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    Summary
    EudraCT Number:2010-022239-12
    Sponsor's Protocol Code Number:ISIS 183750-CS3
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-05-31
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2010-022239-12
    A.3Full title of the trial
    A Phase 1b/2 Study of Docetaxel and Prednisone, with or without ISIS 183750 (an eIF4E Inhibitor), inPatients with Castrate-Resistant Prostate Cancer
    A.3.2Name or abbreviated title of the trial where available
    N/A
    A.4.1Sponsor's protocol code numberISIS 183750-CS3
    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 SponsorIsis 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 nameeIF-4E Antisense Oligonucleotide
    D.3.2Product code ISIS 183750
    D.3.4Pharmaceutical form Solution for injection
    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.3.9.2Current sponsor codeISIS 183750
    D.3.9.3Other descriptive nameLY2275796
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 Yes
    D.3.11.13.1Other medicinal product typeAntisense Oligonucleotide
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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.2.5The 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 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.3.8INN - Proposed INNDOCETAXEL
    D.3.9.1CAS number 114977-28-5
    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 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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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.2.5The 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 Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNPREDNISONE
    D.3.9.1CAS number 53-03-2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 castrate-resistant prostate cancer
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 13.1
    E.1.2Level LLT
    E.1.2Classification code 10062904
    E.1.2Term Hormone-refractory prostate cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 13.1
    E.1.2Level PT
    E.1.2Classification code 10036909
    E.1.2Term Prostate 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
    In Part 1, the primary objective is to examine the safety and tolerability of ISIS 183750 in combination with
    docetaxel and prednisone in order to determine the ISIS 183750 dose for evaluation in Part 2.
    In Part 2, the primary objective is to estimate the progression-free survival in patients treated with ISIS 183750 in
    combination with docetaxel and prednisone.
    E.2.2Secondary objectives of the trial
    Part 1:
    • To characterize the plasma and urine PK parameters of ISIS 183750 in the absence and presence of docetaxel
    • To characterize the plasma PK parameters for docetaxel in the presence of ISIS 183750
    • To explore anticancer effects of ISIS 183750 in combination with docetaxel and
    prednisone
    Part 2:
    • To estimate overall survival
    • To estimate the effect of treatment on PSA parameters including:
    - Percent change from baseline to the end of the 4th treatment cycle
    - Maximum post-baseline percent reduction
    - Time to PSA progression
    • To examine tumor response by RECIST version 1.1 including:
    - Percent change of tumor size from baseline to the end of the 4th treatment cycle
    - Objective tumor response rate
    - Duration of objective tumor response for responding patients
    - Time to tumor progression
    • To determine the 7-day plasma trough levels of ISIS 183750
    • To determine the safety and tolerability of ISIS 183750 in combination with docetaxel and prednisone
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients with castrate-resistant prostate cancer are eligible to be included in the study only if they meet all of the
    following criteria:
    1. Provide written informed consent prior to Screening.
    2. Age ≥ 18 years.
    3. Histological or cytological diagnosis of adenocarcinoma of the prostate.
    4. Metastatic disease for which no curative therapy exists and for which systemic
    chemotherapy is indicated.
    5. Progression of disease despite either medical or surgical castration. If the patient
    received medical androgen ablation, a castrate level of testosterone (≤ 50 ng/dL)
    must have been present concurrent with disease progression. Progressive disease is
    defined as any one of the following:
    • Rising serum PSA levels: two consecutive increases in PSA levels documented
    over a previous reference value obtained at least one week apart with the value of
    the third point being ≥ 2 ng/mL. If the third PSA level is less than the second, an
    additional fourth test to confirm a rising PSA (i.e., the fourth value is ≥ the second
    value and is ≥ 2 ng/mL) is acceptable.
    • Progressive measurable disease defined as an increase in the sum of the diameters of measurable lesions over
    the smallest sum observed or the appearance of one or more new lesions as assessed by CT scan.
    • Bone progressions: appearance of 2 or more new lesions on bone scan or other
    imaging.
    6. If patient did not have a surgical orchiectomy:
    • The patient must be on androgen suppression treatment (e.g. LHRH agonist), have
    a castrate level of testosterone (≤ 50 ng/dL), and must be willing to continue the
    treatment throughout the study.
    • The patient must have discontinued treatment with anti-androgens (discontinued
    ≥ 4 weeks for flutamide and ≥ 6 weeks for nilutamide or bicalutamide prior to
    Screening) and have documented disease progression following discontinuation.
    7. PSA ≥ 2 ng/mL during the Screening period.
    8. Performance status of 0 or 1 on the ECOG Performance Status Scale.
    9. Have an estimated life expectancy of at least 12 weeks.
    10. Adequate organ function within 14 days prior to first study dose (ISIS 183750 or
    docetaxel, whichever occurs first) including the following:
    a. Absolute neutrophil count (ANC) ≥ 1.5 x 10(9)/L.
    b. Platelet count ≥ 100 x 10(9)/L.
    c. Total bilirubin ≤ 1.0 x upper limit of normal (ULN).
    d. Aspartate aminotransferase (AST) ≤ 1.5 x ULN.
    e. Alanine aminotransferase (ALT) ≤ 1.5 x ULN.
    f. Serum creatinine ≤ 1.5 x ULN.
    g. Prothrombin time (PT) and international normalized ratio (INR) within normal limits.
    h. Activated partial thromboplastin time (aPTT) within normal limits.
    11. Part 1: Have had no more than 1 prior chemotherapy or biological therapy regimen (approved or
    experimental; all previous hormonal therapies are allowed and not counted as biological therapy for this
    inclusion criterion) for prostate cancer. This does not include treatments that may have been received in the
    adjuvant or
    neoadjuvant setting. A regimen is defined as two or more consecutive cycles of
    treatment.
    Part 2: Have had no prior chemotherapy or biological therapy (approved or
    experimental; all previous hormonal therapies are allowed and not counted as
    biological therapy for this inclusion criterion) in any setting for prostate cancer.
    12. Have discontinued all previous therapies for cancer (except treatment with LHRH
    analogues) as follows:
    a. Part 1: cytotoxic chemotherapy must be discontinued at least 4 weeks prior to
    screening; Part 2: see Inclusion Criteria 11.
    b. Part 1: biological treatment (other than hormonal treatments) must be discontinued for at least 6 weeks prior to
    screening; Part 2: see Inclusion Criteria 11.
    c. Hormone therapies (e.g., abiraterone, MDV3100) must have been discontinued 4 weeks prior to screening.
    d. Radiotherapy must be discontinued at least 4 weeks prior to screening, and the
    patient must have recovered from the acute effects of therapy.
    13. Recovery from all toxicities of prior therapy to ≤ Grade 2 by NCI CTCAE, version
    4.0 (Exception: any toxicity that in the view of the Investigator is not a clinically
    significant safety risk for further therapy administration, including, but not limited
    to: anemia, fatigue, erectile dysfunction, hot flashes, lymphedema of an extremity,
    dizziness, cough, and urinary incontinence).
    14. Men of reproductive potential must agree to use an effective form of contraception, as determined by the
    Investigator, during the treatment period of the study and for 10 weeks following the last dose of study drug.
    15. The patient is willing and able to comply with the study visit schedule and
    procedures, and geographic proximity (Investigator’s discretion) that allows
    adequate follow-up.
    E.4Principal exclusion criteria
    Patients will be excluded from the study if they meet any of the following criteria:
    1. Treatment with another investigational drug or device within 4 weeks or biological
    agent within 6 weeks before Screening or 5 half-lives of study agent, whichever is
    longer.
    2. Pre-existing peripheral neuropathy ≥ Common Terminology Criteria for Adverse
    Events, Version 4.0 (CTCAE) Grade 2.
    3. Patients with treated or untreated parenchymal brain metastases or leptomeningeal disease. Currently active
    malignant epidural disease is also excluded. Previously treated epidural disease does not exclude the patient from
    the study. (Note: CT or MRI of brain is not needed to rule these out unless the patient has clinical symptoms
    suggestive of CNS metastases).
    4. Have active infection or serious concomitant systemic disorder (for example, heart
    failure) incompatible with the study (at the discretion of the Investigator).
    5. Presence or history of other malignancies except non-melanoma skin cancer or solid tumors curatively treated
    at least 5 years previously with no subsequent evidence of recurrence.
    6. Presence of an underlying disease state associated with active bleeding.
    7. Ongoing therapy with oral or parenteral anticoagulants (e.g., heparin, warfarin/coumadin). Low-dose
    anticoagulants for maintenance of catheter patency
    and low dose aspirin (≤ 325 mg/day) and nonsteroidal antiinflammatory agents are
    not exclusionary.
    8. Concurrent treatment with other anticancer drugs.
    9. Inability to comply with protocol or study procedures.
    10. Previous therapy with strontium or samarium.
    11. Patients who have had irradiation of ≥ 25% of the bone marrow (e.g. pelvic
    irradiation).
    12. Use of any herbal products, including saw palmetto within 1 week of screening and throughout the study.
    13. Initiation of treatment with bisphosphonates, or change in dose, within 4 weeks of assignment to dosing in
    this study. Patients taking bisphosphonates should not have their dosing regimen altered during the study unless
    medically warranted.
    14. Known history of HIV, HCV, or chronic HBV infection.
    15. Previous treatment with a therapeutic antisense oligonucleotide or siRNA.
    16. Planned concomitant participation in another clinical trial of an experimental agent, vaccine, or device.
    17. Have any other medical conditions that, in the opinion of the Investigator, would
    make the patient unsuitable for enrollment, or could interfere with the patient
    participating in or completing the study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the progression-free survival, with progression defined as:
    • PSA progression according to PCWG2 criteria (including the recommendation
    that rising PSA alone as the basis for progression should be avoided),
    • Tumor progression in lung, liver, lymph nodes and other soft tissue, by modified
    RECIST 1.1 criteria,
    • Bone progression defined as two or more new lesions on bone scan,
    • Worsening symptoms and/or
    • Death
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase 1b
    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 Yes
    E.8.1.7.1Other trial design description
    Part 1:uncontrolled, open-label, dose escalation; Part 2:randomized, open-label
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Part 2: IMP+docetaxel+prednison versus docetaxel+prednison
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA19
    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 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months7
    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 No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 112
    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)
    As per protocol
    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 Decision2011-05-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-04-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-11-15
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