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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Glioma

Intervention / Treatment
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* Drug: pazopanib
* Drug: lapatinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination<br>Pazopanib and Lapatinib in combination. Subjects remain on treatment until disease progression or withdrawal from study. | Drug: pazopanib<br>* Pazopanib is a novel compound being developed for the treatment of various cancers.<br>Drug: lapatinib<br>* Lapatinib is a novel compound being developed for the treatment of various cancers.<br>* Other names: pazopanib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Indicated Change From Baseline to Study Completion in Systolic Blood Pressure | Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline (BL) values to investigate what changes occurred. mmHg, millimeters of mercury. | Baseline to study completion (up to 844 days for Phase I, up to 878 days for Phase II) | 
| Number of Participants With the Indicated Change From Baseline to Study Completion in Diastolic Blood Pressure | Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline (BL) values to investigate what changes occurred. mmHg, millimeters of mercury. | Baseline to study completion (up to 844 days for Phase I, up to 878 days for Phase II) | 
| Number of Participants With the Indicated Change From Baseline to Study Completion in Heart Rate | Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline (BL) values to investigate what changes occurred. bpm, beats per minute. | Baseline to study completion (up to 844 days for Phase I, up to 878 days for Phase II) | 
| Mean Change From Baseline to Maximum Value in Phase II of the Study for Albumin | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 878 days for Phase II) | 
| Mean Change From Baseline to Maximum Value in Phase II of the Study for Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, and Lactate Dehydrogenase | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 878 days for Phase II) | 
| Mean Change From Baseline to Maximum Value in Phase II of the Study for Amylase and Lipase | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 878 days for Phase II) | 
| Mean Change From Baseline to Maximum Value in Phase II of the Study for Total Bilirubin and Creatinine | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 878 days for Phase II) | 
| Mean Change From Baseline to Maximum Value in Phase II of the Study for Calcium, Glucose, Potassium, Magnesium, Inorganic Phosphorus, Sodium, and Urea | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 878 days for Phase II) | 
| Mean Change From Baseline to Maximum Value in Phase II of the Study for Thyroxine and Free T3 (Triiodothyronine) | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 878 days for Phase II) | 
| Mean Change From Baseline to Maximum Value in Phase II of the Study for Thyroid Stimulating Hormone | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 878 days for Phase II) | 
| Mean Change From Baseline to Maximum Value in Phase II of the Study for Total T3 | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 878 days for Phase II) | 
| Mean Change From Baseline to Maximum Value in Phase II of the Study for Hemoglobin | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 878 days for Phase II) | 
| Mean Change From Baseline to Maximum Value in Phase II of the Study for Hematocrit | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. The hematocrit is the proportion of blood volume that is occupied by red blood cells. | Baseline to study completion (up to 878 days for Phase II) | 
| Mean Change From Baseline to Maximum Value in Phase II of the Study for Lymphocytes, Neutrophils, Platelet Count, and White Blood Count | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 878 days for Phase II) | 
| Mean Change From Baseline to Maximum Value in Phase II of the Study for International Normalized Ratio (Prothrombin Time) | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. Prothrombin time is a measure of the extrinsic pathway of coagulation that is used to determine the clotting tendency of blood. The International Normalized Ratio is the ratio of a patient's prothrombin time to a normal (control) sample. | Baseline to study completion (up to 878 days for Phase II) | 
| Mean Change From Baseline to Maximum Value in Phase II of the Study for Partial Thromboplastin Time and Prothrombin Time | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. Partial thromboplastin time is a performance indicator detecting abnormalities in blood clotting. | Baseline to study completion (up to 878 days for Phase II) | 
| Mean Change From Baseline to Maximum Value in Phase I of the Study for Albumin | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 844 days for Phase I) | 
| Mean Change From Baseline to Maximum Value in Phase I of the Study for Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, and Lactate Dehydrogenase | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 844 days for Phase I) | 
| Mean Change From Baseline to Maximum Value in Phase I of the Study for Amylase and Lipase | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 844 days for Phase I) | 
| Mean Change From Baseline to Maximum Value in Phase I of the Study for Total Bilirubin and Creatinine | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 844 days for Phase I) | 
| Mean Change From Baseline to Maximum Value in Phase I of the Study for Calcium, Glucose, Potassium, Magnesium, Inorganic Phosphorus, Sodium, and Urea | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 844 days for Phase I) | 
| Mean Change From Baseline to Maximum Value in Phase I of the Study for Thyroxine | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 844 days for Phase I) | 
| Mean Change From Baseline to Maximum Value in Phase I of the Study for Free T3 (Triiodothyronine) | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 844 days for Phase I) | 
| Mean Change From Baseline to Maximum Value in Phase I of the Study for Thyroid Stimulating Hormone | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 844 days for Phase I) | 
| Mean Change From Baseline to Maximum Value in Phase I of the Study for Total T3 | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 844 days for Phase I) | 
| Mean Change From Baseline to Maximum Value in Phase I of the Study for Hemoglobin | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 844 days for Phase I) | 
| Mean Change From Baseline to Maximum Value in Phase I of the Study for Hematocrit | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. The hematocrit is the proportion of blood volume that is occupied by red blood cells. | Baseline to study completion (up to 844 days for Phase I) | 
| Mean Change From Baseline to Maximum Value in the Study for Lymphocytes, Neutrophils, Platelet Count, and White Blood Count | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. | Baseline to study completion (up to 844 days for Phase I) | 
| Mean Change From Baseline to Maximum Value in Phase I of the Study for International Normalized Ratio (Prothrombin Time) | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. Prothrombin time is a measure of the extrinsic pathway of coagulation that is used to determine the clotting tendency of blood. The International Normalized Ratio is the ratio of a patient's prothrombin time to a normal (control) sample. | Baseline to study completion (up to 844 days for Phase I) | 
| Mean Change From Baseline to Maximum Value in Phase I of the Study for Partial Thromboplastin Time and Prothrombin Time | Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. Partial thromboplastin time is a performance indicator detecting abnormalities in blood clotting. | Baseline to study completion (up to 844 days for Phase I) | 
| Number of Participants Experiencing a Dose-limiting Toxicity at the Indicated Dose | A dose-limiting toxicity (DLT) is defined as predefined adverse events or events that prevented participants from receiving 75% of their scheduled doses or from starting their next treatment period. The dose at which no more than 1 out of 6 participants experiences a DLT is defined as the optimally tolerated regimen. The OTR is important because it determines the highest dose combination that can be given without significant toxicity. | Cycle 1 in Phase I (up to Day 28) | 
| Overall Response (OR) in Phase II Based GlaxoSmithKline's Evaluation | OR is the number of participants whose response was classified as a complete response or partial response (disappearance of enhancing tumor (ET) or reduction of ET by >=50%, respectively, on consecutive scans [CS] >=1 month (m) apart, off steroids, and neurologically stable/improved), progressive disease (increase of ET of >=25% on CS >=1 m apart or neurologically worse, and steroids stable/increased), or stable disease (all other situations) per MacDonald criteria. Participants were evaluated with magnetic resonance imaging. Baseline and the 4- and 8-w assessments are categorized as <8 w. | Date of first dose of study drug to date of documented and confirmed progression, or to date of death due to any cause (assessed at baseline, 4 and 8 weeks, and every 8 weeks thereafter until study withdrawal; up to Day 878) | 
| Overall Response (OR) in Phase II Based on the Investigator-assigned Response | OR is the number of participants whose response was classified as a complete response or partial response (disappearance of enhancing tumor (ET) or reduction of ET by >=50%, respectively, on consecutive scans [CS] >=1 month (m) apart, off steroids, and neurologically stable/improved), progressive disease (increase of ET of >=25% on CS >=1 m apart or neurologically worse, and steroids stable/increased), or stable disease (all other situations) per MacDonald criteria. Participants were evaluated with magnetic resonance imaging. Baseline and the 4- and 8-w assessments are categorized as <8 w. | Date of first dose of study drug to date of documented and confirmed progression, or to date of death due to any cause (assessed at baseline, 4 and 8 weeks, and every 8 weeks thereafter until study withdrawal; up to Day 878) | 
| Overall Response (OR) in Phase II Based on an Independent Radiologist's Review | OR is the number of participants whose response was classified as a complete response or partial response (disappearance of enhancing tumor (ET) or reduction of ET by >=50%, respectively, on consecutive scans [CS] >=1 month (m) apart, off steroids, and neurologically stable/improved), progressive disease (increase of ET of >=25% on CS >=1 m apart or neurologically worse, and steroids stable/increased), or stable disease (all other situations) per MacDonald criteria. Participants were evaluated with magnetic resonance imaging. Baseline and the 4- and 8-w assessments are categorized as <8 w. | Date of first dose of study drug to date of documented and confirmed progression, or to date of death due to any cause (assessed at baseline, 4 and 8 weeks, and every 8 weeks thereafter until study withdrawal; up to Day 878) | 
| Progression-free Survival at 6 Months | Progression-free survival (PFS) analysis was performed on all participants. PFS is presented as the number of participants experiencing disease progression or death due to any cause. Participants who are alive and have not progressed at the time of analysis are considered censored, and the date associated with the last visit with disease assessment will be used. The participants who are still alive and whose follow-up extends to at least 6 months are considered At Risk. | Date of the first dose of study drug to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. |  | Completed during first cycle of treatment. | 
| 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. |  | Completed during first cycle of treatment. | 
| Phase II: Plasma Concentrations of the Circulating Biomarkers VEGF, sVEGFR-1, and sVEGFR-2. |  | Completed during first cycle of treatment. | 
| Progression-free Survival | Progression-free survival (PFS) analysis was performed on all participants. PFS is presented as the number of participants experiencing disease progression or death due to any cause. Participants who are alive and have not progressed at the time of analysis are considered censored, and the date associated with the last visit with disease assessment will be used. | Date of the first dose of study drug to the date of documented and confirmed progression by Mac Donald criteria, or to date of death due to any cause (up to Day 878) | 
| Time to Disease Progression or Death Due to Any Cause |  | Date of the first dose of study drug to the date of documented and confirmed progression by Mac Donald criteria, or to date of death due to any cause (up to Day 878) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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relapsed, lapatinib, Pazopanib, glioblastoma