Delta-like protein 3 (DLL3) is an atypical Notch receptor family ligand expressed in high-grade neuroendocrine carcinomas (NECs), but not in normal tissue. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting DLL3. A Phase 1 study of Rova-T in small cell lung cancer showed encouraging antitumor activity in patients (pts) with DLL3 expression, and was well-tolerated1. Rova-T may also be active in other DLL3-expressing tumors.
This is a Phase 1/2, open-label, multicenter study (NCT02709889) to determine safety and tolerability of Rova-T in 8 cohorts: malignant melanoma, medullary thyroid cancer (MTC), glioblastoma (GBM), large cell NEC (LCNEC), neuroendocrine prostate cancer (NEPC), high-grade gastroenteropancreatic NEC (GEP NEC), other NEC and other solid tumors. Eligible adults have a histologically confirmed, DLL3-expressing, advanced solid tumor relapsed/refractory to standard therapy, and no prior exposure to a pyrrolobenzodiazepine-based drug. A 3 + 3 dose escalation is used in each cohort, at doses 0.2-0.4 mg/kg of Rova-T administered intravenously on Day 1 of each 42-day cycle, and proceeding until a maximum tolerated dose (MTD) is determined. A 2-stage design will be used for disease-specific expansion cohorts.
As of 3 April 2017, 31 pts (2 melanoma, 2 MTC, 3 GBM, 3 LCNEC, 3 NEPC, 3 GEP NEC, 10 other NEC, 5 other solid tumor) have been treated (26 pts at 0.2 mg/kg, 5 pts at 0.3 mg/kg Rova-T). The MTD has not been reached. Twenty-six pts (84%) had an adverse event (AE), and only 3/31 pts (10%) had a Grade 3+ AE deemed to be related to Rova-T. Common AEs were fatigue (32%), nausea (29%), and constipation (23%). Four pts had serosal effusions, 2 (6%) of which were assessed to be drug-related, and 3 pts (10%) had adverse skin reactions. Ten pts (32%) discontinued treatment, 5 for progressive disease and 4 due to AEs. Eleven pts have had post-baseline tumor assessments, and anti-tumor activity has been observed in multiple disease cohorts.
Preliminary safety and efficacy data of Rova-T warrant continued study in these disease populations, and will be updated at time of presentation. 1. Rudin et al., Lancet Oncol 2016.
Clinical trial identification
Legal entity responsible for the study
A. Mansfield: Consulting to Genentech, BMS and Trovagene with honoraria provided to institution. H. Beltran, K. Lewis: Research funding from AbbVie Stemcentrx. A.F. Farago: Consulting or advisory role for AbbVie, Pharmamar, Merrimack Pharmaceuticals, Takeda, Intervention Insights. Honorarium from Foundation Medicine. C.L. Hann: Advisory board for AbbVie Stemcentrx and BMS. Research funding from GlaxoSmithKline and Merrimack Pharmaceuticals. S. Richey: Employee of Texas Oncology. Consulting or advisory role for Exelixis, Pfizer, Prometheus and Sanofi. Research funding from Novartis, BMS, Eisai, Genentech/Roche, GSK, and AbbVie. D. Smith: Research funding from US Oncology. H.P. Soares: Advisory board for Cornerstone Pharmaceuticals. Research funding from Novartis. Consultant fees/honoraria for Ipsen. A. Spira: Consultant for AbbVie. Research funding from AbbVie (to institution). S. Lally, M. Rossi, L. Saunders, S.J. Dylla, E. Kavalerchik: Employee of AbbVie Stemcentrx and may own stock. L. Anthony: Research funding from AbbVie Stemcentrx, Lexicon Pharmaceuticals, Novartis, Markey Cancer Center Foundation. All other authors have declared no conflicts of interest.