• Exam, vital signs, & labs: [ Time Frame: screening, Day(D) 1 of each cycle, & follow-up (f/u). ]
• Phone call [ Time Frame: D2 & 3 of Cycle 1 ]
• 12-lead ECG: [ Time Frame: screening & f/u ]
• ECHOG/MUGA: [ Time Frame: screening, D1 of Cycle 5, w/in 7 days of next cycle & f/u ]
• Pre-treatment plasma TS mRNA and pretreatment tumor TS mRNA in colon tumor biopsies.
• Plasma TS mRNA and comparison of plasma TS mRNA to clinical response.
• 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.
• Genetic aberrations in somatic (tumor) DNA.
• PGx (Part 1 and Part 2): Genetic variants in germline (host) DNA and comparison to the efficacy and safety of the study drugs.

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.

• Advanced Colorectal Cancer
• Metastatic Colorectal Cancer
• Responsive to Fluoropyrimidines

• Drug: lapatinib
• Drug: oxaliplatin
• Drug: capecitabine

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 at least 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 not more than 2.
• Provided written informed consent.
• Clinical lab results with ranges as stated within the protocol.

Specific to Part 1:

• 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 not more than three prior chemotherapy regimens without pelvic radiotherapy or not more than two prior chemotherapy regimens if received pelvic radiotherapy.
• Platelet count of at least 75,000/mm3 (75 x 109/L).

Exclusion criteria:

• 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 as per protocol.
• 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) 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) > 450 msecs.