First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor

Abstract

Background: This phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor.

Methods: E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50-800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines.

Results: Forty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumour types). The most common grade ≥3 treatment-related adverse event was fatigue (n = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n = 4, 800 mg; anaphylaxis, n = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumour activity in solid tumours, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 weeks) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumour activity and significant concentration-dependent PARP inhibition following 50-800-mg oral dosing.

Conclusion: The results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP.

Clinical trial registration: www.ClinicalTrials.gov code: NCT01618136.

Conflict of interest statement

Ruth Plummer has received honoraria for attending advisory boards from Pierre Faber, Genmab, Bayer, Octimet, Clovis Oncology, Novartis, Karus Therapeutics, Biosceptre, BMS, Cybrexa, Ellipses and Sanofi Aventis, and for delivery of educational talks or chairing educational meetings by AstraZeneca, Novartis, Bayer, Tesaro and BMS. R.P. is named on the patent of use for rucaparib. Yvette Drew has participated on advisory boards for Clovis Oncology, AstraZeneca, Merck, Tesaro, Inc. and Genmab. Y.D. has received research grant funding from Clovis Oncology, and was involved in the preclinical and clinical development of rucaparib. Newcastle University (Y.D.’s employer) and Y.D. have received royalties for their involvement in the development of rucaparib. Y.D. has received research grant funding from AstraZeneca and Tesaro, Inc. Y.D. is an investigator on clinical trials of olaparib and rucaparib. Marie Foegh and Steen Knudsen are employees of, and have ownership interest in Oncology Venture, which owns rights related to the contents of this article. Pallavi Sachdev, Bipin M. Mistry, Vaishali Dixit, Sharon McGonigle, Nancy Hall, Mark Matijevic and Shannon McGrath are/were full-time employees of Eisai Inc., at the time of the study. Nicola Cresti and Divyanshu Dua have no relevant conflicts of interest to declare. Dr Peter Stephens has received honoraria for serving on advisory boards for Novartis, and educational support from Eisai and Daiichi Sankyo. Dr Debashis Sarker has received honoraria from Pfizer, Bayer and Ipsen, and has had consultancy/advisory roles with Novartis, Ipsen and Eisai.

Figures

Fig. 1. Maximum percentage of inhibition of PARP by patient and E7449 dose during cycle 1 (any time point).

aAll patients in the 600-mg cohort exceeded the maximum % PARP inhibition measurement at 1 or more time points. Maximum inhibition was calculated when the measured PAR in peripheral blood mononuclear cells was below the assay lower detection limit. The measured value was then replaced by the assay lower detection limit. PAR, polyadenosine diphosphate–ribose; PARP, polyadenosine diphosphate–ribose polymerases.

Fig. 2. Biomarker predicted tumour sensitivity to E7449 versus clinical outcome (ORR).

The prediction score was corrected for differences in dose by multiplying with the dose (50–800 mg) and dividing by 518. The grey mid-line shows the prespecified cut-off score of 50 used to divide patients into sensitive and not sensitive (a). Overall survival of the two groups of patients predicted sensitive or resistant (b).