Phase II Proof-of-Concept Study of Pazopanib Monotherapy in Treatment-Naive Patients With Stage I/II Resectable Non–Small-Cell Lung Cancer

Altorki, Nasser K.; Lane, Maureen E.; Bauer, Thomas; Lee, Paul C.; Guarino, Michael J.; Pass, Harvey I.; Felip, Enriqueta; Peylan‐Ramu, Nili; Gúrpide, Alfonso; Grannis, Frederic W.; Mitchell, John D.; Tachdjian, Sabrina; Swann, Ruth; Huff, Anne; Roychowdhury, Debasish; Reeves, Anthony P.; Ottesen, Lone H.; Yankelevitz, David F.

doi:10.1200/jco.2009.23.9749

Cited by 127 publications

(69 citation statements)

References 41 publications

(10 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8) and advanced soft-tissue sarcoma (STS) who have received prior chemotherapy (9). Short-term treatment with pazopanib 800 mg demonstrated single-agent activity in patients with earlystage NSCLC in the preoperative setting in a proof-of-concept study that supported further exploration of pazopanib in NSCLC (20).…”

Section: Introductionmentioning

confidence: 88%

A Multicenter Phase I Study of Pazopanib in Combination with Paclitaxel in First-Line Treatment of Patients with Advanced Solid Tumors

Kendra

Plummer

Salgia

et al. 2015

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

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 3þ3 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 Ã 3 Ã 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.

show abstract

Section: Introductionmentioning

confidence: 88%

A Multicenter Phase I Study of Pazopanib in Combination with Paclitaxel in First-Line Treatment of Patients with Advanced Solid Tumors

Kendra

Plummer

Salgia

et al. 2015

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

show abstract

“…In a preoperative study, pazopanib produced notable reduction in tumor volume in 30 out of 35 patients [44] .…”

Section: Pdgframentioning

confidence: 99%

Genomics of Squamous Cell Lung Cancer

2013

View full text Add to dashboard Cite

show abstract

“…Several studies evaluating the use of neoadjuvant EGFR TKIs have been conducted in early-stage NSCLC; however, such studies were generally performed in unselected patient populations (37,38) and/or lacked PD assessments of target inhibition (37)(38)(39). Recently, a window-of-opportunity study was performed in patients with NSCLC with stage I/II disease who were treated with neoadjuvant pazopanib (36). This study included gene-expression profiling on pre-and posttreatment specimens, which revealed transcriptional changes in pazopanib target genes and other angiogenic factors (e.g., VEGFR-1, PDGFR-a) following treatment suggestive of on-target effects.…”

Section: Window-of-opportunity Studiesmentioning

confidence: 99%

“…Also, to be of value, a significant response after a brief period of experimental therapy is needed to provide proof of concept. Some authors have therefore proposed requirements for window-of-opportunity trials (36), such as (i) the targeted therapy should have an adequate safety profile, (ii) the agent should have demonstrated preliminary activity in advanced disease, and (iii) there should be a strong rationale for use of the agent in the intended disease setting.…”

Section: Window-of-opportunity Studiesmentioning

confidence: 99%

Pharmacodynamic Biomarkers: Falling Short of the Mark?

Gainor

Longo

Chabner

2014

Clinical Cancer Research

View full text Add to dashboard Cite

In recent years, the clinical development of targeted therapies has been advanced by a greater understanding of tumor biology and genomics. Nonetheless, drug development remains a slow and costly process. An additional challenge is that targeted therapies may benefit only a subset of patients treatedtypically those patients whose tumors are dependent on the target of interest. Thus, there is a growing need for the incorporation of both predictive and pharmacodynamic (PD) biomarkers in drug development. Predictive biomarkers are important to help guide patient selection, while PD biomarkers can provide information on the pharmacologic effects of a drug on its target. PD studies may provide insights into proof of mechanism (i.e., Does the agent hit its intended target?) and proof of concept (i.e., Does hitting the drug target result in the desired biologic effect?). PD studies may also provide information on the optimal biologic dosing or scheduling of a targeted agent. Herein, we review PD endpoints in the context of targeted drug development in non-small cell lung cancer, highlighting some of the key challenges encountered to date. In doing so, we discuss recent experiences with repeat tumor biopsies, surrogate tissue analysis, alternative clinical trial designs (e.g., window-of-opportunity trials), circulating biomarkers, and mechanism-based toxicity assessments. The application of such technologies and biomarkers in early clinical trials may facilitate rational drug development, while enhancing our understanding of why certain targeted therapies succeed or fail.

show abstract

Phase II Proof-of-Concept Study of Pazopanib Monotherapy in Treatment-Naive Patients With Stage I/II Resectable Non–Small-Cell Lung Cancer

Cited by 127 publications

References 41 publications

A Multicenter Phase I Study of Pazopanib in Combination with Paclitaxel in First-Line Treatment of Patients with Advanced Solid Tumors

A Multicenter Phase I Study of Pazopanib in Combination with Paclitaxel in First-Line Treatment of Patients with Advanced Solid Tumors

Genomics of Squamous Cell Lung Cancer

Pharmacodynamic Biomarkers: Falling Short of the Mark?

Contact Info

Product

Resources

About