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    Summary
    EudraCT Number:2020-000820-20
    Sponsor's Protocol Code Number:NVG111-101
    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:2020-07-31
    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 ConcernedUK - MHRA
    A.2EudraCT number2020-000820-20
    A.3Full title of the trial
    AN OPEN-LABEL, PHASE 1/2, FIRST IN HUMAN STUDY INVESTIGATING THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND EFFICACY OF NVG-111 IN SUBJECTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKAEMIA AND MANTLE CELL LYMPHOMA.

    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The first study in humans testing a new drug called NVG-111 for blood and lymph gland cancer
    A.4.1Sponsor's protocol code numberNVG111-101
    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 SponsorNovalGen Ltd
    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 supportNovalGen Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovalGen
    B.5.2Functional name of contact pointDr Peter Phillips
    B.5.3 Address:
    B.5.3.1Street AddressArgyle House, Joel St., Level 3 Northside,
    B.5.3.2Town/ cityNorthwood Hills,
    B.5.3.3Post codeHA6 1NW,
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+447939156066
    B.5.5Fax number+442076812180
    B.5.6E-mailp.phillips@novalgen.co.uk
    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 nameNVG-111
    D.3.2Product code NVG-111
    D.3.4Pharmaceutical form 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 INNNone
    D.3.9.2Current sponsor codeNVG-111
    D.3.9.3Other descriptive nameNVG-111
    D.3.10 Strength
    D.3.10.1Concentration unit µg/ml microgram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number140
    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) Yes
    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
    RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKAEMIA AND MANTLE CELL LYMPHOMA
    E.1.1.1Medical condition in easily understood language
    blood and lymph gland cancer
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10008976
    E.1.2Term Chronic lymphocytic leukemia
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10026801
    E.1.2Term Mantle cell lymphoma refractory
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objectives (Part A): To establish the safety and tolerability, maximum tolerated dose and the recommended phase 2 dose in subjects with CLL/SLL and mantle cell lymphoma

    Primary objectives (Part B): To establish the efficacy of NVG-111 in subjects with CLL/SLL and mantle cell lymphoma
    E.2.2Secondary objectives of the trial
    Secondary objectives (Part A): To establish the pharmacokinetic (PK) profile of NVG-111 in subjects with CLL/SLL and mantle cell lymphoma

    Secondary objectives (Part B):
    • To establish the effect of NVG-111 on other parameters of efficacy in subjects with CLL/SLL and mantle cell lymphoma
    • To establish the safety and tolerability of NVG-111 in subjects with CLL/SLL and mantle cell lymphoma
    • To establish the PK profile of NVG-111 in subjects with CLL/SLL and mantle cell lymphoma
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Principal inclusion criteria
    1. Provide signed informed consent to participate in the study.
    2. Adult males or females ≥18 years of age.
    3. Subject has CLL/SLL or MCL with the following characteristics:
    CLL/SLL
    (i) Relapsed or refractory CLL or SLL according to iwCLL criteria [Hallek et al, 2019]
    (ii) Subject has achieved a best tumour response of PR, present at Screening, after at least 12 months ongoing treatment with a Bruton’s Tyrosine Kinase inhibitor (BTKi) or 6 months ongoing treatment with venetoclax (with or without anti-CD20 Mab), and has received at least 1 prior line of systemic therapy.
    MCL
    (i) Documented pathological diagnosis of MCL (including chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1) according to WHO criteria [Swerdlow et al, 2016].
    (ii) Subject has relapsed or refractory MCL and has achieved a best tumour response of PR, present at Screening, with at least 6 months of ongoing treatment with a BTKi, and has received at least 1 prior line of systemic therapy.
    (iii) Subject has bone marrow involvement at Screening bone marrow biopsy and/or a positive PET scan at Screening, defined for this study as a score of 4 or 5 on the 5 point scale (Cheson et al, 2014)
    4. MCL and SLL subjects must have archived tumor biopsy tissue available; a formalin fixed paraffin embedded sample at any time point since diagnosis is acceptable. If an archived biopsy tissue is not available, a new biopsy (core or excision) must be taken of at least one tumour-involved lymph node, unless FACs of blood or bone marrow aspirate/biopsy at Screening show detectable ROR1 expression.
    5. All acute toxic effects of prior antitumor therapy resolved to Grade ≤1 (other than alopecia or vitiligo).
    6. Life expectancy >6 months.
    7. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2.
    8. Body weight ≥ 45 kg.
    9. Adequate organ function defined by the following laboratory safety parameters:
    - bilirubin ≤1.5 x ULN, unless elevated bilirubin is due to Gilbert’s syndrome (and fractionated direct bilirubin is <35%), and
    - aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x ULN in subjects without hepatic CLL or MCL site of disease, or AST and ALT ≤5 x ULN in subjects with hepatic CLL or MCL site of disease, and
    - activated partial thromboplastin time (APTT) and prothrombin time (PT) ≤1.5 x ULN, and
    - neutrophils ≥0.5 x 109/L (independent of growth factor support) and platelets ≥ 30 x 109/L (independent of transfusion within 14 days of screening), and
    - serum creatinine ≤2 x ULN, and
    - estimated creatinine clearance (eCCr) ≥30 mL/min using 24-hour creatinine clearance or modified Cockcroft-Gault equation (using Ideal Body Mass [IBM] instead of Mass)
    10. Ability to adhere to the study visit schedule and other protocol requirements.
    11. Must be willing and able to have a study-specific peripherally inserted central catheter (PICC line) or Hickman line inserted, unless pre-existing central venous access such as a port, PICC or Hickman line is already in situ.
    12. If female, must be either:
    (i) of non-reproductive potential (i.e. post-menopausal by history with no menses for ≥1 year; or have a history of hysterectomy, bilateral tubal ligation or bilateral oophorectomy).
    (ii) OR, if of reproductive potential, have a negative pregnancy test result at screening AND be willing to use a highly effective method of birth control (<1% failure rate per year) throughout the study up to 28 days after last dose (see protocol Section 4.3.1.1).
    13. If male, must be willing to use a condom during penile-vaginal intercourse with female partners of child-bearing potential, throughout the study and up to 28 days after the last dose
    E.4Principal exclusion criteria
    Principal exclusion criteria
    1. Diagnosis of Richter's transformation (note: subjects who have previously responded to therapy for Richter's transformation may be eligible at the investigators discretion).
    2. History or presence of CNS or leptomeningeal lymphoma involvement.
    3. Subject has either of the following:
    - any lymph node/site of disease >10 cm in diameter on Screening CT scan
    and/or
    - absolute lymphocyte count >50 x 109/L at Screening
    4. Allogeneic or autologous hematopoietic stem cell transplant or donor lymphocyte infusion within 6 months prior to Screening.
    5. Uncontrolled autoimmune haemolytic anaemia or idiopathic thrombocytopenic purpura within 8 weeks of Screening.
    6. History or presence of clinically significant neurological disease such as epilepsy, generalised seizure disorder, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome or psychosis.
    7. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, uncontrolled hypertension or cardiac arrhythmia, unstable angina, or acute coronary syndrome within 6 months prior to Screening.
    8. Known clinically significant lung disease potentially associated with high risk of complications from COVID-19, including but not limited to:
    - severe asthma according to GINA guidelines i.e. requiring at least high dose inhaled corticosteroids (>500µg per day of fluticasone propionate or equivalent)/long acting beta-2 agonists for disease control.
    - severe COPD according to GOLD guidelines (FEV1 <50% predicted)
    - severe lung fibrosis (e.g. including FVC <50% predicted)
    - severe bronchiectasis (e.g. Bronchiectasis Severity Index of ≥9, or FEV1 <50% predicted or >2 infective exacerbations in prior year)
    9. Active infection as demonstrated at Screening with COVID-19, HIV, hepatitis B or hepatitis C. This includes:
    - Positive for active COVID-19 infection with an approved diagnostic test
    - Positive HIV test result
    - Positive for hepatitis B surface antigen (HbsAg)
    - Negative HbsAg and positive for hepatitis B core antibody (HbcAb)
    - Positive Hepatitis C virus antibody (HCVAb)
    10. Any other chronic or current active infectious disease requiring systemic antibiotics, antifungal or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis or tuberculosis.
    11. Live vaccines administered within 28 days of Screening or planned during the study up to Safety Follow-up.
    12. Major surgery within 28 days prior to Screening or planned during the study up to Safety Follow-up.
    13. History of hypersensitivity to therapeutic antibodies or any of the IMP components (e.g. excipients/buffer components such as histidine, polysorbate-80) to be administered in the study.
    14. Subject is unable to receive at least one of the following prophylactic medications for tumour lysis syndrome: allopurinol, febuxostat or rasburicase e.g. due to contraindications in the respective product labels. Contraindications for each agent include known hypersensitivity. In addition, rasburicase is contraindicated in subjects with known glucose 6-phosphate dehydrogenase (G6PD) deficiency or other cellular metabolic disorder known to cause haemolytic anaemia.
    15. Subject has received any of the following:
    - nitrosoureas, chemotherapy, radiotherapy or corticosteroids (for antineoplastic intent) within 28 days prior to Screening. The use of corticosteroids for non-neoplastic indications at doses of up to 10 mg/day prednisolone or equivalent within 14 days of Screening is permitted.
    - specific concomitant therapy for CLL/SLL or MCL other than stated in inclusion criterion 3, within 28 days of Screening e.g. phosphoinositide 3 (PI3) kinase inhibitors, lenalidomide, bortezomib, temsirolimus,
    - therapeutic antibodies (for any indication) within 12 weeks of Screening.
    - any non-marketed drug substance or experimental therapy within 5- terminal half-lives or 28 days of Screening (whichever is longer), or the subject is currently participating in any other interventional clinical study.
    16. History of other malignancies, except the following:
    - non-melanoma skin cancer or carcinoma in situ (e.g. skin, cervix, bladder, breast); or
    - indolent prostate cancer defined as clinical stage T1 or T2a, Gleeson score ≤8, and prostate specific antigen (PSA) 3 years prior to Screening. requiring no ongoing treatment or only luteinizing hormone releasing hormone (LHRH) agonist; or
    - any other cancer that has been in remission for > 3 years prior to Screening.
    17. Pregnant or currently breastfeeding.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint
    Part A
    • Frequency of treatment emergent adverse events (TEAEs), including SAEs and dose limiting toxicities (DLTs)
    • Safety laboratory tests (e.g. haematology, chemistry, urinalysis), vital signs, 12-lead ECGs, ECOG performance status

    Part B
    • Complete response rate (CRR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary endpoint
    Part A
    • Frequency of treatment emergent adverse events (TEAEs), including SAEs and dose limiting toxicities (DLTs)
    Time point(s) of evaluation: 15 weeks

    • Safety laboratory tests (e.g. haematology, chemistry, urinalysis), vital signs, 12-lead ECGs, ECOG performance status
    Time point(s) of evaluation: 15 weeks

    Part B
    • Complete response rate (CRR)
    Time point(s) of evaluation: 11 weeks
    E.5.2Secondary end point(s)
    Secondary endpoints
    Part A
    PK:
    AUC, AUC0-t, CL, Cmax, tmax, t1/2, and Vz

    Part B

    Efficacy:
    • Progression Free Survival (PFS) as determined by iwCLL criteria for CLL/SLL and by Lugano criteria for MCL
    • Duration of Response (DoR) as determined by iwCLL criteria for CLL/SLL and by Lugano criteria for MCL
    • Overall survival (OS)
    • Health related quality of life (HRQoL)
    - EORTC QLQ-C30 and EQ-5D-3L (in CLL/SLL and MCL)
    - EORTC QLQ-CLL17 (in CLL/SLL)

    Safety:
    • Frequency of TEAEs, including SAEs
    • Safety laboratory tests (e.g. haematology, chemistry, urinalysis), vital signs, 12-lead ECGs, ECOG performance status

    PK:
    • AUC, AUC0-t, CL, Cmax, tmax, t1/2, and Vz
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints
    Part A
    PK:
    AUC, AUC0-t, CL, Cmax, tmax, t1/2, and Vz
    Time point(s) of evaluation: 15 weeks

    Part B
    Efficacy:
    • PFS
    Time point(s) of evaluation: 28 months
    • DoR
    Time point(s) of evaluation: 28 months
    • Overall survival (OS)
    Time point(s) of evaluation: 28 months
    • HRQoL
    - EORTC QLQ-C30 and EQ-5D-3L (in CLL/SLL and MCL)
    - EORTC QLQ-CLL17 (in CLL/SLL)
    Time point(s) of evaluation: 28 months

    Safety:
    • Frequency of TEAEs, including SAEs
    • Safety laboratory tests (e.g. haematology, chemistry, urinalysis), vital signs, 12-lead ECGs, ECOG performance status
    Time point(s) of evaluation: 15 weeks

    PK:
    • AUC, AUC0-t, CL, Cmax, tmax, t1/2, and Vz
    Time point(s) of evaluation: 15 weeks
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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 Yes
    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 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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Not Applicable
    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 concerned15
    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 No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS
    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 months3
    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 months3
    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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 state90
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 90
    F.4.2.2In the whole clinical trial 90
    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 Decision2020-09-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-10-30
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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