Abstract 562P
Background
Targeting aberrant NOTCH pathway activation in cancer has been a challenge due to dose limiting toxicities (DLT) and limited clinical efficacy. CB-103 is a selective inhibitor of the NOTCH transcription complex, and has shown potent anti-cancer activity in preclinical models. We designed a dose escalation/expansion phase I/IIa study to assess safety, maximum tolerated dose (MTD) and recommended phase II dose (RP2D), preliminary activity, pharmacokinetics and pharmacodynamics of CB-103. Preliminary results of the dose escalation are presented.
Methods
Adult pts with advanced or recurrent selected solid tumors are eligible. In the dose escalation part, pts were unselected for NOTCH mutations which were evaluated retrospectively. CB-103 is being administered orally once-daily (OD) at escalating doses, in 28 days cycles until disease progression or toxicity. Once the RP2D will be defined, the study will include only patients with NOTCH altered cancers.
Results
To date, 36 pts (17 adenoid cystic carcinoma (ACC), 15 colorectal and 4 other) were assigned to increasingdose levels starting from 15mg OD. Median age was 56 years (range 25-76). Median number of prior lines of therapy was 2 (range 0-7). CB-103 plasma concentrations increased with increasing dose levels. The elimination half-life was ∼20 hours, steady state levels were reached within 1 week. Thirty-two pts completed the 28-day DLT window. One DLT (asymptomatic grade (G) 3 GGT increase) was observed. Related treatment emergent adverse events (TEAEs) occurring in >10% of pts were eye disorder (22%), nausea (22%), diarrhea (17%), fatigue (11%), and dyspepsia (11%) all G 1/2. Two G3 TEAEs occurred at low doses: drug-induced liver injury and hypertension. Median time on treatment was 43 days (range 15-245). Best response was stable disease (SD) observed in 18 pts. Among ACC pts, 2 pts harboring NOTCH1 gain-of-function mutations had stable disease (SD) ≥ 6 months with downregulation of NOTCH signaling in hair follicles and blood cells.
Conclusions
CB-103 in pts with advanced tumors is well tolerated at doses showing significant and sustained target engagement, and yielded long-term SD in NOTCH positive ACC pts. The RP2D has not been reached yet and enrollment is ongoing.
Clinical trial identification
NCT03422679.
Editorial acknowledgement
Legal entity responsible for the study
Cellestia Biotech AG.
Funding
Cellestia Biotech AG.
Disclosure
A.B. Azaro Pedrazzoli: Advisory/Consultancy: Orion Pharma; Advisory/Consultancy, Research grant/Funding (self): Amcure GmbH. J.M. Perez Garcia: Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Lilly. J. Cortés: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Celgene; Advisory/Consultancy: Cellestia; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Biothera Pharmaceutical; Advisory/Consultancy: Merus; Advisory/Consultancy: SeattleGenetics; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy: Erytech; Advisory/Consultancy: Athenex; Advisory/Consultancy: Polyphor; Honoraria (self), Advisory/Consultancy: Lilly; Advisory/Consultancy, Research grant/Funding (institution): Servier; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck Sharp & Dohme; Advisory/Consultancy: GSK; Advisory/Consultancy: Leuko; Advisory/Consultancy: Bioasis; Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Eisai; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Samsung Bioepis; Research grant/Funding (institution): Ariad pharmaceuticals; Research grant/Funding (institution): Bayer Healthcare; Research grant/Funding (institution): Guardanth Health; Research grant/Funding (institution): Piqur Therapeutics; Research grant/Funding (institution): Puma C; Research grant/Funding (institution): Queen Mary University of London; Shareholder/Stockholder/Stock options: MedSIR. I. Colombo: Travel/Accommodation/Expenses: Tesaro. E. Garralda: Research grant/Funding (institution): Novartis; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Roche ; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Thermo Fisher; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: F.Hoffmann-La Roche ; Advisory/Consultancy: Ellipses Pharma; Advisory/Consultancy: Neomed Therapeutics1 Inc; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Janssen Global Services; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: TFS; Advisory/Consultancy: Alkermes; Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Travel/Accommodation/Expenses: Menarini; Travel/Accommodation/Expenses: Glycotope. O. Schoenborn-Kellenberger: Advisory/Consultancy: Cellestia Biotech AG. M. Vigolo: Full/Part-time employment: Cellestia Biotech AG. L. Beni: Full/Part-time employment: Cellestia Biotech AG. R. Lehal: Leadership role, Full/Part-time employment, Officer/Board of Directors: Cellestia Biotech AG. M. Murone: Leadership role, Full/Part-time employment, Officer/Board of Directors: Cellestia Biotech AG. M. Bauer: Leadership role, Full/Part-time employment, Officer/Board of Directors: Cellestia Biotech AG. P. Pisa: Full/Part-time employment: Cellestia Biotech AG. F.D. Vogl: Leadership role, Full/Part-time employment, Officer/Board of Directors: Cellestia Biotech AG. A. Stathis: Research grant/Funding (institution): Roche; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): MEI-Pharma; Research grant/Funding (institution): ADC Therapeutics; Research grant/Funding (institution): Cellestia; Travel/Accommodation/Expenses: PharmaMar; Travel/Accommodation/Expenses: AbbVie. All other authors have declared no conflicts of interest.