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    Summary
    EudraCT Number:2009-014876-23
    Sponsor's Protocol Code Number:EZN-2208-04
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-07-05
    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 ConcernedUK - MHRA
    A.2EudraCT number2009-014876-23
    A.3Full title of the trial
    A Phase 2 Study of EZN-2208 (PEG-SN38) administered with or without Cetuximab in patients with Metastatic Colorectal Carcinoma (mCRC)
    A.4.1Sponsor's protocol code numberEZN-2208-04
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEnzon Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 No
    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.3.1Product namePEG-SN38
    D.3.2Product code EZN-2208
    D.3.4Pharmaceutical form Powder and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 100963-53-7
    D.3.9.2Current sponsor codeEZN-2208
    D.3.9.3Other descriptive namePEG-SN38
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.7
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Colorectal Carcinoma (mCRC)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 13.1
    E.1.2Level PT
    E.1.2Classification code 10052358
    E.1.2Term Colorectal cancer metastatic
    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
    • For Arms A, B, and C: Determine the overall response rate (RR) of EZN-2208 for two distinct cohorts of patients with mCRC
    - Patients with mutated K-RAS tumors (Arm A)
    - Patients with wild-type K-RAS tumors (Arms B and C)
    • For Arms B and C (wild-type K-RAS tumors): Determine the progression-free survival (PFS)
    E.2.2Secondary objectives of the trial
    • Evaluate the duration of response for each treatment arm
    • Evaluate the PFS for Arm A
    • Evaluate overall survival (OS) for each treatment arm
    • Evaluate safety and toxicity for each treatment arm
    • For patients with wild-type K-RAS tumors, benchmark the primary and secondary endpoints observed in Arm B (EZN-2208 + cetuximab) with those observed in Arm C (irinotecan + cetuximab)
    • If possible, to evaluate the peripheral blood mononuclear cell (PBMC) genotype (e.g., uridine diphosphate-glucuronosyl-transferase isoform 1A1 [UGT1A1]) to detect changes in genes that may affect how the anticancer drugs work or are degraded, and to see if these changes affect the study treatment or side effects. Patients may participate in this study even if they do not agree to the molecular profile testing.
    • If possible, to evaluate biomarkers in a sample of the original tumor biopsy. Patients may participate in this study even if they do not agree to allow the tumor biopsy testing.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Capable of understanding the protocol requirements and risks and providing written informed consent
    2. Histologically confirmed CRC adenocarcinoma that is metastatic or locally recurrent CRC that is nonresectable
    3. Patients must agree to genetic testing of the original or metastatic CRC tumor biopsy tissue for K-RAS mutational status. Participation in study requires the availability of the tumor biopsy and written patient consent for K-RAS genotyping of the tumor tissue. Lack of tumor tissue or patient refusal to allow genotyping makes the patient ineligible for the study.
    Note: If a patient’s K-RAS mutational status was tested using the DxS assay before enrolling in this trial, the patient’s K-RAS mutational test will not be duplicated if it was performed using a validated assay at a certified laboratory (see Appendix 3). If a patient’s K-RAS mutational status was tested before enrolling in this trial using other assays that evaluate mutations in codons 12 or 13, the patient may enroll in the study on the basis of these results; however, the patient’s K-RAS mutational test will be duplicated using a validated assay at a certified laboratory. Patients will need to consent to repeat testing of tumor genotype. Lack of tumor tissue or patient refusal to allow genotyping makes the patient ineligible for the study.
    4. Disease progression
    5. Previous therapy with irinotecan, oxaliplatin, and fluoropyrimidine either alone or in any combination(s). Patients must have radiographically documented progressive disease while receiving, or within 3 months of receiving, these agents alone or in combination.
    6. Maximum of 2 progressions from the time the patient had metastatic disease.
    a. Progression <6 months after completion of adjuvant therapy counts as one of the 2 progressions.
    b. Progression before reintroduction of oxaliplatin does not count as one of the 2 progressions if the oxaliplatin-containing regimen had been stopped for reasons other than progression.
    7. Age 18 years or older
    8. Measurable disease by RECIST Version 1.1 [52] is required: ≥1 tumor with ≥10 mm (assuming computed tomography [CT] slice thickness of 5 mm minimum).
    9. ECOG performance status of 0 or 1
    10. Adequate bone marrow, renal, and hepatic function
    • Absolute neutrophil count (ANC) ≥1,000/μL
    • Platelet count ≥75,000/μL
    • Serum creatinine ≤1.5 times the upper limit of normal (ULN)
    • Total bilirubin within normal limits
    • Transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [(ALT]) ≤2.5 times the ULN (may be ≤5 times the ULN if the increase is due to metastatic disease to the liver)
    E.4Principal exclusion criteria
    1. Concurrent serious medical illness that could potentially interfere with protocol compliance
    2. Previous cancer treatment with cetuximab (Erbitux®), panitumumab (Vectibix®), or any other anti-EGFR therapies. Patients previously treated with such therapy who are found to have mutated K-RAS tumors and who meet all other eligibility criteria are eligible for participation in Arm A of the study. Patients having received adjuvant cetuximab and progressing >12 months after completion of adjuvant cetuximab are eligible for Arms B and C.
    3. Positive screening pregnancy test or is breast-feeding
    4. Female or male patient of reproductive capacity unwilling to use methods appropriate to prevent pregnancy during this study
    5. Known chronic infectious disease, such as acquired immunodeficiency syndrome (AIDS)
    6. Major surgery within 3 weeks before study start
    7. Known or suspected brain metastases requiring intervention with steroids and/or radiation therapy. Patients with previously treated brain metastases who are currently asymptomatic and not requiring steroids are eligible.
    8. Prior chemotherapy, immunotherapy, non-investigational agent, or other therapy used to treat the cancer within 3 weeks (6 weeks for prior treatment with mitomycin C) before the scheduled administration of EZN-2208
    9. History of other primary cancer within 5 years of enrollment, unless
    a. Curatively resected non-melanomatous skin cancer, or
    b. Curatively resected cervical cancer
    10. Lack of recovery to Grade 1 from any reversible side effects (except alopecia or Grade 2 sensory neuropathy) related to the administration of an investigational agent, chemotherapy, immunotherapy, surgery, radiotherapy, or other treatments for the cancer
    11. Any condition such as uncontrollable diabetes, uncontrollable hypertension, or active infection that, in the opinion of the principal investigator (PI) or Enzon, makes the patient unsuitable for the study. The PI must consider the potential side effects of SN38 therapy when evaluating a prospective study patient previously treated with irinotecan.
    12. Current participation in another clinical study with an investigational agent and/or use of an investigational drug (not including investigational use of an approved drug) in the 30 days before the first administration of EZN-2208
    13. Inability to comply with the study protocol
    E.5 End points
    E.5.1Primary end point(s)
    Response rate for each treatment arm
    Progression free survival for Arms B and C
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    cetuximab and/or irinotecan
    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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Yes
    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
    Last visit of last Subject for follow-up
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    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.1.1.1In 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 state80
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 220
    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 Decision2010-08-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-10-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-04-26
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