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Pazopanib In Combination With Lapatinib In Adult Patients With Relapsed Malignant Glioma

Information source: GlaxoSmithKline
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Glioma

Intervention: pazopanib (Drug); lapatinib (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: GlaxoSmithKline

Official(s) and/or principal investigator(s):
GSK Clinical Trials, Study Director, Affiliation: GlaxoSmithKline

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.

Clinical Details

Official title: Phase I and II, Open-Label, Multi-Center Trials of Pazopanib in Combination With Lapatinib in Adult Patients With Relapsed Malignant Glioma

Study design: Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Number of Participants With the Indicated Change From Baseline to Study Completion in Systolic Blood Pressure

Number of Participants With the Indicated Change From Baseline to Study Completion in Diastolic Blood Pressure

Number of Participants With the Indicated Change From Baseline to Study Completion in Heart Rate

Mean Change From Baseline to Maximum Value in Phase II of the Study for Albumin

Mean Change From Baseline to Maximum Value in Phase II of the Study for Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, and Lactate Dehydrogenase

Mean Change From Baseline to Maximum Value in Phase II of the Study for Amylase and Lipase

Mean Change From Baseline to Maximum Value in Phase II of the Study for Total Bilirubin and Creatinine

Mean Change From Baseline to Maximum Value in Phase II of the Study for Calcium, Glucose, Potassium, Magnesium, Inorganic Phosphorus, Sodium, and Urea

Mean Change From Baseline to Maximum Value in Phase II of the Study for Thyroxine and Free T3 (Triiodothyronine)

Mean Change From Baseline to Maximum Value in Phase II of the Study for Thyroid Stimulating Hormone

Mean Change From Baseline to Maximum Value in Phase II of the Study for Total T3

Mean Change From Baseline to Maximum Value in Phase II of the Study for Hemoglobin

Mean Change From Baseline to Maximum Value in Phase II of the Study for Hematocrit

Mean Change From Baseline to Maximum Value in Phase II of the Study for Lymphocytes, Neutrophils, Platelet Count, and White Blood Count

Mean Change From Baseline to Maximum Value in Phase II of the Study for International Normalized Ratio (Prothrombin Time)

Mean Change From Baseline to Maximum Value in Phase II of the Study for Partial Thromboplastin Time and Prothrombin Time

Mean Change From Baseline to Maximum Value in Phase I of the Study for Albumin

Mean Change From Baseline to Maximum Value in Phase I of the Study for Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, and Lactate Dehydrogenase

Mean Change From Baseline to Maximum Value in Phase I of the Study for Amylase and Lipase

Mean Change From Baseline to Maximum Value in Phase I of the Study for Total Bilirubin and Creatinine

Mean Change From Baseline to Maximum Value in Phase I of the Study for Calcium, Glucose, Potassium, Magnesium, Inorganic Phosphorus, Sodium, and Urea

Mean Change From Baseline to Maximum Value in Phase I of the Study for Thyroxine

Mean Change From Baseline to Maximum Value in Phase I of the Study for Free T3 (Triiodothyronine)

Mean Change From Baseline to Maximum Value in Phase I of the Study for Thyroid Stimulating Hormone

Mean Change From Baseline to Maximum Value in Phase I of the Study for Total T3

Mean Change From Baseline to Maximum Value in Phase I of the Study for Hemoglobin

Mean Change From Baseline to Maximum Value in Phase I of the Study for Hematocrit

Mean Change From Baseline to Maximum Value in the Study for Lymphocytes, Neutrophils, Platelet Count, and White Blood Count

Mean Change From Baseline to Maximum Value in Phase I of the Study for International Normalized Ratio (Prothrombin Time)

Mean Change From Baseline to Maximum Value in Phase I of the Study for Partial Thromboplastin Time and Prothrombin Time

Number of Participants Experiencing a Dose-limiting Toxicity at the Indicated Dose

Overall Response (OR) in Phase II Based GlaxoSmithKline's Evaluation

Overall Response (OR) in Phase II Based on the Investigator-assigned Response

Overall Response (OR) in Phase II Based on an Independent Radiologist's Review

Progression-free Survival at 6 Months

Secondary outcome:

Phase I: Pharmacokinetic Parameters Including AUC(0-24), [AUC(0-12) for Patients on Twice Daily Administration], Cmax, the Time to Maximum Observed Concentration (Tmax) and C24 of Pazopanib and Lapatinib When Administered in Combination With EIAC.

Phase II: Pharmacokinetic Parameters Including AUC(0-24), [AUC(0-12) for Patients on Twice Daily Administration], Cmax, Tmax, and C24 of Pazopanib and Lapatinib, as Appropriate, When Administered Together in Combination With Non-EIAC.

Phase II: Plasma Concentrations of the Circulating Biomarkers VEGF, sVEGFR-1, and sVEGFR-2.

Progression-free Survival

Time to Disease Progression or Death Due to Any Cause

Detailed description: 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

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

Locations and Contacts

Additional Information

Starting date: December 2006
Last updated: April 11, 2013

Page last updated: August 23, 2015

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