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    Summary
    EudraCT Number:2017-003549-72
    Sponsor's Protocol Code Number:SMR-3165
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-10-27
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2017-003549-72
    A.3Full title of the trial
    Phase II study of Irofulven in AR-targeted and Docetaxel-Pretreated Metastatic Castration-Resistant Prostate Cancer Patients, who have a Drug Response Predictor (DRP™) indicating a high likelihood of response to Irofulven
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase II study of Irofulven in AR-targeted and Docetaxel-Pretreated Metastatic Castration-Resistant Prostate Cancer Patients, who have a Drug Response Predictor (DRP™) indicating a high likelihood of response to Irofulven
    A.4.1Sponsor's protocol code numberSMR-3165
    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 SponsorOncology Venture Aps
    B.1.3.4CountryDenmark
    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 supportOncology Venture Aps
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRigshospitalet
    B.5.2Functional name of contact pointGedske Daugaard
    B.5.3 Address:
    B.5.3.1Street AddressBlegdamsvej 9
    B.5.3.2Town/ cityKøbenhavn
    B.5.3.3Post code2100
    B.5.3.4CountryDenmark
    B.5.4Telephone number+453545 1125
    B.5.6E-mailGedske.kirsten.daugaard@regionh.dk
    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 nameIrofulven
    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 INNIROFULVEN
    D.3.9.1CAS number 158440-71-2
    D.3.9.2Current sponsor codeIrofulven
    D.3.9.3Other descriptive name6-hydroxymethyacylfulvene
    D.3.9.4EV Substance CodeSUB02773MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.IMP: 2
    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 Prednisolon "DAK"
    D.2.1.1.2Name of the Marketing Authorisation holderTakeda Pharma
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 namePrednisolone "DAK"
    D.3.4Pharmaceutical form Tablet
    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.3.9.3Other descriptive namePREDNISOLONE
    D.3.9.4EV Substance CodeSUB10018MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) 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
    AR-targeted and Docetaxel-Pretreated Metastatic Castration-Resistant Prostate Cancer
    E.1.1.1Medical condition in easily understood language
    Prostate Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    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
    To evaluate the anti-tumour effect after treatment with 0.45mg/kg Irofulven in combination prednisolone in patients who progressed on AR-targeted therapy (abiraterone acetate, enzalutamide or investigational AR-targeted agent) and docetaxel-pretreated metastatic castration-resistant prostate cancer and that were selected by the Irofulven DRP.
    E.2.2Secondary objectives of the trial
    • To determine the safety profile of Irofulven combined with prednisone in castration resistant metastatic prostate cancer patients, pre-treated with docetaxel and AR-targeted therapy
    • To assess duration of response (DOR)
    • To assess radiologic PFS (rPFS)
    • To assess overall survival (OS)
    • To assess PSA response ≥ 50% (all patients)
    • To assess PSA response ≥ 90% (all patients)
    • To assess time to PSA progression
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to participate in this study the subjects must meet all of the following inclusion criteria:
    1. Have a histologically confirmed adenocarcinoma or poorly differentiated carcinoma of the prostate (carcinomas with pure small-cell histology or pure high grade neuroendocrine histology are excluded; neuroendocrine differentiation is allowed)
    2. Surgically or medically castrated, with serum testosterone levels of ≤ 50 ng/dL. For patients currently being treated with luteinizing hormone–releasing hormone (LHRH) agonists, i.e., patients who have not undergone an orchiectomy, therapy must be continued throughout the study
    3. Have evidence of disease progression after prior therapy for mCRPC:
    a.Disease progression after treatment with at least 1 but no more than 2 prior next-generation AR-targeted therapies (abiraterone acetate, enzalutamide, or investigational AR-targeted agent) for metastatic prostate cancer (treatment with the older anti-androgen therapies such as bicalutamide, flutamide, and nilutamide are not counted toward this limit), AND
    b. Disease progression after treatment with docetaxel for metastatic Prostate cancer. Prior Docetaxel therapy administered for hormone-sensitive disease is permitted and is not counted toward this limit. Disease progression after initiation of most recent therapy is based on any of the following criteria:
    • Rise in PSA: a minimum of 2 consecutive rising levels, with an interval of ≥ 1 week between each determination. The most recent screening measurement must have been ≥ 1 ng/mL
    • Transaxial imaging: new or progressive soft tissue masses on CT or MRI scans as defined by RECIST 1.1
    • Radionuclide bone scan: at least 2 new metastatic lesions
    4. Signed informed consent obtained prior to initiation of any study-specific procedures or treatment
    5. Age ≥ 18 years
    6. Life expectancy ≥ 3 months
    7. Performance status 0 - 1
    8. Drug response predictor (DRPTM) in the upper likelihood of response (DRP value is available via the screening procedure performed by Medical Prognosis Institute)
    9. Adequate organ functions
    a. Hematological: absolute neutrophil count (ANC) >1.5 x 109/L, platelet count >100 x 109/L, hemoglobin > 6,2 mmol/L
    b. Hepatic: Bilirubin within normal range, aspartate transaminase (AST) and alanine transaminase (ALT) <2.5 UNL, albumin > 25 g/L
    c. Renal: creatinine clearance >30 mL/min (calculated according to the Cockcroft and Gault method)
    10. Recovered to grade 0 or 1 from any toxic effects of prior chemotherapy, radiotherapy
    E.4Principal exclusion criteria
    In order to participate in the study subjects must not meet any of the following exclusion criteria:
    1. Prior external beam radiation therapy to >25% of the bone marrow
    2. Contraindication to the use of prednisolone (e.g. uncontrolled diabetes mellitus)
    3. Prior treatment with Irofulven.
    4. Ongoing treatment with a corticosteroid at a prednisolone-equivalent dose > 10 mg/day
    5. More than 1 prior treatment with either 153Sm or 89Sr, or radioisotope treatment or treatment with bisphosphonate agents or antibody treatment i.e., denosumab within 2 months prior to initiation of treatment with IMP. Pre-existing treatment with bisphosphonate agents or denosumab is to be continued during the study
    6. Initiation of treatment with bisphosphonate agents or antibody treatment i.e., denosumab, within 4 weeks of study start. Pre-existing treatment with bisphosphonate agents or denosumab is to be continued during the study
    7. Treatment with coumarin derivatives and/or phenytoin most be discontinued and coagulation parameters most be within the normal range before treatment with Irofulven
    8. History of significant gastric or small bowel resection, malabsorption syndrome, or other lack of integrity of the upper gastrointestinal tract that may prevent compliance with oral drug administration
    9. Presence of any serious concomitant systemic disorders and/or psychiatric condition incompatible with the study (at the investigator’s discretion)
    10. History of retinopathy
    11. Presence of any active infection (at the investigator’s discretion).
    12. CNS disease including epilepsy or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures
    E.5 End points
    E.5.1Primary end point(s)
    Anti-Tumour effect of Irofulven with prednisolone on clinical benefit rate defined as complete response, partial response or stable disease > 9 weeks according to RECIST 1.1 for patients with measurable disease and defined as stable disease > 9 weeks according to PCWG3 for bone metastases.
    • All patients who receive at least 2 treatment cycles (4 daily treatments with Irofulven) will be considered evaluable for response.
    • Patients discontinuing early due to disease progression will also be evaluable for response
    E.5.1.1Timepoint(s) of evaluation of this end point
    After at least 2 treatment cycles.
    E.5.2Secondary end point(s)
    • Duration of response (DOR) is defined as Time from documentation of tumour response to disease progression.
    • Radiologic progression free survival (rPFS), rPFS was defined as ≥ two new lesions on an 8-week bone scan plus two additional lesions on a confirmatory scan, ≥ two new confirmed lesions on any scan ≥ 9 weeks after enrolment, and/or progression in nodes or viscera on cross-sectional imaging, or death.
    • Overall survival defined as time from enrolment until death from any cause.
    • PSA response defined as ≥ 50% decline in PSA compared to baseline in all patients according to PCWG3.
    • PSA response defined as ≥ 90% decline in PSA compared to baseline in all patients according to PCWG3.
    • Time to PSA progression will be is defined in accordance with PCWG3.

    Safety variables:
    • Incidence and severity (NCI-CTCAE version 4.03) of clinical adverse events and laboratory abnormalities; occurrence of serious adverse events (SAEs) and treatment discontinuation for adverse events, measurement of vital signs and ECG.
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of treatment.
    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 No
    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 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    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
    Last patient last visit (LPLV)
    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 years1
    E.8.9.2In all countries concerned by the trial months6
    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.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 17
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 27
    F.4.2.2In the whole clinical trial 27
    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)
    Not different from expected normal treatment (standard treatment)
    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 Decision2017-12-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-12-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-06-01
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