START Madrid - FJD, Hospital Universitario Fundación Jimenez Diaz, Madrid, Spain
Victor Moreno , Irene Braña , Juan Manuel Manuel Sepulveda Sanchez , Maria Vieito Villar , Tatiana Hernandez-Guerrero , Bernard Doger , Omar Saavedra , Olga Ferrero , Rafael Sarmiento , Marina Arias , Juan De Alvaro , Jorge F. DiMartino , Marlene Zuraek , Tania Sánchez Pérez , Ellen Filvaroff , Ida Aronchik , Manisha Lamba , Bishoy Hanna , Zariana G. Nikolova
Background: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that control expression of genes involved in cell growth and oncogenesis. CC-90010 is an oral, potent and reversible BET inhibitor that showed promising activity in lymphoma and solid tumor cell lines and reduced tumor growth in xenograft models. Methods: CC-90010-ST-001 (NCT03220347; 2015-004371-79) is a phase I, first-in-human study of CC-90010 in patients (pts) with advanced solid tumors and R/R NHL. Three schedules and 11 dose levels were evaluated (Table). Primary objectives were to determine safety, maximum-tolerated dose and/or recommended phase II dose (RP2D). Secondary objectives were the identification of early activity signals, pharmacokinetics and pharmacodynamics (PD). Results: As of 10 Dec 2018, 69 pts were enrolled, 67 with solid tumors and 2 with R/R NHL. Data shown are from all pts (N = 69). The median age was 57 y (range, 21–80), 38 (55%) were male, and the median number of prior systemic anticancer regimens was 3 (range, 1–9). The RP2Ds were dose cohorts 3A and 4B. Dose-limiting toxicities (n = 6) occurred in dose cohorts 3A, 3C, and 4B. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 17 pts (25%), most commonly (≥2 pts) thrombocytopenia (7%), platelet count decreased (4%), fatigue (3%), and increased alanine aminotransferase (3%). No deaths from toxicity occurred. Two pts (endometrial carcinoma and astrocytoma) had a partial response (PR); 1 occurred after the data cutoff. Seven pts had prolonged stable disease (SD) > 9 mo. Exposures and PD marker regulation increased with dose in each dosing schedule; terminal half-life was ~ 73 h. Conclusions: Most of the TRAEs observed were mild or moderate in severity, reversible, and manageable by dose adjustments and/or supportive care. Promising ongoing anticancer activity with prolonged SD and PRs were observed. The preliminary clinical data provide the rationale for dose expansion of CC-90010 in pts with selected advanced malignancies. Clinical trial information: NCT03220347
Dose Level: | 1 (n = 7) | 2 (n = 7) | 3A (n = 4) | 3B (n = 6) | 3C (n = 6) | 4A (n = 7) | 4B (n = 7) | 4C (n = 7) | 5A (n = 6) | 5B (n = 6) | 5C (n = 6) |
---|---|---|---|---|---|---|---|---|---|---|---|
Dose, mg | 15 | 15 | 25 | 30 | 15 | 40 | 45 | 25 | 30 | 55 | 35 |
Schedule, days on/off | 3/4 | 3/11 | 3/11 | 4/24 | 2/5 | 3/11 | 4/24 | 2/5 | 3/11 | 4/24 | 2/5 |
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Abstract Disclosures
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