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    Summary
    EudraCT Number:2016-003287-39
    Sponsor's Protocol Code Number:PRO-105
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-03-22
    Trial results View 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 number2016-003287-39
    A.3Full title of the trial
    A Phase II Open-Label Study of NUC-1031 in Patients with Platinum-Resistant Ovarian Cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of NUC-1031 for the treatment of platinum-resistant ovarian cancer
    A.4.1Sponsor's protocol code numberPRO-105
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03146663
    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 SponsorNuCana plc
    B.1.3.4CountryUnited Kingdom
    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 supportNuCana plc
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNuCana plc
    B.5.2Functional name of contact pointNuCana Clinical Study Information
    B.5.3 Address:
    B.5.3.1Street Address3 Lochside Way
    B.5.3.2Town/ cityEdinburgh
    B.5.3.3Post codeEH12 9DT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number4401313571111
    B.5.6E-mailinfo@nucana.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 nameAcelarin
    D.3.2Product code NUC-1031
    D.3.4Pharmaceutical form Solution for injection
    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 INNProposed INN to be confirmed in May 2017
    D.3.9.1CAS number 1562406-27-2
    D.3.9.2Current sponsor codeNUC-1031
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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
    Platinum-resistant epithelial cancer of the ovary, fallopian tube or primary peritoneum (here termed ‘ovarian cancer’), who have been treated with 3 or more prior chemotherapy regimens.
    E.1.1.1Medical condition in easily understood language
    Ovarian cancer which progressed despite previous treatment with a platinum-containing chemotherapy.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the anti-tumor activity of NUC-1031 as measured by Objective Response Rate measured by RECIST at the selected dose level (500 mg/m2 or 750 mg/m2). Primary assessment will be done by a blinded independent central reviewer.
    E.2.2Secondary objectives of the trial
    • To assess additional measures of anti-tumor activity, including:
    - Change from baseline in tumor size.
    - Duration of Overall Response (per RECIST).
    - Progression-Free Survival (per RECIST).
    - Time to Disease Progression (per RECIST).
    - Disease Control Rate (CR+PR+SD, per RECIST).
    - Best GCIG Overall Response, combining the change in CA125 from baseline with RECIST assessment (per GCIG criteria).
    - Overall Survival.
    • To further assess the safety profile of NUC-1031 administered over multiple cycles.
    • To explore relationships between NUC-1031 PK, pharmacodynamics and clinical activity.
    • To describe the effects of NUC-1031 on ovarian cancer symptoms.
    Exploratory Objectives:
    • To establish the expression of genomic, transcriptomic and proteomic biomarkers in PBMCs and tissue samples, which may help predict patients who derive additional benefit from NUC-1031.
    • To explore the impact of treatment and disease state on health state utility by EQ-5D-5L.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of signed written informed consent. Patients with easily accessible tumour must also consent to the collection of fresh biopsy tumour tissue to participate in the study. Patients who do not have easily accessible tumour for biopsy should not be put at undue risk for sample collection and these patients remain eligible for the study.
    2. Original diagnosis and/or histological confirmation of high-grade serous, high-grade endometrioid, undifferentiated/unclassifiable epithelial ovarian, fallopian tube or primary peritoneal cancer.
    3. Platinum-free interval since last line of platinum of less than 6 months (182 days).
    4. Received at least 3 prior chemotherapy-containing regimens. Prior treatment with only non-cytotoxic agents (e.g. hormones, antibodies or PARP inhibitors) is permitted, but should not be considered as one of the ‘3 prior chemotherapy-containing regimens’. Adjuvant chemotherapy should be counted as a prior line of chemotherapy.
    5. Age ≥18 years.
    6. ECOG performance status of 0 or 1.
    7. Measurable disease as defined by RECIST.
    8. Adequate bone marrow function as defined by: absolute neutrophil count (ANC) ≥1.5×10^9/l, platelet count ≥100×10^9/l and hemoglobin level ≥10.0 g/dl.
    9. Adequate liver function, as defined by: serum total bilirubin ≤1.5×upper limit of normal (ULN), AST and ALT ≤2.5×ULN (or ≤5×ULN if liver metastases are present).
    10. Adequate renal function assessed as Cr <1.5×ULN or GFR ≥50 ml/min.
    11. Ability to comply with protocol requirements.
    12. Patients are assumed to be infertile as a consequence of treatment for their disease, however, in the event they are not, patients must be postmenopausal (12 months of amenorrhea), agree to be abstinent, or they must agree to use two forms of contraception, one of which must be a barrier method and the other must be a highly effective method. These forms of contraception must be used from the time of signing consent, throughout the treatment period, and for 30 days following the last NUC-1031 dose administration. Oral or injectable contraceptive agents cannot be the sole method of contraception. See protocol Section 10.3.1 for more information. Patients of childbearing potential must have a negative serum pregnancy test within 72 hours prior to the first study drug administration. This criterion does not apply to patients who have had a previous hysterectomy or bilateral oophorectomy.
    E.4Principal exclusion criteria
    1. Disease classified as primary platinum refractory (i.e. progression while receiving initial line of platinum-based therapy or within 4 weeks of the last platinum dose of the initial regimen).
    2. Received fewer than 3 prior chemotherapy-containing regimens.
    3. Prior therapy with single-agent gemcitabine (prior gemcitabine plus carboplatin combination treatment is permitted).
    4. Prior history of hypersensitivity to gemcitabine.
    5. History of allergic reactions attributed to the components of the diluents used with NUC-1031.
    6. Mucinous, low-grade serous, low-grade endometrioid, carcinosarcoma, clear cell or undifferentiated/unclassifiable histology.
    7. Symptomatic CNS or leptomeningeal metastases.
    8. Prior chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy for bone pain), treatment with a VEGF inhibitor, PARP inhibitor or immunotherapy within 21 days of first receipt of study drug (within 6 weeks for nitrosoureas and mitomycin C); hormone therapy within 14 days of first receipt of study drug; or blood transfusion, or use of hematopoietic growth factors within 28 days of first receipt of study drug.
    9. Residual toxicities from chemotherapy or radiotherapy, which have not regressed to Grade ≤1 severity (NCI CTCAE v4), except for neuropathy (Grade 2 allowed) or alopecia.
    10. Patients who have a history of another malignancy diagnosed within the past 5 years, with the exception of adequately treated non-melanoma skin cancer curatively treated carcinoma in situ of the cervix or ductal carcinoma in situ (DCIS) of the breast. Patients with previous invasive cancers are eligible if treatment was completed more than 5 years prior to initiating the current study treatment, and the patient has had no evidence of recurrence since then.
    11. Presence of an uncontrolled concomitant illness or active infection requiring IV antibiotics.
    12. Presence of any serious illnesses, medical conditions, or other medical history, including laboratory results, which, in the Investigator’s opinion, would be likely to interfere with the patient's participation in the study, or with the interpretation of the results.
    13. Known HIV positive or known active hepatitis B or C.
    14. Any condition (e.g. known or suspected poor compliance, psychological instability, geographical location, etc.) that, in the judgment of the Investigator, may affect the patient’s ability to sign the informed consent and undergo study procedures.
    15. Currently pregnant, lactating or breastfeeding.
    16. QTc interval >450 milliseconds.
    17. Concomitant use of drugs known to prolong QT/QTc interval.
    18. History of radiologically confirmed bowel obstruction (including sub-occlusive disease) relating to ovarian cancer within 6 months prior to the first receipt of study drug.
    19. Patients who have received a live vaccination within 4 weeks of first planned NUC-1031 dose administration.
    E.5 End points
    E.5.1Primary end point(s)
    Objective Response Rate (per RECIST) at the selected dose level (500 mg/m2 or 750 mg/m2), assessed by a blinded independent central reviewer.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Tumour measurements and disease response assessments are to be performed every 8 weeks (±7 days) from C1D1. If the patient stops study treatment for reasons other than radiologically confirmed Progressive Disease (PD), tumour measurements and disease response assessments should continue every 8 weeks (±7 days) from C1D1 thereafter until PD is radiologically confirmed.
    E.5.2Secondary end point(s)
    Efficacy
    • Change from baseline in tumour size.
    • Duration of Overall Response (per RECIST).
    • Progression-Free Survival (per RECIST).
    • Time to Disease Progression (per RECIST).
    • Disease Control Rate (CR+PR+SD, per RECIST).
    • Best GCIG Overall Response, combining the change in CA125 from baseline with RECIST assessment (per GCIG criteria).
    • Overall Survival.
    • Assessment of ovarian cancer symptoms using the FOSI-18 questionnaire.
    Safety
    • Treatment-emergent adverse events (per NCI CTCAE v4).
    • Clinically-significant laboratory changes (per NCI CTCAE v4).
    • Changes in physical exam, vital signs and serial ECGs.
    Pharmacokinetics
    The PK of single and multiple-dose NUC-1031 will be assessed, including:
    • Maximum concentration (Cmax).
    • Area under the curve (AUC).
    • Half-life (T1/2).
    • Volume of distribution (Vd).
    • Clearance (CL).
    PK of the following analytes will be measured:
    • In plasma/urine: NUC-1031, dFdC and dFdU.
    • In PBMCs: NUC-1031, dFdC, dFdCMP, dFdCDP, dFdCTP and dFdU.
    Exploratory Endpoints
    • Assessment of candidate genomic, transcriptomic and proteomic biomarkers of resistance/sensitivity to NUC-1031 in PBMCs and tissue samples. Examples of candidate markers include cytidine deaminase (CDA), deoxycytidine kinase (dCK), human equilibrative nucleoside transporter 1 (hENT1), ribonucleotide reductase M1 (RRM1) and RRM2.
    • Assessment of impact of treatment and disease state on health state utility by EQ-5D-5L.
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of study.
    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 Yes
    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 No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned9
    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
    United Kingdom
    United States
    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
    The study will be considered complete when 44 response evaluable patients have been treated at the selected dose and 24 months have elapsed since the final patient was enrolled.
    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 months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months3
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 14
    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 state22
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 22
    F.4.2.2In the whole clinical trial 64
    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)
    Following participating in the PRO-105 clinical study, patients will be referred back to their oncologist and GP, according to local practice.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation NIHR Clinical Research Network (CRN) Portfolio
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-05-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-05
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2019-12-31
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