Novel Agent Shows Potential in Patients With Advanced Solid Tumours: Presented at AACR-NCI-EORTC

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Title: Novel Agent Shows Potential in Patients With Advanced Solid Tumours: Presented at AACR-NCI-EORTC
URL: http://www.pslgroup.com/dg/21651A.htm
Doctor's Guide
October 26, 2007

By Crina Frincu-Mallos, PhD

SAN FRANCISCO, CA -- October 26, 2007 -- A novel agent has a good safety profile and shows potential in patients with advanced solid tumours, researchers reported here at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

AARY-543 is a reversible inhibitor of epidermal growth factor receptor (EGFR) and the tyrosine kinase receptor ErbB2, and was previously found to be active against both EGFR and ErbB2-driven human tumours in xenograft models.

Kevin S. Litwiler Array, PhD, Associate Director, Drug Metabolism, Array BioPharma Inc, Boulder, Colorado, United States, presented preliminary results in humans with cancer here on October 25.

Dr. Litwiler and colleagues aimed to assess the safety and the pharmacokinetics (PK) of ARRY-543 in cancer patients enrolled in a phase 1 open-label trial with escalating daily dosing.

A total of 46 patients with advanced solid tumors (female to male ratio, 24:22), median age 59 years (range, 34-82 years), received the study drug.

ARRY-543 was administered orally to successive cohorts of patients. The patients received initially a single dose and were followed for a week. After the observation period, patients received the investigational drug once daily (QD) or twice daily (BID) starting on day 8 until day 36, the end of the cycle.

Blood samples for PK analysis were collected on day 1 30 minutes after the dose and at various time periods up to 48 hours after the first dose. In addition, blood samples were collected at steady state on day 22, at pre-dose, and at 1, 3, and 6 hours post-dose.

Blood samples containing K₂EDTA were processed to plasma.

Preliminary PK data as of September 2007 were assessed using standard non-compartmental analysis (WinNonlin(R)).

For the single-dose PK, five dose levels were used: 50 mg (n=4), 100 mg (n=9), 200 mg (n=11), 300 mg (n=9), and 400 mg (n=11). The mean terminal half-life of ARRY-543 was 6.6 +- 1.2 hours, independent of dose level.

The single-dose mean apparent time to maximum concentration across all doses was 2.8 +- 1.4 hours post-dose, increasing from 1.5 to 3.6 hours with increasing dose.

The mean peak concentration and area under the curve from time 0 to infinite at single-dose for ARRY-543 increased in a dose-proportional manner, explained Dr. Litwiler.

For the steady-state pharmacokinetics with QD dosing (day 22), five dose levels were used as well: 50 mg (n=4), 100 mg (n=5), 200 mg (n=3), 300 mg (n=5), and 400 mg (n=3). The mean peak-to-trough ratio over the dosing interval was 8.7, decreasing with increasing dose.

For the steady state pharmacokinetics with BID dosing (day 22), the four dose levels were used: 100 mg (n=4), 200 mg (n=4), 300 mg (n=4), and 400 mg (n=4). The mean peak-to-trough ratio over the dosing interval was 2.1 +- 0.5. At the 400 mg BID, maximum concentration was 7.07 mcg/mL and trough concentration was 4.24 mcg/mL.

Mean plasma concentrations of ARRY-543 were maintained at >=1 mcg/mL at doses higher than 200 mg twice daily.

At steady state, exposure tended to increase with increasing dose in both QD and BID dosing schedules, the researchers noted.

The inhibition of pErbB2 by ARRY-543 was assessed in 50% human serum, using the BT474 cell line. The IC₅₀ 50% inhibitory concentration was 308 mg/mL (Hill slope=1.04).

Dr. Litwiler explained that the mean clinical plasma concentrations of ARRY-543 were used to predict pErbB2 inhibition vs. time and dosing schedule.

The maximum tolerated dose (MTD) has been established at 300 mg for the QD dosing schedule, but was not reached for the BID dosing schedule, said Dr. Litwiler.

The BID dosing was chosen for the phase 1/2 studies, based on the PK results, concluded Dr. Litwiler.

The preliminary results show that the most common toxicities reported by the patients treated with the investigational agent ARRY-543 were fatigue, nausea, anorexia, rash, vomiting and diarrhoea. Also, at this time, prolonged stable disease was the best response in the patients undergoing treatment with ARRY-543.

Funding for this study was provided by Array Biopharma, which is developing the investigational agent, ARRY-543.

[Presentation title: Pharmacokinetics of ARRY-543 from a Phase 1 study in cancer patients

. Abstract C164

]

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