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

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

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.

Inclusion criteria

1. 18 years of age or older.

2. 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)

3. Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2.

4. Provided written informed consent.

5. Hemoglobin greater than or equal to 8 gm/dL (5 nmol/L), if clinically stable.

6. Absolute neutrophil count greater than or equal to 1,500/mm^3 (1.5 x 109/L).

7. Calculated creatinine clearance (CrCl) greater than or equal to 50 mls/min.

8. Total bilirubin less than or equal to 1.25 times the institutional upper limit of normal (ULN).

9. 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.

10. 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:

11. 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.

12. 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.

13. Platelet count greater than or equal to 75,000/mm^3 (75 x 109/L).

    Specific to Phase II:

14. Histologically-confirmed, measurable advanced or metastatic CRC previously untreated in the metastatic setting or more than 6 months post an oxaliplatin-containing adjuvant therapy.

15. Archived paraffin-embedded tumor tissue must be available for biomarker analysis.

16. Platelet count greater than or equal to 100,000/mm^3 (100 x 109/L).

Exclusion Critera:

1. Pregnant or lactating female.

2. Prior resection of the small bowel.

3. Brain metastases that require additional treatment.

4. Medically unfit for the study as a result of the medical interview, physical exam, or screening investigations.

5. Taking any medication on the prohibited medications list (see Section 9.2).

6. History of drug or other allergy, which, in the opinion of the Investigator, contraindicates participation.

7. 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.

8. 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.

9. Major surgery within the previous two weeks unless in the opinion of the Investigator, the subject has recovered sufficiently to begin study treatment.

10. Physiological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

11. 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.

12. History of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure.

13. Corrected QT interval (QTc) greater than 450 msecs.

    Specific to Phase I:

14. 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):

15. 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.