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

Sponsor
Jules Bordet Institute
Study ID
NCT04503694
Phase
PHASE2
Status
Active Not Recruiting

Conditions

  • Rectal Cancer Stage II
  • Rectal Cancer Stage III

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • Nivolumab 10 MG/ML Intravenous Solution — DRUG
    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"
  • Regorafenib 30 MG Oral Tablet — DRUG
    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"
  • Radiotherapy — RADIATION
    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.
  • Surgery — PROCEDURE
    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.
  • Non-operative Management — PROCEDURE
    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

Study Details

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.

Key Dates

Start date
Mar 25, 2021
Status verified
May 2026
Primary completion
Dec 31, 2026
Completion
Dec 31, 2032

Study Design

Enrollment
72 participants (estimated)
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT

Arms

  • Experimental: Single arm
    * Induction treatment: treatment with nivolumab (240 mg intravenously on day 1 and 14) and regorafenib (60 mg/day orally from day 1 to 14) * Standard SCRT: consists of 25 Gy delivered in 5 fractions (from day 22 to 26) * Consolidation treatment: 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 (collection of tumour biopsies, blood and stool samples at pre-specified time points) for exploratory molecular and immune contexture analyses. These are mandatory for all study subjects.

Primary Outcome Measure

Evaluation of the efficacy of the combination of nivolumab and regorafenib when administered before and after standard, pre-operative short-course radiation therapy. [ Time Frame: immediately after the surgery ]

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