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

• Published in: British journal of cancer 2020-08, Vol.123 (4), p.525-533
• Main Authors: Plummer, Ruth, Dua, Divyanshu, Cresti, Nicola, Drew, Yvette, Stephens, Peter, Foegh, Marie, Knudsen, Steen, Sachdev, Pallavi, Mistry, Bipin M., Dixit, Vaishali, McGonigle, Sharon, Hall, Nancy, Matijevic, Mark, McGrath, Shannon, Sarker, Debashis
• Format: Article
• Language: English
• Subjects: 631/67; 631/67/1059; Administration, Oral; Adult; Adverse events; Aged; Anaphylaxis; Biomarkers; Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer Research; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Colorectal cancer; Colorectal carcinoma; Dosage; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug dosages; Drug Resistance; Epidemiology; Fatigue; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Isoquinolines - administration & dosage; Isoquinolines - adverse effects; Isoquinolines - pharmacology; Lung cancer; Male; Maximum Tolerated Dose; Middle Aged; Molecular Medicine; Neoplasms - drug therapy; Neoplasms - genetics; Oncology; Oral administration; Pancreas; Patients; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage; Poly(ADP-ribose) Polymerase Inhibitors - adverse effects; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Quinazolinones - administration & dosage; Quinazolinones - adverse effects; Quinazolinones - pharmacology; Solid tumors; Survival Analysis; Toxicity; Treatment Outcome; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-0916-5

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.