A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas

Abstract

Background: Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in non-small-cell lung cancer (NSCLC). TSR-011 is a dual ALK and tropomyosin-related kinase (TRK) inhibitor, active against ALK inhibitor resistant tumours in preclinical studies. Here, we report the safety, tolerability and recommended phase 2 dose (RP2D) of TSR-011 in patients with relapsed or refractory ALK- and TRK-positive advanced cancers.

Methods: In this sequential, open-label, phase 1 trial (NCT02048488), patients received doses of 30 mg, escalated to 480 mg every 24 hours (Q24h), followed by an expansion cohort of patients with ALK-positive cancers. The primary objective was to evaluate safety and tolerability. Secondary objectives included pharmacokinetics.

Results: TSR-011 320- and 480-mg Q24h doses exceeded the maximum tolerated dose. At the RP2D of 40 mg every 8 hours (Q8h), the most common grade 3-4 treatment-emergent adverse events occurred in 3.2-6.5% of patients. Of 14 ALK inhibitor-naive patients with ALK-positive NSCLC, 6 experienced partial responses and 8 had stable disease.

Conclusions: At the RP2D (40 mg Q8h), TSR-011 demonstrated a favourable safety profile with acceptable QTc changes. Limited clinical activity was observed. Based on the competitive ALK inhibitor landscape and benefit/risk considerations, further TSR-011 development was discontinued.

Clinical trial registration number: NCT02048488.

Conflict of interest statement

C.-C.L., H.-T.A., M.M. and W.-C.S. declare no conflict of interest. J.S. reports advisory board, consulting, travel support and grant funding for investigator-initiated trials from Celgene, drug support for investigator-initiated trials from Genentech, funding for investigator-initiated trials from Pfizer and advisory board and consulting fees from TapImmune. J.d.C.C. reports advisory fees from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Roche and Takeda. R.D. reports personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Pfizer and Roche. G.J.W. reports ownership interest from Circulogene, personal fees from Circulogene, GLG Council, Guidepoint Global, IDEA Pharma, Ignyta, Paradigm, Pfizer, Angiex, Imaging Endpoints, Spring Bank Pharmaceuticals, and IBEX Medical Analytics, travel and lodging fees from Cambridge Healthtech Institute, GlaxoSmithKline, and TESARO, and holds a patent (PCT/US2014/8911940) outside the submitted work. S.L., D.B., L.H., J.C. and Z.-Y.Z. are employees and stockholders of TESARO: A GSK Company.

Figures

Fig. 1

Mean ± SEM plasma concentration–time profiles (semi-log) of TSR-011 following single oral daily doses in patients with cancer. a Cycle 1/day 1. b Cycle 2/day 1. Summary of ΔQTcF by plasma concentration and dose. c PK concentration–response (PK-QT) relationship from all dose groups (30 mg QD, 60 mg QD, 80 mg QD, 120 mg QD, 240 mg QD, 320 mg QD, 480 mg QD, 30 mg Q12h, 20 mg Q8h, 60 mg Q12h, 40 mg Q8h and 30 mg QD controlled release). d Plot of dose and regimen versus mean ΔQTcF (ms) from baseline with 90% CI. ΔQTcF change in Fridericia-corrected QT interval, CI confidence interval, Conc concentration, IR immediate release, PK pharmacokinetics, Q8h once every 8 hours, Q12h once every 12 hours, QD once daily, SEM standard error of the mean