Microsatellite stable (MSS), MGMT-silenced metastatic colorectal carcinoma (mCRC). MedDRA version: 21.0 Level: PT Classification code 10061451 Term: Colorectal cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: PT Classification code 10061451 Term: Colorectal cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: OPDIVO - 10 MG/ML- CONCENTRATO PER SOLUZIONE PER INFUSIONE- USO ENDOVENOSO- FLACONCINO (VETRO)- 10 ML- 1 FLACONCINO
Product Name: Nivolumab
Product Code: [-]
Pharmaceutical Form: Concentra
Sponsors
FONDAZIONE IRCCS "ISTITUTO NAZIONALE DEI TUMORI"
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Have provided written informed consent prior to any study specific procedures. 2. Willing and able to comply with the protocol. 3. =18 years of age. 4. ECOG status 0 – 1. 5. At least 12 weeks of life expectancy at time of entry into the study. 6. Histologically confirmed metastatic or inoperable adenocarcinoma of the colon and/or rectum, with centrally confirmed mismatch repair proficiency (microsatellite stable [MSS]) by multiplex polymerase chain reaction (PCR), MGMT promoter methylation by methylation-specific PCR (MSP) and MGMT low expression by IHC. 7. Patients with progressive disease or that are not candidate for oxaliplatin irinotecan fluoropyrimidine based chemotherapy and anti EGFR mAbs (in RAS/BRAF wild type tumors) in the metastatic setting. 8. Patients with documented disease relapsed within 6 months from the completion of adjuvant oxaliplatin-based chemotherapy are considered eligible. 9. Measurable, unresectable disease according to RECIST 1.1. Subjects with lesions in a previously irradiated field as the sole site of measurable disease will be permitted to enroll provided the lesion(s) have demonstrated clear progression and can be measured accurately. 10. Is willing and able to provide an adequate archival tumor sample (FFPE) available for tissue screening for central tissue screening. If the tumor block is not available, a minimum of twentyfive 3-micron unstained sections on charged slides of tumor will be required. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 85 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 15
Exclusion criteria
Exclusion criteria: 1. Requirement for treatment with any medicinal product that contraindicates the use of any of the study medications, may interfere with the planned treatment, affects patient compliance or puts the patient at high risk for treatment-related complications. 2. Inability to swallow pills. 3. Refractory nausea and vomiting, malabsorption, external biliary shunt or significant bowel resection that would preclude adequate absorption. 4. Inadequate hematological function indicated by all of the following: – White Blood Cell (WBC) count 1.5 x ULN or calculated creatinine clearance 1.5 and aPTT > 1.5 x ULN within 7 days prior to the start of study treatment for patients not receiving anti-coagulation. a. NOTE: The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least two weeks prior to the start of study treatment. 8. Active infection requiring intravenous antibiotics at the start of study treatment. 9. Previous or concurrent malignancy, except for adequately treated basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast, or other cancer for which the patient has been disease-free for three years prior to study entry. 10. 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. 11. 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. 12. History or evidence upon physical or neurological examination of central nervous system (CNS) disease (e.g. seizures) unrelated to cancer unless adequately treated with standard medical therapy. For further exclusion criteria please refer to the protocol.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy, measured as 8-month PFS rate, of the combination of TMZ, NIVO and IPI in patients achieving disease control following 2-month lead-in treatment with single agent TMZ.;Secondary Objective: • To estimate the overall response rates (ORR) of the combination regimen of TMZ, NIVO and IPI, as measured by response rate according to RECIST 1.1 and modified RECIST criteria. • To estimate duration of response (DoR) of the combination regimen of TMZ, NIVO and IPI. • To estimate overall survival (OS) of the combination regimen of TMZ, NIVO and IPI. • To estimate ORR, DoR and PFS according to an Imaging Independent Central Review, using RECIST 1.1 and modified RECIST criteria. • To evaluate the safety profile and adverse events encountered by patients treated with the combination of TMZ, NIVO and IPI. • To assess the quality of life as measured by EORTC QLQ-C30 EORTC QLQ-CR29 and EuroQol EQ-5D.;Primary end point(s): The primary efficacy endpoint of this study is the 8-month Progression Free Survival (PFS) rate, defined as the proportion of patients alive and progression-free. The efficacy outcome measures for this study are as follows: • Investigator-assessed PFS according to RECIST v1.1 • Investigator-assessed PFS according to modified RECIST;Timepoint(s) of evaluation of this end point: At 8 months from enrollment in the first treatment phase. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Investigator - assessed response rate per RECIST v1.1 or death from any cause on study.; Investigator - assessed response rate per modified RECIST or death from any cause on study.; Investigator-assessed Duration Of Response (DOR) per RECIST v1.1.; Investigator-assessed Duration Of Response (DOR) DOR per modified RECIST.; Overall Survival (OS); Objective response, DOR, PFS according to RECIST vers 1.1 and modified RECIST.; Incidence, nature, and severity of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v4.0.; Changes in vital signs, physical findings, and clinical laboratory results.;Timepoint(s) of evaluation of this end point: From the date of enrollment in the first treatment phase to the date of death from any cause or censored to the last follow up for patients alive.; From the date of enrollment in the first treatment phase to the date of death from any cause or censored to the last follow up for patients alive.; From the date of first documented response to the date of Progression Disease (PD) or death from any cause, whichever occurred first; time was censored at the date of last follow up for patients alive and without PD.; From the date of first documented response to the date of Progression Disease (PD) or death from any cause, whichever occurred first; time was censored at the date of last follow up for patients alive and without PD.; From the date of enrollment in the first treatment phase to the date | — |
Countries
Italy
Contacts
Public ContactDipartimento Medico
OPIS s.r.l.
Outcome results
None listed