Neoadjuvant Regorafenib in Combination With Nivolumab and Short-course Radiotherapy in Stage II-III Rectal Cancer

Summary

This is a multicenter, single-arm, phase II study of nivolumab in combination with regorafenib in subjects with locally-advanced rectal cancer who are eligible for a curative treatment including pre-operative SCRT and TME(or watch \& wait approach). The study is based on the Simon's two-stage design and a maximum of 60 subjects will be enrolled. In addition to the standard efficacy interim analysis according to the statistical design, a safety interim analysis will be performed on the first 6 subjects who have completed the study treatment to ensure safe continuation of the study investigation.

Eligible subjects will be treated according to the following sequential treatment plan:

* Induction treatment: This consists of treatment with nivolumab (240 mg intravenously, on day 1 and 15) and regorafenib (60 mg/day orally, from day 1 to 14)
* Standard SCRT: This consists of 25 Gy delivered in 5 fractions (from day 22 to 26)
* Consolidation treatment: This consists of treatment with nivolumab (240 mg intravenously, on day 29, 43 and 57) and regorafenib (60 mg/day orally, from day 29 to 49)
* Surgery: Surgical resection will be performed according to the principles of TME (between day 74 and 87, i.e., between 7 to 8 weeks after completion of SCRT). As an alternative to surgery, subjects who achieve cCR can be offered a watch \& wait approach.
* Adjuvant chemotherapy: Administration of adjuvant chemotherapy will be left to the discretion of the treating physician

The study also includes translational procedures (i.e. collection of tumour biopsies, blood samples and stool samples at pre-specified time points) for exploratory molecular and immune contexture analyses. These are mandatory for all study subjects.

Conditions

• Rectal Cancer Stage II
• Rectal Cancer Stage III

Interventions

DRUG

Nivolumab 10 MG/ML Intravenous Solution

Nivolumab will be given at a dose of 240 mg during the pre-operative phase only as indicated below: * On day 1 and 15, during the "Induction treatment" * On day 29, 43 and 57, during the "Consolidation treatment"

DRUG

Regorafenib 30 MG Oral Tablet

Regorafenib will be administered orally once a day at a dose of 60 mg/day (2 tablets of 40 mg), during the pre-operative phase only as indicated below: * From day 1 to 14, during the "Induction treatment" * From day 29 to 49, during the "Consolidation treatment"

RADIATION

Radiotherapy

All study subjects will receive 5 daily fractions of radiotherapy. Each fraction will consist of 5 Gy for a total dose of 25 Gy. Radiotherapy is to start on day 22 and to finish on day 26.

PROCEDURE

Surgery

Subject will undergo surgical resection of the primary tumour in the rectum between day 74 and 87. Surgery must be performed according to the principles of total mesorectal excision as described by Heald et al. The type of surgical approach (low anterior resection or abdominoperineal resection, etc.) will be left to the discretion of the treating surgeon.

PROCEDURE

Non-operative Management

Subjects who achieve cCR after pre-operative treatment can, after discussion with the local investigator, decline surgery and opt for a non-operative management. cCR will need to be confirmed between day 67 and 74 by the following procedures per local practise: * Digital rectal examination * Rectal endoscopy * Rectal MRI Subjects who achieve near cCR at the first assessment time point after pre-operative treatment, can be re-assessed 6 to 8 weeks later with the same procedures. If cCR is diagnosed, they can opt for watch \& wait, otherwise they would need to undergo surgical resection. Subjects who opt for a non-operative management will be followed for tumour recurrence and survival for 5 years after end of treatment visit. Follow-up for these subjects will be more intensive than that for subjects undergoing surgery

Sponsors & Collaborators

• Jules Bordet Institute

  lead OTHER

Principal Investigators

• Francesco Sclafani, MD · Jules Bordet Institute

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2021-03-25

Primary Completion

2026-12-31

Completion

2032-12-31

Countries

• Belgium

Study Locations