5FU/LV, Irinotecan, Temozolomide and Bevacizumab for MGMT Silenced, Microsatellite Stable Metastatic Colorectal Cancer.

• Status: Recruiting
• Trial end date: 2023-01-01
• Target enrollment: 0
• Participant gender: All

Summary

An upfront-intensified treatment combining all the three active cytotoxic agents in metastatic colorectal cancer (mCRC) including fluoropyrimidines, oxaliplatin, irinotecan (FOLFOXIRI) plus antiangiogenic blockade with bevacizumab significantly improved survival. No biomarkers are available for predicting sensitivity/resistance to single chemotherapeutic drugs, the simultaneous delivery of all active chemotherapeutic agents might overcome resistance to single drugs.

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. Clinical and preclinical synergy has been reported for combination of temozolomide with irinotecan and fluoropyrimidines. Temozolomide could be regarded as a "targeted" chemotherapy for patients with MSS and MGMT silenced tumors. In this subgroup of patients, an intensified triplet upfront regimen including temozolomide, fluoropyrimidines, irinotecan, associated with bevacizumab, could be a novel combination in molecularly super-selected mCRC patients.

Moving from this, the investigators designed this open-label, monocentric, phase 1b study evaluating the safety of the combination regimen 5-fluorouracil, leucovorin, irinotecan, temozolomide and bevacizumab in patients with MGMT silenced and MSS mCRC.

The study will consist in a dose-escalation assessment of the safety of the treatment in subjects with previously untreated MGMT silenced, MSS mCRC. A 3 + 3 design will be used to assess the maximum tolerated dose (MTD) or maximum tested dose of the combination FLIRT-bevacizumab.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• Treatments: Bevacizumab; Fluorouracil; Irinotecan; Leucovorin; Temozolomide

Criteria

Inclusion Criteria:

• Histologically confirmed metastatic adenocarcinoma of the colon and/or rectum.

• Confirmed MGMT promoter methylation by PSQ (> 5%) and absent MGMT expression by IHC.

• Confirmed MSS status assessed by multiplex PCR.

• Written informed consent obtained prior to any study procedures.

• Availability of archival tumour tissue (primary tumour and metastases or at least one of the two) for confirmation of MGMT and MSS status and biomarker analyses.

• Patients not previously treated with chemotherapy for metastatic disease.

• At least one measurable lesion according to RECIST 1.1.

• Age≥18and ≤ 75years.

• ECOG PS ≤ 1 if patient < 70 years old; ECOG PS 0 if patient 70-75 years old.

• Life expectancy of at least 12 weeks.

• Previous adjuvant fluoropyrimidine or fluoropyrimidine plus oxaliplatin chemotherapy allowed only if more than 6 months elapsed between the end of adjuvant therapy and first evidence of disease relapse.

• Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hemoglobin ≥ 9 g/dl.

• Total bilirubin ≤1.5 fold the upper-normal limits (UNL), AST (SGOT) and/or ALT (SGPT) ≤ 2.5 x UNL (or <5 x UNL in the case of liver metastases), alkaline phosphatase ≤ 2.5 x UNL (or <5 x UNL in case of liver metastases).

• Creatinine clearance ≥ 50 mL/min or serum creatinine ≤1.5 x UNL.

• 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).

• 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.

• Subjects and their partners must be willing to avoid pregnancy during the trial and until 6 months after the last trial treatment.

• Will and ability to comply with the protocol.

• Is willing and able to provide an adequate archival tumor sample (FFPE) available for molecular screening and exploratory analyses. If the tumour block is not available, a minimum of 25 3-micron unstained sections on charged slides of tumor will be required.

Exclusion Criteria:

• 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.

• Metastatic disease deemed R0 resectable upfront or after induction therapy by means of multidisciplinary team assessment.

• Radiotherapy to any site within 4 weeks before the study.

• Presence of one of the following: DPYD2a (c.1905+1G>A); DPYD13 (c.1679 T>G); DPYD D949V (c.2846 A>T); DPYD IVS10 (c.1129-5923 C>G).

• Presence of one of the following UGT1A1 1(TA)6/UGT1A1 36(TA)5; UGT1A1 28(TA)7/UGT1A1 37(TA)8 (homozygous genotype).

• Untreated brain metastases or spinal cord compression or primary brain tumors.

• History or evidence upon physical examination of central nervous system disease unless adequately treated.

• Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration.

• Evidence of bleeding diathesis or coagulopathy.

• Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy.

• Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication.

• Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment.

• Any previous venous thromboembolism ≥ NCI CTCAE Grade 4.

• History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to the first study treatment.

• Treatment with any investigational drug within 30 days prior to enrollment or 2 investigational agent half-lives (whichever is longer).

• Other co-existing malignancies or malignancies diagnosed within the last 3 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ.

• Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.

• Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.

• Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.

• 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.