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    Summary
    EudraCT Number:2012-002766-13
    Sponsor's Protocol Code Number:1088/12
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2012-09-03
    Trial 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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2012-002766-13
    A.3Full title of the trial
    A phase 2 study of temozolomide in patients affected by metastatic colonrectal cancer with hypermethylation of 06-methylguanine-dna-methyltransferase
    Studio di fase 2 con Temozolomide in pazienti affetti da carcinoma colon-rettale metastatico con ipermetilazione di 06-metilguanina-DNA-metil transferasi
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase 2 study of temozolomide in patients affected by metastatic colonrectal cancer with hypermethylation of 06-methylguanine-dna-methyltransferase
    Studio di fase 2 con Temozolomide in pazienti affetti da carcinoma colon-rettale metastatico con ipermetilazione di 06-metilguanina-DNA-metil transferasi
    A.4.1Sponsor's protocol code number1088/12
    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 SponsorPOLICLINICO UNIVERSITARIO AGOSTINO GEMELLI
    B.1.3.4CountryItaly
    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 supportPOLICLINICO GEMELLI
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPoliclinico Gemelli
    B.5.2Functional name of contact pointOncologia medica
    B.5.3 Address:
    B.5.3.1Street AddressL.go Gemelli 8
    B.5.3.2Town/ cityRoma
    B.5.3.3Post code00168
    B.5.3.4CountryItaly
    B.5.4Telephone number0630154844
    B.5.6E-mailcarlobarone@rm.unicatt.it
    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 TEMOZOLOMIDE TEVA*5CPS 5MG
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA ITALIA Srl
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTEMOZOLOMIDE
    D.3.9.1CAS number 85622-93-1
    D.3.9.4EV Substance CodeSUB10889MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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 No
    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
    metastatic colonrectal cancer
    carcinoma colonrettale
    E.1.1.1Medical condition in easily understood language
    metastatic colonrectal cancer
    carcinoma colonrettale
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.0
    E.1.2Level HLT
    E.1.2Classification code 10010023
    E.1.2Term Colorectal neoplasms malignant
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To assess the activity (in terms of response rate according to RECIST 1.1 criteria) of temozolomide (TMZ) in patients with refractory metastatic colorectal cancer with hypermethylation of MGMT
    - Valutazione dell’efficacia (in termini di tasso di risposte obiettive secondo criteri RECIST 1.1) di Temozolomide (TMZ) in pazienti affetti da carcinoma colorettale metastatico resistente ai trattamenti standard e con ipermetilazione di MGMT
    E.2.2Secondary objectives of the trial
    - Disease control rate
    - Duration of response
    - Progression free survival
    - Tolerability and safety
    - Quality of life
    - Tasso di controllo della malattia
    - Durata della risposta
    - Sopravvivenza libera da progressione
    - Tollerabilità e sicurezza del trattamento
    - Qualità della vita
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Pathologically confirmed colorectal adenocarcinoma and documented metastatic disease
    - MGMT promoter hypermethylation assessed by MS-PCR. The analysis will be performed at Università Cattolica del Sacro Cuore, Molecular Pathology Lab.
    - Disease progression during or following at least two lines of chemotherapy including fluoropyrimidines, irinotecan, oxaliplatin, anti-VEGF and (if KRAS wild-type) anti EGFR drugs, or unacceptable toxicity to these drugs.
    - Progression free interval less than 6 months from the end of the previous treatment
    - Male and female patients, age ≥ 18 years
    - Performance Status (ECOG): ≤ 2
    - At least one measurable lesion meeting the RECIST 1.1 criteria
    - Written and signed informed consent obtained prior to beginning any protocol-specific procedures.
    - Life expectancy ≥12 weeks
    - Effective means of contraception (i.e. sexual abstinence) during the study and for a period of at least 6 mon ths after the last administration of the study drug.
    - Adequate hematological function (White Blood Cell count ≥ 3 x 109/l, Absolute neutrophil count ≥ 1.5 x 109/l, and platelet count ≥ 100 x 109/l)
    - Adequate liver function (total bilirubin < 1.5 x upper limit of normal, unless the patient has documented Gilbert’s syndrome; ALT ≤ 2.5 x upper limit of normal or ≤ 5 x upper limit of normal in patients with liver metastases)
    - Adequate renal function: serum creatinine ≤ 1.5 x upper limit of normal or creatinine clearance ≥ 50 ml/min (according to the formula of Crockcroft and Gault)
    - INR and aPTT ≤ 1.5 x upper limit of normal (unless on therapeutic anti-coagulation)
    - Diagnosi di adenocarcinoma del colon confermata istologicamente e malattia metastatica documentata
    - Ipermetilazione della regione promoter di MGMT valutata mediante MSP (reazione a catena della polimerasi specifica per la metilazione), presso il Laboratorio di Patologia Molecolare del Policlinico Universitario Agostino Gemelli
    - Progressione attraverso o dopo almeno due linee di terapia comprendenti fluoropirimidine, irinotecan, oxaliplatino, agenti anti-VEGF e, in caso di tumori KRAS wild-type, agenti anti-EGFR, o impossibilità a ricevere tali trattamenti per tossicità
    - Intervallo libero da progressione inferiore a 6 mesi dal termine del precedente trattamento chemioterapico
    - Uomini e donne di età ≥ 18 anni
    - Performance Status (ECOG): ≤ 2
    - Presenza di almeno una lesione misurabile
    - Consenso informato scritto, ottenuto prima di qualsiasi altra procedura prevista dal protocollo
    - Aspettativa di vita di almeno 12 settimane
    - Adeguate misure anticoncezionali (astinenza dall’attività sessuale) per l’intera durata del trattamento e fino a sei mesi dopo l’ultima assunzione di TMZ
    - Adeguata funzionalità midollare (Numero dei globuli bianchi &gt; 3 x 109/L con neutrofili &gt; 1.5 x 109/L, numero di piastrine &gt; 100 x 109/L, emoglobina &gt; 9 g/dL)
    - Bilrubina totale &lt; 1.5 volte il limite superiore di riferimento (a meno che il paziente non abbia una sindrome di Gilbert documentata)
    - ALT ≤ 2.5 volte il limite superiore della norma (≤ 5 volte il limite superiore della norma in caso di metastasi epatiche)
    - Creatinina sierica ≤ 1.5 volte il limite superiore della norma o creatinina clearance ≥ 50 ml/min (calcolata mediante formula di Cockroft e Gault)
    - INR e aPTT ≤ 1.5 volte il limite superiore della norma (ad eccezione dei pazienti in terapia anticoagulante)
    E.4Principal exclusion criteria
    - History of any other serious or uncontrolled disease that contraindicates the use of the investigational drug
    - Pregnancy or breast feeding (female patients with childbearing potential must have a negative serum beta-HCG).
    - Bowel obstruction
    - Alcohol or drug abuse.
    - Legal incapacity or limited legal capacity
    - Existing acute reversible effects of prior treatment. This generally means at least 3 weeks should have elapsed since prior chemotherapy and at least 4 weeks since prior (radical) radiotherapy or major surgery with full recovery
    - History of another malignancy within 5 years prior of enrollment, except for adequately treated carcinoma in situ of the cervix and non-melanoma skin cancer. Patients treated for other malignancies with curative intent and disease free at least for 5 years are elegible.
    - Brain metastasis not well controlled. Eligible patients must be asymptomatic, can not be receiving steroids or anticancer treatment, and must be enrolled at least 1 month after the end of the radiotherapy treatment. CT or MRI scan of the brain is mandatory in case of clinical suspicion of CNS metastases.
    - Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to study screening.
    - Current known infection with HIV, HBV, or HCV
    - Known hypersensitivity to the study drug or to one of the excipients
    - Documented intolerance to galactose, lattase deficiency or galactose malabsorption
    - Anamnesi di patologia seria o incontrollata per la quale il paziente non potrebbe ricevere il trattamento in studio
    - Gravidanza (per le donne in età fertile l’assenza di gravidanza deve essere confermata da test negativo per la b-HCG) o allattamento
    - Occlusione intestinale
    - Abuso di alcool o droghe
    - Incapacità legale o limitata capacità legale
    - Persistenza di effetti collaterali acuti e reversibili del precedente trattamento; in genere devono trascorrere almeno tre settimane tra la precedente chemioterapia ed almeno 4 settimane da un precedente intervento di chirurgia maggiore, con recupero completo
    - Anamnesi di altra neoplasia maligna, ad eccezione del carcinoma in situ della cervice e di tumori cutanei ad eccezione del melanoma. Sono eleggibili i pazienti trattati per altre neoplasie con intento curativo e liberi da malattia per almeno 5 anni.
    - Metastasi cerebrali non ben controllate. Pazienti con metastasi cerebrali sono eleggibili se asintomatici, in assenza di terapia antiedemigena steroidea, e dopo almeno 4 settimane dal termine di eventuale radioterapia sull’encefalo. TC o RMN del cranio sono obbligatorie in caso di sospetto clinico di metastasi cerebrali
    - Trattamenti concomitanti con altri farmaci sperimentali o partecipazione ad altri studi clinici entro i 30 giorni precedenti l’inizio delle procedure di screening
    - Infezione attiva nota da HIV, HBV o HCV
    - Allergia o ipersensibilità documentata al principio attivo o ad uno degli eccipienti del prodotto in studio
    - Intolleranza al galattosio, deficit di lattasi o malassorbimento di galattosio documentati
    E.5 End points
    E.5.1Primary end point(s)
    - Objective tumor response rate according to RECIST 1.1 criteria
    - Duration of response, as the time period from first documentation of response (complete or partial response) to the date of first occurrence of documented disease progression
    - Progression-free survival, defined as the time period from start of the treatment to the date of first occurrence of documented disease progression or death from any cause within 60 days from the last disease assessment or from cycle 1, day 1
    - Overall survival, defined as the time period from enrollment to death from any cause.
    - Risposta del tumore alla terapia sulla base della diagnostica per immagini e classificata secondo i criteri RECIST 1.1
    - Durata della risposta, definita come tempo dal momento dell’ottenimento della risposta (completa o parziale) alla documentata progressione della malattia
    - Sopravvivenza libera da progressione, definita come tempo in mesi dall’inizio del trattamento fino al momento della progressione della malattia o morte per qualsiasi causa entro 60 giorni dall’ultima valutazione dello stato di malattia o dal giorno 1 del ciclo 1.
    - Sopravvivenza globale, definita come tempo dall’inizio del trattamento fino al giorno della morte.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1 month
    1 mese
    E.5.2Secondary end point(s)
    Incidence and grading of adverse events and serious adverse events classified according to NCI-CTCAE 4.0
    Quality of life assessment:
    - Quality of life will be assessed by EORTC QLQ C-30 questionnaire
    - Incidenza e severità degli eventi avversi e degli eventi avversi seri, classificati secondo NCI-CTCAE 4.0
    - valutazione qualità della vita
    E.5.2.1Timepoint(s) of evaluation of this end point
    1 month
    1 mese
    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 No
    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 No
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial1
    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 No
    E.8.4.1Number of sites anticipated in Member State concerned1
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months20
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months20
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    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.1.2.1Number of subjects for this age range: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 21
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-09-03. Yes
    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 state41
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 41
    F.4.2.2In the whole clinical trial 41
    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)
    standard care
    normale pratica clinica
    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 Decision2013-01-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-06-21
    P. End of Trial
    P.End of Trial StatusOngoing
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