- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04942626
Capecitabine-based Chemoradiotherapy in Combination With the IL-1 Receptor Antagonist Anakinra for Rectal Cancer Patients (ACO/ARO/AIO-21)
Capecitabine-based Chemoradiotherapy in Combination With the IL-1 Receptor Antagonist Anakinra for Rectal Cancer Patients. A Phase I Trial of the German Rectal Cancer Study Group
Study Overview
Status
Conditions
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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-
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Frankfurt, Germany, 60590
- University Hospital Goethe University Frankfurt
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- 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.
- Aged at least 18 years. No upper age limit
- WHO/ECOG Performance Status ≤1
Adequate hematological, hepatic, renal and metabolic function parameters:
- Leukocytes ≥ 3.000/mm^3, ANC ≥ 1.500/mm^3, platelets ≥ 100.000/mm^3, Hb > 9 g/dl
- Serum creatinine ≤ 1.5 x upper limit of normal
- Bilirubin ≤ 2.0 mg/dl, SGOT-SGPT, and AP ≤ 3 x upper limit of normal
- Informed consent of the patient
Exclusion Criteria:
- 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
- Major surgery within the last 4 weeks prior to inclusion
- 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.
- On-treatment participation in a clinical study in the period 30 days prior to inclusion
- 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
- Neutropenia (neutrophil count <1.5x109/l)
- Known hypersensitivity to Anakinra or E. coli derived proteins, Anakinra or any of the components of the product
- Asthma
- Patients with clinically significant bacterial, fungal, parasitic or viral infection, which require acute therapy. Patients with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed
- Patients with known active hepatitis B, C or who are HIV-positive or who are at risk for HBV reactivation. At risk for HBV reactivation is defined as hepatitis B surface antigen positive or anti-hepatitis B core antibody positive. Prior test results obtained as part of standard of care that confirm a subject is immune and not at risk for reactivation (ie, hepatitis B surface antigen negative, surface antibody positive) may be used for purposes of eligibility and tests do not need to be repeated. Subjects with prior positive serology results must have negative polymerase chain reaction results. Subjects whose immune status is unknown or uncertain must have results confirming immune status before enrollment.
Subjects who are already using the following medications will not be allowed:
- Tumor necrosis alpha inhibitors: Use on any of these biologics within 8 weeks of screening or baseline visit.
- IL-6 inhibitors: Use of any IL-6 inhibitors within 8 weeks of screening or baseline visit
- Janus Kinase inhibitors: Use of baricitinib, tofacinitib, upadacitinib, and ruxolitinib, oclacitinib, fedratinib, within 2 weeks from screening or baseline visit.
- Bruton's tyrosine kinase inhibitors: Ibrutinib, acalabrutinib, zanubrutinib
- CCR5 antagonist (CCR5 = C-C Chemokine Receptor Type 5; DMARD = Disease Modifying Anti-Rheumatic Drug): Leronlimab is also an immunomodulator.
- DMARDs: cyclosporine, cyclophosphamide, mycophenolic acid, chlorambucil, penicillamine, azathioprine: Use within 6 months prior to screening or baseline visit.
- Rituximab: Use of rituximab within 1 year of screening or baseline visit.
- Abatacept: Use of abatacept within 8 weeks of screening or baseline visit.
- Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation such as severe impaired lung functions as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air
- Patients under ongoing treatment with another investigational medication or having been treated with an investigational medication within 30 days (incl. live attenuated vaccine) of screening or 5 half-lives (whichever is longer) prior to the first dose of investigational product
- Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed
- History of any other disease, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or that might affect interpretation of the results of this study, or render the subject at high risk for treatment complications.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Other: Chemoradiotherapy with Anakinra followed by either TME surgery or Watch and Wait
Capecitabine 500 mg/m2 bid or Capecitabine 650 mg/m2 bid or Capecitabine 825 mg/m2 bid combined with Radiotherapy and Kineret
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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.
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.
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
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.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Analysis of safety for capecitabine administered concomitantly with standard radiotherapy in combination with Anakinra at a fixed dose of 100 mg s.c.
Time Frame: 16 weeks
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Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
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16 weeks
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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
Time Frame: 16 weeks
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Identification of the maximum tolerated dose for capecitabine in combination with radiotherapy and Anakinra based on 3+3 design
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16 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Postoperative complications of (salvage) surgery
Time Frame: 1 year
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Postoperative complications of (salvage) surgery
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1 year
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Late toxicity assessment according to NCI CTCAE V.5.0
Time Frame: 3 years
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Late toxicity assessment according to NCI CTCAE V.5.0
|
3 years
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Rate of W&W with or without local regrowth
Time Frame: 3 years
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Rate of W&W with or without local regrowth
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3 years
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Cumulative incidence of locoregional regrowth after cCR
Time Frame: 3 years
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cumulative incidence of locoregional regrowth after cCR
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3 years
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Rate of salvage surgery (LE/TME with or without APR/stoma) after locoregional regrowth
Time Frame: 3 years
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Rate of salvage surgery (LE/TME with or without APR/stoma) after locoregional regrowth
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3 years
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Cumulative incidence of local recurrence after (salvage) surgery
Time Frame: 3 years
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Cumulative incidence of local recurrence after (salvage) surgery
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3 years
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Cumulative incidence of distant recurrences
Time Frame: 3 years
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Cumulative incidence of distant recurrences
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3 years
|
Disease-free survival
Time Frame: 3 years
|
Disease-free survival
|
3 years
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Overall survival
Time Frame: 3 years
|
Overall survival
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3 years
|
Pathological TNM-staging
Time Frame: 3 years
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Pathological TNM-staging based on TNM Classification of Malignant Tumors, 8th edition
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3 years
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R0 resection rate;
Time Frame: 3 years
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Rate of complete resection (R0)
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3 years
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negative circumferential resection rate
Time Frame: 3 years
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negative circumferential resection rate
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3 years
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Tumor regression grading according to Dworak
Time Frame: 3 years
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Tumor regression grading according to Dworak
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3 years
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Quality of TME according to MERCURY
Time Frame: 3 years
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Pathological tumor evaluations according to MERCURY classification
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3 years
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Quality of life based on treatment arm and surgical procedures/organ preservation
Time Frame: 3 years
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Quality of life based on EORTC-QLQs-C30
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3 years
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functional outcome based on treatment arm and surgical procedures/organ preservation
Time Frame: 3 years
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functional outcome based on Wexner score
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3 years
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Quality of life based on treatment arm and surgical procedures/organ preservation
Time Frame: 3 years
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Quality of life based on EORTC-QLQs-CR29
|
3 years
|
Quality of life based on treatment arm and surgical procedures/organ preservation
Time Frame: 3 years
|
Quality of life based on EORTC-QLQs-CPIN20
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3 years
|
Collaborators and Investigators
Sponsor
Investigators
- Study Chair: Claus Roedel, Prof. MD, University Hospital Goethe University Frankfurt
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- Neoplasms
- Neoplasms by Site
- Gastrointestinal Neoplasms
- Digestive System Neoplasms
- Gastrointestinal Diseases
- Intestinal Diseases
- Intestinal Neoplasms
- Rectal Diseases
- Colorectal Neoplasms
- Rectal Neoplasms
- Molecular Mechanisms of Pharmacological Action
- Antirheumatic Agents
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Capecitabine
- Interleukin 1 Receptor Antagonist Protein
Other Study ID Numbers
- ACO/ARO/AIO-21
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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