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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04689347
Recruitment Status : Recruiting
First Posted : December 30, 2020
Last Update Posted : April 4, 2022
Sponsor:
Information provided by (Responsible Party):
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Brief 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.


Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Drug: Bevacizumab Drug: Irinotecan Drug: Leucovorin Drug: 5Fluorouracil Drug: Temozolomide Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description: A 3 + 3 design will be used to assess the maximum tolerated dose (MTD) or maximum tested dose of the combination FLIRT-bevacizumab. The MTD will be defined as the dose level at which ≥2/3 or ≥2/6 subjects experience a dose-limiting toxicity (DLT). When the MTD or maximum tested dose has been determined or reached, the RP2D to be tested in a future phase II trial will be one dose level below the MTD or the maximum tested dose if MTD will not be reached. At least 6 patients should be treated at the RD during the dose escalation.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1b Trial of 5-fluorouracil, Leucovorin, Irinotecan in Combination With Temozolomide (FLIRT) and Bevacizumab for the First-line Treatment of Patients With MGMT Silenced, Microsatellite Stable Metastatic Colorectal Cancer.
Actual Study Start Date : January 1, 2021
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : January 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: FLIRT-bevacizumab

Bevacizumab intravenous infusion (IV), irinotecan IV, leucovorin (LV) IV, 48-hours continuous intravenous infusion of 5-fluorouracil (5-FU), given every 14 days, in combination with oral (PO) temozolomide with progressive dose escalation at inter-patient level over days 1-5 every 28 days.

The treatment will consist of an induction period of four 28-day cycles of FLIRT- bevacizumab followed by maintenance regimen of 5-FU/LV-bevacizumab administered every 14 days in combination with PO temozolomide according to dose level over days 1-5 every 28 days in patients without progressive disease at the end of the induction period.

Drug: Bevacizumab
Bevacizumab 5 mg/kg intravenous infusion every 2 weeks

Drug: Irinotecan
irinotecan 165 mg/sqm intravenous infusion every 2 weeks

Drug: Leucovorin
leucovorin 200 mg/sqm intravenous infusion every 2 weeks

Drug: 5Fluorouracil
48-hours continuous intravenous infusion of 5-fluorouracil (5-FU) 3200 mg/sqm every 2 weeks

Drug: Temozolomide
Oral temozolomide with progressive dose escalation at inter-patient level over days 1-5 every 28 days. (75 mg/sqm; 100 mg/sqm; 125 mg/sqm or 150 mg/sqm)




Primary Outcome Measures :
  1. To evaluate the safety and to determine the recommended phase 2 dose of the combination of FLIRT- bevacizumab in patients with MGMT silenced and MSS mCRC, previously untreated for advanced disease [ Time Frame: 24 months ]
    The RD to be tested in a future phase 2 trial will be one dose level below the MTD or the maximum tested dose if MTD will not be reached. he MTD will be defined as the dose level at which ≥2/3 or ≥2/6 subjects experience a dose-limiting toxicity. At least 6 patients should be treated at the RD during the dose escalation.


Secondary Outcome Measures :
  1. ORR obtained by FLIRT bevacizumab [ Time Frame: 24 months ]
    To assess ORR per RECIST version 1.1

  2. Quality of life as assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) [ Time Frame: 24 months ]
    EORTC QLQ-C30 administered every 8 weeks

  3. Quality of life as assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal Cancer 29 (EORTC QLQ-CR29) [ Time Frame: 24 months ]
    EORTC QLQ-CR29 administered every 8 weeks

  4. Quality of life as assessed using the Euro Quality of Life 5 Dimensions Questionnaire (EQ-5D-5L) [ Time Frame: 24 months ]
    EQ-5D-5L administered every 8 weeks


Other Outcome Measures:
  1. Evaluate tumor biomarkers in archival tumor tissue [ Time Frame: 24 months ]
    Quantification of the percentage of MGMT methylation by digital PCR methylBEAMing will be performed in archival tumor tissue. Mutational load will be assessed in archival tumor tissues by means of whole exome sequencing.

  2. Evaluate plasma biomarkers in longitudinal blood samples (plasma and PBMCs) [ Time Frame: 24 months ]
    Digital PCR for MGMT methylation status will be performed in cell-free circulating DNA (cfDNA). Mutational load will be assessed in cfDNA by means of whole exome sequencing.

  3. PFS of FLIRT bevacizumab [ Time Frame: 24 months ]
    FS is defined as the time from enrolment to the first documentation of objective disease progression determined by investigator assessment or death due to any cause, whichever occurs first. PFS will be censored on the date of the last evaluable on study tumour assessment documenting absence of progressive disease for patients who are alive, on study and progression free at the time of the analysis. Alive patients having no tumour assessments after baseline will have time to event censored on the date of enrolment

  4. OS of FLIRT bevacizumab [ Time Frame: 24 months ]
    OS is defined as the time from enrolment to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04689347


Contacts
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Contact: Filippo Pietrantonio, MD +390223903807 filippo.pietrantonio@istitutotumori.mi.it
Contact: Federica Morano, MD +390223903842 federica.morano@istitutotumori.mi.it

Locations
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Italy
Fondazione IRCCS Istituto Nazionale dei Tumori Recruiting
Milan, Italy, 20133
Contact: Filippo Pietrantonio, MD    +390223903807    filippo.pietrantonio@istitutotumori.mi.it   
Contact: Federica Morano, MD    +390223903842    federica.morano@istitutotumori.mi.it   
Sponsors and Collaborators
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Investigators
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Principal Investigator: Filippo Pietrantonio, MD Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Publications:
Cremolini C, Antoniotti C, Rossini D, Lonardi S, Loupakis F, Pietrantonio F, Bordonaro R, Latiano TP, Tamburini E, Santini D, Passardi A, Marmorino F, Grande R, Aprile G, Zaniboni A, Murgioni S, Granetto C, Buonadonna A, Moretto R, Corallo S, Cordio S, Antonuzzo L, Tomasello G, Masi G, Ronzoni M, Di Donato S, Carlomagno C, Clavarezza M, Ritorto G, Mambrini A, Roselli M, Cupini S, Mammoliti S, Fenocchio E, Corgna E, Zagonel V, Fontanini G, Ugolini C, Boni L, Falcone A; GONO Foundation Investigators. Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020 Apr;21(4):497-507. doi: 10.1016/S1470-2045(19)30862-9. Epub 2020 Mar 9.

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Responsible Party: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
ClinicalTrials.gov Identifier: NCT04689347    
Other Study ID Numbers: INT 151/20
First Posted: December 30, 2020    Key Record Dates
Last Update Posted: April 4, 2022
Last Verified: March 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano:
Temozolomide
MGMT
microsatellite stable
First-line
Phase 1
Colorectal cancer
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Bevacizumab
Fluorouracil
Irinotecan
Temozolomide
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Topoisomerase I Inhibitors
Topoisomerase Inhibitors