Dataset Information

A Phase I, Dose-Escalation Trial of Pazopanib in Combination with Cisplatin in Patients with Advanced Solid Tumors: A UNICANCER Study.

ABSTRACT:

Introduction

To determine the feasibility, maximum-tolerated dose (MTD), and dose-limiting toxicities (DLT) of pazopanib in combination with cisplatin.

Methods

Patients with advanced malignancies were included in a 3 + 3 dose-escalation phase I study. Pazopanib administration started 8 days before the first infusion of cisplatin; some patients were treated according to a reverse sequence (cisplatin first). Five dose levels (DLs) were planned. MTD was based on DLT observed during cycles 1 and 2.

Results

Thirty-five patients were enrolled. The MTD was reached at the first DL, (pazopanib 400 mg daily + cisplatin 75 mg/m² every 21 days). Main DLTs were pulmonary embolism, neutropenia, thrombocytopenia, and elevation of liver enzymes. Overall, most common adverse events were anemia (83%), fatigue (80%), thrombocytopenia (80%), neutropenia (73%), hypertension (59%), neurotoxicity (56%), and anorexia (53%). Sixteen patients (46%) discontinued the study due to toxicity. One patient (sarcoma) had a complete response, and three patients (one with breast cancer and two with ovarian cancers) had a partial response. Pharmacokinetic (PK) analyses showed interactions with aprepitant, resulting in increased exposure to pazopanib, which might explain partly the poor tolerance of the combination.

Conclusion

Cisplatin and pazopanib could not be administered at their single agent full doses, partly due to a PK interaction between pazopanib and aprepitant.

Funding

This work was funded by GlaxoSmithKline and by the charity Ligue Nationale de Lutte Contre le Cancer.

Trial registered

ClinicalTrials.gov identifier, NCT01165385.

SUBMITTER: Dieras V

PROVIDER: S-EPMC5315079 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

A Phase I, Dose-Escalation Trial of Pazopanib in Combination with Cisplatin in Patients with Advanced Solid Tumors: A UNICANCER Study.

Diéras Véronique V Bachelot Thomas T Campone Mario M Isambert Nicolas N Joly Florence F Le Tourneau Christophe C Cassier Philippe P Bompas Emmanuelle E Fumoleau Pierre P Noal Sabine S Orsini Christine C Jimenez Marta M Imbs Diane Charlotte DC Chatelut Etienne E

Oncology and therapy 20160818 2

<h4>Introduction</h4>To determine the feasibility, maximum-tolerated dose (MTD), and dose-limiting toxicities (DLT) of pazopanib in combination with cisplatin.<h4>Methods</h4>Patients with advanced malignancies were included in a 3 + 3 dose-escalation phase I study. Pazopanib administration started 8 days before the first infusion of cisplatin; some patients were treated according to a reverse sequence (cisplatin first). Five dose levels (DLs) were planned. MTD was based on DLT observed during c ...[more]

PMID: 28261651

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Project description:BackgroundThe RAS/RAF/MEK/ERK pathway is constitutively activated in many cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life that has shown clinical activity as monotherapy in phase I and II studies of advanced cancer. Preclinical data suggest that selumetinib may enhance the activity of chemotherapeutic agents. We assessed the safety, tolerability, and pharmacokinetics (PK) of selumetinib (AZD6244, ARRY-142886) in combination with docetaxel or dacarbazine in patients with advanced solid tumors.MethodsThis study was a phase I, open-label, multicenter study in patients aged ≥18 years with advanced solid tumors who were candidates for docetaxel or dacarbazine treatment. Part A of the study (dose escalation) evaluated safety, tolerability, PK, and maximum tolerated dose (MTD) of selumetinib twice daily (BID) with docetaxel 75 mg/m2 or dacarbazine 1000 mg/m2 administered every 21 days. Patients receiving docetaxel could be administered primary prophylactic granulocyte-colony stimulating factor according to standard guidelines. Part B of the study (dose expansion) further evaluated safety, tolerability, and PK in 12 additional patients at the MTD combinations determined in part A.ResultsA total of 35 patients received selumetinib plus docetaxel, and 25 received selumetinib plus dacarbazine. The MTD of selumetinib was 75 mg BID in combination with either docetaxel (two dose-limiting toxicity [DLT] events: neutropenia with fever, and thrombocytopenia) or dacarbazine (one DLT event: thrombocytopenia). Common adverse events occurring with each treatment combination were diarrhea, peripheral/periorbital edema, fatigue, and nausea. PK parameters for selumetinib and docetaxel or dacarbazine were similar when administered alone or in combination. Partial responses were reported in 6/35 patients receiving selumetinib plus docetaxel and 4/25 patients receiving selumetinib plus dacarbazine.ConclusionsThe combinations of selumetinib plus docetaxel and selumetinib plus dacarbazine demonstrated manageable safety and tolerability profiles and preliminary signs of clinical activity in patients with advanced solid tumors.Trial registrationClinicalTrials.gov NCT00600496; registered 8 July 2009.

Dataset Information

A Phase I, Dose-Escalation Trial of Pazopanib in Combination with Cisplatin in Patients with Advanced Solid Tumors: A UNICANCER Study.

Introduction

Methods

Results

Conclusion

Funding

Trial registered

Publications

A Phase I, Dose-Escalation Trial of Pazopanib in Combination with Cisplatin in Patients with Advanced Solid Tumors: A UNICANCER Study.

Similar Datasets

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