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
| Original language | English (US) |
|---|---|
| Article number | 254 |
| Journal | Journal of Hematology and Oncology |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| State | Published - Mar 10 2016 |
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Keywords
- ALK inhibitor
- ASP3026
- Neoplasms
- Pharmacokinetics
- Phase I
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research
- Molecular Biology
Cite this
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. / Li, Tianhong; LoRusso, Patricia; Maitland, Michael L.; Ou, Sai Hong Ignatius; Bahceci, Erkut; Ball, Howard A.; Park, Jung Wook; Yuen, Geoffrey; Tolcher, Anthony.
In: Journal of Hematology and Oncology, Vol. 9, No. 1, 254, 10.03.2016.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Li, Tianhong
AU - LoRusso, Patricia
AU - Maitland, Michael L.
AU - Ou, Sai Hong Ignatius
AU - Bahceci, Erkut
AU - Ball, Howard A.
AU - Park, Jung Wook
AU - Yuen, Geoffrey
AU - Tolcher, Anthony
PY - 2016/3/10
Y1 - 2016/3/10
N2 - 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
AB - 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
KW - ALK inhibitor
KW - ASP3026
KW - Neoplasms
KW - Pharmacokinetics
KW - Phase I
UR - http://www.scopus.com/inward/record.url?scp=84960934050&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84960934050&partnerID=8YFLogxK
U2 - 10.1186/s13045-016-0254-5
DO - 10.1186/s13045-016-0254-5
M3 - Article
C2 - 26966027
AN - SCOPUS:84960934050
VL - 9
JO - Journal of Hematology and Oncology
JF - Journal of Hematology and Oncology
SN - 1756-8722
IS - 1
M1 - 254
ER -