Temozolomide and Irinotecan in Patients With MGMT Silenced Colorectal Cancer After Adjuvant Chemotherapy

NCT05031975 | Unknown Phase 2

• 1 other identifier: INT 03/21
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

Surgical resection is curative for 75% of stage II and 50% of stage III colon cancer patients. The magnitude of benefit of adjuvant chemotherapy in terms of disease-free (DFS) and overall survival (OS) varies according to TNM stage and microsatellite status. Standard adjuvant chemotherapy includes fluoropyrimidine and oxaliplatin regimens for up to six months. Circulating tumor DNA (ctDNA) detected after surgical resection reflects the presence of micrometastatic disease and pivotal observational studies addressed the prognostic value of ctDNA in the post-surgical setting. Adjuvant chemotherapy can promote the clearance of ctDNA, and ctDNA clearance after adjuvant chemotherapy is prognostic for better DFS in patients with stage III resected cancers and post-operative positive ctDNA. ctDNA may be investigated as a potential real-time surrogate biomarker of the efficacy of adjuvant therapy, but suggest that patients with ctDNA persistence after standard chemotherapy might be "molecularly metastatic" and may benefit from additional "consolidation" non-cross resistant strategies aimed at clearing micrometastatic disease. Temozolomide has modest but non-negligible activity (about 10%) in chemo-refractory patients with MGMT methylated mCRC. The response rate to temozolomide-based therapy in pretreated patients is increased to up to 20% when restricting the focus on those with MGMT IHC-negative/MGMT methylated and MSS cancers Significant activity (ORR 26%) and favorable safety profile were reported by the combination of temozolomide and irinotecan (TEMIRI regimen) in patients with pretreated MGMT methylated/MSS mCRC, thus suggesting that the two agents may have synergist activity in line with preclinical data. Based on all these considerations, there is a strong rationale for investigating TEMIRI regimen as consolidation non-cross resistant therapy in a liquid-biopsy driven interventional trial. Eligible patients with MGMT-silenced, MSS, radically resected CRC and detectable ctDNA after standard chemotherapy will be enrolled and will receive 6-month post-adjuvant/consolidation TEMIRI (given for up to 6 monthly cycles).

Conditions

Colorectal Cancer

Keywords

Temozolomide; MGMT; microsatellite stable; ctDNA; TEMIRI; Stage II; Stage III; post-adjuvant

Outcome Measures

Primary Outcomes (1)

• To assess the activity in terms of seroreversion of TEMIRI consolidation regimen administered to patients with high-risk stage II (pT4) or III MSS, MGMT silenced CRC and positive post-adjuvant ctDNA after standard oxaliplatin-based adjuvant chemotherapy.

  The activity of TEMIRI will be measured as the rate of patients with post-treatment seroreversion and disease-free at 2 years

  2 years from randomization

Secondary Outcomes (6)

• Disease-free survival (DFS) of patients treated with TEMIRI as consolidation regimen

  36 months

• Overall survival (OS) of patients treated with TEMIRI as consolidation regimen

  36 months

• Safety profile of TEMIRI consolidation regimen

  36 months

• Quality of life as assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)

  Assessed up to 24 months from enrollment

• Quality of life as assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Colorectal Cancer 29 (EORTC QLQ-CR29)

  Assessed up to 24 months from enrollment

Other Outcomes (2)

• Identify a gene expression signature (name of mutated gene/genes) associated to temozolomide resistance/sensitivity

  36 months

• To assess the accuracy of ctDNA as disease recurrence biomarker

  36 months

Study Arms (1)

TEMIRI

EXPERIMENTAL

Irinotecan intravenous infusion (IV) given every 14 days in combination with oral (PO) temozolomide over days 1-5 every 28 days. The treatment will consist of six 28-days cycles of TEMIRI.

Drug: Irinotecan; Drug: Temozolomide

Interventions

Irinotecan DRUG

Irinotecan 100 mg/smq intravenous infusion every 14 days

TEMIRI

Temozolomide DRUG

Oral temozolomide 150 mg/sqm over days 1-5 every 28 days.

TEMIRI

Eligibility Criteria

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

You may qualify if:

• Have provided written informed consent prior to any study specific procedures.
• Age ≥ 18 years.
• Histologically confirmed diagnosis of stage III or T4N0 stage II colon cancer (located 12 cm from the anal verge by endoscopy and above the peritoneal reflection at surgery) or histologically confirmed diagnosis of locally-advanced resectable rectal cancer (proximal margin located at \< 12 cm from the anal verge).
• Radical surgery for patients with colon cancer or preoperative (chemo)-radiotherapy followed by radical surgery for patients with rectal cancer.
• Completion of at least 3 months of oxaliplatin-based (CAPOX or FOLFOX) adjuvant chemotherapy (or candidate to oxaliplatin-based adjuvant chemotherapy if post-surgery pre-screening).
• Availability of the archival FFPE tumor tissue obtained prior to any treatment.
• Acceptance to undergo all the interventional and exploratory liquid biopsies.
• Absent MGMT expression by IHC, MGMT promoter methylation by pyrosequencing (\> 5%) and MSS by standard assessment.
• Presence of ctDNA in the liquid biopsies collected at 2-6 weeks after the last dose of standard adjuvant chemotherapy
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Completion of adjuvant chemotherapy for a duration of at least three months.
• Adequate organ function as defined below:
• Hematological function indicated by all of the following:
• White Blood Cell (WBC) count ≥ 2 x 109/L Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L Hemoglobin ≥ 9 g/dL (patients may have transfusions and/or growth factors to attain adequate Hb).
• \- Liver function indicated by all of the following: Total bilirubin \< 1.5 x upper limit of normal (ULN) Aspartate transaminase (AST) and alanine aminotransferase (ALT) \< 3 x ULN Alkaline phosphatase (ALP) \< 2 x ULN.

You may not qualify if:

• History of another neoplastic disease, unless in remission for ≥ 5 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• Had an incomplete diagnostic colonoscopy and/or polyps removal.
• Microscopic or macroscopic evidence of residual tumor (R1 or R2 resections). Patients should never have had any evidence of metastatic disease (including presence of tumor cells in the peritoneal lavage).
• Current or recent treatment with another investigational drug or participation in another investigational study.
• Inability to swallow pills.
• Active infection requiring intravenous antibiotics at the start of study treatment.
• Evidence of any other disease, neurologic or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of any of the study medications, puts the patient at higher risk for treatment-related complications or may affect the interpretation of study results.
• Patient unable to comply with the study protocol owing to psychological, social or geographical reasons.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
• Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 6 months after the last trial treatment.
• Clinically significant (i.e. active) cardiovascular disease, for example cerebrovascular accidents ≤ 6 months prior to start of study treatment, myocardial infarction ≤ 6 months prior to study enrolment, unstable angina, New York Heart Association (NYHA) Functional Classification Grade II or greater congestive heart failure, or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment.
• Known presence of one of the following UGT1A1 1(TA)6/UGT1A1 36(TA)5; UGT1A1 28(TA)7/UGT1A1 37(TA)8 (homozygous genotype).
• Known presence of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption

Sponsors & Collaborators

• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano: lead

Study Sites (1)

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, MI, 20133, Italy

RECRUITING

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MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Irinotecan; Temozolomide

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring

Study Officials

• Filippo Pietrantonio, MD

  Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Filippo Pietrantonio, MD

CONTACT

+390223903807; filippo.pietrantonio@istitutotumori.mi.it

Federica Morano, MD

CONTACT

+390223903842; 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

Study Record Dates

• First Submitted: August 24, 2021
• First Posted: September 2, 2021
• Study Start: May 2, 2022
• Primary Completion: June 1, 2024
• Study Completion: June 1, 2024
• Last Updated: September 2, 2022

Record last verified: 2022-08

Locations

IT (1)