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    Summary
    EudraCT Number:2020-002090-10
    Sponsor's Protocol Code Number:19-BI-1808-01
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2020-08-19
    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 number2020-002090-10
    A.3Full title of the trial
    Phase 1/2a Open-Label, Dose-Escalation, Multicenter, First-in-Human, Consecutive-Cohort, Clinical Trial of BI-1808, a Monoclonal Antibody to Tumor Necrosis Factor Receptor 2 (TNFR2), as a Single Agent and in Combination with Pembrolizumab in Subjects with Advanced Malignancies
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 1/2a Open-Label, Dose-Escalation, Multicenter, First-in-Human Study of BI-1808, a Monoclonal Antibody to Tumor Necrosis Factor Receptor 2, as a Single Agent and with Pembrolizumab in Treatment of Advanced Malignancies
    A.4.1Sponsor's protocol code number19-BI-1808-01
    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 SponsorBioInvent International AB
    B.1.3.4CountrySweden
    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 supportBioInvent International AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBioInvent International AB
    B.5.2Functional name of contact pointSusanne Gertsson
    B.5.3 Address:
    B.5.3.1Street AddressIdeongatan 1
    B.5.3.2Town/ cityLund
    B.5.3.3Post codeSE-223 70
    B.5.3.4CountrySweden
    B.5.4Telephone number+46462868550
    B.5.6E-mailSusanne.Gertsson@bioinvent.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 nameBI-1808
    D.3.2Product code BI-1808
    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.3.9.2Current sponsor codeBI-1808
    D.3.9.3Other descriptive nameBI-1808
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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 Yes
    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 KEYTRUDA®
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 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 INNPembrolizumab
    D.3.9.1CAS number 1374853-91-4
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 Yes
    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
    Phase 1, Parts A and Part B of the trial will recruit subjects with all types of malignancies whose tumors have progressed after standard anticancer treatment.
    Phase 2a, Parts A and Part B of the trial will recruit patients with all tumor types, NSCLC, OC, TCL and unresectable or metastatic melanoma.
    E.1.1.1Medical condition in easily understood language
    Advanced solid tumors
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10065147
    E.1.2Term Malignant solid tumor
    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 assess the safety and tolerability profile of increasing doses of BI-1808, as a single agent (Phase 1, Part A), and in combination with pembrolizumab (BI-1808 with pembrolizumab [Phase 1, Part B]) in subjects with advanced malignancies.

    To identify dose-limiting toxicities (DLTs), determine the maximum tolerated dose (MTD) and select a recommended Phase 2 dose (RP2D) of BI-1808, given via intravenous (IV) infusion, as a single agent (Phase 1, Part A), and in combination with pembrolizumab (Phase 1, Part B) in subjects with advanced malignancies.
    E.2.2Secondary objectives of the trial
    To assess the pharmacokinetic (PK) profile of BI-1808 when administered every 3 weeks as a single agent (Phase 1, Part A), and in combination with pembrolizumab (Phase 1, Part B) in subjects with advanced malignancies.

    To assess the immunogenicity of BI-1808 in subjects with advanced malignancies (Phase 1, Parts A and B, and Phase 2a, Parts A and B).

    To evaluate the receptor occupancy (RO) of BI-1808 as a single agent and in combination with pembrolizumab on T-cells expressing TNFR2 in subjects with advanced malignancies (Phase 1, Parts A and B, and Phase 2a, Parts A and B).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Is willing and able to provide written informed consent for the trial.
    2. Is ≥18 years of age on the day of signing informed consent.
    3. Has a histologically confirmed advanced malignancy. Subjects with TCL [MF or SS] who satisfy the Phase 2a, Cohort 3-specific eligibility criteria may be enrolled into the Phase 1 part of the study.
    4.Has received standard of care or is intolerant of, refuses, or is not eligible for standard antineoplastic therapy.
    5. Has at least 1 measurable disease lesion as defined by RECIST v1.1.
    6.Is willing to safely undergo tissue biopsies of involved tissue, if required. However, if the Investigator considers that a baseline tumor tissue biopsy is not safe and technically feasible, then the subject will not be required to undergo the biopsy. The Screening biopsy, if required, must be performed prior to the first dose of BI-1808 (on non previously irradiated lesions only) and аt least 4 weeks following the last dose of tumor directed therapy. The biopsy at Screening can be replaced with a formalin-fixed archival tumor tissue sample collected from a previous standard of care biopsy, provided that the biopsy was performed after the subject's last tumor-directed therapy and prior to study entry. Subjects who do not have an archival tissue sample at
    Screening may still be enrolled in the study.
    7. Has a life expectancy of ≥12 weeks.
    8. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1.
    9. Has adequate organ function as confirmed by laboratory values.
    E.4Principal exclusion criteria
    1. Needs doses of prednisolone >10 mg daily (or equipotent doses of other corticosteroids) while on the trial other than as premedication (except for subjects with TCL). During the Screening period, doses of up to 20 mg/day may be given but the dose must be reduced to 10 mg/day within 7 days prior to the first dose of study drug (except for subjects with TCL). Steroids are allowed as premedication in subjects with allergies to contrast scans.
    2. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated CNS metastases may participate provided they are radiologically stable (without evidence of progression for at least 4 weeks by repeat imaging [note that the repeat imaging should be performed during study Screening]); have no newly onset or worsening symptomatology of brain metastases; and have not required steroids for at least 14 days before study treatment.
    3. Has known or suspected hypersensitivity to BI-1808 (all subjects) or pembrolizumab (subjects in Phase 1, Part B and Phase 2a, Part B) or any of their excipients. Previous isolated infusion-related reactions are not to be considered a reason for exclusion unless Grade 4 in intensity.
    4. Has cardiac or renal amyloid light-chain amyloidosis.
    5. Has received the following:
    a. Chemotherapy or small molecule products within 4 weeks of first dose of BI 1808.
    b. Radiotherapy within 2 weeks of first dose of BI-1808. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) for non-CNS disease. Subjects who have previously had radiation pneumonitis are not allowed.
    c. Immunotherapy within 4 weeks prior to the first dose of BI-1808.
    6. Has not recovered from AEs to at least Grade 1 by NCI CTCAE (version 5.0) due to prior anticancer therapies. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator should not exclude the subject. Subjects with ≤Grade 2 neuropathy may be eligible, after discussion with the Medical Monitor.
    7. Has had Grade ≥3 autoimmune manifestations of previous immune checkpoint inhibitor treatments (eg, anti-PD-1, anti-PD-L1, or anti-CTLA-4).
    8. Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
    9. Has an active, known, or suspected autoimmune disease. However, subjects with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, mild psoriasis, or alopecia not requiring systemic treatment), or conditions not expected to recur in the absence of an external trigger will be permitted to participate.
    10. Is a female subject and has the ability to become pregnant (or already pregnant or lactating/breastfeeding). However, those female subjects who have a negative serum or urine pregnancy test up to 72 hours prior to their first dose of study treatment and agree to use a highly effective method of birth control for 4 weeks before entering the trial, during the trial, and for 12 months after their last dose of study treatment (BI-1808 or pembrolizumab), are considered eligible.
    11. Is a male subject with partner(s) of childbearing potential (unless he agrees to use a barrier method of contraception [condom plus spermicide gel] with the female partner(s) who are using one highly effecting method of contraception during the trial and for 12 months after completing treatment). Men with pregnant or lactating partners should be advised to use barrier method contraception (condom plus spermicidal gel) to prevent exposure to the fetus or neonate.
    12. Has had major surgery from which the subject has not yet recovered.
    13. Is at high medical risk because of nonmalignant systemic disease including severe active infections on treatment with antibiotics, antifungals, or antivirals.
    14. Has presence of chronic graft versus host disease.
    15. Has had an allogenic tissue/solid organ transplant.
    16. Has known human immunodeficiency (HIV) and/or history of hepatitis B or C infections, or has a positive test for HIV antibody, hepatitis B antigen/hepatitis B virus DNA or hepatitis C antibody or RNA.
    17. Has a history of active tuberculosis (Bacillus tuberculosis).
    18. Has received a live vaccine within 30 days before the first dose of study treatment. COVID-19 vaccines based on viral RNA or protein fragments are allowed. COVID 19 vaccines based on live replicating viral or bacterial vectors (eg, adenoviruses, adeno-associated viruses, vesicular stomatitis virus, vaccinia viruses, or measles virus) are not allowed.
    19. Has uncontrolled or significant cardiovascular disease as per protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Adverse events (AEs) and serious adverse events (SAEs) (graded according to National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 5.0), clinically significant laboratory parameters and physical findings and their causality to BI-1808, or BI-1808 in combination with pembrolizumab.

    Occurrence of dose-limiting toxicities (DLTs) of BI-1808 and in combination with pembrolizumab.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1 year after start of treatment
    E.5.2Secondary end point(s)
    Standard PK parameters for BI-1808 (including, but not limited to area under the serum concentration-time curve [AUC], maximum concentration [Cmax], and terminal half life [t½]).

    Antidrug antibodies (ADA) response to BI-1808.

    TNFR2 receptor occupancy on CD14+ and/or CD16+ cells.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1 year after start 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 No
    E.6.4Safety Yes
    E.6.5Efficacy No
    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) 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.8.3 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 EEA9
    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
    Denmark
    Hungary
    Sweden
    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
    Last subject completed the safety off treatment follow up visit
    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 months11
    E.8.9.1In the Member State concerned days17
    E.8.9.2In all countries concerned by the trial years6
    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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 146
    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 state47
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 236
    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 Decision2020-09-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-09-09
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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