Phase I/II Study of Lapatinib in Combination With Oxaliplatin and Capecitabine in Subjects With Advanced Colorectal Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine the highest, tolerated dose level and safety of lapatinib, capecitabine and oxaliplatin in subjects with advanced cancer and to determine the clinical activity of the combination of drugs in subjects with previously untreated advanced or metastatic colorectal cancer.

Official Title
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A Phase I/II Study of Lapatinib in Combination With Oxaliplatin and Capecitabine in Subjects With Advanced or Metastatic Colorectal Cancer

Conditions
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Neoplasms, Colorectal

Intervention / Treatment
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* Drug: lapatinib
* Drug: oxaliplatin
* Drug: capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria 18 years of age or older. A female is eligible to enter and participate in the study if she is of: Non-child-bearing potential (i.e., physiologically incapable of becoming pregnant), including any female who: Has had a hysterectomy, or Has had a bilateral oophorectomy (ovariectomy), or Has had a bilateral tubal ligation, or Is considered post-menopausal (defined as amenorrheic for greater than or equal to 1 year). Childbearing potential, has a negative serum pregnancy test at Screening and agrees to one of the following from 2 weeks prior to enrolment and continue through the post-study visit: Complete abstinence from sexual intercourse Oral Contraceptive, either combined or progestogen alone (must use a back up method, if have taken for less than 3 cycles) Injectable progestogen Implants of levonorgestrel Estrogenic vaginal ring Percutaneous contraceptive patches Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject Double barrier method: condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2. Provided written informed consent. Hemoglobin greater than or equal to 8 gm/dL (5 nmol/L), if clinically stable. Absolute neutrophil count greater than or equal to 1,500/mm^3 (1.5 x 109/L). Calculated creatinine clearance (CrCl) greater than or equal to 50 mls/min. Total bilirubin less than or equal to 1.25 times the institutional upper limit of normal (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 2 times the ULN. For subjects with liver metastases: AST or ALT less than or equal to 5 times the ULN. LVEF greater than or equal to 50% or greater than or equal to LLN for the institution based on multiple gated acquisition scan (MUGA) or echocardiogram (ECHO). Specific to Phase I: Recurrent, advanced, or metastatic cancer that is known to be potentially responsive to treatment with fluoropyrimidines or oxaliplatin. Examples include gastrointestinal tumors, HER2 (ErbB2)-positive breast cancer, and lung cancers. Received less than or equal to 3 prior chemotherapy regimens without pelvic radiotherapy or less than or equal to 2 prior chemotherapy regimens if received pelvic radiotherapy. Platelet count greater than or equal to 75,000/mm^3 (75 x 109/L). Specific to Phase II: Histologically-confirmed, measurable advanced or metastatic CRC previously untreated in the metastatic setting or more than 6 months post an oxaliplatin-containing adjuvant therapy. Archived paraffin-embedded tumor tissue must be available for biomarker analysis. Platelet count greater than or equal to 100,000/mm^3 (100 x 109/L). Exclusion Critera: Pregnant or lactating female. Prior resection of the small bowel. Brain metastases that require additional treatment. Medically unfit for the study as a result of the medical interview, physical exam, or screening investigations. Taking any medication on the prohibited medications list (see Section 9.2). History of drug or other allergy, which, in the opinion of the Investigator, contraindicates participation. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs. These include other anilinoquinazolines, such as gefitinib [Iressa], or erlotinib [Tarceva]. The subject has received treatment with any investigational drug in the previous four weeks. Treatment with any biologic, cytotoxic, radiation , or hormonal (other than for contraception or replacement) therapy within four weeks. Treatment with hormones with short half-lives is allowed up to 1 week prior to study treatment after consultation with GSK medical monitor. Major surgery within the previous two weeks unless in the opinion of the Investigator, the subject has recovered sufficiently to begin study treatment. Physiological, familial, sociological, or geographical conditions that do not permit compliance with the protocol. Receiving concurrent coumadin therapy. Minidose coumadin for maintenance of catheters (0.5 to 1.0 mg/day), and other anticoagulation therapy are allowed on study. Subjects receiving minidose coumadin must have prothrombin time (PT) or International normalized ratio (INR) and partial thromboplastin time (PTT) within 1.2 times the ULN. History of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure. Corrected QT interval (QTc) greater than 450 msecs. Specific to Phase I: Residual chemotherapy related toxicity of greater than or equal to Grade 2 that is clinically felt likely to be exacerbated by the treatment regimen. Specific to Phase II (amendment written after the completion of Phase 1): Have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment.

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

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I<br>Dose escalation of lapatinib along with capecitabine and oxaliplatin until the maximum tolerated dose is reached. | Drug: oxaliplatin<br>* Day one of each cycle<br>|
| Experimental: Phase II<br>Treatinng subjects at the maximum tolerated dose of lapatinib, capecitabine, and oxaliplatin | Drug: lapatinib<br>* onced daily Days 1-21<br>Drug: oxaliplatin<br>* Day one of each cycle<br>Drug: capecitabine<br>* given BID days 1-14<br>* Other names: oxaliplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response in Phase II | The overall response is defined as the number of participants whose tumor response was classified as a complete response (CR; disappearance of all target lesions) or partial response (PR; 30% decrease in the sum of the longest diameter of target lesions) per Response Evaluation Criteria in Solid Tumors. Response was measured for participants in Phase II only. To determine response, radiographic images were taken at baseline, 8 weeks, and every 8 weeks thereafter until the participant withdrew from the study. | Baseline to response (up to 135 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relationship Between Pretreatment Plasma TS mRNA and Pretreatment Tumor TS mRNA in Colon Tumor Biopsies. | Exploring if there is an association with a reduction in thymidylate synthase (TS) gene expression in both plasma and tumor prior to treatment and increased sensitivity in clinical activity. This analysis was not completed due to the study being closed early and the small number of participants enrolled in Phase II. | Plasma TS mRNA is collected at screening. Pre-treatment tumor sample can be archived tissue if collected within 5 years from screening; if not, tumor sample should be collected at screening. | 
| Effect of Lapatinib, Oxaliplatin, and Capecitabine on Plasma TS mRNA and the Relationship Between Plasma TS mRNA and Clinical Response | A possible association between a reduction in thymidylate synthase (TS) gene expression and increased sensitivity in clinical activity was to be explored. This analysis was not completed due to the study being closed early and the small number of participants enrolled in Phase II. | Blood samples were collected to determine TS levels at screening phase; Days 43 and 85; after every 2 cycles of treatment (+/- 3 days); and at discontinuation (if possible). | 
| Tumor-derived Biomarkers (Encoded in Protein or RNA) Associated With Clinical Outcome to Treatment | Exploring tumor-derived biomarkers including TS, DPD, TP, EGFR (ErbB1), and additional downstream markers involved in the mechanism of action of each compound (e.g., ERCC1) and comparison to clinical response. This analysis was not completed due to the study being closed early and the small number of participants enrolled in Phase II. | Pre-treatment tumor sample should have been provided for the most recent biopsy (not older than 5 years) prior to dosing. The post-treatment sample is suggested, not mandatory, and should have been collected at 43 +/-3 days. | 
| Genetic Aberrations in Somatic (Tumor) DNA Derived From the Tumor Tissue Biopsies That May Associate With Clinical Outcomes in Response to Therapy | DNA sequencing was done to identify genetic aberrations in somatic (tumor) DNA that may associate with clinical outcomes in response to therapy. This analysis was not completed due to the study being closed early and the small number of participants enrolled in Phase II. | Pre-treatment tumor sample should have been provided for the most recent biopsy (not older than 5 years) prior to dosing. The post-treatment sample is suggested, not mandatory, and should have been collected at end of Cycle 2, +/-3 days from Cycle 3. | 
| Genetic Variants in Germline (Host) DNA and Comparison to the Efficacy and Safety of the Study Drugs | This outcome measure was conducted to investigate a possible genetic relationship to handling or response to lapatinib, oxaliplatin, and capecitabine. This measure was not analyzed due to the small number of participants who signed the optional pharmacogenetics consent. | Optional pharmacogenetics sample may be collected at any time during the study after consent has been obtained; however, it is recommended that it be collected at the earliest time point possible | 
| Progression-free Survival (PFS) After Lapatinib, Oxaliplatin, and Capecitabine Administered at the MTD Level of Phase II | Both participants that entered Phase II of the study were censored for progression-free survival. Progression-free survival (PFS) is defined as the time from first dose until the first documented sign of disease progression or death due to any cause. For participants who do not progress or die, PFS was censored at the time of last radiological scan preceding the initiation of alternative anti-cancer therapy. Of the 2 participants in Phase II of the study, one discontinued due to adverse events, and the other was referred for a surgical resection. | Date of the first dose of study drug to the date of documented and confirmed progression by clinical, radiographic, or biochemical criteria, whichever occurred earliest, or to date of death due to any causes (up to 135 Days) | 
| Change From Baseline to Study Completion in Weight | Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline values to investigate what changes occurred. This analysis was not completed due to the study being closed early and the small number of participants enrolled in Phase II. | Baseline to study completion (up to 135 days) | 
| Change From Baseline to Study Completion in Heart Rate | Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline values to investigate what changes occurred. This analysis was not completed due to the study being closed early and the small number of participants enrolled in Phase II. | Baseline to study completion (up to 135 days) | 
| Change From Baseline to Study Completion in Blood Pressure | Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline values to investigate what changes occurred. This analysis was not completed due to the study being closed early and the small number of participants enrolled in Phase II. | Baseline to study completion (up to 135 days) | 
| Change From Baseline to Study Completion in Hemoglobin and Neutrophils | Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline values to investigate what changes occurred. This analysis was not completed due to the study being closed early and the small number of participants enrolled in Phase II. | Baseline to study completion (up to 135 days) | 
| Change From Baseline to Study Completion in White Blood Cells and Platelets | Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline values to investigate what changes occurred. This analysis was not completed due to the study being closed early and the small number of participants enrolled in Phase II. | Baseline to study completion (up to 135 days) | 
| Change From Baseline to Study Completion in Prothrombin Time and Partial Thromboplastin Time | Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline values to investigate what changes occurred. This analysis was not completed due to the study being closed early and the small number of participants enrolled in Phase II. | Baseline to study completion (up to 135 days) | 
| Change From Baseline to Study Completion in International Normalized Ratio | Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline values to investigate what changes occurred. This analysis was not completed due to the study being closed early and the small number of participants enrolled in Phase II. | Baseline to study completion (up to 135 days) | 
| Change From Baseline to Study Completion in Sodium, Potassium, and Calcium | Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline values to investigate what changes occurred. This analysis was not completed due to the study being closed early and the small number of participants enrolled in Phase II. | Baseline to study completion (up to 135 days) | 
| Change From Baseline to Study Completion in Creatinine, Total Bilirubin, and Direct Bilirubin | Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline values to investigate what changes occurred. This analysis was not completed due to the study being closed early and the small number of participants enrolled in Phase II. | Baseline to study completion (up to 135 days) | 
| Change From Baseline to Study Completion in Creatinine Clearance | Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline values to investigate what changes occurred. This analysis was not completed due to the study being closed early and the small number of participants enrolled in Phase II. | Baseline to study completion (up to 135 days) | 
| Change From Baseline to Study Completion in Aspartate Aminotransferase, Alanine Aminotranferease, and Alkaline Phosphatase | Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline values to investigate what changes occurred. This analysis was not completed due to the study being closed early and the small number of participants enrolled in Phase II. | Baseline to study completion (up to 135 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Colorectal Cancer, oxaliplatin, fluoropyrimidines cancers, Advanced Colorectal Cancer, capecitabine, lapatinib