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    Summary
    EudraCT Number:2018-002849-11
    Sponsor's Protocol Code Number:FIRE-5
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-12-27
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2018-002849-11
    A.3Full title of the trial
    Optimal anti-EGFR Treatment of mCRC Patients with Low-Frequency RAS Mutation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Optimal anti-EGFR Treatment of mCRC Patients with Low-Frequency RAS Mutation
    A.3.2Name or abbreviated title of the trial where available
    FIRE-5
    A.4.1Sponsor's protocol code numberFIRE-5
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorKlinikum der Universität München, Ludwig-Maximilians-Universität München, represented by the managing medical director
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAmgen
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKlinikum der Ludwig-Maximilians-Universität München, Medizinische Klinik III, Campus Großhadern
    B.5.2Functional name of contact pointStudy secretariat
    B.5.3 Address:
    B.5.3.1Street AddressMarchioninistr. 15
    B.5.3.2Town/ cityMünchen
    B.5.3.3Post code81377
    B.5.3.4CountryGermany
    B.5.4Telephone number00498944007220
    B.5.5Fax number00498944007525
    B.5.6E-mailMatthias.Wolff@med.uni-muenchen.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Vectibix
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPANITUMUMAB
    D.3.9.1CAS number 339177-26-3
    D.3.9.2Current sponsor codePANITUMUMAB
    D.3.9.4EV Substance CodeSUB25390
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typePanitumumab is a high-affinity fully human IgG2 monoclonal antibody directed against human EGFR .
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    RAS-mutant metastatic colorectal cancer
    E.1.1.1Medical condition in easily understood language
    RAS-mutant metastatic colorectal cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10052362
    E.1.2Term Metastatic colorectal cancer
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to define an optimal cut-off for anti-EGFR treatment with panitumumab in combination with FOLFIRI of patients with low-frequency RAS mutation defined by digital Next Generation Sequencing (dNGS) using the Oncomine cfDNA pan-cancer panel assay (52 genes) on an Ion Torrent S5 Prime platform. This assay combined with unique molecular identifier (UMI) or molecular barcode technique allows the exact quantification of mutation frequencies.
    E.2.2Secondary objectives of the trial
    • To analyze efficacy parameters (progression-free survival [PFS] , overall survival [OS], early tumor shrinkage [ETS] , Depth of response [DpR]) in patients with low-frequency RAS-mutation treated with panitumumab in combination with FOLFIRI
    • To determine retrospectively a cut-off frequency for low-frequency RAS mutation as limit for treatment with anti EGFR agents
    • To analyze safety and tolerance of the first-line treatment
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Histologically confirmed, UICC stage IV metastatic adenocarcinoma of the colon or rectum
    • Primarily non-resectable metastases or surgical resection refused by the patient
    • Documented RAS mutation determined by the local pathology
    • Low level RAS mutation in the tumor (KRAS and NRAS exon 2, 3, 4) with frequency of RAS mutation ≤ 20 % according to the central or local molecular pathology report. Tumour material (biopsy specimen and/or surgical specimen taken at the time of primary diagnosis) will be used.
    Note: The frequency of the RAS mutation (number of mutant RAS alleles/number of analyzed RAS alleles) analyzed by a digital NGS method has to be <20% (or <0.2). The coverage of the NGS method should be >200 copies with respect to the RAS gene. Therefore the number of analyzed RAS genes, the number of RAS mutant alleles and the coverage has to be evident in the local pathological report.
    Refer to Section 8.4.1
    • Age ≥18
    • ECOG performance status 0-2
    • Patients suitable for chemotherapy administration
    • Patient's written declaration of consent obtained
    • Estimated life expectancy > 3 months
    • Presence of at least one measurable reference lesion according to the RECIST 1.1 criteria
    • Tumor tissue from primary tumor or metastasis available and patient consents to storage and molecular and genetic profiling of tumor material. Molecular profiling of blood samples is optionally performed.
    • Females of childbearing potential (FCBPs) and men must agree to use two highly effective contraceptive measures simultaneously (Pearl index <1) or practice true abstinence from any heterosexual intercourse for the duration of the study treatment and for at least 6 months after last administration of study medication. Complete sexual abstinence is acceptable only if the subject is refraining from heterosexual intercourse during the entire study treatment and up to 6 months after the discontinuation of all study drugs and the reliability of sexual abstinence is in line with the preferred and usual lifestyle of the subject. A woman will be considered as being of childbearing potential unless she is at least 50 years old and moreover has gone through menopause for at least 2 years or has been surgically sterilised.
    • Adequate bone marrow function:
    ▫ Leukocytes ≥ 3.0 x 109/L with neutrophils ≥ 1.5 x 109/L
    ▫ Thrombocytes ≥ 100 x 109/L
    ▫ Haemoglobin ≥ 5.6 mmol/L (equivalent to 9 g/dL)
    • Adequate hepatic function:
    ▫ Serum bilirubin ≤ 1.5 x upper limit of normal (ULN)
    ▫ ALAT and ASAT ≤ 2.5 x ULN (in the presence of hepatic metastases, ALAT and ASAT ≤ 5 x ULN)
    • Adequate renal function:
    ▫ Creatinine clearance (calculated according to Cockcroft and Gault) ≥ 50 mL/min
    • No previous chemotherapy for metastatic disease. Patient with need of immediate treatment (high tumor load, symptoms) may have received two cycles of FOLFIRI prior to study treatment.
    E.4Principal exclusion criteria
    • Previous chemotherapy for metastatic disease with the exception of two cycle of FOLFIRI (e.g. while waiting for the result of RAS mutation frequency).
    • Patients planned to be treated with FOLFOX or another oxaliplatin-based regimen as first-line treatment
    • Primarily resectable metastases and the patient agrees to resection
    • Grade III or IV heart failure (NYHA classification)
    • Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study
    • Additional cancer treatment (chemotherapy, radiation, immunotherapy or hormone treatment) during the study treatment (treatments that are conducted as part of an anthroposophic or homeopathic treatment approach, e.g. mistletoe therapy do not represent an exclusion criterion)
    • Previous chemotherapy for the colorectal cancer with the exception of adjuvant treatment, completed at least 6 months before entering the study
    • Participation in an investigational clinical study or experimental drug treatment within 30 days prior to study inclusion or within a period of 5 half-lives of the substances administered in the investigational clinical study or during an experimental drug treatment prior to inclusion in the study, depending on which period is longest or simultaneous participation in another investigational clinical study while taking part in the study
    • Known hypersensitivity or allergic reaction to any of the following substances: 5-fluorouracil, folinic acid, panitumumab, irinotecan, and chemically related substances and/or hypersensitivity to any of the excipients of any of the aforementioned substances including known hypersensitivity reactions to monoclonal antibodies NCI CTCAE Grade ≥ 3.
    • Known hypersensitivity to Chinese hamster ovary cell (CHO) – cellular products or other recombinant human or humanised monoclonal antibodies
    • History of uncontrolled bronchial asthma
    • Patients with interstitial pneumonitis or pulmonary fibrosis
    • Patients with known brain metastasis
    • History of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhoea
    • Symptomatic peritoneal carcinomatosis
    • Severe, non-healing wounds, ulcers or bone fractures
    • Patients with acute or chronic infection requiring systemic therapy
    • Known history of positive testing for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
    • Active or chronic Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive; serologic tests required).
    • Known complete DPD deficiency (specific screening as recommended in the respective SmPC for 5-FU in effect; patients with a known complete DPD deficiency must be excluded; patients with a known partial DPD deficiency may be included at the discretion of the investigator)
    • Known glucuronidation deficiency (Gilbert's syndrome);(specific screening not required)
    • Treatment with sorivudine or brivudine within 28 days before study enrollment or requirement for concomitant antiviral treatment with sorivudine or brivudine
    • History of a second primary malignancy during the past 5 years before inclusion in the study or during participation in the study, with the exception of a basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ, if these were treated curatively.
    • Known previous or ongoing alcohol or drug abuse
    • Pregnant or breast-feeding patients
    • Any other severe concomitant disease or disorder which, in the investigator’s opinion, could influence the patient’s ability to participate in the study or influence his/her safety during the study or interfere with interpretation of study results
    • Both, absent and restricted legal capacity
    E.5 End points
    E.5.1Primary end point(s)
    As primary endpoint ORR according to RECIST 1.1 will be evaluated separately for each group of patients with defined low-frequency RAS mutation (Groups A, B and C).
    E.5.1.1Timepoint(s) of evaluation of this end point
    8 weeks after start of panitumumab and every 12 Treatment weeks thereafter
    E.5.2Secondary end point(s)
    Efficacy variables:
    • PFS, separately for each group of patients with defined low-frequency RAS mutation (Groups A, B and C)
    • OS, separately for each group of patients with defined low-frequency RAS mutation (Groups A, B and C)
    • ETS, separately for each group of patients with defined low-frequency RAS mutation (Groups A, B and C)
    • DpR, separately for each group of patients with defined low-frequency RAS mutation (Groups A, B and C)
    • Retrospectively determined optimal cut-off frequency for low-frequency RAS mutation leading to RR, PFS and OS in ranges comparable to that of RAS-wildtype first-line patients treated with panitumumab in combination with chemotherapy
    • Prospective analysis of tumor marker level evolution (CEA and CA 19-9)
    Safety variables:
    • Type, incidence, relatedness, and severity of adverse events according to NCI CTCAE version 5.0
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Treatment Phase
    - 8 weeks after start of panitumumab and every 12 Treatment weeks thereafter
    - until progression
    - Follow-up Phase
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned50
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state135
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-05-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-17
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2021-06-16
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