Abstract 3695
Background
FOLFOX (5-flourouracil, leucovorin, oxaliplatin) and FOLFIRI (fluorouracil, leucovorin, irinotecan) in combination with targeted agents are standard-of-care options for patients for mCRC with response rates >50% in first line. In the second line setting, efficacy of chemotherapy and targeted agents are much lower with response rates of 4% for FOLFIRI + bevacizumab (Tabernero 2014) and treatment options are limited in particular for the 50 % of patients harboring a RAS mutation. Polo-like kinase 1 (PLK1) is a serine/threonine kinase, master regulator of G2/M cell-cycle progression and genome wide RNAi screens identified PLK1 to be synthetic lethal for KRAS mutated tumor cells inducing arrest and apoptosis (Luo 2009). Onvansertib is an oral, highly selective PLK1 inhibitor that demonstrates single agent and synergistic activity with irinotecan in preclinical CRC models. Additionally, KRAS mutated vs wild-type tumor cells showed higher sensitivity to onvansertib. PLK1 inhibition is a potential target in KRAS-mutated mCRC and onvansertib + FOLFIRI may provide a new second-line treatment option.
Trial design
The primary objective of this single-arm study is to assess the safety and preliminary efficacy of onvansertib in combination with FOLFIRI and bevacizumab in the second line setting for KRAS-mutated mCRC patients by determining the MTD and RP2D in the Phase 1b segment of the trial, and using the RP2D to treat patients in the Phase 2 continuation segment. For the phase 1b, a standard 3 + 3 dose-escalation design will be used with enrollment stopping when 6 patients have been treated at the highest dose level at which 1 or fewer patients experience a DLT. For the phase 2, based on a one-sided one sample log-rank test with 10% Type I error, there will be at least 90% power to detect an improvement in ORR from 5% to 20% with 26 patients. Preliminary efficacy will be determined by objective response (RECIST v1.1) and exploratory studies include quantitation of KRAS circulating tumor DNA (ctDNA) and genomic studies of circulating tumor cells and ctDNA to determine activated pathways that correlate with patient response.
Clinical trial identification
NCT03829410.
Editorial acknowledgement
Legal entity responsible for the study
Trovagene.
Funding
Trovagene.
Disclosure
M. Erlander: Full / Part-time employment: Trovagene. All other authors have declared no conflicts of interest.
Resources from the same session
2107 - Role of Individualized Intervention(s) on Quality of Life (QOL) and Adherence to Adjuvant Endocrine Therapy in Premenopausal Women with Early-Stage Breast Cancer (BC): MyChoice Study
Presenter: Shahid Ahmed
Session: Poster Display session 2
Resources:
Abstract
5812 - Correlation between the density of tumor-infiltrating lymphocytes, immune cell subsets in tumor stroma and response to systemic therapy in breast cancer
Presenter: Cvetka Grasic Kuhar
Session: Poster Display session 2
Resources:
Abstract
4734 - BRCA1/2 Testing in HER2- Advanced Breast Cancer (ABC): Results from the European Component of a Multi-Country Real World Study
Presenter: Michael Patrick Lux
Session: Poster Display session 2
Resources:
Abstract
1686 - In vitro and in vivo rescue of resistance to BET inhibitors by targeting PLK1 in triple negative breast cancer.
Presenter: Cristina Nieto-jiménez
Session: Poster Display session 2
Resources:
Abstract
5020 - Neoadjuvant endocrine therapy in combination with melatonin and metformin in locally advanced breast cancer
Presenter: Tatiana Semiglazova
Session: Poster Display session 2
Resources:
Abstract
5082 - Melatonin and metformin in neoadjuvant chemotherapy in locally advanced breast cancer
Presenter: Tatiana Semiglazova
Session: Poster Display session 2
Resources:
Abstract
2642 - Patient-tailored tamoxifen dosing based on an increased quantitative understanding of its complex pharmacokinetics: A novel integrative modelling approach
Presenter: Anna Mueller-Schoell
Session: Poster Display session 2
Resources:
Abstract
2461 - Lack of benefit of neoadjuvant pertuzumab in high risk HER2 positive breast cancer. A retrospective case-control study of 355 cases with biomarker analysis.
Presenter: Manuela Tiako Meyo
Session: Poster Display session 2
Resources:
Abstract
4776 - Targeting CDCA3 to improve chemotherapy response in triple-negative breast cancer patients
Presenter: Kenneth O'Byrne
Session: Poster Display session 2
Resources:
Abstract
1674 - Activity of BET-proteolysis targeting chimeric (PROTAC) compounds in triple negative breast cancer
Presenter: María Del Mar Noblejas López
Session: Poster Display session 2
Resources:
Abstract