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    Summary
    EudraCT Number:2019-001318-40
    Sponsor's Protocol Code Number:SN38-SPL9111-001
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-05-09
    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 number2019-001318-40
    A.3Full title of the trial
    A phase 1/2 dose-escalation study to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of SN38-SPL9111 (DEP®-SN38), a SN38 dendrimer conjugate, in patients with advanced solid tumours.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase 1/2 dose-escalation study to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of SN38-SPL9111 (DEP®-SN38), a SN38 dendrimer conjugate, in patients with advanced solid tumours.
    A.3.2Name or abbreviated title of the trial where available
    SN38-SPL9111 in advanced solid tumours
    A.4.1Sponsor's protocol code numberSN38-SPL9111-001
    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 SponsorStarpharma Pty Ltd
    B.1.3.4CountryAustralia
    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 supportStarpharma Pty Ltd
    B.4.2CountryAustralia
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationStarpharma Pty Ltd
    B.5.2Functional name of contact pointClinical Development
    B.5.3 Address:
    B.5.3.1Street Address4-6 Southampton Crescent
    B.5.3.2Town/ cityAbbotsford
    B.5.3.3Post codeVIC 3067
    B.5.3.4CountryAustralia
    B.5.6E-mailclinicaltrials@starpharma.com
    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 nameDEP™-SN38
    D.3.2Product code SN38-SPL9111
    D.3.4Pharmaceutical form Powder 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 INNSN38-SPL9111
    D.3.9.2Current sponsor codeSN38-SPL9111
    D.3.9.3Other descriptive nameSN38-SPL9111
    D.3.9.4EV Substance CodeSUB197752
    D.3.10 Strength
    D.3.10.1Concentration unit millilitre(s)/gram
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number200
    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
    Advanced solid tumours.
    E.1.1.1Medical condition in easily understood language
    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 LLT
    E.1.2Classification code 10007050
    E.1.2Term 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
    To establish the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of SN38-SPL9111 given intravenously (IV)
    E.2.2Secondary objectives of the trial
    To characterise the safety and tolerability profile of SN38-SPL9111 in patients with advanced cancer
    To characterise the pharmacokinetics (PK) of SN38-SPL9111 and SN38
    To define a recommended dose for phase 2 studies of SN38-SPL9111 dosed IV
    To explore preliminary anti-tumour efficacy
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Signed informed consent form.
    2.At least 18 years old.
    3. Patients with histologically or cytologically confirmed advanced or metastatic cancer for which no standard therapy is available and who in the opinion of the investigator, could potentially benefit from treatment with irinotecan or SN38-SPL9111. For phase 2 dose expansion, preference will be given to patients with colorectal, pancreatic, ovarian, upper gastrointestinal and breast cancers. Patients may also be irinotecan naïve. Exceptionally, tumours in other locations may be enrolled subject to sponsor approval.
    4. Willing to be tested for uridine diphosphate-glucuronosyl transferase 1 family, polypeptide A1 (UGT1A1) genotype (if this result is not already available).
    5. Measurable disease per RECIST version 1.1 or applicable radiological or biochemical assessment. In the dose escalation/ assessment parts, patients with measurable or evaluable disease will be enrolled; in the dose expansion parts, only patients with measurable disease will be enrolled.
    6.Adequate bone marrow reserve as demonstrated by an absolute neutrophil count (ANC) ≥ 1.5 × 109/L or platelet count ≥ 100 × 109/L (cannot be post-transfusion) or haemoglobin ≥ 9 g/dL (can be post-transfusion).
    7.Serum bilirubin < 1.5 x upper limit of normal (ULN)
    8.Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level < 2.5 × ULN or < 5x ULN for patients with liver metastases
    9.Serum creatinine < 1.5 × ULN; however, an exception can be made if the calculated (by the Cockcroft-Gault formula) or measured creatinine clearance is > 50 mL/min.
    10.Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
    11.Life expectancy of greater than 12 weeks.
    12.Reproductive inclusion criteria:
    a)If of childbearing potential, willing to use an effective form of contraception (see below) during chemotherapy treatment and for at least six months thereafter.
    Such methods include (if using hormonal contraception this method must be supplemented with a barrier method, preferably male condom):
    •combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
    ooral
    ointravaginal
    otransdermal
    •progestogen-only hormonal contraception associated with inhibition of ovulation:
    ooral
    oinjectable
    oimplantable
    •intrauterine device (IUD)
    •intrauterine hormone-releasing system (IUS)
    •bilateral tubal occlusion
    •vasectomised partner
    •true sexual abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception.
    b) Women must have a negative pregnancy test at study entry.
    c) Men who are truly sexually abstinent when this is in line with the preferred and usual lifestyle of the subject or vasectomized or willing to ensure that their female sexual partners use a highly-effective means of contraception (i.e. as outlined in Inclusion criterion 12.a.) for the duration of study therapy and 6 months afterwards. In addition, men must be willing to use a condom during sexual intercourse from the first dose of SN38-SPL9111 until 6 months after their final dose, so as to protect their partner from exposure to study drug.
    E.4Principal exclusion criteria
    1.Uncontrolled brain metastases or spinal cord compression. Patients who were treated with surgical resection or radiation therapy completing at least 4 weeks earlier are eligible if they are neurologically stable and have a follow-up Magnetic Resonance Imaging (MRI) scan performed within the previous 4 weeks showing no tumour progression.
    2.Patients homozygous for the UGT1A1*28 allele (Gilbert syndrome) or patients with a congenital deficiency of UGT1A1 (Crigler-Najjar syndrome) will be excluded from the Phase 1 dose-escalation/ dose assessment part of the study; they may be enrolled in the Phase 2 dose expansions part starting at a reduced dose and incrementing to the full recommended dose, if no excessive toxicity is encounted.
    3.History of an untreated bleeding diathesis.
    4.Active bowel obstruction, history of inflammatory bowel disease or chronic or acute gastrointestinal disorders with diarrhoea as a major symptom.
    5.Allergy/hypersensitivity to irinotecan and SN38-containing preparations, pegylated drugs or other components of study therapy or compounds of similar chemical composition.
    6.Myocardial infarction within 6 months of enrolment, congestive heart failure of New York Heart Association class > II, unstable angina or unstable cardiac arrhythmias.
    7. Other uncontrolled intercurrent illness, including active infection.
    8. Participation in a study of an investigational agent within 30 days prior to first dose of study therapy.
    9. Anti-tumour therapy (including chemotherapy, radiation therapy, targeted therapeutics or hormonal therapy) within 28 days or 5-half-lives (whichever is shorter) prior to first study therapy.
    10. Cumulative dose of corticosteroid ≥ 150 mg prednisone (or equivalent doses of corticosteroids) within two weeks of the first IMP administration.
    11. Unresolved toxicity from prior anti-tumour therapy, defined as toxicities (excluding alopecia) that have not resolved to < grade 2 or baseline as scored using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Exceptions may be allowed for stable toxicities after investigator discussion with the Medical Monitor and sponsor.
    12. Major surgery within 28 days of commencing first dose of study therapy.
    13. Pregnant or breast-feeding females.
    14. Concurrent or planned treatment with strong inhibitors of UDP-Glucuronosyl transferase 1A1 (UGT1A1) (e.g., atazanavir, gemfibrozil, indinavir). A 1-week washout period is necessary for patients already on these treatments.
    15. Any concurrent, clinically significant condition which, in the Investigator's opinion, makes it undesirable for the subject to participate in this study or which would jeopardize compliance with the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome for the study is safety. Safety assessments will include medical review of AEs and the results of vital sign measurements, physical examinations, ECGs and clinical laboratory tests. Toxicity will be graded using the NCI CTCAE v 5.0 scale.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Last patient last visit
    E.5.2Secondary end point(s)
    Pharmacokinetic Endpoints
    Plasma concentrations of free and total SN38-SPL9111 versus time will be analysed using non-compartmental methods and a validated PK analysis program to generate the following PK parameters for each patient:
    Cmax: Maximum observed plasma concentration.
    Tmax: Time to maximum observed plasma concentration.
    AUC: Area under the concentration-time curve.
    t1/2: Apparent terminal half-life.

    Efficacy Endpoints
    RECIST 1.1 criteria will be used to classify tumour responses to SN38-SPL9111 into the following categories: (1) complete response; (2) partial response; (3) stable disease; or (4) progressive disease. Where RECIST is not applicable, relevant radiological or biochemical evaluation criteria based on the cancer type and a modality generally accepted for its assessment will be used following consultation between the investigator and the sponsor’s medical monitor.

    The following efficacy variables will be derived:
    •Objective Response Rate (ORR)
    •Progression Free Survival (PFS) which equals time from enrolment to progression or death whichever comes first
    •Overall Survival (OS) which equals time from enrolment to death
    •Duration of best overall response
    •Duration of stable disease

    If progression or death are not observed then the time will be censored at the last tumour assessment for PFS, and the last observation for survival.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Last patient last visit
    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 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 Yes
    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.8.2.4Number 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 Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    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 Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days1
    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: 74
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 75
    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 state120
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 149
    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 Decision2019-06-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-08-07
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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