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

NCT05136326 | Recruiting Phase 2

• 1 other identifier: INT 188/21
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

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.

Conditions

Rectal Cancer

Keywords

locally advanced rectal cancer; temozolomide; MGMT; MSS

Outcome Measures

Primary Outcomes (1)

• To evaluate the rate of complete pathologic response (pCR)

  pCR, defined as complete histological regression with no available tumor cells yT0N0

  24 months

Secondary Outcomes (7)

• To assess the R0 resection rate

  24 months

• To assess the tumor downstaging rate

  24 months

• To assess the rate of sphincter preservation

  24 months

• To assess the rate of local recurrence rate

  24 months

• To assess the disease-free survival

  The disease-free survival will be evaluated during a follow up of 5 years

Study Arms (1)

Catartic: chemoradiotherapy plus temozolomide

EXPERIMENTAL

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; Drug: Capecitabine; Drug: Temozolomide

Interventions

External-beam radiation RADIATION

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

Catartic: chemoradiotherapy plus temozolomide

Capecitabine DRUG

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

Catartic: chemoradiotherapy plus temozolomide

Temozolomide DRUG

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

Catartic: chemoradiotherapy plus temozolomide

Eligibility Criteria

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

You may qualify if:

• 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:
• Distal tumor margin at \<15 cm from the anal verge;
• cT3N0 or cT1-3N1 (with the definition of a clinically positive lymph node being any node ≥ 1 cm);
• Less than four lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease;
• No evidence of enlarged lateral pelvic clinically positive lymph node (\> 1 cm);
• No evidence of extramural vascular invasion (EMVI);
• No evidence of metastatic disease by CT scan of the chest and abdomen and total body fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan;
• 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);

You may not qualify if:

• 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.

Sponsors & Collaborators

• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano: lead

Study Sites (1)

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, 20133, Italy

RECRUITING

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• Jeong JH, Hong YS, Park Y, Kim J, Kim JE, Kim KP, Kim SY, Park JH, Kim JH, Park IJ, Lim SB, Yu CS, Kim JC, Kim TW. Phase 1 Study of Preoperative Chemoradiation Therapy With Temozolomide and Capecitabine in Patients With Locally Advanced Rectal Cancer. Int J Radiat Oncol Biol Phys. 2016 Oct 1;96(2):289-295. doi: 10.1016/j.ijrobp.2016.05.009. Epub 2016 May 17.

  PMID: 27473815 BACKGROUND

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

Capecitabine; Temozolomide

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)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles

Central Study Contacts

Filippo Pietrantonio, MD

CONTACT

+39 0223903807; filippo.pietrantonio@istitutotumori.mi.it

Federica Morano, MD

CONTACT

+39 0223903842; federica.morano@istitutotumori.mi.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase II, multicentre, non-randomized, open-label trial

Study Record Dates

• First Submitted: November 17, 2021
• First Posted: November 29, 2021
• Study Start: December 1, 2021
• Primary Completion: December 1, 2023
• Study Completion (Estimated): December 1, 2026
• Last Updated: March 1, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)