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History of Changes for Study: NCT04525989
Preoperative Short-Course Radiation Therapy With PROtons Compared to Photons In High-Risk RECTal Cancer (PRORECT) (PRORECT)
Latest version (submitted August 15, 2022) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 August 21, 2020 None (earliest Version on record)
2 February 17, 2021 Study Status
3 May 4, 2021 Recruitment Status, Study Status, Contacts/Locations and Oversight
4 August 15, 2022 Study Status
Comparison Format:

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Study NCT04525989
Submitted Date:  August 21, 2020 (v1)

Open or close this module Study Identification
Unique Protocol ID: PRORECT
Brief Title: Preoperative Short-Course Radiation Therapy With PROtons Compared to Photons In High-Risk RECTal Cancer (PRORECT) (PRORECT)
Official Title: Preoperative Short-Course Radiation Therapy With PROtons Compared to Photons In High-Risk RECTal Cancer (PRORECT): A Prospective Randomized Swedish Phase II Trial
Secondary IDs:
Open or close this module Study Status
Record Verification: August 2020
Overall Status: Not yet recruiting
Study Start: November 2020
Primary Completion: November 2027 [Anticipated]
Study Completion: November 2027 [Anticipated]
First Submitted: August 18, 2020
First Submitted that
Met QC Criteria:
August 21, 2020
First Posted: August 25, 2020 [Actual]
Last Update Submitted that
Met QC Criteria:
August 21, 2020
Last Update Posted: August 25, 2020 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: Alexander Valdman
Responsible Party: Sponsor-Investigator
Investigator: Alexander Valdman
Official Title: MD, PhD, Senior Consultant Radiation Oncologist
Affiliation: Karolinska University Hospital
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug: No
U.S. FDA-regulated Device: No
Data Monitoring: No
Open or close this module Study Description
Brief Summary: To investigate a potential toxicity benefit of preoperative radiation therapy with protons compared to conventional photon beam radiation therapy in patients with locally advanced rectal cancer.
Detailed Description:

The aim of this study is to investigate whether proton beam radiotherapy in locally advanced rectal cancer can offer meaningful reductions in acute gastrointestinal toxicity compared to standard treatment with photons which may improve patient's tolerability of neoadjuvant chemotherapy.

There are currently no published clinical reports evaluating the use of proton therapy in the upfront treatment of locally advanced rectal cancer. There are further no published randomized trials comparing radiotherapy with photon vs proton in locally advanced rectal cancer.

This is a prospective randomized trial, initially run at the limited number of centres but later expanded to other centres participating in the Skandion network. Patients will be treated with short course 5 x 5 Gy radiation scheme with either photons (standard arm) or protons (Skandion clinic) followed by four to six cycles of combination chemotherapy (capecitabine and oxaliplatin) and surgery. The rectal tumour will be removed by TME/PME surgery or more extensive surgery if required because of tumour extent.

All patients will receive at least 4 courses of CAPOX (Capecitabine b.i.d.1000 mg/m2 day 1-14 every 3 weeks, Oxaliplatin 130 mg/m2 day 1 every 3 weeks) week 3-14, followed by surgery at week 17-20.

Open or close this module Conditions
Conditions: Rectal Cancer
Keywords: Proton therapy
Preoperative radiation
Short-course
Primary adenocarcinoma
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Not Applicable
Interventional Study Model: Parallel Assignment
Prospective randomized
Number of Arms: 2
Masking: None (Open Label)
Allocation: Randomized
Enrollment: 254 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: Proton therapy
5 x 5 Gy External radiation therapy with Protons
Radiation: Radiation therapy
5 x 5 Gy external radiation therapy
Active Comparator: Photon therapy
5 x 5 Gy External radiation therapy with Photons
Radiation: Radiation therapy
5 x 5 Gy external radiation therapy
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Incidence of acute grade 2-5 gastrointestinal toxicity
[ Time Frame: From start of radiotherapy to planned start of the third (3) CAPOX cycle (week 9-10 of the trial) ]

The incidence of acute preoperative grade 2-5 gastrointestinal toxicity according to CTCAE v5.0 associated with proton vs. photon radiotherapy
Secondary Outcome Measures:
1. Incidence of grade >2 hematologic and non-hematologic toxicity
[ Time Frame: Baseline up to five years after treatment ]

The incidence of grade >2 hematologic (blood count, febrile neutropenia) and non-hematologic toxicity (general, genitourinary, gastrointestinal, skin) associated with protocol treatment, assessed by CTCAE v5.0 in the preoperative period, the postoperative period, and overall.

Patient reported side-effects will be assessed by European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire, the QLQ-C30, version 3. The QLQ-C30 will be supplemented with the disease specific module (rectal-cancer) QLQ-CR29. During radiotherapy, daily reported symptoms will be investigated by a newly developed symptom scale, Radiotherapy related symptom assessment scale (RSAS). The questionnaire includes 13 items specific for current diagnose. The RSAS is a validated instrument for assessing symptom intensity and distress in patients with different cancer disease undergoing radiotherapy, with psychometric properties within the expected range.

2. Differences in patient reported outcomes (PRO)
[ Time Frame: Baseline, Day 1-5, 2 and 3 weeks, 3, 6, 9, 12, 24, 36 and 60 months ]

Differences in patient reported outcomes (PRO) between treatment arms in the preoperative period, the postoperative period, and overall
3. Proportion of patients being able to undergo full dose neoadjuvant chemotherapy
[ Time Frame: From week 3 until week 20 of the trial ]

Differences between treatment arms in proportion of patients being able to undergo full dose neoadjuvant chemotherapy i.e. at least 4 cycles of CAPOX or 6 cycles of FOLFOX
4. Tumour regression grading (mrTRG)
[ Time Frame: Baseline to response evaluation week 16-17 of the trial ]

Radiological assessment and comparison of tumour regression grading (mrTRG) between treatment arms
5. Cost effectiveness analysis measured by QALY
[ Time Frame: Time from randomization up to 5 years ]

Health economic comparison between proton and photon treatment. Cost effectiveness analysis measured by QALY
Other Outcome Measures:
1. Disease free survival
[ Time Frame: Time from randomization until first recurrence, local/regional/systemic or death ]

Disease free survival after proton vs. photon treatment
2. Overall survival
[ Time Frame: Time from randomization until death ]

Overall survival after proton vs. photon treatment
3. Quality of Life (QLQ-C30)
[ Time Frame: Baseline, 3 weeks, 3, 6, 9, 12, 24, 36 and 60 months ]

Quality of life after proton vs. photon treatment (QLQ-C30)
4. Difference in postoperative complications
[ Time Frame: From week 17-20 of the trial up to 5 years ]

Difference in postoperative complications between study arms measured by LARS score
5. Clinical complete remission (cCR)
[ Time Frame: From start of treatment up to 1 year ]

Proportion of patients who reach a clinical complete remission (cCR), enter a watch-and-wait period and remain free of regrowth at least one year
6. Incidence of acute lumbar plexus neuralgia
[ Time Frame: From baseline until week 4 of the trial ]

Difference between treatment arms in acute lumbar plexus neuralgia grade 1-3 measured as a change from baseline according to CTCAE 5.0
7. Exploratory: Concentrations of CD8+ and FOXP3 + tumour-infiltrating T cells
[ Time Frame: Postoperative pathology from week 17 until week 24 of the trial ]

Difference between treatment arms in concentrations of CD8+ and FOXP3 + tumour-infiltrating T cells after given radiotherapy
8. Exploratory: Difference in concentrations of CEA (carcinoembryonic antigen) between treatment arms
[ Time Frame: CEA measurements at baseline, week 3, 6, 9 and 12 of the trial ]

Change from baseline in concentrations of circulating CEA (carcinoembryonic antigen) between treatment arms
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

Inclusion Criteria - Primary tumour characteristics

  • Biopsy-proven, newly diagnosed primary rectal adenocarcinoma, i.e. with the lowest part of the tumour less than 16 cm from the anal verge detected using a rigid rectoscope.
  • Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically:
    • Clinical stage (c) T4b, i.e. infiltration of an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side-wall (according to TNM version 8).
    • cT4a, i.e. peritoneal involvement.
    • Extramural vascular invasion (EMVI+).
    • N2-status regarded as metastatic according to ESGAR consensus criteria
    • Positive MRF, i.e. tumor or lymph node one mm or less from the mesorectal fascia.
    • Metastatic lateral nodes (lat LN+) according to ESGAR consensus criteria

Inclusion Criteria - General

  • Staging done within 6 weeks before start of radiotherapy. No contraindications to chemotherapy with CAPOX including adequate blood counts, (within 5 weeks prior to randomisation):
    • white blood count ≥4.0 x 10*9/L
    • platelet count ≥100 x 10*9/L
    • clinically acceptable haemoglobin levels
    • creatinine levels indicating renal clearance of ≥50 ml/min
    • bilirubin ˂35 µmol/l.
  • ECOG performance score ≤1
  • Patient is considered to be mentally and physically fit for chemotherapy with CAPOX as judged by the oncologist.
  • Age ≥18 years
  • Written informed consent.
  • Adequate potential for follow-up.

Exclusion Criteria:

  • Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen.
  • Presence of metastatic disease or recurrent rectal tumour. Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn's disease or active ulcerative Colitis.
  • Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years.
  • Known DPD deficiency.
  • Any contraindications to MRI (e.g. patients with pacemakers).
  • Medical or psychiatric conditions that compromise the patient's ability to give informed consent.
  • Concurrent uncontrolled medical conditions.
  • Any investigational treatment for rectal cancer within the past month.
  • Pregnancy or breast feeding.
  • Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract.
  • Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months.
  • Patients with symptoms of peripheral neuropathy.
  • Patients with pacemaker or ICD
  • Patients with bilateral hip protheses
Open or close this module Contacts/Locations
Central Contact Person: Alexander Valdman, MD, PhD
Telephone: +46(0)700021317
Email: alexander.valdman@sll.se
Study Officials: Alexander Valdman, MD, PhD
Principal Investigator
Department of Radiotherapy, Karolinska University Hospital, Stockholm, Sweden
Locations:
Open or close this module IPDSharing
Plan to Share IPD: No
Open or close this module References
Citations:
Links:
Available IPD/Information:

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