Temozolomide and irinotecan consolidation in patients with MGMT silenced, microsatellite stable colorectal cancer with persistence of minimal residual disease in liquid biopsy after standard adjuvant chemotherapy: the ERASE-TMZ study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione IRCCS Istituto Nazionale Dei Tumori

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 May 2022 → ongoing

Decision date (initial)

2024-09-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-515681-14-00

EudraCT number

2020-005437-32

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

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

Secondary objectives 4

1. To estimate the disease-free survival of patients trated with TEMIRI as consolidation regimen and to compare DFS according to seroreversion status (ctDNA clearance vs not)
2. To estimate overall survival (OS) of patients trated with TEMIRI as consolidation regimen and to compare OS according to seroreversion status (ctDNA clearance vs not)
3. To evaluate the safety profile and adverse events during TEMIRI consolidation regimen
4. To assess the quality of life of patients during TEMIRI consolidation regimen

Conditions and MedDRA coding

Stage II (pT4)/III colorectal cancer with positive circulating tumor DNA (ctDNA) after oxaliplatin-based adjuvant chemotherapy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Have provided written informed consent prior to any study specific procedures
2. Age = 18 years
3. 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)
4. Completion of radical surgery for patients with colon cancer and preoperative chemoradiotherapy and radical surgery for patients with rectal cancer.
5. 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).
6. Absent MGMT expression by IHC, MGMT promoter methylation by pyrosequencing (> 5%) and MSS by standard assessment
7. Presence of ctDNA in the liquid biopsies collected at 2-6 weeks after the last dose of standard adjuvant chemotherapy
8. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
9. Completion of adjuvant chemotherapy for a duration of at least three months
10. Adequate organ function
11. Carcinoembryonic antigen (CEA) level = 10 ng/ml
12. No evidence of metastatic disease by chest and abdomen computed tomography (CT) scan
13. 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)
14. Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. 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.

Exclusion criteria 10

1. 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
2. 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)
3. Inability to swallow pills
4. Active infection requiring intravenous antibiotics at the start of study treatment
5. 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
6. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study
7. 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
8. 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
9. Previous treatment with temozolomide or irinotecan for any indication
10. 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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

Secondary endpoints 6

1. Disease-free survival (DFS) of patients treated with TEMIRI as post-adjuvant regimen, defined as the time from enrolment to the first documentation of objective disease relapse determined by investigator assessment or death due to any cause, whichever occurs first
2. Overaal survival (OS), defined as the time from enrolment to the date of death due to any cause. For patients alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive
3. Safety that will be assessed by monitoring the frequency, duration, and severity of AEs through physical examinations, clinical laboratory blood and urine sample evaluations.
4. The analysis of Patient Reported Outcomes (PROs) endpoints (assessed using the EORTC QLQ-C30, the EORTC QLQ-CR29 and the EuroQol EQ-5D questionnaires) will be performed according to the EORTC Scoring and Reference Values Manual. All scores and subscales will be assessed through descriptive summary statistics
5. To develop a gene expression signature associated with temozolomide resistance/sensitivity by profiling tumor tissue blocks obtained prior to any treatment
6. To assess the accuracy of liquid biopsies collected during follow-up to predict recurrence

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione IRCCS Istituto Nazionale Dei Tumori

Sponsor organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Address

Via Giacomo Venezian 1

City

Milan

Postcode

20133

Country

Italy

Scientific contact point

Organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Contact name

Filippo Pietrantonio

Public contact point

Organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Contact name

URP

Locations

1 EU/EEA country · 27 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications