Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 25, No 18S (June 20 Supplement), 2007: 3529
© 2007 American Society of Clinical Oncology

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Abstract

First in human phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of KU-0059436 (Ku), a small molecule inhibitor of poly ADP-ribose polymerase (PARP) in cancer patients (p), including BRCA1/2 mutation carriers

The Royal Marsden Hospital NHS Trust, Surrey, United Kingdom; The Netherlands Cancer Institute, Amsterdam, The Netherlands; The Institute of Cancer Research, London, United Kingdom; KuDOS Pharmaceuticals Limited, Cambridge, United Kingdom

3529

Background: Ku is a novel, potent, orally active PARP-1 and 2 inhibitor. It induces selective cytotoxicity in cells with defective homologous recombination repair such as BRCA1/2 deficient tumor cells. Methods: Starting at 10 mg daily (qd) for 2 out of 3 weeks (w), Ku dose escalation was guided by toxicity and PK data. Cohorts of 3–6 p with advanced solid tumors were treated, with provisions for enrichment with BRCA1/2 mutation carriers. PD studies evaluated PARP functional activity in surrogate tissue, including peripheral blood mononuclear cells (PBMC), and tumor tissue when available. Results: 44 p were treated; 17 M/ 27 F; mean age 56 (range 19–82). ECOG PS =2. 11 p had BRCA1/2 mutations and 2 p had strong family histories suggesting BRCA1/2 mutations. Dose levels tested were 10, 20, 40 and 80 mg qd, then 60 and 100 mg twice daily (bid) - all for 2 out of 3 w; followed by 100, 200, 400 and 600 mg bid continuously. Dose limiting toxicity was seen in 1 of 6 p at 400 mg bid. This p had grade (G) 3 neurocognitive toxicity, nausea and vomiting, all of which resolved within 24 hours of drug discontinuation. Other Ku toxicities included G1–2 fatigue, anorexia, constipation and diarrhea. PK data supports dose proportionality up to 200mg bid; mean elimination half-life was 6 hours (range 4.6–7), mean clearance/bioavailability (F) was 4.55 L/h (range 1.8–9.1), and mean volume of distribution/F was 39.9L (range 17–92.1). PD studies indicate a significant (>50%) inhibition of PARP functional activity in PBMC and tumor at doses >40 mg qd. Encouraging anti-tumor activity was seen. 4 p had significant tumor marker declines, 3 of whom also had radiological evidence of response (including 1 partial response by RECIST criteria for 6 months). 7 other p had stable disease for 3 to 6 months. Several of these p had BRCA1/2 mutations and were chemotherapy resistant. Conclusions: Ku leads to significant PARP inhibition with minimal toxicity. The final dose level (600 mg bid continuously) is being tested to maximize tumor PARP inhibition. Both radiological and biochemical evidence of antitumor activity have been seen in BRCA1/2 cancer p. Exploration of Ku in phase II and combination studies is warranted.

Author Disclosure

Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Expert Testimony Other Remuneration Kudos AstraZeneca Oncology, Kudos Kudos Kudos

Abstract presentation from the 2007 ASCO Annual Meeting