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Preoperative Chemoradiotherapy With CApecitabine and Temozolomide in MGMT Silenced, MSS, Locally Advanced RecTal Cancer (CATARTIC)

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. Identifier: NCT05136326
Recruitment Status : Recruiting
First Posted : November 29, 2021
Last Update Posted : February 8, 2022
Information provided by (Responsible Party):
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Brief Summary:

In patients with locally advanced rectal cancer (LARC), preoperative chemo-radiotherapy (CTRT) is considered the standard of care. Preoperative CTRT approach often results in a significant tumor downstaging and local control, with evidence of complete pathological response (pCR) rate of about 15% in high volume institutions. In high-risk LARC a new strategy called total neoadjuvant therapy (TNT) has emerged, in which systemic chemotherapy with fluorouracil and oxaliplatin (RAPIDO trial) or with the triplet FOLFIRINOX (as was used in the PRODIGE 23 study) is incorporated before or after the administration of short-course RT or neoadjuvant CTRT and prior to surgery. However, given the fact that TNT may represent an overtreatment for a subset of patients, additional therapeutic strategies are warranted to improve the outcomes also in patients with lower risk that are not good candidate for a TNT.

In the era of personalized medicine, tumor molecular profiling may lead to the identification of therapeutic targets for pharmacological intervention potentially useful to enhance treatment outcomes.

O(6)-methylguanine-DNA-methyltransferase (MGMT) repairs DNA damage induced by alkylating agents and MGMT inactivation due to promoter methylation confers enhanced sensitivity to alkylating agents such as temozolomide (TMZ).

TMZ has modest activity in patients with MGMT-methylated pretreated metastatic colorectal cancer and responses are restricted to tumors with complete MGMT loss by immunohistochemistry (IHC) and microsatellite stable (MSS) status.

Both capecitabine and temozolomide induces deoxythymidine triphosphate thymidine pool depletion might induce deoxyribonucleic acid (DNA)-double strand breaks and eventually apoptosis in rapidly dividing cells. On the basis of such evidences, there is a strong biological and clinical rationale for testing the addition of TMZ to capecitabine-based CTRT in patients with MGMT silenced and MSS technically resectable LARC.

The aim of this trial is investigating whether the addition of TMZ to standard concurrent capecitabine-based long-course chemoradiation may increase pCR rate as compared to historical control in patients with locally advanced rectal cancer not candidate to TNT and molecularly selected for the presence of MGMT silencing and microsatellite stable status.

Condition or disease Intervention/treatment Phase
Rectal Cancer Radiation: External-beam radiation Drug: Capecitabine Drug: Temozolomide Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 21 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Phase II, multicentre, non-randomized, open-label trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multicenter Phase II Study of Preoperative Chemoradiotherapy With CApecitabine Plus Temozolomide in Patients With MGMT Silenced and Microsatellite Stable Locally Advanced RecTal Cancer: the CATARTIC Trial
Actual Study Start Date : December 1, 2021
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2026

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Catartic: chemoradiotherapy plus temozolomide

External-beam radiation: 50.4 GY (45 Gy in 25 fractions + Boost 5.4 Gy in 3 fractions over 5 weeks) in association with:

Capecitabine 825 mg/sqm/bid per os (p.o.) 5 days/week for 5 weeks plus Temozolomide 75 mg/sqm p.o. 5 days/week for 5 weeks.

Radiation: External-beam radiation
External-beam radiation 50.4 GY (45 Gy in 25 fractions + Boost 5.4 Gy in 3 fractions over 5 weeks)

Drug: Capecitabine
825 mg/sqm/bid per os (p.o.) 5 days/week for 5 weeks;

Drug: Temozolomide
75 mg/sqm p.o. 5 days/week for 5 weeks

Primary Outcome Measures :
  1. To evaluate the rate of complete pathologic response (pCR) [ Time Frame: 24 months ]
    pCR, defined as complete histological regression with no available tumor cells yT0N0

Secondary Outcome Measures :
  1. To assess the R0 resection rate [ Time Frame: 24 months ]
    R0 defined as the rate of microscopically margin-negative resections

  2. To assess the tumor downstaging rate [ Time Frame: 24 months ]
    Tumor downstaging rate defined as the rate of reduction in the stage of the tumor as a result of pre-operative therapy, from a more to a less threatening stage at the radiologic assessment after the the end of CTRT

  3. To assess the rate of sphincter preservation [ Time Frame: 24 months ]
    Sphincter preservation rate defined as the percentage of patients with preserved ano-rectal sphincter after surgery

  4. To assess the rate of local recurrence rate [ Time Frame: 24 months ]
    Local recurrence rate defined as the rate of detectable local disease at follow-up after study treatment completion

  5. To assess the disease-free survival [ Time Frame: The disease-free survival will be evaluated during a follow up of 5 years ]
    Disease-free survival defined as the time from the enrollment in the study to the occurrence of disease relapse (local and/or distant) or death from any cause

  6. To assess the overall survival [ Time Frame: The overall survival will be evaluated during a follow up of 5 years ]
    Overall survival defined as the time from the enrollment in the study to the occurrence of death.

  7. To assess the incidence, nature, and severity of adverse events [ Time Frame: 24 months ]
    Adverse events defined and graded according to the NCI CTCAE v5.0

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

Inclusion Criteria:

  • Written informed consent to study procedures;
  • Willing and able to comply with the protocol;
  • Age ≥ 18 years;
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1;
  • Life expectancy of at least 5 years (excluding diagnosis of cancer);
  • Histologically confirmed diagnosis of rectal adenocarcinoma, with centrally confirmed mismatch repair proficiency (MSS) by PCR, lack of MGMT expression by IHC and MGMT promoter methylation by pyrosequencing;
  • Locally advanced, resectable disease defined by the presence of at least one of the following features:

    1. Distal tumor margin at <15 cm from the anal verge;
    2. cT3N0 or cT1-3N1 (with the definition of a clinically positive lymph node being any node ≥ 1 cm);
    3. Less than four lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease;
    4. No evidence of enlarged lateral pelvic clinically positive lymph node (> 1 cm);
    5. No evidence of extramural vascular invasion (EMVI);
    6. No evidence of metastatic disease by CT scan of the chest and abdomen and total body fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan;
    7. No clear indication of involvement of the pelvic side walls by imaging;
  • Tumor must be amenable to curative resection (curative resection can include pelvic exenteration);
  • Hematopoietic: absolute neutrophil count ≥1500/mm3; platelet count ≥ 100,000/mm3; haemoglobin level ≥ 10 g/dL;
  • Hepatic total bilirubin ≤1.5 time upper limit of normal (ULN); alkaline phosphatase ≤ 2 times ULN; AST and ALT ≤ 2.5 times ULN Serum creatinine ≤ 1.5 × ULN or renal creatinine clearance ≥ 50 mL/min according to the Cockcroft-Gault formula (or local institutional standard methods);
  • Availability of an adequate archival tumor sample (Formalin Fixed Paraffin-embedded [FFPE]) for central tissue screening. If the tumor block is not available, a minimum of twenty-five (25) 3-micron unstained sections of tumor will be required (5 of those on standard non charged slides for immunochemistry, the others on charged slides);
  • Male subjects with female partners of childbearing potential must be willing to use adequate contraception as approved by the investigator (barrier contraceptive measure or oral contraception) contraception starting with the first dose of study therapy, through 180 days after the last dose of treatment; Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for these subject.
  • Women of childbearing potential must have a negative blood pregnancy test at the baseline visit and must be willing to use an effective means of contraception and to continue its use for the duration of the study and for 180 days after the last infusion of study treatment. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

  • Dihydropyrimidine dehydrogenase (DPD) deficiency;
  • Previous pelvic RT;
  • Any of the following in the 6 months prior to treatment start: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure (≥ New York Heart Association Classification Class II), cerebrovascular accident/stroke, transient ischemic attack, serious cardiac arrhythmia requiring medication or symptomatic pulmonary embolism;
  • Uncontrolled coagulopathy;
  • Active infection requiring systemic therapy;
  • Infection with human immunodeficiency virus (HIV) plus CD4 cells <200/mm3 or AIDS-defining conditions despite HAART;
  • Known prior severe hypersensitivity to investigational product or any component in its. formulations;
  • Lack of upper gastrointestinal tract integrity or malabsorption syndrome; immune colitis; active inflammatory bowel disease (i.e., patients requiring current medical interventions or who are symptomatic);
  • Presence of metastatic disease, recurrent rectal cancer or history of invasive rectal malignancy, regardless of disease-free interval;
  • Other rectal cancers (i.e., sarcoma, lymphoma, carcinoid, squamous cell or cloacogenic carcinoma) or synchronous colon cancer;
  • Patients with prior malignancies, including invasive colon cancer, are eligible provided they have been disease-free for ≥ 3 years and are deemed by their physician to be at low risk for recurrence (patients with effectively treated squamous cell or basal cell skin cancer, melanoma in situ, carcinoma in situ of the cervix, or carcinoma in situ of the colon or rectum are eligible even if diagnosed less than 3 years before study enrollment);
  • Other severe acute or chronic medical conditions including immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study;
  • Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies;
  • Pregnant or lactating women.

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 identifier (NCT number): NCT05136326

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Contact: Filippo Pietrantonio, MD +39 0223903807
Contact: Federica Morano, MD +39 0223903842

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Fondazione IRCCS Istituto Nazionale dei Tumori Recruiting
Milan, Italy, 20133
Contact: Filippo Pietrantonio, MD    +39 0223903807   
Contact: Federica Morano, MD    +39 0223903842   
Sponsors and Collaborators
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

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Responsible Party: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano Identifier: NCT05136326    
Other Study ID Numbers: INT 188/21
INT 188/21 ( Other Identifier: Fondazione IRCCS Istutituo Nazionale dei Tumori )
First Posted: November 29, 2021    Key Record Dates
Last Update Posted: February 8, 2022
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: The trial results concerning the primary, secondary and exploratory outcomes will be published according to the standard guidelines. IPD could eventually be requested to the Sponsor and Principal Investigator, who will carefully evaluate the motivated request

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano:
locally advanced rectal cancer
Additional relevant MeSH terms:
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Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents