Capecitabine-based Chemoradiotherapy in Combination With the IL-1 Receptor Antagonist Anakinra for Rectal Cancer Patients

NCT04942626 | Completed Phase 1 DMC

• 1 other identifier: ACO/ARO/AIO-21
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

The ACO/ARO/AIO-21 investigator-driven, open-labeled, phase I drug re-purposing trial will assess whether the IL-1 receptor antagonist Anakinra can be safely combined with fluoropyrimidine-based chemoradiotherapy (CRT) in patients with rectal cancer.

Conditions

Rectal Cancer

Outcome Measures

Primary Outcomes (2)

• Analysis of safety for capecitabine administered concomitantly with standard radiotherapy in combination with Anakinra at a fixed dose of 100 mg s.c.

  Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

  16 weeks

• Identification of the maximum tolerated dose for capecitabine administered concomitantly with standard radiotherapy in combination with Anakinra at a fixed dose of 100 mg s.c

  Identification of the maximum tolerated dose for capecitabine in combination with radiotherapy and Anakinra based on 3+3 design

  16 weeks

Secondary Outcomes (18)

• Postoperative complications of (salvage) surgery

  1 year

• Late toxicity assessment according to NCI CTCAE V.5.0

  3 years

• Rate of W&W with or without local regrowth

  3 years

• Cumulative incidence of locoregional regrowth after cCR

  3 years

• Rate of salvage surgery (LE/TME with or without APR/stoma) after locoregional regrowth

  3 years

Study Arms (1)

Chemoradiotherapy with Anakinra followed by either TME surgery or Watch and Wait

OTHER

Capecitabine 500 mg/m2 bid or Capecitabine 650 mg/m2 bid or Capecitabine 825 mg/m2 bid combined with Radiotherapy and Kineret

Drug: Kineret 100 MG in 0.67 ML Prefilled Syringe; Drug: Capecitabine; Radiation: Radiotherapy; Procedure: Watch and Wait (cCR) or TME surgery (non-cCR)

Interventions

Kineret 100 MG in 0.67 ML Prefilled Syringe DRUG

Anakinra 100 mg s.c. (Kineret) will be administered from day -10 (i.e. 10 days before initiation of RT) to the last day of RT.

Chemoradiotherapy with Anakinra followed by either TME surgery or Watch and Wait

Capecitabine DRUG

Capecitabine will be administered using a 3+3 dose escalation design (500 mg/m2 bid, 650 mg/m2 bid and 825 mg/m2 bid po, respectively) from day 1 to day 40 of RT including weekends.

Chemoradiotherapy with Anakinra followed by either TME surgery or Watch and Wait

Radiotherapy RADIATION

PTV: 1.8 Gy to 45 Gy (#28 fractions) to the primary tumor and pelvic lymph nodes; followed by a sequential boost of 1.8 Gy to 9 Gy (#5 fractions) to the gross tumor volume

Chemoradiotherapy with Anakinra followed by either TME surgery or Watch and Wait

Watch and Wait (cCR) or TME surgery (non-cCR) PROCEDURE

Restaging to evaluate tumor response will be conducted 10 weeks after completion of CRT. For patients achieving a clinical complete response (cCR), a Watch and Wait (W\&W) option with close follow-up is scheduled. In case of non-cCR, immediate total mesorectal excision (TME) surgery is recommended. According to the current German S3-guidelines, adjuvant chemotherapy is optional.

Also known as: W&W or TME

Chemoradiotherapy with Anakinra followed by either TME surgery or Watch and Wait

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female patients with histologically confirmed diagnosis of rectal adenocarcinoma localized 0 - 12 cm from the anocutaneous line as measured by rigid rectoscopy (i.e. lower and middle third of the rectum)
• Staging requirements: High-resolution, thin-sliced (i.e. 3 mm) magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.
• Patients with MRI-defined low risk rectal cancer with the presence of at least one of the following conditions:
• cT2N0 or cT3a/bN0 tumors ≤6 cm from the anocutaneous line that would require abdominoperineal resection or permanent colostomy
• Any rectal cancer of the upper third (12-16 cm) requiring FU-CRT according to German S3 guideline recommendations (i.e. cT4, mrCRM+, extensive N+)
• Patients with MRI-defined intermediate/high risk rectal cancer, but not eligible for TNT (oxaliplatin-containing) protocols:
• any cT3 if the distal extent of the tumor is \< 6 cm from the anocutaneous line, or
• cT3c/d in the middle third of the rectum (≥ 6-12 cm) with MRI evidence of extramural tumor spread into the mesorectal fat of more than 5 mm (\>cT3b), or
• cT3 with clear cN1 based on strict MRI-criteria (see appendix)
• cT4 tumors, or
• Tany middle/low third of rectum with clear MRI criteria for N2
• mrCRM+ (≤ 1mm), or
• Extramural venous invasion (EMVI+)
• Trans-rectal endoscopic ultrasound (EUS) is additionally used when MRI is not definitive to exclude early cT1 disease in the lower third or middle third of the rectum.
• Spiral-CT of the abdomen and chest to exclude distant metastases.

You may not qualify if:

• Distant metastases (to be excluded by CT scan of the thorax and abdomen)
• Prior antineoplastic therapy for rectal cancer
• Prior radiotherapy of the pelvic region
• Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
• Subject (male or female) is not willing to use highly effective methods of contraception during treatment and for 6 months after the end of treatment.
• Previous or current drug abuse
• Other concomitant antineoplastic therapy
• Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder
• Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 6 months before enrolment
• Prior or concurrent malignancy ≤ 3 years prior to enrolment in study (Exception: non-melanoma skin cancer or cervical carcinoma FIGO stage 0-1), if the patient is continuously disease-free
• Known allergic reactions on study medication
• Known dihydropyrimidine dehydrogenase deficiency
• Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule (these conditions should be discussed with the patient before registration in the trial).
• History of severe hepatic impairment (e.g. Child-Pugh = Grade C)
• Moderate (Creatinine Clearance 30 to 49 mL/minute), severe (Creatinine Clearance \<30 mL/minute) renal impairment

Sponsors & Collaborators

• Goethe University: lead

Study Sites (1)

University Hospital Goethe University Frankfurt

Frankfurt, 60590, Germany

Location

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

Interleukin 1 Receptor Antagonist Protein; Capecitabine; Radiotherapy; Receptors, CCR

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Therapeutics; Receptors, Chemokine; Receptors, G-Protein-Coupled; Receptors, Cell Surface; Membrane Proteins; Receptors, Cytokine; Receptors, Immunologic

Study Officials

• Claus Roedel, Prof. MD

  University Hospital Goethe University Frankfurt

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. med. Dr., Clinical Chair

Model Details: 3+3 design

Study Record Dates

• First Submitted: May 25, 2021
• First Posted: June 28, 2021
• Study Start: August 20, 2021
• Primary Completion: December 31, 2024
• Study Completion: December 31, 2024
• Last Updated: February 21, 2025

Record last verified: 2025-02

Locations

DE (1)