448PD - RXDX-101, an oral Pan-Trk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alterations

Date 28 September 2014
Event ESMO 2014
Session Developmental therapeutics
Topics Drug Development
Translational Research
Presenter Filippo De Braud
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors F.G.M. De Braud1, L. Pilla1, M. Niger1, S. Damian1, B. Bardazza1, A. Martinetti1, G. Pelosi1, G. Marrapese1, L. Palmeri2, G. Cerea2, E. Valtorta2, S. Veronese3, A. Sartore-Bianchi2, E. Ardini4, M. Martignoni5, A. Isacchi4, P. Pearson6, D. Luo7, J.L. Freddo7, S. Siena2
  • 1Division Of Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, 20133 - Milano/IT
  • 2Oncologia Falck, Ospedale Niguarda Ca Granda, IT-20162 - Milano/IT
  • 3Laboratory Medicine Molecular Pathology Unit, Ospedale Niguarda Ca Granda, Milano/IT
  • 4Clinical, Nerviano Medical Sciences, Nerviano/IT
  • 5Nms Group, CLInical Organization for Strategies & Solutions (CLIOSS), Nerviano/IT
  • 6Clinical Pharmacology, Ignyta, Inc, San Diego/US
  • 7Clinical, Ignyta, Inc, San Diego/US

 

Abstract

Aim

RXDX-101 is a small molecule inhibitor of TrkA, TrkB, TrkC, ROS1 and ALK, with high potency and selectivity. RXDX-101 demonstrated potent pharmacological activity in preclinical studies and is potentially first-in-class against the Trk family of kinases. This study aims to determine MTD, PD, PK and anti-tumor activity in patients with advanced cancer and applicable molecular alterations.

Methods

Phase 1 dose escalation in patients with advanced solid tumors. RXDX-101 was dosed orally once/day in a 4 day on, 3 day off schedule for 3 weeks, followed by a 7 day rest period, in continuous 28-day cycles. Minimum of 3 patients were enrolled at each dose level. Endpoints include safety, PK, and tumor response by RECIST.

Results

19 patients have been treated at 6 dose levels (100, 200, 400, 800,1200 and 1600 mg/m2). RXDX-101 has been well tolerated to date; the MTD has not been reached. No DLT has been seen at any dose level. The most common AEs (mainly grade 1-2) considered possibly treatment-related included asthenia, paresthesias, nausea and diarrhea. Possibly related grade 3/4 AEs include asthenia and increased lipase. No treatment-related SAEs were observed. A patient with colorectal carcinoma (TrkA+) has a PR and is in cycle 2. Two patients with NSCLC (1 ROS1 + ; 1 ALK+) have also achieved PRs. An additional patient with neuroblastoma (ALK+) has a PR and is currently in cycle 16. Two patients have had prolonged stabilization of their disease and remain on treatment: a patient with NSCLC (ALK+) in cycle 14 and a patient with pancreatic cancer (ROS1+) in cycle 11. PK analysis shows maximum concentrations of RXDX-101 were generally achieved within 2 to 4 hours following dosing and exposure increased in an approximate dose proportional manner up to doses of 800 mg/M2 with minimal accumulation following multiple doses. Mean terminal half-life was 21- 32 hours and steady state reached within 4 days.

Conclusions

RXDX-101 has been well tolerated in patients with advanced solid tumors. Early responses in patients with 3 different relevant molecular alterations are promising. PK profile seems suitable for once daily dosing, which is being evaluated. A global phase I/II trial was recently initiated.

Disclosure

F.G.M. De Braud: Consultant or Advisory Roles Novartis Compensated Bristol-Myers Squibb; ompensated Roche Compensated Stock Ownership No Honoraria No Research Funding Yes; E. Ardini: Senior Scientist, Nerviano Medical Sciences Employee Compensated; M. Martignoni: CLIOSS Employee, Clinical Leader Compensated; A. Isacchi: Director, Nerviano Medical Sciences Compensated Employee; P. Pearson: Consultant Role Ignyta, Inc. Compensated Stock Ownership Ignyta, Inc.; D. Luo: Ignyta, Inc. Employee Sr. Director, Clinical Operations Compensated; J.L. Freddo: Consultant Role; Member Board of Directors Ignyta, Inc. Compensated Stock Ownership, Ignyta, Inc. Yes; S. Siena: Consultant or Advisory Role Amgen Compensated Bayer Compensated Celgene Compensated Sanofi Compensated Roche Compensated; tock Ownership No Research Funding Bayer. All other authors have declared no conflicts of interest.