Abstract P3-14-20: Phase 1 Dose-Escalation Study of the Investigational HER2/EGFR Inhibitor TAK-285 in Patients with Advanced Cancer
Authors: LoRusso P , Chiorean EG , Heath E , Weise A , Foley M , Olivo YS , Chi X , Corvez M , Venkatakrishnan K , Sausville E. 
Published: April 2011

Abstract
Background and Objectives: TAK-285 is a novel, orally active, dual HER2/EGFR inhibitor. Nonclinical data show that TAK-285 has high selectivity and specificity for binding to HER family kinases, and has demonstrated anti-tumor activity in a BT-474 mouse xenograft model of breast cancer. Nonclinical data also indicate that TAK-285 is not a substrate for the efflux transporters P-gp and BCRP and penetrates an intact blood-brain barrier in rats. This phase 1 dose-escalation study in patients with advanced cancer aimed to determine the safety and pharmacokinetic (PK) profile.
Methods: Adults had advanced histologically confirmed non-hematologic malignancies, life expectancy &gt;12 weeks, adequate bone marrow, liver and renal function, ECOG PS 0-2, and were refractory to other treatments. Oral TAK-285 was escalated from 50 to 500 mg QD or BID for 21 or 28 consecutive days of a 28-day cycle until disease progression or unacceptable toxicity was observed.
Results: At the data cut-off of 04/23/10, the dose-escalation portion was complete, and the RP2D expansion cohort is ongoing. Preliminary data from the dose-escalation cohorts are reported. 43 patients (median age 60 years [43-76]) were enrolled: 30% ≥65 years, 51% female, and 86% white. Dose levels were 50 mg QD (N=4), 50 mg BID (N=7), and 75 mg BID (N=6) on d 1-21; and 150 mg (N=6), 225 mg (N=4), 325 mg (N=3), 400 mg (N=6), and 500 mg (N=7) BID on d 1-28. Median duration of exposure across all cohorts was 52 days (3-267). Four patients experienced a DLT in Cycle 1: 1 patient (50 mg BID) had Grade 3 pancreatitis; 1 patient (150 mg BID) had Grade 3 chest pain and Grade 3 hypoxia; 1 patient (500 mg BID) had Grade 3 increased ALT; and 1 patient (500 mg BID) had Grade 3 diarrhoea and Grade 3 hypokalaemia. The MTD was 400 mg BID d 1-28. 30 patients (70%) discontinued TAK-285, primarily due to disease progression (n=19, 44%) or an AE (n=9, 21%). Most frequent AEs were fatigue (37%), diarrhoea (35%), nausea (26%), anorexia (21%), vomiting (16%), and elevated AST (16%). 58% of patients had a drug-related AE; the most frequent were diarrhoea (21%), fatigue (19%), and rash (includes rash, rash maculo-papular and rash macular; 12%). 35% of patients had a grade 3/4 AE; the most common were hypokalaemia (7%), ileus, abdominal pain, and hypoxia (5% each). Grade 3/4 AEs related to TAK-285 were the DLTs in Cycle 1 and Grade 4 rhabdomyolysis in 1 patient (400 mg BID, d 1-28) in Cycle 3. 42% of patients experienced a serious AE (SAE); the only SAE seen in &gt;1 patient was ileus (n=2). 4 (9%) patients had fatal AEs; none were considered related to TAK-285. Absorption was fast: plasma concentrations peaked 2-3 hours post-dose. Steady-state plasma exposures increased with dose in a greater than dose-proportional manner, with PK steady-state achieved by Day 8. Accumulation was noted with BID dosing (mean accumulation ratio, 2.4 at MTD); there was moderate fluctuation in plasma concentrations over the steady-state dosing interval (mean Cmax:Cmin ratio, 2.4 at MTD).
Conclusions: The MTD for TAK-285 was 400 mg BID d 1-28. The RP2D cohort is ongoing and includes CSF collection to assess the CNS distribution of TAK-285. Updated safety as well as efficacy data for the dose escalation cohorts will be presented.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-20.