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J Hematol Oncol. 2016 Mar 10;9:23. doi: 10.1186/s13045-016-0254-5.

First-in-human, open-label dose-escalation and dose-expansion study of the safety, pharmacokinetics, and antitumor effects of an oral ALK inhibitor ASP3026 in patients with advanced solid tumors.

Author information

1
Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, 4501 X St #3016, Sacramento, CA, 95817, USA. thli@ucdavis.edu.
2
Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
3
Present address: Yale Smilow Cancer Center, New Haven, CT, USA.
4
Section of Hematology/Oncology, Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago Medicine, Chicago, IL, USA.
5
Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA, USA.
6
Astellas Pharma Global Development, Northbrook, IL, USA.
7
South Texas Accelerated Research Therapies (START) Center for Cancer Care, San Antonio, TX, USA.

Abstract

BACKGROUND:

ASP3026 is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has potent in vitro activity against crizotinib-resistant ALK-positive tumors. This open-label, multicenter, first-in-human phase I study ( NCT01284192 ) assessed the safety, pharmacokinetic profile, and antitumor activity of ASP3026.

METHODS:

Advanced solid tumor patients received oral ASP3026 in 3 + 3 dose-escalation cohorts at doses of 25-800 mg once daily in 28-day cycles. The endpoints were to identify the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the pharmacokinetic profile of ASP3026. A phase Ib expansion cohort enrolled patients with metastatic, crizotinib-resistant ALK-positive solid tumors at the RP2D, and response was evaluated by RECIST 1.1.

RESULTS:

The dose-escalation cohort enrolled 33 patients, including three crizotinib-resistant, ALK-positive patients, and the dose-expansion cohort enrolled another 13 crizotinib-resistant, ALK-positive non-small cell lung cancer (NSCLC) patients. ASP3026 demonstrated both linear pharmacokinetics and dose-proportional exposure for area under the plasma concentration-time curve and maximum concentration observed with a median terminal half-life of 35 h, supporting the daily dosing. Grade 3 rash and elevated transaminase concentrations were dose-limiting toxicities observed at 800 mg; hence, 525 mg daily was the MTD and RP2D. The most common treatment-related adverse events were nausea (38%), fatigue (35%), and vomiting (35 %). Among the 16 patients with crizotinib-resistant ALK-positive tumors (15 NSCLC, 1 neuroblastoma), eight patients achieved partial response (overall response rate 50%; 95% confidence interval 25-75%) and seven patients (44%) achieved stable disease.

CONCLUSIONS:

ASP3026 was well tolerated and had therapeutic activity in patients with crizotinib-resistant ALK-positive advanced tumors.

TRIAL REGISTRATION:

ClinTrials.gov: NCT01284192.

KEYWORDS:

ALK inhibitor; ASP3026; Neoplasms; Pharmacokinetics; Phase I

PMID:
26966027
PMCID:
PMC4786998
DOI:
10.1186/s13045-016-0254-5
[Indexed for MEDLINE]
Free PMC Article

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