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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00536809
First received: September 27, 2007
Last updated: March 15, 2012
Last verified: February 2011
  Purpose

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.


Condition Intervention Phase
Metastatic Colorectal Cancer
Responsive to Fluoropyrimidines
Advanced Colorectal Cancer
Neoplasms, Colorectal
Drug: lapatinib
Drug: oxaliplatin
Drug: capecitabine
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Lapatinib in Combination With Oxaliplatin and Capecitabine in Subjects With Advanced or Metastatic Colorectal Cancer

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Overall Response in Phase II [ Time Frame: Baseline to response (up to 135 days) ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Relationship Between Pretreatment Plasma TS mRNA and Pretreatment Tumor TS mRNA in Colon Tumor Biopsies. [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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.

  • Effect of Lapatinib, Oxaliplatin, and Capecitabine on Plasma TS mRNA and the Relationship Between Plasma TS mRNA and Clinical Response [ Time Frame: 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). ] [ Designated as safety issue: No ]
    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.

  • Tumor-derived Biomarkers (Encoded in Protein or RNA) Associated With Clinical Outcome to Treatment [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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.

  • Genetic Aberrations in Somatic (Tumor) DNA Derived From the Tumor Tissue Biopsies That May Associate With Clinical Outcomes in Response to Therapy [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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.

  • Genetic Variants in Germline (Host) DNA and Comparison to the Efficacy and Safety of the Study Drugs [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Progression-free Survival (PFS) After Lapatinib, Oxaliplatin, and Capecitabine Administered at the MTD Level of Phase II [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline to Study Completion in Weight [ Time Frame: Baseline to study completion (up to 135 days) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline to Study Completion in Heart Rate [ Time Frame: Baseline to study completion (up to 135 days) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline to Study Completion in Blood Pressure [ Time Frame: Baseline to study completion (up to 135 days) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline to Study Completion in Hemoglobin and Neutrophils [ Time Frame: Baseline to study completion (up to 135 days) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline to Study Completion in White Blood Cells and Platelets [ Time Frame: Baseline to study completion (up to 135 days) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline to Study Completion in Prothrombin Time and Partial Thromboplastin Time [ Time Frame: Baseline to study completion (up to 135 days) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline to Study Completion in International Normalized Ratio [ Time Frame: Baseline to study completion (up to 135 days) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline to Study Completion in Sodium, Potassium, and Calcium [ Time Frame: Baseline to study completion (up to 135 days) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline to Study Completion in Creatinine, Total Bilirubin, and Direct Bilirubin [ Time Frame: Baseline to study completion (up to 135 days) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline to Study Completion in Creatinine Clearance [ Time Frame: Baseline to study completion (up to 135 days) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline to Study Completion in Aspartate Aminotransferase, Alanine Aminotranferease, and Alkaline Phosphatase [ Time Frame: Baseline to study completion (up to 135 days) ] [ Designated as safety issue: No ]
    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.


Enrollment: 12
Study Start Date: September 2007
Study Completion Date: November 2008
Primary Completion Date: October 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase I
Dose escalation of lapatinib along with capecitabine and oxaliplatin until the maximum tolerated dose is reached.
Drug: lapatinib
onced daily Days 1-21
Drug: oxaliplatin
Day one of each cycle
Drug: capecitabine
given BID days 1-14
Other Names:
  • lapatinib
  • capecitabine
  • oxaliplatin
Experimental: Phase II
Treatinng subjects at the maximum tolerated dose of lapatinib, capecitabine, and oxaliplatin
Drug: lapatinib
onced daily Days 1-21
Drug: oxaliplatin
Day one of each cycle
Drug: capecitabine
given BID days 1-14
Other Names:
  • lapatinib
  • capecitabine
  • oxaliplatin

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00536809

Locations
United States, Wisconsin
GSK Investigational Site
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided by GlaxoSmithKline

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00536809     History of Changes
Other Study ID Numbers: EGF108991
Study First Received: September 27, 2007
Results First Received: January 19, 2010
Last Updated: March 15, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
fluoropyrimidines cancers
Metastatic Colorectal Cancer
Advanced Colorectal Cancer
oxaliplatin
lapatinib
capecitabine

Additional relevant MeSH terms:
Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Oxaliplatin
Capecitabine
Lapatinib
Fluorouracil
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 28, 2014