Pazopanib In Combination With Lapatinib In Adult Patients With Relapsed Malignant Glioma
Condition: Glioma
MeSH terms: Glioma
Intervention: pazopanib; lapatinib
Intervention description: Pazopanib is a novel compound being developed for the treatment of various cancers.; Lapatinib is a novel compound being developed for the treatment of various cancers.
Intervention MeSH terms: Lapatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 75.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: relapsed; lapatinib; Pazopanib; glioblastoma

Summary:

      This study is being conducted to characterize the safety/tolerability of pazopanib and
      lapatinib when administered in combination with enzyme-inducing anticonvulsants in patients
      with recurrent Grade III or IV malignant gliomas.
    

Eligibility criteria:

        Inclusion criteria:

        Phase I

          -  Patients are on EIAC for a minimum of 15 days. Patients may be on more than one
             anti-convulsant (AC). At least one of the ACs must be an EIAC.

          -  Patients with anaplastic astrocytoma, anaplastic oligodendroglioma, mixed anaplastic
             oligoastrocytoma, glioblastoma multiforme, or gliosarcoma at recurrence

          -  Patients whose diagnostic pathology confirmed these pathologies will not need
             re-biopsy

          -  Patients with prior low-grade glioma are eligible if histologic assessment
             demonstrates transformation to Grade III or IV malignant glioma Phase II

          -  Patients must have histologically confirmed glioblastoma multiforme or gliosarcoma in
             first or second recurrence.

          -  Patients may not have received more than two prior cytotoxic chemotherapy containing
             regimen.

          -  Patients must not have received prior treatment with VEGFR, ErbB1, ErbB2 inhibitors
             including but not limited to PTK-787, Sorafenib, Sutent, Tarceva, Iressa, Erbitux, and
             Herceptin. Prior Avastin therapy is permitted provided three months has elapsed before
             Day 1, Treatment Period 1.

          -  Tumor tissue must be analyzed for PTEN and epidermal growth factor receptor (EGFR)
             vIII prior to dosing.

          -  Patients with prior low-grade glioma are eligible if histologic assessment
             demonstrates transformation to Grade IV malignant glioma.

          -  Patients must not be on an EIAC. NOTE: Once the (optimally tolerated regimen) OTR in
             Phase I is determined and all patients in the expanded cohort have completed 1
             treatment period then patients on EIAC may be enrolled in the Phase II component of
             the study.

        Phase I and II

          -  Male or female, age at least 18 years of age.

          -  Eastern Cooperative Oncology Group (ECOG) status 0 to 1 as per protocol.

          -  Clinical lab results as per protocol

          -  Has a left ventricular ejection fraction (LVEF) at least 50% based on echocardiogram
             (ECHO) or Multi Gated Aquisition (MUGA) or within the institutional normal range.

          -  Adequate renal function

          -  Creatinine clearance more than 50 mL/min as calculated by the Cockcroft-Gault formula
             as per protocol.

          -  Urine Protein Creatinine (UPC) ratio of less than or equal to 1 as per protocol.

          -  Able to swallow and retain oral medications.

          -  A woman is eligible to enter and participate in the study if she is of:

             - Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
             including any female who:

          -  Has had a hysterectomy,

          -  Has had a bilateral oophorectomy (ovariectomy),

          -  Has had a bilateral tubal ligation,

          -  Is post-menopausal (total cessation of menses for at least 1 year)

             - Childbearing potential, has a negative serum pregnancy test at screening, and agrees
             to use adequate contraception. Acceptable contraceptive methods, when used
             consistently and in accordance with both the product label and the instructions of the
             physician, are as follows:

          -  An intrauterine device (IUD) 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.

          -  Double-barrier contraception (condom with spermicidal jelly, foam suppository, or
             film; diaphragm with spermicide; or male condom and diaphragm with spermicide).

          -  A man with a female partner of childbearing potential is eligible to enter and
             participate in the study if he uses a barrier method of contraception or abstinence
             during the study.

          -  If sexually active, patients will continue the recommended contraceptive measures for
             the duration of the treatments and for 28 days following discontinuation of therapy.

          -  Signed informed consent approved by the Institutional Review Board prior to patient
             entry.

        Exclusion criteria:

          -  Poorly controlled hypertension as per protocol. NOTE: Initiation or adjustment of BP
             medication is permitted prior to study entry provided that patient has two consecutive
             BP readings less than 140/90 mmHg each separated by a minimum of 24 hrs. These
             readings need to be collected prior to enrolment.

          -  Concurrent severe and/or uncontrolled medical disease (e.g. uncontrolled diabetes,
             congestive cardiac failure, poorly controlled hypertension, history of labile
             hypertension, history of poor compliance with antihypertensive regimen, chronic renal
             disease, or active uncontrolled infection) that could compromise participation in the
             study.

          -  History of myocardial infarction, admission for unstable angina, cardiac angioplasty
             or stenting within three months of Day 1, Treatment Period 1.

          -  Has Class III or IV heart failure as defined by the New York Heart Association (NYHA)
             functional classification system as per protocol.

          -  QTc prolongation defined as a corrected QT (QTc) interval greater than or equal to 470
             milliseconds.

          -  History of venous or arterial thrombosis within 3 months of Day 1, Treatment Period 1.

          -  Current use of therapeutic warfarin. NOTE: both low molecular weight heparin and
             prophylactic low-dose warfarin are permitted; however, prothrombin time/partial
             thromboplastin time (PT/PTT) must meet above inclusion criteria.

          -  Excessive risk of bleeding as defined by stroke within the prior 6 months, history of
             central nervous system (CNS) or intraocular bleed, or septic endocarditis.

          -  Evidence of intratumor hemorrhage on pretreatment diagnostic imaging, except for
             stable post-operative Grade 1 hemorrhage.

          -  Active systemic bleeding, such as gastrointestinal bleeding or gross hematuria.

          -  Female patients who are pregnant or breast feeding.

          -  Acute or chronic liver disease (i.e., hepatitis, cirrhosis).

          -  Patients who received investigational drugs less than 21days prior to Day 1, Treatment
             Period 1, or who have not recovered from the toxic effects of such therapy.

          -  Patients who received chemotherapy less than or equal to 21days prior (6 weeks for
             prior nitrosourea or mitomycin C) to Day 1, Treatment Period 1, or who have not
             recovered from the toxic effects of such therapy.

          -  Patients who received radiation therapy less than or equal to 12 weeks prior to Day 1,
             Treatment Period 1, or who have not recovered from the toxic effects of such therapy
             as per protocol.

          -  Patients who received biologic, immunotherapeutic or cytostatic agents less than or
             equal to 14 days prior to Day 1, Treatment Period 1, or who have not recovered from
             the toxic effects of such therapy.

          -  Patient is less than 3 years free of another primary malignancy except: if the other
             primary malignancy is not currently clinically significant or requiring active
             intervention. Patients with a history of completely resected non-melanoma skin cancer
             or successfully treated in situ carcinoma are eligible.

          -  Surgical resection of brain tumor or any other surgery less than or equal to 21 days
             prior to Day 1, Treatment Period 1, or who have not recovered from side effects of
             such a procedure. Patients who undergo stereotactic biopsy less than or equal to 14
             days prior to Day 1 of Treatment Period 1, or who have not recovered from side effects
             of such a procedure.

          -  Patients with any Grade of intraparenchymal CNS hemorrhage. Exceptions include Grade 1
             intraparenchymal hemorrhage in the immediate post-operative period, or Grade 1
             intraparenchymal hemorrhage that has been stable for at least 3 months.

          -  Patients unwilling to or unable to comply with the protocol.

          -  Any serious and/or unstable pre-existing medical, psychiatric, or other condition
             (including lab abnormalities) that could interfere with patient safety or obtaining
             informed consent.

          -  History of malabsorption syndrome, disease significantly affecting gastrointestinal
             function or major resection of the stomach or small bowel that could affect
             absorption, distribution, metabolism or excretion of study drugs. Has any unresolved
             bowel obstruction or diarrhea.

          -  Psychological, familial, sociological, or geographical conditions that do not permit
             compliance with the protocol.

          -  Is on any specifically prohibited medication or requires any of these medications
             during treatment.