Phase 2
N=34
Pazopanib In Combination With Lapatinib In Adult Patients With Relapsed Malignant Glioma
Glioma
Bottom Line
View on ClinicalTrials.gov: NCT00350727 ↗Enrolled (actual)
34
Serious AEs
38.7%
Results posted
Jun 2011
Primary outcome: Primary: Number of Participants With the Indicated Change From Baseline to Study Completion in Systolic Blood Pressure — 21; 12; 11; 12 participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- pazopanib (Drug); lapatinib (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- GlaxoSmithKline
- Primary completion
- Dec 2009
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With the Indicated Change From Baseline to Study Completion in Systolic Blood Pressure |
21; 12; 11; 12; 3; 8 | — |
| PRIMARY Number of Participants With the Indicated Change From Baseline to Study Completion in Diastolic Blood Pressure |
23; 13; 9; 9; 4; 10 | — |
| PRIMARY Number of Participants With the Indicated Change From Baseline to Study Completion in Heart Rate |
31; 14; 19; 0; 3; 2 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase II of the Study for Albumin |
-5.9; -6.7 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase II of the Study for Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, and Lactate Dehydrogenase |
18.6; 33.9; 56.1; 132.7; 36.4; 52.7 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase II of the Study for Amylase and Lipase |
22.72; 20.05; 131.4; 120.5 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase II of the Study for Total Bilirubin and Creatinine |
6.174; 23.562; 6.93; 9.59 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase II of the Study for Calcium, Glucose, Potassium, Magnesium, Inorganic Phosphorus, Sodium, and Urea |
0.004; 0.019; 0.082; 1.850; 0.17; 0.30 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase II of the Study for Thyroxine and Free T3 (Triiodothyronine) |
-8.052; 10.806; 0.420; -2.442 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase II of the Study for Thyroid Stimulating Hormone |
1.37; 2.59 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase II of the Study for Total T3 |
-0.181; -0.104 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase II of the Study for Hemoglobin |
-4.6; -8.0 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase II of the Study for Hematocrit |
-0.016; -0.027 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase II of the Study for Lymphocytes, Neutrophils, Platelet Count, and White Blood Count |
-0.26; -0.21; -2.87; -4.72; -58.7; -55.7 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase II of the Study for International Normalized Ratio (Prothrombin Time) |
0.030; 0.042 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase II of the Study for Partial Thromboplastin Time and Prothrombin Time |
2.10; 2.62; 0.0; 0.2 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase I of the Study for Albumin |
-4.25; -6.17; -3.80; -5.17; -13.66; -7.17 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase I of the Study for Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, and Lactate Dehydrogenase |
9.8; 22.8; 31.2; 15.8; 22.0; 22.0 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase I of the Study for Amylase and Lipase |
24.3; 24.4; 27.3; 31.0; 44.4; 23.3 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase I of the Study for Total Bilirubin and Creatinine |
-0.000; 2.613; 3.368; 6.130; 4.135; 6.398 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase I of the Study for Calcium, Glucose, Potassium, Magnesium, Inorganic Phosphorus, Sodium, and Urea |
-0.062; -0.045; 0.036; 0.061; 0.047; -0.014 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase I of the Study for Thyroxine |
-0.740; -1.498; 1.105; 1.879; 0.377; -0.781 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase I of the Study for Free T3 (Triiodothyronine) |
-0.07; -0.94 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase I of the Study for Thyroid Stimulating Hormone |
-0.5068; 0.1900; 0.6543; 0.6660; 0.6080; 2.2940 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase I of the Study for Total T3 |
-0.071; 0.214; 0.004 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase I of the Study for Hemoglobin |
-7.25; -7.83; -4.80; -3.33; -16.17; -21.02 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase I of the Study for Hematocrit |
-0.02; -0.02; -0.02; 0.00; -0.09; 0.01 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in the Study for Lymphocytes, Neutrophils, Platelet Count, and White Blood Count |
-0.377; -0.120; -0.153; -0.032; -0.218; -0.250 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase I of the Study for International Normalized Ratio (Prothrombin Time) |
0.077; -0.023; 0.056; 0.000; 0.015; 0.006 | — |
| PRIMARY Mean Change From Baseline to Maximum Value in Phase I of the Study for Partial Thromboplastin Time and Prothrombin Time |
1.10; 2.88; 2.62; -0.38; 2.18; 1.00 | — |
| PRIMARY Number of Participants Experiencing a Dose-limiting Toxicity at the Indicated Dose |
0; 1; 1; 1; 1; 1 | — |
| PRIMARY Overall Response (OR) in Phase II Based GlaxoSmithKline's Evaluation |
0; 0; 1; 2; 7; 6 | — |
| PRIMARY Overall Response (OR) in Phase II Based on the Investigator-assigned Response |
0; 0; 1; 1; 7; 7 | — |
| PRIMARY Overall Response (OR) in Phase II Based on an Independent Radiologist's Review |
0; 0; 0; 0; 5; 4 | — |
| PRIMARY Progression-free Survival at 6 Months |
15; 16; 0; 2; 4; 1 | — |
| SECONDARY 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. |
— | — |
| SECONDARY 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. |
— | — |
| SECONDARY Phase II: Plasma Concentrations of the Circulating Biomarkers VEGF, sVEGFR-1, and sVEGFR-2. |
— | — |
| SECONDARY Progression-free Survival |
15; 18; 0; 2; 4; 2 | — |
| SECONDARY Time to Disease Progression or Death Due to Any Cause |
62; 56 | — |
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 a
Data sourced from ClinicalTrials.gov (NCT00350727). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.