Oral Pazopanib Research Articles

Phase I study of pazopanib and vorinostat: a therapeutic approach for inhibiting mutant p53-mediated angiogenesis and facilitating mutant p53 degradation

We carried out a phase I trial of the vascular endothelial growth factor inhibitor pazopanib and the histone deacetylase inhibitor vorinostat to determine the safety and efficacy. Because these agents are known to target factors activated by TP53 mutation and facilitate mutant p53 degradation, a subgroup analysis may be interesting in patients with TP53 mutant malignancies. Patients with advanced solid tumors (n = 78) were enrolled following a 3 + 3 design, with dose expansion for those with responsive tumors. Hotspot TP53 mutations were tested when tumor specimens were available. Adverse events of ≥grade 3 included thrombocytopenia, neutropenia, fatigue, hypertension, diarrhea and vomiting. Overall, the treatment produced stable disease for at least 6 months or partial response (SD ≥6 months/PR) in 19% of the patients, median progression-free survival (PFS) of 2.2 months, and median overall survival (OS) of 8.9 months. In patients with detected hotspot TP53 mutant advanced solid tumors (n = 11), the treatment led to a 45% rate of SD ≥6 months/PR (1 PR and 3 SD ≥6 months), median PFS of 3.5 months, and median OS of 12.7 months, compared favorably with the results for patients with undetected hotspot TP53 mutations (n = 25): 16% (1 PR and 3 SD ≥6 months, P = 0.096), 2.0 months (P = 0.042), and 7.4 months (P = 0.1), respectively. The recommended phase II dosage was oral pazopanib at 600 mg daily plus oral vorinostat at 300 mg daily. The preliminary evidence supports further evaluation of the combination in cancer patients with mutated TP53, especially in those with metastatic sarcoma or metastatic colorectal cancer. www.clinicaltrials.gov, NCT01339871.

Pharmacokinetics of pazopanib administered in combination with bevacizumab

A combination of monoclonal antibody that binds and inhibits effects induced by vascular endothelial growth factor and tyrosine kinase inhibitor of vascular endothelial growth factor receptor represents a promising concept to block pathological angiogenesis completely. A phase I study combining daily oral pazopanib and bevacizumab (given iv every 2 weeks) was performed in order to determine the maximum tolerated dose of the two drugs in combination. Pazopanib pharmacokinetics were evaluated to compare pharmacokinetic parameters given alone and those observed on the day of the bevacizumab administration. Plasma pazopanib concentrations were obtained in 25 patients treated at two dose levels (400 or 600 mg) at Day 1 (given alone) and Day 15 (the day of the 7.5 mg/kg bevacizumab infusion), and analyzed using the NONMEM program. The apparent oral clearance (CL/F, mean value of 0.60 L/h) presented an inter-individual variability of 40 %, and an inter-occasion of 27 %. A modest but statistically significant decrease in CL/F was observed from Day 1 to Day 15 (-16.4, 95 % confidence interval of -8.5 to -27.2 %). However, trough pazopanib concentrations observed at Day 16 (24 h after the bevacizumab iv infusion) were not significantly higher than those observed just before the beginning of the bevacizumab iv infusion, suggesting that the pharmacokinetic change between Day 1 and Day 15 was not due to an interaction of bevacizumab. Overall, the mean observed concentrations at the maximum tolerated pazopanib dose (600 mg) at both Day 1 and Day 15 were higher than those observed at 800 mg once daily level (corresponding to the recommended dose when given alone) during the first-in-man phase 1 study of pazopanib in monochemotherapy. This first population pharmacokinetic analysis of pazopanib shows that inter-individual and inter-study pharmacokinetic variability emphasize the need for further evaluation of therapeutic drug monitoring for pazopanib as suggested for other tyrosine kinase inhibitors.

Pazopanib exposure decreases as a result of an ifosfamide-dependent drug–drug interaction: results of a phase I study

Background:The vascular endothelial growth factor receptor (VEGFR) pathway plays a pivotal role in solid malignancies and is probably involved in chemotherapy resistance. Pazopanib, inhibitor of, among other receptors, VEGFR1–3, has activity as single agent and is attractive to enhance anti-tumour activity of chemotherapy. We conducted a dose-finding and pharmacokinetic (PK)/pharmacodynamics study of pazopanib combined with two different schedules of ifosfamide.Methods:In a 3+3+3 design, patients with advanced solid tumours received escalating doses of oral pazopanib combined with ifosfamide either given 3 days continuously or given 3-h bolus infusion daily for 3 days (9 g m−2 per cycle, every 3 weeks). Pharmacokinetic data of ifosfamide and pazopanib were obtained. Plasma levels of placental-derived growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), soluble VEGFR2 (sVEGFR2) and circulating endothelial cells were monitored as biomarkers.Results:Sixty-one patients were included. Pazopanib with continuous ifosfamide infusion appeared to be safe up to 1000 mg per day, while combination with bolus infusion ifosfamide turned out to be too toxic based on a variety of adverse events. Ifosfamide-dependent decline in pazopanib exposure was observed. Increases in PlGF and VEGF-A with concurrent decline in sVEGFR2 levels, consistent with pazopanib-mediated VEGFR2 inhibition, were observed after addition of ifosfamide.Conclusion:Continuous as opposed to bolus infusion ifosfamide can safely be combined with pazopanib. Ifosfamide co-administration results in lower exposure to pazopanib, not hindering biological effects of pazopanib. Recommended dose of pazopanib for further studies combined with 3 days continuous ifosfamide (9 g m−2 per cycle, every 3 weeks) is 800 mg daily.

Initial Exploration of Oral Pazopanib in Healthy Participants and Patients With Age-Related Macular Degeneration

Neovascular age-related macular degeneration (AMD) is managed with intravitreal anti-vascular endothelial growth factor therapy; however, the burden of care is high and alternate approaches could be beneficial. OBJECTIVE To identify an acceptable dose of oral pazopanib for investigation in AMD. Fourteen-day, placebo-controlled, dose-rising study in 72 healthy participants and 28-day phase 2a open-label study in 15 patients with subfoveal choroidal neovascularization secondary to AMD at a clinical unit for healthy participants and outpatient for patients with AMD. Oral pazopanib tablets, 5 to 30 mg daily (healthy participants) and 15 mg daily (patients with AMD). Safety, pharmacokinetics, best-corrected visual acuity, central retinal lesion thickness, and central retinal thickness at day 29. Oral pazopanib up to 30 mg daily in healthy participants and 15 mg daily in patients with AMD was well tolerated. Six of 15 patients received rescue therapy before day 29; all had the CFH Y402H CC "high-risk" genotype for AMD. Nine patients completed the study without rescue with improvements from baseline in best-corrected visual acuity (8 Early Treatment Diabetic Retinopathy Study letters), central retinal lesion thickness (-50.94 µm), and central retinal thickness (-50.28 µm). There was a trend for association between the CFH Y402H T allele ("low risk" for AMD, n = 6) and improvement. Oral pazopanib (15 mg daily) was well tolerated and resulted in improvements in mean best-corrected visual acuity, central retinal lesion thickness, and central retinal thickness at day 29 in a per-protocol, nonrescued AMD population (n = 9). It is postulated that CFH Y402H genotype may help predict which patients respond to pazopanib. The size and length limitations of this study warrant further investigation to determine if oral pazopanib may be an appropriate treatment for a subset of neovascular patients with AMD or as an adjunct to standard of care. clinicaltrials.gov Identifier: NCT01051700 and NCT01154062.

An Open-Label, Multicenter, Randomized, Phase II Study of Pazopanib in Combination with Pemetrexed in First-Line Treatment of Patients with Advanced-Stage Non–Small-Cell Lung Cancer

This randomized open-label phase II study evaluated the efficacy, safety, and tolerability of pazopanib in combination with pemetrexed compared with the standard cisplatin/pemetrexed doublet in patients with previously untreated, advanced, nonsquamous non-small-cell lung cancer. Patients were randomized (2:1 ratio) to receive pemetrexed 500 mg/m(2) intravenously once every 3 weeks plus either oral pazopanib 800 mg daily or cisplatin 75 mg/m(2) intravenously once every 3 weeks up to six cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis. The primary endpoint was progression-free survival (PFS). The study was terminated after 106 of 150 patients were randomized due to a higher incidence of adverse events leading to withdrawal from the study and severe and fatal adverse events in the pazopanib/pemetrexed arm than in the cisplatin/pemetrexed arm. At the time enrolment was discontinued, there were three fatal adverse events in the pazopanib/pemetrexed arm, including ileus, tumor embolism, and bronchopneumonia/sepsis. Treatment with pazopanib/pemetrexed was discontinued resulting in more PFS data censored for patients in the pazopanib/pemetrexed arm than those in the cisplatin/pemetrexed arm. There was no statistically significant difference between the pazopanib/pemetrexed and cisplatin/pemetrexed arms for PFS (median PFS, 25.0 versus 22.9 weeks, respectively; hazard ratio = 0.75; 95% confidence interval, 0.43%-1.28%; p = 0.26) or objective response rate (23% versus 34%, respectively; 95% confidence interval, -30.6% to 7.2%; p = 0.21). The combination of pazopanib/pemetrexed in first-line treatment of non-small-cell lung cancer showed some antitumor activity but had unacceptable levels of toxicity.

Abstract C71: Phase II study of maintenance therapy with pazopanib or pemetrexed in patients with advanced non-small cell lung cancer (NSCLC) who have not progressed following platinum-based chemotherapy.

Abstract Background: Platinum-based chemotherapy combinations are the standard of care in first-line treatment of advanced NSCLC. Maintenance therapy with a chemotherapeutic agent (continuation maintenance) or a targeted agent (switch maintenance) has been explored to delay recurrence. The purpose of this trial (NCT01313663) was to evaluate the clinical activity and safety profile of pazopanib as switch maintenance in patients with stable disease or better as best response after induction therapy in advanced NSCLC. Methods: Eligible patients had received 4-6 cycles of induction therapy with cisplatin/carboplatin plus pemetrexed and should have had best response of complete response, partial response, or stable disease before entering the study. In this 2-arm, open-label, phase II study, patients were randomized to receive either oral pazopanib 800 mg daily or intravenous pemetrexed 500 mg/m2 on Day 1 of a 21-day cycle. The primary endpoint was to estimate the hazard ratio (HR) for investigator-assessed progression-free survival; secondary endpoints included overall survival, best overall response, and safety. Results: Planned enrollment was 200 patients. The trial was terminated due to evolving standards of care that resulted in a slow enrollment rate. Twenty patients were randomized and 19 received treatment (10 received pazopanib; 9 received pemetrexed). Progression-free survival was 10.3 weeks in the pemetrexed arm and 12.7 weeks in the pazopanib arm (HR = 0.92; 90% confidence interval: 0.32, 2.65). However, the number of evaluable patients was too small to draw conclusions for efficacy, as evidenced by the width of the 90% confidence interval for the HR. Best response was stable disease (2 patients in each arm). All patients experienced at least 1 adverse event (AE). Hepatic toxicities were more common with pazopanib, but low enrollment prevented a complete characterization of AE frequency. There were no fatal serious adverse events (SAEs) in the pazopanib arm and there were 2 fatal SAEs in the pemetrexed arm (respiratory failure and pneumonia). Conclusions: Low accrual and early termination prevented evaluation of the primary endpoint. No new safety signals emerged. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C71. Citation Format: Kartik Konduri, David Smith, Natalie Compton, Denise Elmore Lockheed, Debasis Chakrabarti, Kamal Bhatt. Phase II study of maintenance therapy with pazopanib or pemetrexed in patients with advanced non-small cell lung cancer (NSCLC) who have not progressed following platinum-based chemotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C71.

An open-label study of the safety and tolerability of pazopanib in combination with FOLFOX6 or CapeOx in patients with colorectal cancer

Although combining targeted agents with conventional, first-line cytotoxic therapy has improved survival outcomes in patients with advanced colorectal cancer, further improvements in outcomes and tolerability are needed. This phase I study evaluated the feasibility of combining oral pazopanib, an agent that targets multiple proangiogenic factors, with FOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil) or CapeOx (oxaliplatin and capecitabine). This phase I study evaluated the optimally tolerated regimen of daily pazopanib (dose-escalated) plus standard FOLFOX6 or CapeOx in patients with advanced colorectal cancer. At the optimally tolerated regimen, each cohort was expanded to further evaluate safety and clinical response. The optimally tolerated regimens were pazopanib 800 mg plus FOLFOX6 and pazopanib 800 mg plus reduced CapeOx (capecitabine 850 mg/m(2)). The most commonly reported adverse events in the FOLFOX6 cohorts included decreased appetite, neutropenia, diarrhea, peripheral neuropathy, and vomiting. Similarly, the most commonly reported adverse events in the CapeOx cohorts included fatigue, vomiting, and decreased appetite. The overall response rate was 40 % (8/20 patients) in the pazopanib plus FOLFOX6 cohorts and 38 % (8/21 patients) in the pazopanib plus CapeOx cohorts. Pazopanib combined with FOLFOX6 or reduced CapeOx was adequately tolerated in this patient population.

Phase I study of safety, tolerability, and pharmacokinetics of pazopanib in combination with oral topotecan in patients with advanced solid tumors.

2536 Background: To determine the maximum-tolerated dose (MTD), safety, tolerability and pharmacokinetics of the oral anti-angiogenic drug pazopanib in combination with oral topotecan, an inhibitor of topoisomerase-I. Methods: Two-stage, two-arm, dose escalation and pharmacokinetic phase I study of pazopanib and oral topotecan in patients with advanced solid tumors, (NCT00732420, www.clinicaltrials.gov). This interim report describes the bioavailability and safety results for daily pazopanib combined with oral topotecan (days 1, 8, 15) in a 28-day cycle. Results: Twenty-eight of 32 patients completed at least one cycle and were evaluable for analysis. Three dose-limiting toxicities (DLTs) occurred: grade 3 hand-foot-syndrome, diarrhea and neutropenia. Pazopanib 800 mg/topotecan 10 mg exceeded the MTD with two DLTs in six patients. The most frequent treatment-related toxicities were grade 3 anemia (3/28), leukocytopenia, neutropenia and fatigue (2/28 each). One death due to hepatic failure occurred at pazopanib 800mg/toptecan 2mg in a heavily pre-treated patient with sarcoma that may have been related to paracetamol ingestion but attribution to the pazopanib can not be excluded. Topotecan AUC0-∞ increased 1.58-fold (90%CI: 1.09–1.29) and Cmax increased 1.78-fold (90%CI: 1.08-2.92) when given with pazopanib compared to single administration (n=7). Pazopanib AUC0-24 and Cmax ratios were not increased when co-administered with topotecan: 0.98 (90%CI: 0.95-1.02) and 0.96 (90%CI: 0.92-1.01). Twenty-three patients were evaluable for response (RECIST): PR (2/23; 9%, both ovarian cancer); SD (13/23; 57%) and PD (8/23; 35%). Pazopanib 800 mg/topotecan 8 mg is currently being explored in an expansion cohort. A second treatment arm of pazopanib 800 mg with topotecan daily x5 is ongoing and will be reported separately. Conclusions: Daily pazopanib and weekly oral topotecan is tolerable with handfoot syndrome, neutropenia and fatigue as dose limited side effects. Pazopanib increased topotecan exposure 1.58-fold (AUC0-∞) and 1.78-fold (Cmax). Clinical trial information: NCT00732420.

Abstract 962: Prolonged antiangiogenic therapy with oral metronomic topotecan and pazopanib in pediatric solid tumor mouse model.

Abstract Background: We have previously observed that the combination of daily oral Low Dose Metronomic (LDM) Topotecan (TP) and Pazopanib (PZ) significantly delayed the tumor growth and enhanced the survival in neuroblastoma (NB) mouse models (Kumar et al, 2011). However, this combination (TP+PZ) did not stop tumor growth and the animals eventually died due to disease during the course of therapy. Therefore, we planned to investigate the factors contributing to resistance to this antiangiogenic therapy in NB mouse model. Objectives: To investigate the effect of prolonged TP+PZ therapy on angiogenesis by testing the effect of therapy at different durations in NB mice xenograft model. Methods: Mice bearing subcutaneous SK-N-BE(2) NB xenografts were treated with either of the four regimens, daily, orally: vehicle (untreated), PZ (150 mg pazopanib), TP (1.0 mg/Kg topotecan), TP+PZ (combination of topotecan and pazopanib, same doses as single agents). Durations of treatment planned for each regimen were 28 days, 56 days and 80 days. Animals were sacrificed after these durations or upon end point, whichever was earlier. The criteria for end point are tumor sizes exceeding 2.0 cms in diameter or animals showing signs of morbidity. Results: The animals in control, PZ, TP reached the end point after 23d, 28d and 46d respectively. TP+PZ halted the tumor growth for up to 40 days, after which gradual growth was observed. The mean tumor diameters in the third TP+PZ group reached 1.8 cms at the day 80. CD31 immunofluorescence revealed that all the three durations of TP+PZ significantly lowered microvessel densities compared to the control (P= 0.02, 0.04 and 0.009 respectively for 28, 56 and 80 days respectively). However the ratio of CD31 to α- smooth muscle actin (pericyte marker) stained areas were significantly higher in animals treated with TP+PZ for 56 and 80days, compared to control (P=0.0006; 56d and 0.004; 80d) indicating higher pericyte coverage. TP+PZ (28d) showed signs of necrosis and cell cycle arrest (Ki67 staining), which were not observed in later durations (56 and 80 days) with TP+PZ. Long-term TP+PZ therapy also increased the levels of HIF-1 alpha, VEGF and Oct-4 within the tumor tissue. Conclusion: This study indicates that even though prolonged TP+PZ therapy demonstrates sustained antiangiogenic activity, it encounters resistance in NB, potentially mediated by pericyte coverage. Long-term TP+PZ therapy may also increase tumor stemness. Citation Format: Sushil Kumar, Reza Bayat Mokhtari, Syed Islam, Herman Yeger, Sylvain Baruchel. Prolonged antiangiogenic therapy with oral metronomic topotecan and pazopanib in pediatric solid tumor mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 962. doi:10.1158/1538-7445.AM2013-962

Topical Pazopanib Blocks VEGF-Induced Vascular Leakage and Neovascularization in the Mouse Retina but Is Ineffective in the Rabbit

To test the effect of pazopanib, a tyrosine kinase inhibitor that blocks VEGF and platelet-derived growth factor (PDGF) receptors and c-Kit, on vascular leakage and neovascularization (NV) in the retina. Pazopanib was tested to determine its effect on VEGF-induced vascular permeability via measurement of [(3)H]mannitol retina to lung (RLLR) and retina to renal leakage ratios (RRLR) and in rho/VEGF mice with subretinal NV. In rabbits, the effect of intravitreal, topical, and systemic pazopanib on VEGF-induced leakage was tested by vitreous fluorophotometry. In mice, oral pazopanib (40 mg/kg twice a day [bid]) reduced RLLR (0.84 to 0.58, P = 0.0014) and RRLR (0.55 to 0.30, P = 0.0018) in VEGF-injected eyes. After intraocular injection of VEGF into both eyes, topical pazopanib (10 mg/mL three times a day [tid] for 14 days) reduced RLLR (0.85 vs. 0.56, P = 0.001), RRLR (0.44 vs. 0.28, P = 0.0075), and immunoreactive albumin in the retina compared to values in fellow eye controls. Treatment of one eye of rho/VEGF mice with 10 mg/mL, but not 5 mg/mL, pazopanib tid reduced the mean area of subretinal NV compared to that in fellow eyes (0.0055 vs. 0.0025 mm(2), P = 0.020). In rabbits, intravitreal pazopanib suppressed VEGF-induced fluorescein leakage, but topical (10 mg/mL four times a day [qid] or 12 mg/mL bid) had no significant effect. Systemic administration of pazopanib by osmotic pump with or without 10 mg/mL drops tid also failed to suppress VEGF-induced leakage. Administration of pazopanib topically or systemically suppressed retinal vascular leakage in mice, but not rabbits. These data suggest differences in the blood-retinal barrier (BRB) of mice and rabbits and indicate that penetration through the outer BRB may be needed for topically administered drugs to exert effects in the retina.

Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer

1. Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma.2. In this two-part study, we investigated the metabolism, disposition of [14C]pazopanib, and the oral bioavailability of pazopanib tablets in patients with advanced cancer.3. In part A, three men each received a single oral dose of [14C]pazopanib in suspension (400 mg, 70 µCi). Pazopanib was the predominant drug-related component in circulation. Two metabolites derived from hydroxylation and one from N-demethylation were also circulating, but were minor, each accounting for <5% of plasma radioactivity. Faecal elimination predominated, accounting for 82.2% of the administered radio-dose, with negligible renal elimination (2.6% of dose). Pazopanib was primarily excreted as the unchanged drug in faeces (67% of dose).4. In part B, seven additional patients received a single intravenous administration of 5 mg pazopanib (day 1) followed by oral administration of 800 mg pazopanib tablet once daily for 26 days (days 3 or 5–28). In the three evaluable patients from part B, pazopanib had a slow plasma clearance and a small volume of distribution. The absolute oral bioavailability of the 800 mg pazopanib tablet ranged from 14% to 39%.

Pazopanib

Pazopanib inhibits multiple receptor tyrosine kinases, through which it mediates antiangiogenic and antitumour effects. The clinical efficacy of oral pazopanib in patients with metastatic soft tissue sarcoma (STS) was demonstrated in a randomized, double-blind, placebo-controlled, phase III trial (PALETTE), generally confirming the findings of an earlier, noncomparative phase II study. In the multicentre PALETTE trial, pazopanib 800 mg once daily significantly prolonged median progression-free survival (PFS; primary endpoint) ≈3-fold relative to placebo (4.6 vs 1.6 months) in adults with progressive metastatic STS following standard chemotherapy. According to subgroup analyses, pazopanib provided benefit over placebo in terms of PFS regardless of whether the tumour was low/intermediate or high grade and regardless of tumour histology (leiomyosarcoma, synovial sarcoma, other STS), although patients with adipocytic STS were among those excluded from the PALETTE trial, as sufficient benefit had not been shown with the drug in patients with adipocytic STS in the phase II study. At final analysis of the PALETTE trial, median overall survival was ≈2 months longer with pazopanib than with placebo, although this between-group difference was not statistically significant. Oral pazopanib generally had no detrimental effect on health-related quality of life and had an acceptable tolerability profile in patients with STS in the PALETTE trial, with adverse events generally being grade 1 or 2 in severity.

Phase I trial of metronomic oral topotecan in combination with pazopanib utilizing a daily dosing schedule to treat recurrent or persistent gynecologic tumors.

5014 Background: Metronomic oral topotecan has antiangiogenic properties. Oral pazopanib is also a potent inhibitor of VEGF angiogenesis with clinical benefit. This study investigated the safety and efficacy of daily topotecan and pazopanib. Methods: This phase I, single-center, open-label, dose ranging study comprised 28-day cycles of daily oral topotecan/pazopanib at dose levels of 0.50/400, 0.25/800, 0.25/600, and 0.25/400 mg. A standard 3+3 dose escalation design was used. Dose limiting toxicity (DLT) was defined as ≥ grade 3 adverse event (AE) occurring in cycle 1, noncompletion of cycle 1 at prescribed dose, or inability to start cycle 2 as scheduled due to toxicities. Imaging was conducted after every 2 cycles for response assessment. Confirmed responses were evaluated per RECIST 1.0. Results: 25 extensively pretreated patients (pts) with gynecologic tumors (6 cervical, 7 endometrial, 8 ovarian, 4 other) were enrolled. Mean age was 61 years; 19 Caucasian, 6 African American. Median number of cycles received was 4 (range 1-19). DLTs occurred ≥ 2 pts for A (2/6), B (2/7), C (3/7). For level D, 1/5 had a DLT, but one dose level C pt with a DLT received level D dosing due to unavailability of pazopanib. 9/25 pts had any serious adverse event (SAE), and respiratory SAEs were most common (4/16 SAEs). Nausea, fatigue, dysgeusia, diarrhea, and vomiting were the most common conditions reported as non-serious AEs. The Table shows best overall response (28%) by dose level. Conclusions: DLTs in dose levels C and D were effectively managed with minor dose and schedule adjustments. 4 pts with DLTs at these doses remained on treatment for 4, 5, and 6 months, with one pt still on treatment at 9 months. Given the initial biologically favorable signal in this heavily pretreated group and low toxicity, we recommend a randomized phase II trial to define efficacy using the 0.25/600 regimen allowing for dose reduction if needed. [Table: see text]

Pazopanib therapy for cerebellar hemangioblastomas in von Hippel–Lindau disease

von Hippel-Lindau (VHL) disease is a genetically acquired multisystem tumor syndrome of the viscera and central nervous system (CNS). The most common tumors associated with this disease are histologically benign, slow-growing CNS hemangioblastomas affecting the retina, cerebellum, brainstem, spinal cord or nerve roots. With mean age at diagnosis of 30 years, CNS hemangioblastomas are usually the first manifestation of the disease. Ongoing clinical and radiological surveillance is required, with symptomatic lesions necessitating treatment. As tumor growth is inevitable during the lifetime of most VHL patients, and the multiplicity of tumors may preclude surgical cure, the search for effective therapies is ongoing. Here we provide the first report demonstrating clinical and radiological anti-tumor response using pazopanib, a small molecule multi-receptor tyrosine kinase inhibitor, in a patient with treatment-refractory VHL-associated CNS hemangioblastoma. Treatment initiation with daily oral pazopanib (800 mg/day) resulted in significant neurologic improvement and radiologic tumor volume reduction.

Abstract C108: An expanded imaging cohort of pazopanib in children and adolescents with relapsed or refractory soft tissue sarcoma (ADVL0815): A Children's Oncology Group phase I consortium trial.

Abstract Background: Pazopanib (NCT00929903) is an orally available small molecule inhibitor of VEGFR 1–3, PDGFR α/β, and c-kit, which has been shown to prolong progression free survival in adults with soft tissue sarcoma (STS). Following a standard phase I dose escalation trial to determine the pediatric maximum tolerated dose (MTD), an expanded cohort of children and adolescents with relapsed and refractory STS and at least one lesion amenable to dynamic contrast enhanced MRI (DCE-MRI) was studied to explore changes in tumor blood volume and vascular permeability following initiation of pazopanib, and to correlate these changes with clinical outcome. Methods: Oral pazopanib was administered at 450mg/m2 once daily in 28 day cycles, for up to 24 cycles. DCE-MRI scans were obtained at baseline and within 15 × 2 days after initiation of pazopanib. DCE-MRI data sets were analyzed using a two compartment kinetic model yielding estimates of fractional blood volume and the permeability transfer constant (Ki). Results: 10 subjects were enrolled [5 male; median age 17 yrs (range, 8–23)], of whom 8 had paired DCE-MRI scans of sufficient quality to be evaluable. Subjects received a median of 4 cycles (range 1–7; 3 remain on study receiving courses 6, 7 and 8). One subject had a dose limiting toxicity of Gr3 back and extremity pain with Gr3 sensory neuropathy. Other non-dose limiting toxicities occurring in &amp;gt;10% of subjects (n=10) during the first cycle included mild myelosuppression, sinus bradycardia, fatigue, diarrhea, nausea, vomiting, anorexia, dehydration, dizziness, headache, liver transaminase elevation and hyperglycemia. All subjects with evaluable DCE-MRI (n=8) experienced a decrease in tumor blood volume following initiation of pazopanib, with a mean pre-treatment level of 16% (range 1–29%) versus 7% (0–15%) post-treatment (p&amp;lt;0.01). Similarly all subjects had a decrease in Ki with mean pretreatment values of 7.74 (range 2.31–20.38) ml/100g/min, decreasing post-treatment to 4.28 (range 0.19–12.60) ml/100g/min (p&amp;lt;0.01). Although limited by the small sample size, there is a suggestion that patients with best response of stable disease appear to have lower tumor blood volume at baseline than those with progressive disease. Conclusions: DCE-MRI changes in tumor blood volume and Ki in pediatric and adolescent patients with soft tissue sarcoma are supportive of physiological activity and the antiangiogenic mechanism of pazopanib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C108.

Highlights of This Issue

Adoptive T-cell therapy generally fails to trigger clinically relevant anticancer immunity in patients with solid tumors. In this issue de Bruyn and colleagues developed a novel strategy to augment antitumor T-cell activity by selectively delivering TRAIL to the cell surface of T cells. T cells armed with TRAIL in this manner were up to 500-fold more effective against cancer cell lines, primary patient-derived cancer cells, and in a xenograft model of advanced colon carcinoma. The reported approach may easily be integrated into current adoptive T-cell strategies and thus may be useful for optimizing adoptive T cell therapy in patients suffering from solid cancers.The oncogene TCL1 plays a key role in promoting leukemic transformation in B chronic lymphocytic leukemia (B-CLL).Voltan and colleagues show, with primary cells from patients with B-CLL and in B leukemic cell lines with different p53 status, that activation of p53represses the transcription of TCL1. They obtained these results through ex vivo analysisof the effect of Nutlin-3, a nongenotoxic activator of the p53 pathway, on TCL1 regulation, and the results were confirmed by p53 knockdown and TCL1 overexpression experiments. The data suggest that TCL1 downregulation is an important mediator of Nutlin-3 cytotoxicity and that therapeutic strategies should be further explored to improve its antileukemic activity.The antitumor and antiangiogenic activity of oral low-dose metronomic topotecan in combination with oral pazopanib has been established in pediatric neuroblastoma, rhabdomyosarcoma, and osteosarcoma mouse models. The activity of this regimen across multiple pediatric tumor types, including metastatic models, creates an opening for development of pediatric clinical trials that incorporate this oral maintenance regimen. The hope is that this strategy will lead to control of minimal residual disease and increase survival in children with these aggressive tumors.Clusterin (CLU) is a stress-activated cytoprotective chaperone upregulated by a variety of anticancer therapies that confers treatment resistance when it is overexpressed. Preclinical studies have shown that CLU suppression resensitizes docetaxelrefractory cancer cells to docetaxel.This clinical trial provides evidence that a combination of the CLU inhibitor custirsen with chemotherapy is feasible in patients with progressive metastatic castrateresistant prostate cancer (CRPC) after first-line docetaxel therapy. In addition, because anticancer activity and pain responses were higher than expected, the results show some evidence of enhanced docetaxel activity as well. Moreover, these results reaffirm that custirsen decreases levels of serum CLU, and for the first time identify correlations between serum CLU and survival.

A phase I pharmacokinetic and safety evaluation of oral pazopanib dosing administered as crushed tablet or oral suspension in patients with advanced solid tumors

Because cancer patients may have difficulty swallowing whole tablets, crushing tablets or ingesting an oral suspension is a practical alternative. This open-label, 2-part, randomized crossover, phase I study evaluated the pharmacokinetics and tolerability of pazopanib administered as a crushed tablet or an oral suspension relative to whole tablet in patients with advanced cancer (Part 1). Patients completing Part 1 were eligible for continuous daily pazopanib 800 mg (Part 2). Administration of a single pazopanib 400 mg crushed tablet increased the area under the curve from 0 to 72 h (AUC((0-72)); 46%) and maximum observed plasma concentration (C(max); ~2-fold), and decreased time to achieve maximum plasma concentration (T(max); ~2 h), indicating increased rate and extent of oral absorption relative to whole-tablet administration. Similarly, a single dose of pazopanib 400 mg suspension increased AUC((0-72)) (33%) and C(max) (29%), and decreased T(max) (1 h). These changes in pharmacokinetic parameters were not associated with increases in the magnitude or duration of short-term (ie, up to 72 h) blood pressure elevation compared with whole-tablet administration.

Phase I study of pazopanib in children with relapsed or refractory solid tumors (ADVL0815): A Children’s Oncology Group Phase I Consortium Trial.

9501 Background: Pazopanib, an orally available potent and selective small molecule tyrosine kinase inhibitor, targets VEGFR 1-3, PDGFR α/β, and c-kit. A phase I trial to determine the toxicities, maximum tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics of pazopanib in children with refractory solid tumors (including CNS) was performed. Methods: Oral pazopanib (tablet formulation) was administered once daily in 28 day cycles, for up to 24 cycles. Cohorts were enrolled at 4 dose levels (275 to 600 mg/m2) using the rolling-six design. Dose determination for subsequent cohorts was based on cycle 1 toxicity (CTC v3) in the prior cohort. Results: 27 subjects were enrolled; 25 were eligible and 23 were evaluable for dose-limiting toxicity (DLT) [13 male, median age 13 yrs (range, 4-21)]. Subjects received a median of 3 cycles (range 1-13). Observed cycle 1 DLTs included: Gr3 lipase elevation (n=1, 275 mg/m2), Gr3 proteinuria and Gr3 hypertension (n=1, 450 mg/m2), Gr3 amylase elevation (n=1, 600 mg/m2) and Gr3 hypertension (n=1, 600 mg/m2). Thus, the MTD was 450 mg/m2. Cycle 1 non-hematologic toxicities observed in >10% of patients included Gr2 hypertension (n=6), left ventricular dysfunction (n=1), fatigue (n=3), rash (n=2), hypothyroidism (n=1), diarrhea (n=1), nausea (n=1) vomiting (n=2), amylase (n=1), lipase (n=2), proteinuria (n=1), abdominal pain (n=2) and headache (n=5); and reversible Gr3 hypophosphatemia (n=1). Prolonged QTc was not observed. Later adverse events requiring treatment discontinuation included: intolerable Gr2 diarrhea; Gr3 myalgia associated with Gr3 microangiopathic hemolytic anemia; Gr3 hand foot syndrome; and recurrent Gr3 neutropenia (each, n=1). PK data will be presented. One subject with hepatoblastoma had a PR by cycle 6, but was removed for neutropenia after cycle 12 (now receiving via compassionate use), and 4 pts had SD > 6 cycles (3 remain on therapy). Plasma VEGF (p=0.006) and PlGF (p<0.001) increased, whereas endoglin (p=0.005) and soluble VEGFR2 (p<0.001) decreased from baseline to d15 (n=22). Conclusions: The MTD of pazopanib in children with solid tumors is 450 mg/m2with toxicities similar to other VEGF blocking agents.

A Phase I Study of the Pharmacokinetic and Safety Profiles of Oral Pazopanib With a High-Fat or Low-Fat Meal in Patients With Advanced Solid Tumors

Pazopanib is an oral angiogenesis inhibitor of vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, and cytokine receptor. This open-label, randomized, crossover, phase I study evaluated the effect of low- and high-fat meals on the pharmacokinetics (PK) of pazopanib in patients with advanced solid tumors. Patients participated in either the lead-in cohort or randomized food-effect cohort. Patients in the lead-in cohort were administered a single dose of pazopanib 400 mg with a high-fat meal. Patients in the food-effect cohort were randomized to receive single doses of pazopanib 800 mg in fed condition (high- or low-fat meal) or fasting condition, in random sequence 14 days apart. After completion of the study, patients were given the opportunity to continue treatment with daily pazopanib 800 mg. Administration of pazopanib with both low- and high-fat meals increased maximum observed plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) by approximately twofold as compared with the corresponding values when administered to patients in the fasted condition. Therefore, pazopanib should be administered to patients in the fasted state so as to minimize within- and between-day variability in the systemic exposure to pazopanib in patients with cancer.

Pazopanib

Pazopanib is an orally administered, multi-tyrosine kinase inhibitor that interrupts tumor growth in renal cell carcinoma. In a randomized, double-blind, placebo-controlled, multinational trial in patients with locally advanced or metastatic renal cell carcinoma, the median progression-free survival (PFS) of patients who were treated with pazopanib 800 mg once daily was significantly longer than that of placebo recipients (9.2 vs 4.2 months; hazard ratio 0.46 [95% CI 0.34, 0.62]). In prespecified analyses in treatment-naive and cytokine-pretreated patients, grouped according to prior treatment history, age, sex, Memorial Sloan-Kettering Cancer Center risk category, and Eastern Cooperative Oncology Group performance status, median PFS was significantly longer in pazopanib than placebo recipients in all subgroups. Pazopanib recipients also had a significantly higher overall response rate than placebo recipients; in pazopanib recipients, the median time to response was 11.9 weeks and the median duration of response was 58.7 weeks. Oral pazopanib had an acceptable tolerability profile in patients with advanced renal cell carcinoma. Adverse events were common in pazopanib and placebo recipients and were mostly of mild to moderate severity.