ABSTRACT
Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia (MLL) gene rearrangements (MLL-r) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 25) at pinometostat doses of 54 and 90 mg/m2 per day by continuous intravenous infusion in 28-day cycles. Because a maximum tolerated dose was not established in the dose-escalation phase, the expansion doses were selected based on safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady-state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remission at 54 mg/m2 per day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using the single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe, with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as NCT01684150.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzimidazoles/therapeutic use , Histones/metabolism , Leukemia, Myeloid, Acute/drug therapy , Methyltransferases/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Benzimidazoles/adverse effects , Female , Histone-Lysine N-Methyltransferase , Humans , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Male , Methylation/drug effects , Methyltransferases/metabolism , Middle Aged , Young AdultABSTRACT
The induction of CYP2C9 by dabrafenib using S-warfarin as a probe and the effects of a CYP3A inhibitor (ketoconazole) and a CYP2C8 inhibitor (gemfibrozil) on dabrafenib pharmacokinetics were evaluated in patients with BRAF V600 mutation-positive tumors. Dabrafenib single- and repeat-dose pharmacokinetics were also evaluated. S-warfarin AUC(0- ∞) decreased 37% and Cmax increased 18% with dabrafenib. Dabrafenib AUC(0- τ) and C(max) increased 71% and 33%, respectively, with ketoconazole. Hydroxy- and desmethyl-dabrafenib AUC(0-τ) increased 82% and 68%, respectively, and AUC for carboxy-dabrafenib decreased 16%. Dabrafenib AUC(0-τ) increased 47%, with no change in C(max), after gemfibrozil co-administration. Gemfibrozil did not affect systemic exposure to dabrafenib metabolites. Single- and repeat-dose dabrafenib pharmacokinetics were consistent with previous reports. All cohorts used the commercial capsules. More-frequent monitoring of international normalized ratios is recommended in patients receiving warfarin during initiation or discontinuation of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A or CYP2C8 is recommended during treatment with dabrafenib.
Subject(s)
Gemfibrozil/pharmacology , Imidazoles/administration & dosage , Imidazoles/pharmacokinetics , Ketoconazole/pharmacology , Oximes/administration & dosage , Oximes/pharmacokinetics , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Anticoagulants/pharmacokinetics , Cytochrome P-450 CYP2C8 Inhibitors/pharmacology , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Drug Interactions , Female , Humans , Imidazoles/metabolism , Imidazoles/pharmacology , Male , Middle Aged , Oximes/metabolism , Oximes/pharmacology , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Warfarin/pharmacokineticsABSTRACT
This study was designed to evaluate the safety, pharmacokinetics, and clinical activity of pazopanib combined with paclitaxel to determine the recommended phase II dose in the first-line setting in patients with advanced solid tumors. Patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated regimen (MTR) of once daily pazopanib plus paclitaxel administered every 3 weeks at four dose levels (DL1-4). Safety, pharmacokinetics, pharmacogenetics, and disease assessments were performed. Twenty-eight patients received treatment. One patient at DL1 had dose-limiting toxicity (DLT) of elevated hepatic enzymes. After pazopanib discontinuation, liver enzyme concentrations remained high until a concurrent medication, simvastatin, was discontinued. This patient had the defective CYP2C8*3*3 genotype. At DL2, 1 patient had DLT of elevated hepatic enzymes with rash and 1 patient had DLT of rash. The MTR was paclitaxel 150 mg/m(2) plus pazopanib 800 mg. The most common toxicities were alopecia, fatigue, hypertension, nausea, diarrhea, dysgeusia, neutropenia, myalgia, hair color changes, and peripheral neuropathy. Coadministration of pazopanib and paclitaxel resulted in a 38% increase in systemic exposure to paclitaxel, relative to administration of paclitaxel alone, at the MTR. Of the 28 patients treated with the combination, 10 achieved a partial response and 10 achieved stable disease of ≥12 weeks. Pazopanib 800 mg daily plus paclitaxel 150 mg/m(2) every 3 weeks was the recommended phase II dose, with a manageable safety profile, and with clinical activity in both melanoma and non-small cell lung cancer that suggest further evaluation of this combination is warranted.
Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Paclitaxel/therapeutic use , Pyrimidines/therapeutic use , Sulfonamides/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dose-Response Relationship, Drug , Female , Humans , Indazoles , Leukocyte Count , Male , Middle Aged , Neoplasm Staging , Neoplasms/blood , Neoplasms/pathology , Paclitaxel/adverse effects , Paclitaxel/pharmacokinetics , Paclitaxel/pharmacology , Pyrimidines/adverse effects , Pyrimidines/pharmacology , Sulfonamides/adverse effects , Sulfonamides/pharmacologyABSTRACT
BACKGROUND: Pazopanib is a multi-targeted tyrosine kinase inhibitor shown to be clinically active in the treatment of various cancer types. This study aimed to evaluate the maximum tolerated regimen (MTR), safety, and pharmacokinetics of pazopanib in combination with irinotecan and cetuximab in adult patients with relapsed or refractory metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: This was a Phase I, 3 + 3 design, open-label, dose-escalation study (NCT0050943; VEG108925) conducted in sequential cohorts to determine the MTR of pazopanib and irinotecan administered with cetuximab. Twenty-five patients received treatment in three dosing cohorts and were evaluated for safety and tolerability of the combination and pharmacokinetics of individual drugs. RESULTS: The MTR was determined to be 400 mg pazopanib per day orally in combination with 150 mg/m(2) irinotecan biweekly and 250 mg/m(2) cetuximab weekly by infusion. Neutropenia was the main dose-limiting toxicity. Pharmacokinetic results suggested that the overall systemic exposure to SN-38, the active metabolite of irinotecan, was affected by pazopanib to a greater extent than was the systemic exposure to irinotecan itself. CONCLUSIONS: This study provided evidence for the manageable safety profile and feasibility of using the novel triplet combination of pazopanib, irinotecan, and cetuximab in patients with refractory mCRC. Further large-scale Phase II studies are warranted.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Colorectal Neoplasms/drug therapy , Adult , Aged , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/pharmacokinetics , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/analogs & derivatives , Camptothecin/pharmacokinetics , Cetuximab , Colorectal Neoplasms/metabolism , Drug Resistance, Neoplasm , Female , Humans , Indazoles , Irinotecan , Male , Maximum Tolerated Dose , Middle Aged , Neutropenia/chemically induced , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Recurrence , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/pharmacokinetics , Topoisomerase I Inhibitors/administration & dosage , Topoisomerase I Inhibitors/adverse effects , Topoisomerase I Inhibitors/pharmacokinetics , Treatment OutcomeABSTRACT
IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTION: Oral pazopanib tablets, 5 to 30 mg daily (healthy participants) and 15 mg daily (patients with AMD). MAIN OUTCOMES AND MEASURES: Safety, pharmacokinetics, best-corrected visual acuity, central retinal lesion thickness, and central retinal thickness at day 29. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01051700 and NCT01154062.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Pyrimidines/administration & dosage , Sulfonamides/administration & dosage , Wet Macular Degeneration/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/pharmacokinetics , Complement Factor H/genetics , Female , Genotype , Humans , Indazoles , Male , Middle Aged , Pharmacogenetics , Polymorphism, Single Nucleotide , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Single-Blind Method , Sulfonamides/adverse effects , Sulfonamides/pharmacokinetics , Treatment Outcome , Visual Acuity/physiology , Wet Macular Degeneration/genetics , Wet Macular Degeneration/physiopathology , Young AdultABSTRACT
PURPOSE: The purpose of this study is to characterize tumor growth kinetics in patients with renal cell carcinoma (RCC) after treatment with pazopanib or placebo and to identify predictive patient-specific covariates. METHODS: Different tumor growth models that included patient-specific covariates were fit to tumor growth data from Phase 2 (n = 220) and Phase 3 (n = 423) clinical trials using nonlinear mixed-effects modeling. Logistic regression was used to determine whether individual model parameters or covariates were related to occurrence of new lesions. RESULTS: A modified Wang model that included a quadratic growth term and a mixture model adequately described the data. Patients in Group 1 (93 %) showed treatment-dependent tumor shrinkage followed by treatment-independent regrowth. Patients in Group 2 (7 %) showed treatment-independent tumor shrinkage that did not regrow. In Group 1, pazopanib 800 mg increased the tumor shrinkage rate by 267 % compared to placebo. Baseline tumor size was dependent on baseline hemoglobin, baseline lactate dehydrogenase, study, and prior nephrectomy. Logistic regression analysis showed that prior radiotherapy, baseline tumor size, tumor shrinkage rate, tumor regrowth rate, study, and treatment (P < 0.01 for all) were all important predictors of new lesions. Patients treated with placebo were approximately twice as likely to develop new lesions than patients treated with pazopanib. CONCLUSIONS: Mathematical modeling of tumor growth kinetics can quantify the effect of anticancer therapies. Pazopanib 800 mg was shown to be an effective treatment for RCC that increased the tumor shrinkage rate by 267 % compared with placebo and reduced the likelihood of developing new lesions.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Kidney/drug effects , Models, Biological , Pyrimidines/therapeutic use , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Sulfonamides/therapeutic use , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/radiotherapy , Carcinoma, Renal Cell/surgery , Combined Modality Therapy , Double-Blind Method , Female , Humans , Indazoles , Kidney/pathology , Kidney/radiation effects , Kidney/surgery , Kidney Neoplasms/pathology , Kidney Neoplasms/radiotherapy , Kidney Neoplasms/surgery , Kinetics , Logistic Models , Male , Middle Aged , Pharmacogenetics/methods , Tumor Burden/drug effectsABSTRACT
PURPOSE: The metabolism of pazopanib is primarily mediated by CYP3A4. The solubility of pazopanib is pH-dependent, and an elevated gastric pH may decrease its bioavailability. This study evaluated the effect of a potent CYP3A4 inhibitor, ketoconazole, and the proton pump inhibitor esomeprazole on the pharmacokinetics and safety of pazopanib and its metabolites. METHODS: In Arm A, patients received pazopanib 400 mg alone once daily for 7 days followed by pazopanib 400 mg plus ketoconazole 400 mg once daily for 5 days. In Arm B, patients received pazopanib 800 mg once daily for 7 days, followed by pazopanib 800 mg plus esomeprazole 40 mg once daily for 5 days, and then pazopanib alone on the last day. RESULTS: Arm A enrolled 21 patients. In the presence of ketoconazole, mean area under the plasma concentration-time curve 24 h post-dose (AUC(0-24)) and mean maximum observed concentration (C max) of pazopanib increased by 66 and 45 %, respectively; mean AUC(0-24) and C max for pazopanib metabolites were lower or remained unchanged. Arm B enrolled 13 patients. In the presence of esomeprazole, mean pazopanib AUC(0-24) and C max decreased by 40 and 42 %, respectively; mean values of those parameters for metabolites of pazopanib also decreased. CONCLUSIONS: Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If coadministration is necessary, pazopanib should be reduced to 400 mg. Concomitant use of pazopanib and proton pump inhibitors should also be avoided. Alternative dosing regimens that do not increase gastric pH at the time of pazopanib dosing should be considered.
Subject(s)
Angiogenesis Inhibitors/pharmacokinetics , Esomeprazole/pharmacology , Ketoconazole/pharmacology , Neoplasms/drug therapy , Proton Pump Inhibitors/pharmacology , Pyrimidines/pharmacokinetics , Sulfonamides/pharmacokinetics , Adult , Aged , Aged, 80 and over , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/therapeutic use , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP3A Inhibitors , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Interactions , Esomeprazole/administration & dosage , Esomeprazole/adverse effects , Female , Humans , Indazoles , Ketoconazole/administration & dosage , Ketoconazole/adverse effects , Male , Middle Aged , Neoplasms/metabolism , Proton Pump Inhibitors/administration & dosage , Proton Pump Inhibitors/adverse effects , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/therapeutic useABSTRACT
PURPOSE: Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction. EXPERIMENTAL DESIGN: Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used. RESULTS: Ninety-eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and area under the curve [AUC(0-24)] in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose-proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites. CONCLUSIONS: In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (FDA)-approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Liver Diseases/etiology , Neoplasms/drug therapy , Neoplasms/pathology , Pyrimidines/therapeutic use , Sulfonamides/therapeutic use , Adult , Aged , Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/pharmacokinetics , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Female , Humans , Indazoles , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Neoplasms/complications , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Sulfonamides/adverse effects , Sulfonamides/pharmacokinetics , Treatment Outcome , Young AdultABSTRACT
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 [(14)C]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 [(14)C]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%.
Subject(s)
Angiogenesis Inhibitors/pharmacokinetics , Pyrimidines/pharmacokinetics , Sulfonamides/pharmacokinetics , Aged , Aged, 80 and over , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/therapeutic use , Carbon Radioisotopes , Humans , Indazoles , Male , Middle Aged , Pyrimidines/administration & dosage , Pyrimidines/therapeutic use , Sulfonamides/administration & dosage , Sulfonamides/therapeutic useABSTRACT
Relationships between plasma pazopanib concentrations and the probability of elevations in blood pressure, a marker of vascular endothelial growth factor receptor inhibition, and alanine aminotransferase (ALT) were investigated with logistic regression models. Data from a Phase I dose-escalation study in cancer patients (n = 57) were examined to determine the relationship between steady-state trough plasma pazopanib concentrations (Cτ ) and a clinically significant blood pressure increase, using a Bayesian logistic regression model. Data from 5 monotherapy studies in cancer patients (n = 344) were pooled to investigate the relationship between Cτ and maximum ALT ≥ 3× the upper limit of normal (ULN), using a Bayesian logistic regression model incorporating an asymptote. Both models were fit using WinBUGS. The median (95% credible interval, CrI) Cτ at which the probability of a clinically significant increase in blood pressure was 50% (EC50 ) was 12.3 µg/mL (6.12, 18.4). The median (95% CrI) EC50 for the maximum probability of ALT ≥ 3 × ULN was 15.4 µg/mL (3.8, 41.2) and the median (95% CrI) maximum probability of ALT ≥ 3 × ULN was 21% (14.5, 43.1). Results suggest that dose adjustments could be useful in managing the potential for hepatotoxicity.
Subject(s)
Alanine Transaminase/blood , Angiogenesis Inhibitors/pharmacology , Blood Pressure/drug effects , Pyrimidines/pharmacology , Sulfonamides/pharmacology , Adult , Aged , Aged, 80 and over , Alkaline Phosphatase/blood , Angiogenesis Inhibitors/blood , Aspartate Aminotransferases/blood , Bayes Theorem , Humans , Indazoles , Logistic Models , Middle Aged , Models, Biological , Neoplasms/blood , Neoplasms/drug therapy , Neoplasms/physiopathology , Pyrimidines/blood , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Sulfonamides/blood , Young AdultABSTRACT
PURPOSE: Increased mitogenic signaling and angiogenesis, frequently facilitated by somatic activation of EGF receptor (EGFR; ErbB1) and/or loss of PTEN, and VEGF overexpression, respectively, drive malignant glioma growth. We hypothesized that patients with recurrent glioblastoma would exhibit differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib. EXPERIMENTAL DESIGN: A phase II study evaluated the antitumor activity of pazopanib 400 mg/d plus lapatinib 1,000 mg/d in patients with grade 4 malignant glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing anticonvulsants (EIAC). The phase II study used a two-stage Green-Dahlberg design for futility. An independent, parallel phase I component determined the maximum-tolerated regimen (MTR) of pazopanib and lapatinib in patients with grade 3/4 glioma receiving EIACs. RESULTS: The six-month progression-free survival (PFS) rates in phase II (n = 41) were 0% and 15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative cohorts, respectively, leading to early termination. Two patients (5%) had a partial response and 14 patients (34%) had stable disease lasting 8 or more weeks. In phase I (n = 34), the MTR was not reached. On the basis of pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 1,000 mg, each twice daily, was considered safe. Concomitant EIACs reduced exposure to pazopanib and lapatinib. CONCLUSIONS: The antitumor activity of this combination at the phase II dose tested was limited. Pharmacokinetic data indicated that exposure to lapatinib was subtherapeutic in the phase II evaluation. Evaluation of intratumoral drug delivery and activity may be essential for hypothesis-testing trials with targeted agents in malignant glioma.
Subject(s)
Antineoplastic Agents/administration & dosage , Brain Neoplasms/drug therapy , Glioma/drug therapy , Pyrimidines/administration & dosage , Quinazolines/administration & dosage , Sulfonamides/administration & dosage , Adult , Angiogenesis Inhibitors/administration & dosage , Anticonvulsants/administration & dosage , Anticonvulsants/pharmacokinetics , Antineoplastic Agents/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols , Brain Neoplasms/pathology , Disease-Free Survival , Drug Delivery Systems , ErbB Receptors/metabolism , Glioma/pathology , Humans , Indazoles , Lapatinib , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Pyrimidines/pharmacokinetics , Quinazolines/pharmacokinetics , Recurrence , Sulfonamides/pharmacokineticsABSTRACT
PURPOSE: As tyrosine kinase inhibitors have been associated with cardiotoxicity, we evaluated the effect of pazopanib, an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, on electrocardiographic parameters in patients with cancer. METHODS: This double-blind, placebo-controlled, parallel-group study randomized patients (N = 96) to moxifloxacin (positive control) or placebo on Day 1 followed by pazopanib or placebo 800 mg/day (fasted) on Days 2-8 and 1,600 mg (with food) on Day 9. Treatment effects were evaluated by baseline-adjusted, time-matched, serial Holter electrocardiograms. RESULTS: Sixty-five patients were evaluable for preplanned analyses. On Day 1, the maximum mean difference in baseline-adjusted, time-matched Fridericia-corrected QT (QTcF) interval in moxifloxacin-treated patients versus placebo was 10.6 ms (90% confidence interval [CI]: 4.2, 17.0). The administration scheme increased plasma pazopanib concentrations approximately 1.3- to 1.4-fold versus the recommended 800 mg once-daily dose. Pazopanib caused clinically significant increases from baseline in blood pressure, an anticipated class effect, and an unexpected reduction in heart rate from baseline that correlated with pazopanib exposure. On Day 9, the maximum mean difference in baseline-adjusted, time-matched QTcF interval in pazopanib-treated patients versus placebo was 4.4 ms (90% CI: -2.4, 11.2). Mixed-effects modeling indicated no significant concentration-dependent effect of pazopanib or its metabolites on QTcF interval. CONCLUSIONS: Pazopanib as administered in this study achieved supratherapeutic concentrations, produced a concentration-dependent decrease in heart rate, and caused a small, concentration-independent prolongation of the QTcF interval.
Subject(s)
Angiogenesis Inhibitors/adverse effects , Heart Conduction System/drug effects , Neoplasms/complications , Pyrimidines/adverse effects , Sulfonamides/adverse effects , Adult , Aged , Algorithms , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/pharmacokinetics , Anti-Bacterial Agents/pharmacokinetics , Aza Compounds/pharmacokinetics , Blood Pressure/drug effects , Confidence Intervals , Double-Blind Method , Electrocardiography, Ambulatory , Female , Fluoroquinolones , Heart Rate/drug effects , Humans , Indazoles , Long QT Syndrome/chemically induced , Long QT Syndrome/physiopathology , Male , Middle Aged , Moxifloxacin , Neoplasms/drug therapy , Neoplasms/physiopathology , Pyrimidines/administration & dosage , Pyrimidines/pharmacokinetics , Quinolines/pharmacokinetics , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics , Young AdultABSTRACT
This phase I, open-label, dose-escalation study assessed the maximum-tolerated dose, safety, pharmacokinetics, and preliminary antitumor activity of pazopanib plus lapatinib combination therapy in patients with solid tumors. Patients were to take pazopanib and lapatinib orally once daily in a fasting condition. During the escalation phase, pazopanib and lapatinib doses were escalated in serial patient cohorts, and a limited blood sampling scheme was applied for pharmacokinetic evaluation. In the expansion phase, potential pharmacokinetic interaction between pazopanib and lapatinib was evaluated more extensively. Seventy-five patients were treated. Multiple dosing levels were studied, combining pazopanib up to 800 mg/day with lapatinib up to 1,500 mg/day. Dose-limiting toxicities observed included grade 3 neutropenia, fatigue, asymptomatic decline in left ventricular ejection fraction, diarrhea, and liver enzyme elevations. The most common drug-related adverse events were diarrhea, nausea, anorexia, fatigue, vomiting, rash, hair depigmentation, and hypertension. The dose recommended for further evaluation was pazopanib 800 mg plus lapatinib 1,500 mg (paz-800/lap-1500). No clinically significant drug-drug interaction was observed at the paz-400/lap-1000 level. However, at paz-800/lap-1500, an increase in both the AUC0-t and Cmax of pazopanib was observed. Four partial responses were observed in patients with renal cancer (n=2), giant-cell tumor of the bone (n=1), and thyroid cancer (n=1). Stable disease for ≥ 18 weeks was seen in 12 patients. Pazopanib and lapatinib can be administered in combination at their respective single-agent doses with an acceptable safety profile. Further evaluation of the combination will be pursued, exploring both paz-800/lap-1500 and paz-400/lap-1000.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Female , Humans , Indazoles , Lapatinib , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/blood , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Quinazolines/administration & dosage , Quinazolines/adverse effects , Quinazolines/pharmacokinetics , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/pharmacokinetics , Young AdultABSTRACT
INTRODUCTION: As angiogenic pathways have become important targets for inhibition of tumor growth, we examined the concept of dual pathway blockade by small-molecule tyrosine kinase inhibitors targeting vascular endothelial and epidermal growth factor receptors. METHODS: Escalating doses of pazopanib (400-800 mg once daily [QD]) plus erlotinib (100-150 mg QD) doses were evaluated in cohorts of 3-6 adults with advanced solid tumors. Twelve additional patients were enrolled in an expansion cohort to confirm the maximum tolerated dose (MTD). RESULTS: The MTD, defined during assessment of 20 patients, was pazopanib 600 mg plus erlotinib 150 mg. Two dose-limiting toxicities, rash and elevated liver enzymes, occurred at pazopanib 800 mg and erlotinib 150 mg. Overall, 30 % and 27 % of patients required dose interruption of pazopanib or erlotinib, respectively; 15 % of patients required a dose reduction of erlotinib to manage toxicities. The most common adverse events in patients treated with any dose regimen of pazopanib plus erlotinib (N = 33) were diarrhea, rash, nausea, and decreased appetite. The adverse-event profile of the combination did not appear to differ from that of each compound administered alone. Coadministration of pazopanib 600 mg QD and erlotinib 150 mg QD did not consistently affect the pharmacokinetics of either compound relative to that observed for either compound administered alone. Of 26 patients evaluated for efficacy, 3 (12 %; all non-small-cell lung cancer) had partial response and 10 (38 %) had stable disease. CONCLUSIONS: Concomitant administration of pazopanib 600 mg and erlotinib 150 mg is feasible, with a manageable toxicity profile. These results support further clinical development of the pazopanib-erlotinib combination.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pyrimidines/administration & dosage , Pyrimidines/therapeutic use , Quinazolines/administration & dosage , Quinazolines/therapeutic use , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Administration, Oral , Adult , Aged , Aged, 80 and over , Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Demography , Dose-Response Relationship, Drug , Erlotinib Hydrochloride , Female , Humans , Indazoles , Male , Maximum Tolerated Dose , Middle Aged , Treatment OutcomeABSTRACT
INTRODUCTION: We sought to define the maximum tolerated dose (MTD) and evaluate the safety, pharmacokinetics, and preliminary clinical activity of pazopanib plus pemetrexed in patients with solid tumors. METHODS: This dose-escalation study used a standard 3 + 3 design to evaluate once daily pazopanib (400-800 mg) plus pemetrexed (400-500 mg/m(2) on Day 1 of each 21-day cycle). Eight additional patients were enrolled into an expansion cohort. RESULTS: Twenty-five patients were enrolled. Pazopanib 800 mg plus pemetrexed 500 mg/m(2) was the MTD. The most common adverse events at all dose levels included fatigue, neutropenia, diarrhea, and thrombocytopenia. The frequencies of non-hematologic adverse events were consistent with those of the individual agents. The rates of all-grade and Grade 4 hematologic toxicities (reversible neutropenia with median duration of 4 days) were higher with the combination regimen than with either monotherapy. Exploratory analyses revealed no association between the plasma levels of 3 biomarkers of vitamin B12 metabolism (cystathionine, homocysteine, and methylmalonic acid) and the risk of Grade 4 neutropenia and Grade 3 febrile neutropenia. Of 20 patients evaluated for efficacy, 2 (10 %) had a partial response. Pazopanib did not affect pemetrexed clearance, but increased pemetrexed maximal concentration by 22 %. In exploratory pharmacogenetic analyses, allelic variants of the VEGFA gene demonstrated weak correlation with development of severe neutropenia. CONCLUSIONS: Concomitant administration of pazopanib 800 mg once daily plus pemetrexed 500 mg/m(2) once every 21 days is feasible, albeit associated with a high frequency of brief, reversible neutropenia. Preliminary activity was observed in non-small-cell lung cancer.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Glutamates/therapeutic use , Guanine/analogs & derivatives , Neoplasms/drug therapy , Neoplasms/pathology , Pyrimidines/therapeutic use , Sulfonamides/therapeutic use , Administration, Oral , Adult , Aged , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/pharmacokinetics , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Biomarkers, Tumor/metabolism , Demography , Dose-Response Relationship, Drug , Female , Glutamates/administration & dosage , Glutamates/adverse effects , Glutamates/pharmacokinetics , Guanine/administration & dosage , Guanine/adverse effects , Guanine/pharmacokinetics , Guanine/therapeutic use , Humans , Indazoles , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Pemetrexed , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/pharmacokineticsABSTRACT
Several phase III trials have shown that the addition of an antiangiogenic agent to conventional chemotherapy can improve clinical benefit in patients with advanced solid tumors. This study examined the feasibility of combining pazopanib (Votrient), an oral antiangiogenic agent, with paclitaxel and carboplatin. This 3 + 3 dose-escalation phase I study evaluated the maximum-tolerated regimen (MTR) of daily pazopanib in combination with paclitaxel 175 mg/m(2) and carboplatin [dosed at area under the curve (AUC) 5 or 6] given every 21 days in patients with advanced solid tumors. Plasma samples were collected to evaluate the effect of pazopanib on the pharmacokinetics of paclitaxel and carboplatin. Thirty-four patients were enrolled. The MTR was paclitaxel 175 mg/m(2) and carboplatin AUC5 with pazopanib 200 mg. The most common dose-limiting toxicities were neutropenia and thrombocytopenia. Two patients with esophageal cancer had a complete response and four patients, one each with breast, small-cell lung, pancreatic, and gastroesophageal junction cancer, had partial responses. Pazopanib at 200 mg increased paclitaxel maximal concentration (C(max)) by 43% and carboplatin (AUC5 or AUC6) C(max) by 54%. Paclitaxel and carboplatin given every 21 days at standard doses was not feasible in combination with the monotherapy pazopanib dose of 800 mg daily because of dose-limiting myelosuppression. Coadministration of pazopanib increased exposure to paclitaxel and carboplatin and likely contributed to this effect. Given the antitumor activity of this regimen, further studies are underway to determine a clinically tolerable schedule of pazopanib with paclitaxel and carboplatin.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Neoplasms/pathology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carboplatin/administration & dosage , Female , Humans , Indazoles , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Paclitaxel/administration & dosage , Pyrimidines/administration & dosage , Sulfonamides/administration & dosage , Treatment OutcomeABSTRACT
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.
Subject(s)
Neoplasms/drug therapy , Neoplasms/pathology , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Sulfonamides/adverse effects , Sulfonamides/pharmacokinetics , Administration, Oral , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Demography , Dose-Response Relationship, Drug , Female , Humans , Indazoles , Male , Middle Aged , Neoplasm Staging , Pyrimidines/administration & dosage , Pyrimidines/therapeutic use , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Suspensions , Tablets , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: A phase I dose-escalating study of pazopanib was conducted to determine the maximum tolerated dose (MTD), pharmacokinetic/pharmacodynamic relationships, and clinical activity in patients with advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Asian patients (N = 28) were dose escalated on pazopanib (200-800 mg) once daily (QD) on 21-day cycles, with MTD as the primary endpoint using a modified 3 + 3 design. Changes in tumor vasculature were evaluated by dynamic contrast-enhanced MRI (DCE-MRI). RESULTS: Two of five patients at the 800-mg dose level experienced dose-limiting toxicities [grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations and grade 3 malaise]. The MTD in patients with HCC (Child-Pugh class A) was 600 mg QD. Diarrhea, skin hypopigmentation, and AST elevation were the most commonly reported adverse events at the MTD. Mean C(max) and area under the concentration-time curve (AUC(0-6)) of pazopanib and its metabolites did not increase dose proportionally across the 200 to 800 mg range. Reductions in IAUGC and K(trans) were shown at all pazopanib doses evaluated, with the greatest reductions at 600 and 800 mg. Although larger DCE-MRI parameter decreases were associated with larger C(24) and C(max) values, there was no constant relationship between tumor perfusion decreases measured by DCE-MRI and plasma pazopanib pharmacokinetic parameters. Overall, 19 patients (73%) had either partial response or stable disease. CONCLUSION: Pazopanib has a manageable safety profile in patients with advanced HCC, and 600 mg was chosen for further development of pazopanib in advanced HCCs. Moreover, pazopanib reduced tumor vessel leakage, as shown by DCE-MRI, indicating a direct effect on HCC vasculature that might be associated with its antitumor activity.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Pyrimidines/administration & dosage , Pyrimidines/pharmacokinetics , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics , Adult , Aged , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/pharmacokinetics , Carcinoma, Hepatocellular/blood , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Humans , Indazoles , Liver Neoplasms/blood , Male , Middle Aged , Pyrimidines/adverse effects , Sulfonamides/adverse effects , alpha-Fetoproteins/metabolismABSTRACT
PURPOSE: To evaluate the maximum tolerated regimen (MTR), dose-limiting toxicities, and pharmacokinetics of pazopanib, an oral small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, in combination with paclitaxel. PATIENTS AND METHODS: Pazopanib was given daily with weekly paclitaxel on days 1, 8, and 15 every 28 days. Dose levels of pazopanib (mg/day)/paclitaxel (mg/m(2)) were 400/15, 800/15, 800/50, and 800/80. An expanded cohort was enrolled at the MTR. Plasma samples were collected to evaluate the effect of pazopanib, an inhibitor of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP3A4 and CYP2C8 substrate. RESULTS: Of 26 enrolled patients, 17 were treated at the MTR of 800 mg pazopanib and 80 mg/m(2) paclitaxel. Dose-limiting toxicities included a grade 3 abscess and grade 2 hyperbilirubinemia. Other toxicities included elevated liver transaminases and diarrhea. Six patients (23%) had partial responses and 15 patients (58%) had stable disease. Administration of 800 mg pazopanib resulted in a 14% lower paclitaxel clearance and a 31% higher paclitaxel maximal concentration than with administration of paclitaxel alone at 15, 50, and 80 mg/m(2). At the MTR, coadministration of 800 mg pazopanib and 80 mg/m(2) paclitaxel resulted in a 26% higher geometric mean paclitaxel area under the curve. CONCLUSION: Pazopanib, at a dose of 800 mg daily, can be safely combined with a therapeutic dose of paclitaxel at 80 mg/m(2) when administered on days 1, 8, and 15, every 28 days. The observed greater plasma concentrations of paclitaxel given concurrently with pazopanib suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2C8.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Adult , Aged , Female , Humans , Indazoles , Lymphatic Metastasis , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Neoplasms/pathology , Paclitaxel/administration & dosage , Pyrimidines/administration & dosage , Sulfonamides/administration & dosage , Survival Rate , Tissue Distribution , Treatment OutcomeABSTRACT
PURPOSE: The safety, pharmacokinetics, and clinical activity of pazopanib (GW786034), an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, were evaluated in patients with advanced-stage refractory solid tumors. EXPERIMENTAL DESIGN: Patients were enrolled into sequential dose-escalating cohorts (50 mg three times weekly to 2,000 mg once daily and 300-400 mg twice daily). Escalation or deescalation was based on toxicities observed in the preceding dose cohort. Pharmacokinetic and biomarker samples were obtained. Clinical response was assessed every 9 weeks. RESULTS: Sixty-three patients were treated (dose escalation, n = 43; dose expansion, n = 20). Hypertension, diarrhea, hair depigmentation, and nausea were the most frequent drug-related adverse events, the majority of which were of grade 1/2. Hypertension was the most frequent grade 3 adverse event. Four patients experienced dose-limiting toxicities at 50 mg, 800 mg, and 2,000 mg once daily. A plateau in steady-state exposure was observed at doses of >or=800 mg once daily. The mean elimination half-life at this dose was 31.1 hours. A mean target trough concentration (C(24)) >or=15 microg/mL (34 micromol/L) was achieved at 800 mg once daily. Three patients had partial responses (two confirmed, one unconfirmed), and stable disease of >or=6 months was observed in 14 patients; clinical benefit was generally observed in patients who received doses of >or=800 mg once daily or 300 mg twice daily. CONCLUSION: Pazopanib was generally well tolerated and showed antitumor activity across various tumor types. A monotherapy dose of 800 mg once daily was selected for phase II studies.