Pazopanib Plus Lapatinib Compared To Lapatinib Alone In Subjects With Inflammatory Breast Cancer
Condition: Neoplasms, Breast
MeSH terms: Breast Neoplasms; Inflammatory Breast Neoplasms
Intervention: lapatinib; Pazopanib
Intervention description: Oral administration; Oral administration
Intervention MeSH terms: Lapatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 163.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: GW572016; Breast Cancer; RECIST; Inflammatory Breast Cancer; Pazopanib; ErbB2; Cutaneous Disease; Tykerb; Inflammatory; Skin; Her2; Lapatinib; GW786034

Summary:

      The double blind part of the study is being conducted to compare the efficacy and safety of
      pazopanib in combination with lapatinib with that of lapatinib alone in subjects with
      inflammatory breast cancer whose tumors overexpress the ErbB2 protein. There is also an
      Open-label pazopanib arm to this study designed to test whether pazopanib given alone and
      lapatinib given alone would be safe and effective to treat patients with inflammatory breast
      cancer.
    

Eligibility criteria:

        Inclusion criteria:

        Specific information regarding warnings, precautions, contraindications, adverse events,
        and other pertinent information on the investigational product that may impact patient
        eligibility is provided in the pazopanib IB and lapatinib prescribing information (or the
        lapatinib IB).

        For Cohort 1 of this study, eligible patients met inclusion criteria outlined in the
        original version of the protocol and protocol amendment 1.

        For Cohort 2 of this study, eligible patients must meet all of the following criteria:

          -  Patients must have evaluable Inflammatory Breast Cancer (IBC) substantiated by all of
             the following prior to randomization:

          -  History of invasive breast cancer documented by a biopsy and accompanying pathology
             report

          -  Current photographs* (global view and close-up views of all skin lesions) submitted at
             screening demonstrating unequivocal evidence of IBC as determined by either the
             medical monitor alone or in consultation with one or more of the study Principal
             Investigators.

          -  All patients must have photography at screening. Canfield Scientific Inc. will provide
             centralized monitoring, tracking, and collection of patients' photographs throughout
             the study. Screening photographs must be uploaded to the Canfield Scientific Inc
             website and approved by Canfield Scientific Inc, as the central photography vendor.
             The photographs, along with the completed Inflammatory Breast Cancer Skin Assessment
             Tool (IBSAT), must be reviewed and approved by GSK before a patient can be randomized.
             Sites should allow a minimum of 3 business days for this process. Sites submitting
             quality photographs and IBSATs on a regular basis will receive an exemption from this
             requirement for future patients.

          -  Patients with secondary IBC are eligible.

          -  Measurable lesions (cutaneous or radiographic) may be in the field of prior standard
             or palliative radiation therapy; however, there must be at least a 4 week period
             between the last radiation treatment and the baseline scan documenting disease status
             for the lesion to be measurable. If the irradiated lesion is the only site of disease,
             documented progression of the irradiated lesion is required.

          -  Disease progression or relapse following treatment for invasive breast cancer, which
             must have included a chemotherapy regimen. In regions where trastuzumab is available
             with no barriers to access*, patients must have received prior trastuzumab in addition
             to chemotherapy in order to be eligible. * (Barriers to access may include financial
             considerations.)

          -  Unequivocal ErbB2 overexpressing breast cancer, defined as 3+ staining by
             immunohistochemistry (IHC), or 2+ staining by IHC in conjunction with ErbB2 gene
             amplification by FISH/CISH, or ErbB2 gene amplification by FISH/CISH alone (in
             subjects whose tumor blocks were not assessed by IHC). ErbB2 gene amplification is
             defined by: > six (6) ErbB2 gene copies/nucleus for test systems without an internal
             control probe or an ErbB2/CEP 17 ratio of more than 2.2.

        Sites must submit a copy of the laboratory report demonstrating unequivocal ErbB2
        overexpression, if testing performed at a local laboratory, with the screening worksheet.
        Archived tumor must be provided for all patients for ErbB2 FISH testing by the central
        laboratory. Patients will remain on study based on local ErbB2 expression results. If
        archived tumor is not available, a biopsy must be obtained at screening and sent to TMD
        Laboratories for ErbB2 FISH testing.

        - Patients must provide written informed consent prior to performance of study-specific
        procedures or assessments, and must be willing to comply with treatment and follow up.
        Procedures conducted as part of the patient's routine clinical management (e.g., blood
        count, imaging study) and obtained prior to signing of informed consent may be utilized for
        screening or baseline purposes provided these procedures are conducted as specified in the
        protocol.

        Note: Informed consent may be obtained prior to the protocol-specified screening window
        (i.e. Day -14 to Day -1).

          -  Females age ≥ 18 years, except in Tunisia. In Tunisia, patients must be ≥ 20 years to
             be eligible for this study.

          -  Adequate organ function as defined below:

          -  System (Laboratory Values)

          -  Hematologic:Absolute neutrophil count (ANC)(≥ 1.5 X 10^9/L)Hemoglobin1(≥9
             g/dL)Platelets(≥100 X 10^9/L)International normalized ratio (INR)(≤ 1.2 X upper limit
             of normal (ULN))Partial thromboplastin time (PTT)(≤1.2 X ULN)

          -  Hepatic:Total bilirubin2 (≤ 1.5 X upper limit of normal (ULN))AST and ALT(≤ 2.5 X ULN)

          -  Renal:Serum Creatinine (≤ 1.5 mg/dL)Or, if serum creatinine >1.5 mg/dL,

          -  Calculated creatinine clearance(≥50 mL/min)

          -  Urine Protein to Creatinine Ratio(<1)

          -  Patients may not have had a transfusion within 7 days of screening assessment.

          -  Exception: Patients with elevated bilirubin levels due to Gilberts syndrome are
             eligible.

          -  Cardiac ejection fraction within the institutional range of normal as measured by
             echocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot be
             performed or is inconclusive or where MUGA scans are the accepted standard. Patients
             with known history of uncontrolled or symptomatic angina, arrhythmias, or congestive
             heart failure are not eligible.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

          -  A female is eligible to enter and participate in this study if she is of:

        Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
        including any female who has had:

          -  A hysterectomy

          -  A bilateral oophorectomy (ovariectomy)

          -  A bilateral tubal ligation

          -  Is post-menopausal

          -  Patients not using hormone replacement therapy (HRT) must have experienced total
             cessation of menses for ≥ 1 year and be greater than 45 years in age, OR, in
             questionable cases, have a follicle stimulating hormone (FSH) value >40 mIU/mL and an
             estradiol value < 40pg/mL (<140 pmol/L).

        Patients must discontinue HRT prior to study enrollment due to the potential for inhibition
        of CYP enzymes that metabolize estrogens and progestins (See Section 8). For most forms of
        HRT, at least 2-4 weeks must elapse between the cessation of HRT and determination of
        menopausal status; length of this interval depends on the type and dosage of HRT. If a
        female patient is determined not to be post-menopausal, they must use adequate
        contraception, as defined immediately below.

        Childbearing potential, including any female who has had a negative serum pregnancy test
        within 2 weeks prior to the first dose of study treatment, preferably as close to the first
        dose as possible, has used adequate contraception since the pregnancy test and agrees to
        use adequate contraception as described below. GSK acceptable contraceptive methods, when
        used consistently and in accordance with both the product label and the instructions of the
        physician, are as follow:

          -  An intrauterine device with a documented failure rate of less than 1% per year.

          -  Vasectomized partner who is sterile prior to the female patient's entry and is the
             sole sexual partner for that female.

          -  Complete abstinence from sexual intercourse for 14 days before exposure to
             investigational product, through the dosing period, and for at least 21 days after the
             last dose of investigational product.

          -  Double-barrier contraception (condom with spermicidal jelly, foam suppository, or
             film; diaphragm with spermicide; or male condom and diaphragm with spermicide).

        Note: Oral contraceptives are not reliable due to potential drug drug interactions.

        Female patients who are lactating should discontinue nursing prior to the first dose of
        investigational product and should refrain from nursing throughout the treatment period and
        for 14 days following the last dose of investigational product.

        - French patients: In France, a patient will be eligible for inclusion in this study only
        if either affiliated to or a beneficiary of a social security category.

        Exclusion Criteria:

          -  Patients meeting any of the following criteria must not be enrolled in the study:

          -  Treatment in the 14 days prior to randomization with any cancer therapy (tumor
             embolization, chemotherapy, immunotherapy, biological therapy, or hormonal therapy) or
             treatment with mitomycin within 6 weeks prior to randomization. Such treatment may not
             be resumed or begun after study entry. Note: Patients receiving LH-RH analogue therapy
             prior to the study may continue to receive LH-RH analogues for the duration of study
             participation. Bisphosphonates are permitted if started prior to Day 1.

          -  Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is
             progressing in severity (with the exception of alopecia).

          -  Prior lapatinib therapy or other Her2/ErbB2 targeted therapy (except trastuzumab).

          -  Prior therapy with an anti-VEGF antibody or other VEGF/VEGF-R targeted therapy.

          -  Use of an investigational agent, including an investigational anti-cancer agent,
             within 28 days or 5 half-lives, whichever is longer, prior to the first dose of
             investigational product.

          -  Use of any prohibited medication within the timeframes listed in Section 8.1.3

          -  History of another malignancy.

          -  Note: Subjects who have had another malignancy and have been disease-free for 5 years,
             or subjects with a history of completely resected non-melanomatous skin carcinoma or
             successfully treated in situ carcinoma are eligible. If subject previously had breast
             cancer, it must have been HER2+ with either 3+ overexpression by IHC or unequivocal
             HER2 gene amplification by FISH or CISH.

          -  History or clinical evidence of central nervous system (CNS) metastases or
             leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS
             metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure
             medication for 2 months prior to first dose of study drug. Screening with CNS imaging
             studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required
             only if clinically indicated or if the subject has a history of CNS metastases.

          -  Clinically significant gastrointestinal abnormalities that may increase the risk for
             GI bleeding including, but not limited to:

          -  Active peptic ulcer disease

          -  Known intraluminal metastatic lesion/s with suspected bleeding

          -  Inflammatory bowel disease

          -  Ulcerative colitis, or other gastrointestinal conditions with increased risk of
             perforation

          -  History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess
             within 28 days prior to beginning study treatment.

          -  Clinically significant gastrointestinal abnormalities that may affect absorption of
             investigational product including, but limited to:

          -  Malabsorption syndrome

          -  Major resection of the stomach or small bowel.

          -  Presence of uncontrolled infection.

          -  Prolongation of corrected QT interval (QTc) > 480 msecs.

          -  History of any one or more of the following cardiovascular conditions within the past
             6 months:

          -  Cardiac angioplasty or stenting

          -  Myocardial infarction

          -  Unstable angina

          -  Arterial thrombosis

          -  Symptomatic peripheral vascular disease

          -  Class III or IV congestive heart failure, as defined by the New York Heart Association
             (NYHA) (see Section 15.9 Appendix 9 for description).

          -  Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140mmHg
             or diastolic blood pressure (DBP) of ≥ 90mmHg].

        Note: Initiation or adjustment of antihypertensive medication(s) is permitted during the
        screening period, in order to control a patient's BP prior to randomization. Blood pressure
        must be re-assessed on two occasions that are separated by a minimum of 1 hour. The mean
        SBP / DBP values from each blood pressure assessment must be < 140/90mmHg in order for a
        patient to be eligible for the study. See Section 6.2 and Section 6.4.2 for details on
        blood pressure control and reassessment prior to study enrollment.

          -  History of cerebrovascular accident, including TIA, pulmonary embolism or deep venous
             thrombosis (DVT).

          -  Prior major surgery or trauma within 28 days prior to first dose of investigational
             product and/or presence of any non-healing wound, fracture, or ulcer (other than
             ulcers due to inflammatory breast cancer).

          -  Evidence of active bleeding or bleeding diathesis.

          -  Hemoptysis within 6 weeks prior to first dose of investigational product.

          -  Known endobronchial lesions or involvement of large pulmonary vessels by tumor.

          -  Any serious and/or unstable pre-existing medical, psychiatric, or other condition that
             could interfere with patient's safety, provision of informed consent, or compliance to
             study procedures.

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to pazopanib or lapatinib.

          -  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).