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Total Neoadjuvant Treatment Without Surgery For Locally Advanced Rectal Cancer (NO-CUT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03565029
Recruitment Status : Recruiting
First Posted : June 21, 2018
Last Update Posted : July 25, 2019
Sponsor:
Information provided by (Responsible Party):
Niguarda Hospital

Brief Summary:
NO-CUT is a one-stage phase II trial seeking to establish whether an oxaliplatin-based chemotherapy preceding standard neo-adjuvant fluoropyrimidines-based chemo radiotherapy, can safely spare demolitive surgical intervention in patients with operable rectal cancer, without increasing the risk of distant relapse. The trial also has a translational component aimed at establishing whether selected genomic, epigenetic, and transcriptomic markers are predictive of tumor and patient outcome.

Condition or disease Intervention/treatment Phase
Colo-rectal Cancer Drug: XELOX Radiation: Radiotherapy Phase 2

Detailed Description:

Colorectal cancer is the third most common cancer worldwide and the second leading cause of cancer death in Europe. Rectal cancer accounts for about 25-30% of all colorectal cancer diagnoses. Five-year survival rates depend on stage at diagnosis, about 92% for stage I, 87% for stage II A, 63% for stage II B, 89% for stage III A, 69% for stage III B, and for stage III C cancers the survival rate is about 53%; stage IV rectal cancers have a 5-year relative survival rate of about 11%. With the chemoradiation therapy (CRT), the resulting pathologic complete response (pCR) across all stages has been documented in up to 30% of patients. Most importantly, patients achieving pCR have lower rates of tumor recurrence, and improved survival, compared to those who do not achieve pCR. Moreover, data from the National Surgical Quality Improvement Project document a 35% risk of morbidity associated with both low anterior and abdominoperineal resection. Long-term morbidity includes bowel and bladder incontinence, sexual dysfunction, and complications associated with temporary and permanent stomas.

Due to the observation of the absence of residual tumor in the pathological specimens of a significant proportion of patients treated with CRT for local or locally advanced rectal cancer, in the early-2000s, two clinical issues arose: firstly, if pCR could be predicted after CRT with clinical, radiological, or endoscopic restaging assessment thus defining clinical complete response (cCR); and secondly if patients with cCR should necessarily undergo radical surgery to achieve cure at the cost of morbidity, mortality, and functional consequences associated with radical rectal surgery. Consequently, an increasing number of reports suggested that non-operative management (NOM), consisting of close surveillance of patients with cCR, could be an acceptable alternative to rectal surgery (proctectomy). Led by small prospective series published since the late 90's by Habr-Gama and colleagues, several small international series have reported similar oncologic outcomes in cCR patients followed by close active surveillance (the so-called watch-and-wait (W&W) or NOM approach) compared to those treated with radical surgery.

Between 2011 and 2013 a NOM approach was carried out in 31 patients achieving cCR out of 259 (12%). In their analysis, a further 98 patients, selected from a United Kingdom regional registry, similarly managed from 2005 to 2015, were added to the NOM group (129 patients). Overall Survival and Disease Free Survival rates resulted at least comparable to that of patients treated with standard surgery following neo-adjuvant CRT.

On the other hand, these small single institution pilot studies have been conducted enrolling small cohorts of patients with less than 500 patients having been evaluated worldwide. A high variability in stage at diagnoses, local recurrence rate, distant recurrence rate (0-60% and 0-17%, respectively) and type and outcome of salvage therapy (0 to 100%) have been reported and no reliable data on long term outcomes are available. Based on these limitations, the NOM of rectal cancer deserves consideration within purposely designed clinical trials.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: one-stage phase II trial seeking to establish whether an oxaliplatin-based chemotherapy preceding standard neo-adjuvant fluoropyrimidines-based chemo radiotherapy, can safely spare demolitive surgical intervention in patients with operable rectal cancer, without increasing the risk of distant relapse. The trial also has a translational component aimed at establishing whether selected genomic, epigenetic, and transcriptomic markers are predictive of tumor and patient outcome.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Total Neoadjuvant Treatment Without Surgery For Locally Advanced Rectal Cancer: Prospective Clinical Trial To Assess Tumor Complete Response, Circulating Tumor Genetic And Epigenetic Biomarkers, And Stromal Transcriptome To Interpret Clinical Outcome
Actual Study Start Date : June 1, 2018
Estimated Primary Completion Date : October 31, 2022
Estimated Study Completion Date : December 31, 2022

Arm Intervention/treatment
Experimental: Medium/low locally advanced rectal cancer
Patients with Stage II (cT3-4 N0) or Stage III (cT1-4, N1-3) locally advanced rectal cancer amenable to Total Mesorectal Excision (TME)/Abdominal-Perineal Amputation
Drug: XELOX
Capecitabine and Oxaliplatin (4x cycles)

Radiation: Radiotherapy
Pelvic radiotherapy




Primary Outcome Measures :
  1. Distant Relapse-Free Survival (DRFS) [ Time Frame: 2.5 years ]
    Disease free survival rate


Secondary Outcome Measures :
  1. Clinical complete response rate [ Time Frame: 2 months ]
    Clinical complete response rate

  2. Local recurrence and organ preservation rate [ Time Frame: 6 months ]
    Local recurrence and organ preservation rate

  3. Colostomy-free survival [ Time Frame: 6 months ]
    Colostomy-free survival

  4. Overall survival [ Time Frame: 2.5 years ]
    Overall survival

  5. Patient reported outcomes [ Time Frame: 2.5 years ]
    European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire-C30 and its colorectal cancer specific module Quality of Life Questionnaire-38)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed diagnosis of adenocarcinoma of the medium/lower rectum
  • Patients must have Stage II (cT3-4 N0) or Stage III (cT1-4, N1-3) tumor
  • Locally advanced rectal cancer amenable to Total Mesorectal Excision (TME)/Abdominal-Perineal Amputation
  • No evidence of distant metastases by chest, abdomen, and pelvis contrast enhanced CT scan (TC-positron emission computed tomography (PET) Whole Body (WB) is acceptable alternative in patient allergic to iodate contrast medium)
  • No prior pelvic radiation therapy
  • No prior oncologic medical therapy or surgery for rectal cancer
  • Age >18 years
  • No infections requiring systemic antibiotic treatment
  • Performance status 0-1 (ECOG Scale)
  • absolute neutrophil count (ANC) > 1.5 cell/mm3, Hb>8.0 g/ dL, Platelet Count (PLT)>150,000/mm3, total bilirubin < or equal or 1.5 x upper limit of normal, Aspartate Aminotransferase (AST) < or equal to three times upper limit of normal, Alanine Aminotransferase (ALT)< or equal to three times upper limit of normal; Serum creatinine level < or equal to 1.5 times the upper limit of normal
  • Patients must read, agree to, and sign a statement of Informed Consent prior to participation
  • Women with childbearing potential who are negative for pregnancy test (urine or blood) and who agree to use effective contraceptive methods
  • Male subjects must also agree to use effective contraception

Exclusion Criteria:

  • Recurrent rectal cancer
  • Patients with a history of any arterial thrombotic event within the past 6 months, including angina (stable or unstable), MI, or CVA
  • Intolerance or contraindication to Magnetic Resonance (MR) procedure
  • Patients with any other concurrent medical or psychiatric condition
  • Gastro-intestinal abnormalities, inability to take oral medication, any condition affecting absorption
  • Patients with a history of a prior malignancy within the past 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer.
  • Patients with a history of thrombotic episodes, such as deep venous thrombosis, pulmonary embolus, Myocardial Infarction (MI) or cerebral vascular accident (CVA) occurring more than 6 months prior to enrollment may be considered for protocol participation, provided they are on stable doses of anticoagulant therapy. Patients who are anticoagulated for atrial fibrillation or other conditions may participate, provided they are on stable doses of anticoagulant therapy.
  • Patients receiving other anticancer or experimental therapy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03565029


Contacts
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Contact: Salvatore Siena, MD +396444 ext 2291 salvatore.siena@ospedaleniguarda.it
Contact: Andrea Sartore Bianchi, MD +396444 ext 3708 andrea.sartorebianchi@ospedaleniguarda.it

Locations
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Italy
ASST GOM Niguarda Recruiting
Milano, Italy, 20162
Contact: Salvatore Siena, MD    +39026444 ext 2291    salvatore.siena@ospedaleniguarda.it   
Contact: Silvia ghezzi, Biologist    +39026444 ext 3695    silvia.ghezzi@ospedaleniguarda.it   
Sponsors and Collaborators
Niguarda Hospital
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Responsible Party: Niguarda Hospital
ClinicalTrials.gov Identifier: NCT03565029    
Other Study ID Numbers: 2017‐003671‐60
First Posted: June 21, 2018    Key Record Dates
Last Update Posted: July 25, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Weekly Scientific Board Commission meetings
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Weekly

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Niguarda Hospital:
rectal cancer
neoadjuvant
non operative management
Additional relevant MeSH terms:
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Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases