Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Pazopanib · 35 trials · 35 indications
PFS was defined as the time interval between the date of randomization and the earliest date of either disease progression or death due to any cause. The diagnosis of progression was based on tumor measurements, according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 criteria, by independent radiologic assessment. The Kaplan-Meier method was used for PFS estimates.
An adverse event (AE) is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; or is a congenital anomaly/birth defect. Medical or scientific judgment should be exercised in other situations.
An adverse event (AE) is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; or is a congenital anomaly/birth defect. Medical or scientific judgment should be exercised in other situations. Adverse events were graded for severity according to the NCI CTCAE, version 3.0: Grade 1, mild; Grade 2, moderate; Grade 3 (G3), severe; Grade 4 (G4), life-threatening or disabling; Grade 5, death.
An adverse event (AE) is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The investigator assessed relatedness between the AE and the investigational product.
The time on investigational product (including dose interruptions) is defined as the difference between the date of the last dose of investigational product and the date of the first dose of investigational product plus one.
Clinical chemistry parameters were summarized according to NCI CTCAE, version 4.0: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling; Grade 5, death. Data are presented for only those parameters for which an increase from Baseline occurred. Clinical chemistry parameters included: alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin (TB), calcium (hypercalcemia and hypocalcemia), creatinine, glucose (hyperglycemia and hypoglycemia), potassium (hyperkalemia and hypokalemia), magnesium (hypermagnesemia and hypomagnesemia), sodium (hypernatremia and hyponatremia), and phosphate.
Hematology parameters were summarized according to NIH CTCAE, version 4.0. Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling; Grade 5, death. Data are presented for only those parameters for which an increase from Baseline occurred. Hematology parameters included: hemoglobin (anemia), lymphocytes (lymphocytopenia), neutrophils (neutropenia), platelets (thrombocytopenia), white blood cells (WBC \[leukopenia\]), and prothrombin time international normalized ratio (PT \[INR\]). Participants with missing Baseline grades are assumed to have a Baseline grade of 0.
Blood pressure measurements included systolic blood pressure (SBP, millimeters of mercury \[mmHg\]) and diastolic BP (DBP). The number of participants with a post-Baseline shift from Baseline in blood pressure (\<90 mmHg, 90 to 139 mmHg, 140 to 169 mmHg, \>=170 mmHg) was assessed.
Heart rate is the measure of heart beats per minute (bpm). The number of participants with a post-Baseline shift from Baseline in heart rate of \<44 bpm, 44 to 100 bpm, 101 to 120 bpm, and \>120 bpm was assessed.
The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. A lengthened QT interval can be a biomarker for ventricular tachyarrhythmias. The QT interval corrected for heart rate using Bazett's formula (QTcB) was calculated; the faster the heart rate, the shorter the QT interval. Electrocardiogram values (Bazett's QTc value) were summarized using the following reference ranges: \<450, 450 to 479, 480 to 499, 500 to 549, and \>550 milliseconds.
Progression-free survival (PFS) is defined as the interval between the date of randomization and the earliest date of disease progression or death due to any cause. Assessments of progression and non-progression were made by an independent imaging review committee (IRC) for the primary analysis.
Disease control at week 16 defined as complete response (CR), Disappearance of all target lesions; plus partial response (PR), At least a 30% decrease in the sum of diameters of the target lesions taking as reference the Baseline sum diameters; plus stable disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum diameters while on the study; where tumor response is defined by RECIST (Response Evaluation Criteria in Solid Tumors) guidelines version 1.1. Repeat radiologic imaging is performed after every 2 cycles of treatment (approximately every 8 weeks).
Proportion of patients with complete and partial response (CR and PR). CR defined as disappearance of target lesions; PR defined as at least a 30% decrease in the sum of the longest diamater of target lesions.
The ratio of patients with CR (complete remission) + PR (partial remission) + SD (stable disease) at week 12 after start of treatment
The tumor response rate was assessed per the Response Evaluation Criteria In Solid Tumors (RECIST). RECIST criteria are a set of published rules that define when cancer patients improve ("respond"); stay the same ("stable"); or worsen ("progression") during treatments. RECIST criteria offer a simplified and conservative extraction of imaging data suitable for wide application in clinical trials. The criteria presume that linear measures are an adequate substitute for 2-dimensional (2D) methods and includes 4 response categories: * Complete response (CR) = Disappearance of all target lesions * Partial response (PR) = 30% decrease in the sum of the longest diameter of target lesions * Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions * Stable disease (SD) = Small changes that do not meet above criteria Objective tumor response means those with response better than stable disease, ie, complete response (CR) + partial response (PR).
pCR was defined as no histologic evidence of invasive tumor cells in the surgical breast specimen, axillary nodes, or sentinel node identified after neoadjuvant chemotherapy.
Change from Baseline is the value at indicated time point minus the Baseline value. Baseline measurement was recorded at Day 1. SBP and DBP were recorded from Baseline up to 6 months. At screening and Baseline, if the single measured value of blood pressure was above 150 millimeters of mercury (mm Hg) systolic or 95 mm Hg diastolic, then blood pressure measurement could not be repeated. If, the SBP was \<80 or \>140 mm Hg and DBP was \<40 or \>90 mm Hg, then measurement of BP was repeated. Three consecutive blood pressure readings that were less than 150 mmHg systolic and 95 mmHg diastolic were taken with each measurement separated by at least 1 hour.
Heart rate was measured over 6 months. Baseline value was recorded on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value. Heart rate measurement were repeated in case it was in range \< 50 beats per minute (bpm) or \>110 bpm.
Albumin and hemoglobin values were recorded at Baseline, Month2, and till follow-up (Month 6). Baseline was recorded on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.
ALP, ALT and AST values were measured over 5 months and till the follow-up period. Baseline value was recorded pre-dose Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.
Change from Baseline is the value at indicated time point minus the Baseline value. Baseline measurement was recorded at Day 1. The above mentioned hematological parameters were recorded from Baseline up to 5 months.
Change from Baseline is the value at indicated time point minus the Baseline value. Over here, the change is % Basophils at month x - % Basophils at Baseline. Baseline measurement was recorded at Day 1. Percentage change in the hematological parameter mentioned above was recorded from Baseline up to 5 months.
Change from Baseline is the value at indicated time point minus the Baseline value. Baseline measurement was recorded at Day 1. Direct bilirubin, total bilirubin, and creatinine were recorded from Baseline up to 6 months
Change from Baseline (Day 1) is the value at indicated time point minus the Baseline value. Baseline measurement was recorded at Day 1. Calcium, chloride, carbon di oxide equivalent content (CO2), glucose, potassium, sodium, and urea/blood urea nitrogen (BUN) was recorded from Baseline up to Follow-up.
Change from Baseline is the value at indicated time point minus the Baseline value. Baseline measurement was recorded at Day 1. MCV was recorded from Baseline up to Follow-up.
Change from Baseline is the value at indicated time point minus the Baseline value. Baseline measurement was recorded at Day 1. Intra-ocular pressure was recorded from Baseline up to Follow-up.
In this dipstick test, the level of blood occult and glucose, ketones, protein in urine samples were recorded as negative, trace, 1+, 2+, and 3+ (the plus sign increases with a higher level of glucose, ketones, or proteins in the urine: 1+=slightly positive, 2+=positive, 3+=high positive).
Number of participants with ocular and non-ocular AEs and SAEs were separately recorded. An AE is an unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain time period after the study has ended. This change may or may not be caused by the intervention being studied. An SAE is an adverse event that results in death, is life-threatening, requires inpatient hospitalization or extends a current hospital stay, results in an ongoing or significant incapacity or interferes substantially with normal life functions, or causes a congenital anomaly or birth defect. Medical events that do not result in death, are not life-threatening, or do not require hospitalization may be considered serious adverse events if they put the participant in danger or require medical or surgical intervention to prevent one of the results listed above.
Visual acuity was measured over 5 months and also during follow-up period. Visual acuity was measured using standardized early treatment of diabetic retinopathy study (ETDRS) visual acuity charts. Visual acuity measurement was performed by an examiner that had been appropriately trained. Screening, Month 2 and Month 5 data were considered as Best Corrected Visual Acuity (BCVA) data. A loss of greater than or equal to 15 letters in BCVA from Baseline was considered of PCI. Data for number of participants who met the criteria for PCI have been presented.
Pupil abnormalities were of different types. Meibomian gland dysfunction was measured as obvious inspissation (debris). Mild injection, no trichiasis (lid thickening), or two step worsening was analyzed. Afferent pupillary defect, motility examination, PERRL, confrontation visual field was measured as a new definite abnormality. Left and right both eyes were examined.
A two step worsening in the conjunctival examination was considered a value of PCI. Participants were analyzed for conjunctival examination up to follow-up (6 months).
A two step worsening in the anterior chamber examination was considered a value of PCI. The participants were examined for any anterior chamber abnormality. Fibrinous response and obvious aqueous haze were considered abnormalities related to anterior chamber examination.
A two step change in any of the lens opacity categories was categorized as of PCI. Corneal epithelium was defined as abnormal when punctate keratopathy was measured as mild, moderate, severe; epithelial edema was measured as subtle epithelial haze, mild patchy microcystic changes, diffuse microcystic changes, and/or investigator determined abnormality. Stromal opacity/ edema was measured by investigator when stroma identifies opacity or edema. Corneal staining was measured as obvious (\<=20) localized or diffuse punctate staining areas, severe localized or diffuse punctate staining. Participants were analyzed for any of the mentioned abnormality over 6 weeks (up to follow-up period).
A two step change in any of the lens opacity categories was considered a value of PCI. Aphakia (surgical removal of lens) or pseudophakia was noted if any. Stroma opacity or edema was measured by investigator when it was detected as edema or opacity in stroma.
Tear film abnormalities were based on the clinical judgment of investigator. Tear film thickness was analyzed and it was reported whether the film was increased or decreased or was normal. Presence of debris or mucus was also reported. Other test were tear lake analysis and checking of discharge from eyes.
Meibomian gland dysfunction was measured as obvious insipisation/debris, mild injection, no trichiasis or lid thickening; inspisation, debris, obvious injection, lid thickening, may have trsichiasis; or a two step worsening. Any 2+ worsening of Meibomian gland function was considered a value of PCI.
Dilation of fundus was examined post dosing up to 6 months. Number of participants with abnormal change from Baseline indicating dilation of fundus of eye was reported. Change from Baseline was the value at indicated time point minus the Baseline value. The abnormalities were posterior vitreous separation, pale optic nerve, fluid in the posterior pole, drusen, thick arterio-venous changes, pigment changes, cystoids, macular edema, drying of posterior fluid or sub-retinal fluid, underlying central atrophy, and retinal pigment epithelial changes etc. Refraction measurement were determined at the screening and 2 month/5 month visits in order to determine BCVA.
CRLT was measured by the Carl Zeiss Meditec Stratus OCT scanner based on the manual measurement of the distance between the inner and outer retina, inclusive of subretinal fluid and any choroidal neovascularization (CNV) as measured in the central 1 millimeter (mm) area of the 7 mm Posterior Pole Scan. OCT scans/images were collected by trained and certified photographer and analyzed by investigator. Two datasets were used for analysis namely Last observation carried forward (LOCF) which included missing assessment for a participant who completed at least 7 days of pazopanib eye drop replaced by the last non-missing assessment post 7 days of pazopanib eye drop treatment. OC dataset included a missing assessment at any scheduled time was considered unevaluable and was not imputed. Baseline was defined as the assessments performed between Day -3 to -1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-randomization value at Day 29.
Safety and tolerability were measured by the number of participants with serious adverse events and non-serious adverse events. See the "Adverse Event" section of the results record for additional details and data.
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.
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.
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.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
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.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
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.
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.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
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.
Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.
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.
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.
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.
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.
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.
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.
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.
PFS is defined as the interval between the date of randomization and the date of disease progression or death due to any cause. The study was designed to test Combination vs. Lapatinib first. The result indicated that Combination would not show improvement over Lapatinib even if followed until the final analysis and the Combination arm was terminated. The monotherapy arms continued to the final analysis. Data shown here are from this interim analysis.
PFS is defined as the interval between the date of randomization and the date of disease progression or death due to any cause. This study began as a 3-arm study. The combination arm was terminated at the interim analysis. The monotherapy arms continued to final analysis. Data shown here are from the final analysis.
Tumor shrinkage was assessed as the change in tumor volume using high-resolution computed tomography scans of the thorax following treatment with pazopanib. Response is defined as the number of participants achieving at least 50% tumor volume reduction following pazopanib treatment. "Responder" is a participant whose tumor volume reduced at least 50% following pazopanib treatment. "Non-responder" is a participant whose tumor volume did not reduce at least 50% following treatment. Tumor assessments were conducted by a central reviewer.
The percentage of participants with progressive disease (PD) 12 weeks after randomization was measured. Per Response Evaluation Criteria In Solid Tumors (RECIST), a response of PD is defined as a \>=20% increase in target lesions. Participants were also classified as having PD if their response at Week 12 was unknown or missing. Response was determined by an independent radiologist and by an investigator.
Progression free survival at week 12 is the number of participants who had a complete response (CR, all detectable tumor had disappeared) or a partial response (PR, a \>=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum) or stable disease (SD, no change) 12 weeks from start of therapy, per response evaluation criteria in solid tumors (RECIST v1.0). Clinical progression is progression of disease without documented radiological evidence. Progressive disease (PD), a \>=20% increase in target lesions.
To evaluate the Recommended Phase 2 Dose (RP2D) of pazopanib in oral route in addition to the maintenance phase of the Stupp protocol, regarding the toxicities that should not be more than 33 %
MTD and recommended phase II dose (RP2D) determination for the combination of temozolomide in combination with 400mg pazopanib in patients with advanced PNET will be achieved using a standard "3+3" dose escalation/de-escalation design. After each 3 patients are enrolled into the study, further enrollment will be temporarily suspended until safety has been reviewed for the first 28 days of treatment to determine if dose limiting toxicities have been experienced by patients and if a further 3 patients should be enrolled at the current dose or dose escalation/de-escalation for the next 3 patients should occur.
Overall response rate will be determined by the number of patients who's best response as assessed by RECIST 1.1 is complete response (CR) and partial response (PR) in patients with PNET that are enrolled at the recommended phase II dose (RP2D) (PK cohort included). CR= Disappearance of all target lesions PR = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
The safety and tolerability endpoints will consist of the evaluation of adverse events (AEs), and changes in vital signs and laboratory values.
| Arm | Type | Description |
|---|---|---|
| PLACEBO | PLACEBO_COMPARATOR | matching placebo 800 mg once daily orally |
| PAZOPANIB | EXPERIMENTAL | 800 mg once daily orally |
| pazopanib arm | EXPERIMENTAL | This was a single arm study, therefore no control arm. |
| placebo arm | PLACEBO_COMPARATOR | matching placebo (800 mg tablet) once daily |
| Open label | OTHER | Single arm pazopanib |
| pazopanib + paclitaxel | EXPERIMENTAL | Cycle of 28 days. Pazopanib: 800mg daily Cycle of 28 days Paclitaxel: 80mg/m2 on days 1,8 and 15 |
| Arm 1 | EXPERIMENTAL | Investigational treatment (pazopanib and pemetrexed) |
| Arm 2 | ACTIVE_COMPARATOR | Standard treatment (pemetrexed and cisplatin) |
| Treatment Arm | EXPERIMENTAL | Preoperative Cycles 1-4 Doxorubicin 60 mg/m2 IV over 15 minutes + Cyclophosphamide 600 mg/m2 IV over 30 minutes of Day 1 every 21 days followed by: Cycles 5-8 Paclitaxel 80 mg/m2 IV over 60 minutes (Days 1, 8, and 15) every 28 days in combination with pazopanib (800 mg) PO once daily (2 tablets taken at the same time each day either 1 hour before or 2 hours after a meal) Daily beginning on Day 1 of the first paclitaxel cycle Until 7 days before surgery Followed by Surgery Postoperative Pazopanib 800 mg PO once daily (2 tablets taken at the same time each day either 1 hour before or 2 hours after a meal) Daily beginning 4-6 weeks after surgery 6 months from first postoperative dose |
| 5 mg/ml TID | EXPERIMENTAL | eligible participants received 5 mg/ml Pazopanib eye drops three times daily (TID) |
| 2 mg/ml TID | EXPERIMENTAL | eligible participants received 2 mg/ml Pazopanib eye drops three times daily |
| 5 mg/ml QD | EXPERIMENTAL | eligible participants received 5 mg/ml Pazopanib eye drops once daily (QD) |
| Arm 3 | EXPERIMENTAL | Pazopanib eye drop formulation 2mg/mL TID for 28 days |
| Arm A | EXPERIMENTAL | Oral Pazopanib 800 mg once a day+ carboplatin area under the concentration-time curve (AUC) 5 intravenous (IV) over 1 hour every 3 weeks + paclitaxel 175 mg/m\^2 IV over three hours day one q 3 weeks for six cycles |
| Arm B | EXPERIMENTAL | Oral Pazopanib 800 mg once a day+ carboplatin AUC 6 IV over 1 hour every 3 weeks + paclitaxel 175 mg/m\^2 IV over three hours day one q 3 weeks for six cycles |
| Combination | EXPERIMENTAL | Pazopanib and Lapatinib in combination. Subjects remain on treatment until disease progression or withdrawal from study. |
| Combination arm | EXPERIMENTAL | Pazopanib plus lapatinib |
| Lapatinib monotherapy | ACTIVE_COMPARATOR | Lapatinib |
| Pazopanib monotherapy | ACTIVE_COMPARATOR | Pazopanib |
| Single Arm | EXPERIMENTAL | 800 mg pazopanib oral daily |
| monotherapy arm | EXPERIMENTAL | 1500 mg (6 x 250 mg tablets) oral lapatinib once daily |
| Cohort 1 combination arm | EXPERIMENTAL | 1000 mg (4 x 250 mg tablets) of oral lapatinib and 400 mg (4 x 100 mg tablets) of oral pazopanib taken together once daily |
| Cohort 2 combination arm | EXPERIMENTAL | 1500 mg (6 x 250 mg tablets) of oral lapatinib and 800 mg (1 x 500 mg tablets plus 3 x 100 mg tablets) of oral pazopanib taken together once daily |
| A Pazopanib | OTHER | Open label study with one group |
| Temozolomide 100 mg/m2 and Pazopanib 400 mg | EXPERIMENTAL | Temozolomide 100 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28 |
| Temozolomide 75 mg/m2 and Pazopanib 400 mg | EXPERIMENTAL | Temozolomide 75 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28 |
| Temozolomide 150 mg/m2 and Pazopanib 400 mg | EXPERIMENTAL | Temozolomide 150 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28 |
| low dose | EXPERIMENTAL | Pazopanib tablet |
| 1.6 mg | EXPERIMENTAL | The actual dosage is 10 mg/ml (GW786034) given 4 times a day for a maximum daily dosage of 1.6mg |
| TBD COHORT 2 | EXPERIMENTAL | Dose escalation amount to be determined (TBD) after results from Cohort 1 analyzed |
| TBD COHORT 3 | EXPERIMENTAL | Dose escalation amount to be determined (TBD) after results from Cohort 2 analyzed |
| Phase I | EXPERIMENTAL | oral pazopanib once daily (Phase I starting dose 800 mg) and paclitaxel IV once every 3 weeks (Phase I starting dose 135 mg/m2). |
| Treatment Arm A | EXPERIMENTAL | Daily oral pazopanib in combination with weekly oral topotecan. Initially rising dose to determine the maximum tolerated dose: finally an expanded cohort treated at the maximum tolerated dose. |
| Treatment Arm B | EXPERIMENTAL | Daily oral pazopanib in combination with oral topotecan given for 5 consecutive days every 21 days. Initially rising dose to determine the maximum tolerated dose; finally an additional cohort of patients treated at the maximum tolerated dose. |
| Arm C | EXPERIMENTAL | epirubicin (bolus intravenous administration) on Day 1 with once-daily oral administration of pazopanib for Days 14-21 of a 3-week cycle |
| Arm D | EXPERIMENTAL | once-daily oral administration of pazopanib (according to schedule selected from either Arm A, B, or C) (3 week cycle) in combination with doxorubicin (bolus intravenous administration) on Day 1 or 3, depending on the schedule selected from either Arm A, B, or C |
| pazopanib + erlotinib | EXPERIMENTAL | Pazopanib and erlotinib are to be combined at different specified dose levels until an optimally tolerated dose level is identified. Pazopanib, a multi-targeted tyrosine kinase inhibitor of VEGFR-1, -2, and -3, PDGFR-alpha and beta, and c-kit and erlotinib, an epidermal growth factor (EGFR) inhibitor, are to be combined in an effort to simultaneously block two tightly woven cell signaling pathways. |
| pazopanib + pemetrexed | EXPERIMENTAL | Pazopanib and pemetrexed are to be combined at different specified dose levels until an optimally tolerated dose regimen is identified. Combination of an anti-VEGF therapy (such as bevacizumab) with systemic chemotherapy has demonstrated increased clinical efficacy in comparison with systemic chemotherapy alone in several malignancies. Hence, pazopanib, a multi-targeted tyrosine kinase inhibitor of VEGFR-1, -2, and -3, PDGFR-alpha and beta, and c-kit, was chosen to be combined with pemetrexed, a chemotherapeutic agent that inhibits the enzyme thymidylate synthase, in an effort to determine if an anti-angiogenesis inhibitor would enhance the activity of the approved chemotherapeutic agent pemetrexed. |
| FOLFOX 6 + Pazopanib | EXPERIMENTAL | Subjects will receive escalating doses of Pazopanib in combination with FOLFOX 6. |
| CapeOx + Pazopanib | EXPERIMENTAL | Subjects will receive escalating doses of Pazopanib in combination with CapeOx. CapeOx treatment consisted of IV oxaliplatin (130 mg/m\^2) on Day 1 plus oral capecitabine (1000 mg/m\^2) twice daily on Days 2 through 14 of every 21-day cycle. Reduced CapeOx treatment was administered according to the same schedule as the CapeOx treatment, but the dose of capecitabine was reduced to 850 mg/m\^2 twice daily. |
| Lead-In cohort | EXPERIMENTAL | In Part 1 of Lead-In cohort, subjects will be dosed with a single dose of pazopanib with a high-fat breakfast to establish safety and tolerability. |
| Part 1 | EXPERIMENTAL | pazopanib and paclitaxel |
| Part 2 | EXPERIMENTAL | pazopanib, paclitaxel, and carboplatin |
| Part 3 | EXPERIMENTAL | pazopanib, paclitaxel, and lapatinib |
| Subjects receiving treatment A | EXPERIMENTAL | Eligible subjects will receive 0.1 percent pazopanib ointment. |
| Subjects receiving treatment B | EXPERIMENTAL | Eligible subjects will receive 0.5 percent pazopanib ointment. |
| Subjects receiving treatment C | EXPERIMENTAL | Eligible subjects will receive 1 percent pazopanib ointment. |
| Subjects receiving treatment D | PLACEBO_COMPARATOR | Eligible subjects will receive pazopanib vehicle as negative control. |
| Subjects receiving treatment E | PLACEBO_COMPARATOR | Eligible subjects will receive 0.1 percent betamethasone valerate ointment as steroid positive control. |
| Subjects receiving treatment F | PLACEBO_COMPARATOR | Eligible subjects will receive 0.005 percent calcipotriol ointment as vitamin D agonist positive control. |
| Name | Type | Description |
|---|---|---|
| PAZOPANIB | DRUG | 800 mg once daily orally |
| Placebo | DRUG | matching placebo 800 mg once daily orally |
| Placebo comparator | DRUG | Placebo 800 mg daily for 24 months |
| Pazopanib (GW786034) | DRUG | Cycle of 28 days. Pazopanib: 800mg/day |
| Paclitaxel | DRUG | Cycle of 28 days Paclitaxel: 80mg/m2 days 1,8 and 15 |
| pazopanib and pemetrexed | DRUG | oral pazopanib 600 mg once daily and pemetrexed intravenous (IV) 500mg/m\^2 once every 3 weeks, then pazopanib 800 mg once daily |
| pemetrexed and cisplatin | DRUG | pemetrexed IV 500 mg/m\^2 and cisplatin IV 75 mg/m\^2 once every 3 weeks |
| doxorubicin + cyclophosphamide | DRUG | 4 cycles of doxorubicin + cyclophosphamide followed by 4 cycles of paclitaxel + pazopanib. |
| paclitaxel + pazopanib | DRUG | 4 cycles of paclitaxel + pazopanib |
| surgery | PROCEDURE | neoadjuvant surgery for breast cancer |
| pazopanib monotherapy | DRUG | 6 months of treatment with pazopanib monotherapy |
| carboplatin | DRUG | IV over one hour every 3 weeks of 6 cycles |
| lapatinib | DRUG | Lapatinib is a novel compound being developed for the treatment of various cancers. |
| lapatinib (GW572016) | DRUG | - |
| pazopanib (GW786034) 400 mg | DRUG | 400 mg administered orally once daily |
| lapatinib (GW572016) 1500 mg | DRUG | 1500 mg administered orally once daily. |
| lapatinib (GW572016) 1000 mg | DRUG | 1000 mg administered orally once daily |
| pazopanib (GW786034) 800 mg | DRUG | 800 mg administered orally once daily |
| temozolomide | DRUG | Given PO |
| pazopanib hydrochloride | DRUG | Given PO |
| Placebo for pazopanib | OTHER | Control for comparison with pazopanib |
| Moxifloxacin | DRUG | Comparator for pazopanib |
| Placebo for moxifloxacin | OTHER | Placebo for moxifloxacin |
| topotecan | DRUG | Topoisomerase I inhibition. |
| Doxorubicin | DRUG | Arm D - doxorubicin given as a intravenous bolus injection on Day 1 or Day 3 depending on schedule selected from Arm A, B or C - starting dose 60 mg/m2 and increase to 75mg/m2 |
| Epirubicin | DRUG | Arm A and Arm B - epirubicin given as a bolus intravenous injection on Day 3 starting dose 60mg/m2 increase to 90mg/m2 if tolerated; Arm C - epirubicin given as a bolus intravenous injection on Day 1 starting dose 60mg/m2 increase to 90mg/m2 if tolerated |
| Gemcitabine | DRUG | Gemcitabine on Days 1 and 8 of each cycle; initial dose 600 mg/m2 increase to 1,000mg/m2 after evaluation of safety and tolerability; increase to 1250mg/m2 after evaluation of safety and tolerability |
| Cisplatin | DRUG | Cisplatin on Day 1 of each 21-day cycle initial dose 60mg/m2; increase to 80mg/m2 after evaluation of safety and tolerability |
| erlotinib | DRUG | oral tablet taken daily in dosages of 100-150 mg. |
| pemetrexed | DRUG | IV chemotherapeutic agent administered every 21 days in dosages of 400-500 mg/m2 |
| Cetuximab | DRUG | Cetuximab will be supplied as a single-use 50 milliliter vial containing 100 micrograms of cetuximab as a sterile, preservative-free, injectable liquid at a concentration of 2 milligram per milliliter in phosphate. buffered saline |
| Irinotecan | DRUG | Irinotecan hydrochloride trihydrate is an antineoplastic agent of the topoisomerase I inhibitor class. |
| FOLFOX 6 | DRUG | FOLFOX 6 treatment consists of intravenous (IV) oxaliplatin (100 milligram per meter\^2\[mg/m\^2\]), and folinic acid (400 mg/m\^2), IV 5-fluorouracil bolus (400 mg/m\^2) followed by IV 5-fluorouracil (2400 to 3000 mg/m\^2) infusion over 48 hours on Day 1 of every 14-day cycle. |
| CapeOx | DRUG | CapeOx treatment consists of IV oxaliplatin (130 mg/m\^2) on Day 1 plus oral capecitabine (1000 mg/m\^2) twice daily on Days 2 through 14 of every 21-day cycle. Reduced CapeOx treatment will be administered according to the same schedule as the CapeOx treatment, but the dose of capecitabine will be reduced to 850 mg/m\^2 twice daily. |
| Pazopanib vehicle | DRUG | Pazopanib vehicle will be given to subjects. |
| Betamethasone valerate | DRUG | Betamethasone valerate ointment with 0.1 percent concentration will be given to subjects. |
| Calcipotriol | DRUG | Calcipotriol ointment with 0.005 percent concentration will be given to subjects. |
Inclusion/Exclusion Criteria: * High or intermediate grade of soft tissue sarcoma; Low grade tumours allowed provided there is disease progression. * Metastatic and measurable disease (RECIST); * Subjects can have received maximum of 4 prior lines of systemic therapies (including up to 2 combinatio...
Pazopanib is an investigational small molecule being studied for bladder cancer, breast neoplasms, macular degeneration, primary peritoneal carcinoma, ovarian neoplasms, and glioma. It is in Phase 2 clinical development for these oncology and ophthalmology indications, though it remains investigational and is not approved for any use.
Pazopanib targets multiple kinases, including FGFR1, FGFR3, CSF1R, PDGFRB, PDGFRA, KIT, ITK, LCK, FLT1, FLT4, and KDR. It acts as an inhibitor of these molecular targets, which are involved in tumor growth and angiogenesis.
Pazopanib is being developed by GSK plc, which trades under the ticker GSK. The company is conducting clinical trials to evaluate the drug's safety and efficacy across several oncology and ophthalmology indications.
Pazopanib is in Phase 2 clinical development. It has completed five trials and has one active trial, with a total enrollment of 575 participants across studies. The drug is investigational and has not received FDA approval.
Pazopanib has been studied in several clinical trials, including NCT00612456, a Phase 2 study of pazopanib drops in adults with neovascular AMD, and NCT00733304, an extension study. Other trials include NCT01072214 and NCT01154062, which evaluated pazopanib eye drops and tablets in healthy volunteers and patients with macular degeneration.
Pazopanib is also known by the brand name Votrient, which is approved for certain cancers. However, the clinical trials listed here focus on its investigational use in macular degeneration and other conditions, and the drug remains in Phase 2 development for these indications.