scholarly journals Phase I Pharmacokinetic and Pharmacodynamic Study of Pazopanib in Children With Soft Tissue Sarcoma and Other Refractory Solid Tumors: A Children's Oncology Group Phase I Consortium Report

2013 ◽  
Vol 31 (24) ◽  
pp. 3034-3043 ◽  
Author(s):  
Julia L. Glade Bender ◽  
Alice Lee ◽  
Joel M. Reid ◽  
Sylvain Baruchel ◽  
Timothy Roberts ◽  
...  
Keyword(s):  
Growth Factor ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Phase I ◽  
Solid Tumors ◽  
Angiogenesis Inhibitor ◽  
Antiangiogenic Effect ◽  
Dce Mri ◽  
Potential Clinical Benefit ◽  
Pharmacodynamic Study

Purpose Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors. Patients and Methods Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m2) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD. Results Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m2 for tablet and 160 mg/m2 for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41). Conclusion Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma.

scholarly journals Phase I Study of Rivoceranib, a Selective VEGFR-2 Angiogenesis Inhibitor, Administered Daily in Patients With Advanced Solid Tumors

2021 ◽  
Author(s):  
Yoon-Koo Kang ◽  
Min-Hee Ryu ◽  
Yong Sang Hong ◽  
Chang-Min Choi ◽  
Tae Won Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Safety Profile ◽  
Phase I Study ◽  
Angiogenesis Inhibitor ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Potential Clinical Benefit ◽  
Dose Levels

Abstract Rivoceranib is a highly potent and selective inhibitor of VEGFR-2 and subsequent angiogenesis through this receptor signaling pathway. This phase I study was the first global study with rivoceranib outside of China in Korean and Caucasian patients and was designed to determine the safety profile (including maximum tolerated dose), pharmacokinetics, and efficacy in patients with advanced solid tumors. Thirty-one adult patients with advanced malignant solid tumors were enrolled to investigate 6 dose levels of rivoceranib. Twenty-five patients were initially enrolled to 5 dose levels of rivoceranib from 81 to 685 mg and an additional 6 patients were later enrolled in a supplemental study to evaluate the 805 mg dose level. Rivoceranib was very well tolerated. At the 805 mg dose level, 2 dose-limiting toxicities were observed but the 685 mg dose was well tolerated over multiple cycles of therapy. The maximum tolerated dose for rivoceranib was 685 mg (equivalent to 850 mg rivoceranib mesylate) and recommended for further study in patients with advanced solid tumors. The most common adverse events were hypertension (all grades %/≥G3%: 58/29), nausea (42/0), diarrhea (39/0), anorexia (32/3), and fatigue (29/6). Rivoceranib pharmacokinetics were proportional across all dose levels but interpatient variability was high. Of the 31 patients enrolled, 21 were evaluable for efficacy. In this evaluable group, partial response was recorded in 5 patients, stable disease in 10, and disease progression in 6. Results indicate the potential clinical benefit of daily rivoceranib in patients with advanced malignant solid tumors with a tolerable safety profile.Trial registration: NCT01497704 (ClinicalTrials.gov) registered on December 22, 2011 and NCT02711969 (ClinicalTrials.gov) registered on March 17, 2016.

Pazopanib, a Multikinase Angiogenesis Inhibitor, in Patients With Relapsed or Refractory Advanced Soft Tissue Sarcoma: A Phase II Study From the European Organisation for Research and Treatment of Cancer–Soft Tissue and Bone Sarcoma Group (EORTC Study 62043)

2009 ◽  
Vol 27 (19) ◽  
pp. 3126-3132 ◽  
Author(s):  
Stefan Sleijfer ◽  
Isabelle Ray-Coquard ◽  
Zsuzsa Papai ◽  
Axel Le Cesne ◽  
Michelle Scurr ◽  
...  
Keyword(s):  
Growth Factor ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Performance Status ◽  
Angiogenesis Inhibitor ◽  
Growth Factor Receptor ◽  
Bone Sarcoma ◽  
Cytotoxic Agents ◽  
End Point ◽  
Synovial Sarcomas

PurposeGiven the importance of angiogenesis in soft tissue sarcoma (STS), pazopanib, an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptor and platelet-derived growth factor receptor, was explored in patients with advanced STS.Patients and MethodsPatients with intermediate- or high-grade advanced STS who were ineligible for chemotherapy or who had received no more than two prior cytotoxic agents for advanced disease, who had documented progression, who had adequate performance status, and who had good organ function were eligible. Pazopanib 800 mg was given daily. The primary end point was progression-free rate at 12 weeks (PFR12 weeks). Secondary end points were response, safety, and overall survival. Four different strata were studied: adipocytic STS, leiomyosarcomas, synovial sarcomas, and other STS types. A Simon two-stage design was applied (P1 = 40%; P0 = 20%; α = β = .1) for each stratum.ResultsOne hundred forty-two patients were enrolled. The adipocytic STS stratum was closed after the first stage, given insufficient activity (PFR12 weeks, five [26%] of19). PFR12 weekswas 18 (44%) of 41 patients in the leiomyosarcoma cohort, 18 (49%) of 37 in the synovial sarcomas, and 16 (39%) of 41 in the other STS types. Compared with historical controls who were treated with second-line chemotherapy, progression-free and overall survivals were prolonged in the three cohorts in which the primary end point was reached. The most frequent drug-related toxicities were hypertension, fatigue, hypopigmentation, and nausea. Other toxicities included liver enzyme elevations, myelosuppression, and proteinuria, all of which were mostly grades 1 to 2. The most frequent grades 3 to 4 toxicities were hyperbilirubinemia (6.3%), hypertension (7.7%), and fatigue (7.7%).ConclusionPazopanib is well tolerated in patients with relapsed, advanced STS and demonstrates interesting activity that warrants additional study in patients with leiomyosarcomas, synovial sarcomas, and other STS types.

scholarly journals Phase I Study of Intravenous Vascular Endothelial Growth Factor Trap, Aflibercept, in Patients With Advanced Solid Tumors

2010 ◽  
Vol 28 (2) ◽  
pp. 207-214 ◽  
Author(s):  
A. Craig Lockhart ◽  
Mace L. Rothenberg ◽  
Jakob Dupont ◽  
Wendy Cooper ◽  
Paul Chevalier ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Maximum Plasma ◽  
Vascular Endothelial ◽  
Dce Mri ◽  
Endothelial Growth Factor ◽  
Vegf Trap

Purpose Vascular endothelial growth factor (VEGF) Trap (aflibercept) is an angiogenesis inhibitor comprising portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of VEGF Trap administered intravenously (IV) every 2 weeks. Patients and Methods Patients with refractory solid tumors or non-Hodgkin's lymphoma with adequate organ function were eligible. Pharmacokinetic/pharmacodynamic markers included measurement of plasma VEGF bound to VEGF Trap and free VEGF Trap. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was incorporated to measure the biologic effects of the drug on tumor vascularity and permeability. Results The study enrolled 47 patients at doses ranging from 0.3 to 7.0 mg/kg IV every 2 weeks. Dose-limiting toxicities were rectal ulceration and proteinuria at the 7.0 mg/kg dose. Other mechanism-specific toxicities included hypertension. On the basis of these observations and on pharmacokinetics, the recommended phase II dose of VEGF Trap as a single agent is 4 mg/kg every 2 weeks. Three RECIST (Response Evaluation Criteria in Solid Tumors) –defined partial responses were observed, one at the 3.0 mg/kg and two at the 7.0 mg/kg dose level. Maximum plasma concentration of free VEGF Trap increased proportionally with dose. Maximal VEGF-bound VEGF Trap complex levels were reached at doses ≥ 2.0 mg/kg. Changes in volume transfer constant measured by DCE-MRI at baseline and at 24 hours after administration indicate a possible dose-related change in this pharmacodynamic marker. Conclusion IV VEGF Trap was well tolerated at the dose levels tested. Pharmacodynamic and pharmacokinetic markers were indicative of VEGF blockade.

Phase I Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PTK787/ZK 222584 Administered Twice Daily in Patients With Advanced Cancer

2005 ◽  
Vol 23 (18) ◽  
pp. 4162-4171 ◽  
Author(s):  
Anne L. Thomas ◽  
Bruno Morgan ◽  
Mark A. Horsfield ◽  
Anthony Higginson ◽  
Andrea Kay ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Phase I ◽  
Single Agent ◽  
Angiogenesis Inhibitor ◽  
Biologically Active ◽  
Pharmacokinetic Data ◽  
Vegf Receptor ◽  
Dce Mri ◽  
Grade 3

Purpose PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase, and the c-kit protein tyrosine kinase. In this phase I dose-escalating study, PTK/ZK was administered bid to exploit the theoretical advantage of maintaining constant drug levels above a threshold known from preclinical data to interfere with VEGF receptor signaling. Patients and Methods Forty-three patients with advanced cancers received single-agent PTK/ZK at doses of 150 to 1,000 mg orally bid. Assessments for safety and pharmacokinetics were performed. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic marker of response. Results At 1,000 mg bid, the dose-limiting toxicity of reversible grade 3 lightheadedness was observed. Dose-related grade 3 fatigue and vomiting were observed but these were not dose-limiting. Pharmacokinetic data confirmed that PTK/ZK exposure increased with increasing dose up to 500 mg bid and appeared to plateau at higher doses. A greater than 40% reduction in the DCE-MRI bidirectional transfer constant (Ki) at day 2 predicted for nonprogression of disease. Conclusion The maximum-tolerated oral dose of PTK/ZK is 750 mg orally bid. DCE-MRI and pharmacokinetic data indicate that PTK/ZK ≥ 1,000 mg total daily dose is the biologically active dose.

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