439O - A first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies

Date 29 September 2012
Event ESMO Congress 2012
Session Developmental therapeutics
Topics Drug Development
Presenter Scott Gettinger
Authors S. Gettinger1, G.J. Weiss2, R. Salgia3, L. Bazhenova4, N.I. Narasimhan5, D.J. Dorer6, V. Rivera7, J. Zhang8, T. Clackson9, F.G. Haluska10, A. Shaw11, R. Camidge12
  • 1Thoracic Oncology Program, Yale University School of Medicine, New Haven/US
  • 2Virginia G. Piper Cancer Center Clinical Trials, Scottsdale Healthcare, 85258 - Scottsdale/US
  • 3Department Of Medicine, Section Of Hematology/oncology, University of Chicago, Chicago/US
  • 4Division Of Hematology/oncology, UCSD Moores Cancer Center, La Jolla/US
  • 5Dmpk, ARIAD Pharmaceuticals, Inc., Cambridge/US
  • 6Biostatistics, ARIAD Pharmaceuticals, Inc., Cambridge/US
  • 7Biology, ARIAD Pharmaceuticals, Inc., Cambridge/US
  • 8Clinical Research, ARIAD Pharmaceuticals, Inc., Cambridge/US
  • 9Research & Development, ARIAD Pharmaceuticals, Inc., Cambridge/US
  • 10Clinical Research & Development, ARIAD Pharmaceuticals, Inc., Cambridge/US
  • 11Hematology/oncology, Massachusetts General Hospital, Boston/US
  • 12University of Colorado Cancer Center, Aurora/US


AP26113 is a novel, synthetic, orally-active tyrosine kinase inhibitor (TKI) that potently inhibits mutant activated forms of anaplastic lymphoma kinase (ALK+) and epidermal growth factor receptor (EGFRm), as well as TKI-resistant forms including L1196M (ALK) and T790M (EGFR). AP26113 does not inhibit native EGFR. This is the initial report of a phase 1/2 open-label, multicenter study of AP26113. The dose finding phase (3 + 3 design) is ongoing in patients (pts) with advanced malignancies (except leukemia) refractory to available therapies or for whom no standard treatment exists. Initial dosing is once daily. As of 07 May 2012, 15 pts were enrolled: 30 mg n = 3, 60 mg n = 3, 90 mg n = 5, 120 mg n = 4; 67% female, median age 65 (41–77) yrs. Diagnoses were: 11 non-small cell lung cancer (NSCLC), 4 other (1 pancreatic, 1 colon, 1 cholangiocarcinoma, 1 adenocarcinoma of unknown primary [ACUP]). Ten pts had a documented history of ALK+ (n = 5; 4 NSCLC, 1 ACUP) or EGFRm (n = 5; all NSCLC). Pts were heavily pretreated. Four ALK+ NSCLC pts failed prior crizotinib therapy. Four pts with EGFRm failed prior EGFR-targeted therapy. Eight pts discontinued (7 disease progression, 1 investigator decision). The most common adverse events (AEs; >3 patients) were: fatigue (n = 4; 3 grade 1/2, 1 grade 3), nausea (n = 4; grade 1). No treatment-related serious AEs were observed. No DLTs were observed; the 120 mg dose level remains under evaluation. At 90 mg (n = 3), Day 29 geometric mean Cmax, Ctrough, AUC(0-24hr), and t1/2 were: 402 ng/mL, 170 ng/mL, 6130 ng*hr/mL, 29 hr, respectively. At the time of analysis, 8 pts had ≥1 set of tumor response measurements starting ≥8 weeks after first dose. Partial responses were observed in 4 of 4 ALK+ pts (60 mg n = 1; 90 mg n = 3, including the crizotinib-naïve ACUP pt). Anti-tumor activity at 120 mg remains to be evaluated. In summary, AP26113 was well tolerated with preliminary anti-cancer activity in ALK+ pts naïve to or failing prior crizotinib. The phase 2 expansion will include 4 cohorts: ALK+ NSCLC that is 1) naïve or 2) resistant to prior ALK-targeted therapy; 3) EGFRm NSCLC that is resistant to EGFR-targeted therapy; 4) other cancers with abnormalities in ALK or other AP26113 targets. ClinicalTrials.gov: NCT01449461.


G.J. Weiss: GJW has received funds and other support related to participation in this clinical trial from ARIAD Pharmaceuticals, Inc. through his employer, Scottsdale Healthcare. GJW has served on Speakers Bureaus for Genentech, Pfizer, and Eli Lilly.

N.I. Narasimhan: NIN is an employee of ARIAD Pharmaceuticals, Inc.

D.J. Dorer: DJD is an employee of ARIAD Pharmaceuticals, Inc.

V.M. Rivera: VMR is an employee of ARIAD Pharmaceuticals, Inc.

J. Zhang: JZ is an employee of ARIAD Pharmaceuticals, Inc.

T. Clackson: TC is an employee of ARIAD Pharmaceuticals, Inc.

F. Haluska: FH is an employee of and owns stock/stock options in ARIAD Pharmaceuticals, Inc.

A.T. Shaw: ATS has received consulting fees/honorarium from ARIAD, Pfizer, Chugai, and Daiichi. ATS has received support in the form of grants paid to her employer by Novartis and AstraZeneca.

D.R. Camidge: DRC has received consulting fees/honorarium from ARIAD and has served on advisory boards for Pfizer, Chugai, Novartis, and ARIAD.

All other authors have declared no conflicts of interest.