Preoperative Radiotherapy And E7046 in Rectum Cancer (PRAER 1)
Research type
Research Study
Full title
An Open-Label Multicenter Phase 1b Study of E7046 in Combination With Radiotherapy/Chemoradiotherapy (RT/CRT) in Preoperative Treatment of Subjects With Rectum Cancer
IRAS ID
222305
Contact name
Taeera Taib
Contact email
Sponsor organisation
Eisai Ltd
Eudract number
2016-003064-38
Clinicaltrials.gov Identifier
125272, IND number
Duration of Study in the UK
2 years, 11 months, 18 days
Research summary
Summary of Research
This is a multicenter, open-label, Phase 1b study in subjects with locally advanced rectum cancer where primary resection without chemoradiotherapy (CRT) is unlikely to achieve clear margins as defined by Magnetic Resonance Imaging (MRI). The primary objectives of the study is to assess the safety and tolerability of E7046 in combination with preoperative radiotherapy (RT) and chemotherapy in the short course (SCRT) and long course radiotherapy (LCRT) settings and to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of E7046 in combination with preoperative radiotherapy and chemotherapy. Subjects will be on study treatment for 10 weeks in combination with pre-operative SCRT and LCRT and will then be receiving TME surgery and followed up for 2 years. The study comprises E7046 in combination with pre-operative LCRT and concomitant chemotherapy, and E7046 in combination with pre-operative SCRT followed by chemotherapy. There will be approximately 6 sites in Europe and in USA. Approximately 68 subjects will be enrolled (approximately 24 in the Dose Escalation part of the study, and approximately 44 in the Expansion Part). Subjects will be excluded from the study if they have metastatic disease or if they meet criteria such as contraindication to MRI, are unfit to receive study treatment or subsequent surgical resection, or have had previous radiotherapy in the pelvic region, prior rectal surgery, or an investigational treatment for rectal cancer.
Radiation with or without chemotherapy is the most commonly used treatment for localized advanced rectum cancers. Despite significant technological improvements, the local/regional failure rates are high and there is room for improvement in clinical outcomes in most tumors.
The mechanism of action of E7046, the preclinical study results in combination with RT or CRT and the unmet medical need to improve outcomes of Radiotherapy (RT) provide the rationale to study the combination of RT and E7046 in the clinic.Summary of Results
Although definitive conclusions regarding efficacy and dosing differences cannot be determined due to small subject numbers overall and within groups, the combination of AN0025 with preoperative radiotherapy and chemotherapy effectively helped to downstage locally advanced rectal cancer in subjects who were not eligible for surgery due to low chances of complete macroscopic tumor resection with clear resection margins. A total of 65.4% of subjects had MRI-confirmed down-staging of stage 3 or lower following completion of treatment, with comparable numbers across all treatment groups. Following radiotherapy alone, MRI-confirmed down-staging has been shown to occur in 30% of patients.[12] It is worth noting that verifying T-stage via MRI has an accuracy range between 43 and 77%.[12] Nonetheless, the relatively high proportion of subjects improving their T-stage further suggests increased efficacy when using AN0025 in combination with chemoradiotherapy, as suggested by preclinical data in mice with radiotherapy.REC name
London - South East Research Ethics Committee
REC reference
17/LO/0776
Date of REC Opinion
12 Jun 2017
REC opinion
Further Information Favourable Opinion