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
4546 - Efficacy and toxicity of weekly carboplatin and paclitaxel as induction or palliative treatment in advanced esophageal cancer patients
Presenter: Femke de Man
Session: Poster Display session 2
Resources:
Abstract
5908 - Perioperative chemotherapy with Docetaxel, Oxaliplatin, Fluorouracil and Leucovorin (FLOT) versus Epirubicin, Platinum and Capecitabine or Flourouracil (EOX/ECF) in Resectable Gastric or Gastroesophageal Junction Adenocarcinoma- Safety and response data from India.
Presenter: Tanuj Chawla
Session: Poster Display session 2
Resources:
Abstract
937 - Phase II Study of Preoperative Radiotherapy Combined with S-1 plus Cisplatin in Clinically Resectable Type 4 or Large Type 3 Gastric Cancer: OGSG1205
Presenter: Shunji Endo
Session: Poster Display session 2
Resources:
Abstract
1119 - Observational Study of the Peritoneal Washing Cytology Positive Gastric Cancer without Gross Peritoneal Metastasis Underwent Radical D2 Gastrectomy.
Presenter: Jun Eul Hwang
Session: Poster Display session 2
Resources:
Abstract
3744 - Primary results of multicenter phase II study of neoadjuvant chemotherapy with S-1 and oxaliplatin for locally advanced gastric cancer (Neo G-SOX PII)
Presenter: Akira Miki
Session: Poster Display session 2
Resources:
Abstract
5091 - Multicenter Phase I/II Feasibility Study of Adjuvant Treatment with S-1 in Patients after R0-Resection of Adenocarcinoma of the Stomach and Esophagogastric Junction (GMBH-STO-0114)
Presenter: Kathrin Heinrich
Session: Poster Display session 2
Resources:
Abstract
2891 - A phase I study of Docetaxel/Oxaliplatin/S-1 (DOS) combination neoadjuvant chemotherapy for patients with locally advanced adenocarcinoma of the esophagogastric junction
Presenter: Kei Hosoda
Session: Poster Display session 2
Resources:
Abstract
2994 - Apatinib combined with docetaxel in second-line treatment of advanced gastric cancer: a prospective clinical study (Data updated)
Presenter: Mudan Yang
Session: Poster Display session 2
Resources:
Abstract
3000 - A multicenter phase II study of TAS-114 in combination with S-1 in patients with pre-treated advanced gastric cancer (EPOC1604)
Presenter: Daisuke Takahari
Session: Poster Display session 2
Resources:
Abstract
4653 - Impact of Pembrolizumab (pembro) Versus Paclitaxel on Health-Related Quality of Life (HRQoL) in Patients With Advanced Gastric or Gastroesophageal Junction (GEJ) Cancer That Has Progressed After First-Line Chemotherapy (KEYNOTE-061)
Presenter: Eric Van Cutsem
Session: Poster Display session 2
Resources:
Abstract