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

NCT00350727 | Completed Phase 2 Results

• 1 other identifier: VEG102857
• Study Type: interventional
• Target: 75
• Locations: 0 countries
• Sites: N/A

Brief 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.

Conditions

Glioma

Keywords

relapsed; lapatinib; Pazopanib; glioblastoma

Outcome Measures

Primary Outcomes (35)

• 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 Outcomes (5)

• 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

  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)

Study Arms (1)

Combination

EXPERIMENTAL

Pazopanib and Lapatinib in combination. Subjects remain on treatment until disease progression or withdrawal from study.

Drug: pazopanib; Drug: lapatinib

Interventions

pazopanib DRUG

Pazopanib is a novel compound being developed for the treatment of various cancers.

Combination

lapatinib DRUG

Lapatinib is a novel compound being developed for the treatment of various cancers.

Also known as: pazopanib

Combination

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Related Publications (1)

• de Jonge MJ, Hamberg P, Verweij J, Savage S, Suttle AB, Hodge J, Arumugham T, Pandite LN, Hurwitz HI. Phase I and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors. Invest New Drugs. 2013 Jun;31(3):751-9. doi: 10.1007/s10637-012-9885-8. Epub 2012 Oct 6.

  PMID: 23054212 DERIVED

MeSH Terms

Conditions

Glioma; Recurrence; Glioblastoma

Interventions

pazopanib; Lapatinib

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Astrocytoma

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 10, 2006
• First Posted: July 11, 2006
• Study Start: December 1, 2006
• Primary Completion: December 1, 2009
• Study Completion: December 1, 2009
• Last Updated: April 19, 2013
• Results First Posted: June 20, 2011

Record last verified: 2012-05