcium (low and high, respectively): G 1 (<LLN to 8.0 mg/dL; >ULN to 11.5x ULN), mild; G 2 (<8.0 to 7.0 mg/dL; >11.5 to 12.5 ULN), moderate; G 3 (<7.0 to 6.0 mg/dL; >12.5 to 13.5 mg/dL), severe; G 4 (<6 mg/dL; >13.5 mg/dL), life threatening/disabling; G 5 (death), death related to AE. Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 
| Number of Participants With Change From Baseline (Measured as AGI, ItoG3, and ItoG4) in Toxicity Grades for Creatinine at the Indicated Time Points | Blood samples were collected for the evaluation of creatinine. Toxicity was measured in grades (AE severity) per NCI CTCAE, v3.0, displaying Grades (G) 1-5 with unique clinical descriptions of the severity of each AE. For creatinine: G 1 (>ULN to 1.5x ULN), mild; G 2 (>1.5 to 3.0x ULN), moderate; G 3 (>3.0 to 6.0x ULN), severe; G 4 (>6.0x ULN), life threatening/disabling; G 5 (death), death related to AE. Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 
| Number of Participants With Change From Baseline (Measured as AGI, ItoG3, and ItoG4) in Toxicity Grades for Glucose at the Indicated Time Points | Blood samples were collected for the evaluation of glucose. Toxicity was measured in grades (AE severity) per NCI CTCAE, v3.0, displaying Grades (G) 1-5 with unique clinical descriptions of the severity of each AE. For glucose (high and low, respectively): G 1 (>ULN to 160 mg/dL; <LLN to 55 mg/dL), mild; G 2 (>160 to 250 mg/dL; <55 to 40 mg/dL), moderate; G 3 (>250 to 500 mg/dL; <40 to 30 mg/dL), severe; G 4 (>500 mg/dL; <30 mg/dL), life threatening/disabling; G 5 (death), death related to AE. Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 
| Number of Participants With Change From Baseline (Measured as AGI, ItoG3, and ItoG4) in Toxicity Grades for Potassium at the Indicated Time Points | Toxicity was measured in grades (AE severity) per NCI CTCAE, v3.0, displaying Grades (G) 1-5 with unique clinical descriptions of the severity of each AE. For potassium (high and low [per blood samples], respectively): G 1 (>ULN to 5.5 millimoles per liter [mmol/L]; <LLN to 3.0 mmol/L), mild; G 2 (>5.5 to 6.0 mmol/L; value not available), moderate; G 3 (>6.0 to 7.0 mmol/L; <3.0 to 2.5 mmol/L), severe; G 4 (>7.0 mmol/L; <2.5 mmol/L), life threatening/disabling; G 5 (death), death related to AE. Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 
| Number of Participants With Change From Baseline (Measured as AGI, ItoG3, and ItoG4) in Toxicity Grades for Magnesium at the Indicated Time Points | Blood samples were collected for magnesium evaluation. Toxicity was measured in grades (AE severity) per NCI CTCAE, v3.0, displaying Grades (G) 1-5 with unique clinical descriptions of the severity of each AE. For magnesium (high and low, respectively): G 1 (>ULN to 3.0 mg/dL; <LLN to 1.2 mg/dL), mild; G 2 (value not available; <1.2 to 0.9 mg/dL), moderate; G 3 (>3.0 to 8.0 mg/dL; <0.9 to 0.7 mg/dL), severe; G 4 (>8.0 mg/dL; <0.7 mg/dL), life threatening/disabling; G 5 (death), death related to AE. Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 
| Number of Participants With Change From Baseline (Measured as AGI, ItoG3, and ItoG4) in Toxicity Grades for Sodium at the Indicated Time Points | Blood samples were collected for sodium evaluation. Toxicity was measured in grades (AE severity) per NCI CTCAE, v3.0, displaying Grades (G) 1-5 with unique clinical descriptions of each AE severity. For sodium (high and low, respectively): G 1 (>ULN to 150 mmol/L; <LLN to 130 mmol/L), mild; G 2 (>150 to 155 mmol/L; value not available), moderate; G 3 (>155 to 160 mmol/L; <130 to 120 mmol/L), severe; G 4 (>160 mmol/L; <120 mmol/L), life threatening/disabling; G 5 (death), death related to AE. Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 
| Number of Participants With Change From Baseline (Measured as AGI, ItoG3, and ItoG4) in Toxicity Grades for Hemoglobin at the Indicated Time Points | Blood samples were collected for the evaluation of hemoglobin. Toxicity was measured in grades (AE severity) per NCI CTCAE, v3.0, displaying Grades (G) 1-5 with unique clinical descriptions of the severity of each AE. For hemoglobin: G 1 (<LLN to 10 g/dL), mild; G 2 (<10.0 to 8.0 g/dL), moderate; G 3 (<8.0 to 6.5 g/dL), severe; G 4 (<6.5 g/dL), life threatening/disabling; G 5 (death), death related to AE. Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 
| Number of Participants With Change From Baseline (Measured as AGI, ItoG3, and ItoG4) in Toxicity Grades for Lymphocytes at the Indicated Time Points | Blood samples were collected for the evaluation of lymphocytes. Toxicity was measured in grades (AE severity) per NCI CTCAE, v3.0, displaying Grades (G) 1-5 with unique clinical descriptions of the severity of each AE. For lymphocytes: G 1, mild; G 2, moderate; G 3, severe; G 4, life threatening/disabling; G 5, death related to AE; ranges were provided by local laboratories. Change from Baseline was measured as any grade increase (AGI), increase to G 3 (ItoG3), and increase to G 4 (ItoG4). Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 
| Number of Participants With Change From Baseline (Measured as AGI, ItoG3, and ItoG4) in Toxicity Grades for Total Neutrophils at the Indicated Time Points | Blood samples were collected for the evaluation of total neutrophils. Toxicity was measured in grades (AE severity) per NCI CTCAE, v3.0, displaying Grades (G) 1-5 with unique clinical descriptions of the severity of each AE. For neutrophils: G 1 (<LLN to 1500/millimeters cubed [mm^3] of blood plasma [bp]), mild; G 2 (<1500 to 1000/mm^3 of bp), moderate; G 3 (<1000 to 500/mm^3 of bp), severe; G 4 (<500/mm^3 of bp), life threatening/disabling; G 5 (death), death related to AE. Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 
| Number of Participants With Change From Baseline (Measured as AGI, ItoG3, and ItoG4) in Toxicity Grades for Platelet Count at the Indicated Time Points | Blood samples were collected for the evaluation of platelet count. Toxicity was measured in grades (AE severity) per NCI CTCAE, v3.0, displaying Grades (G) 1-5 with unique clinical descriptions of the severity of each AE. For platelet count: G 1 (<LLN to 75000/mm^3 of blood plasma [bp]), mild; G 2 (<75000 to 50000/mm^3 of bp), moderate; G 3 (<50000 to 25000/mm^3 of bp), severe; G 4 (<25000/mm^3 of bp), life threatening/disabling; G 5 (death), death related to AE. Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 
| Number of Participants With Change From Baseline (Measured as AGI, ItoG3, and ItoG4) in Toxicity Grades for White Blood Cell (WBC) Count at the Indicated Time Points | Blood samples were collected for the evaluation of WBC count. Toxicity was measured in grades (AE severity) per NCI CTCAE, v3.0, displaying Grades (G) 1-5 with unique clinical descriptions of the severity of each AE. For WBCs: G 1 (<LLN to 3000/mm^3 of blood plasma [bp]), mild; G 2 (<3000 to 2000/mm^3 of bp), moderate; G 3 (<2000 to 1000/mm^3 of bp), severe; G 4 (<1000/mm^3 of bp), life threatening/disabling; G 5 (death), death related to AE. Worst-case on-therapy reflects the most severe change at any time point measured post treatment. | Baseline (Day 0); Weeks 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, and 84; withdrawal (WD)/study conclusion (up to approximately 87 weeks); and worst-case on-therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tumor biopsy, capecitabine, first line, Gastro Esophageal (GE) Junction Cancer, Gastric cancer, newly diagnosed, GE junction, lapatinib, metastatic or unresectable