E.1 Medical condition or disease under investigation |
E.1.1 | Medical 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.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065147 |
E.1.2 | Term | Malignant solid tumor |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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.2.2 | Secondary 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.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.4 | Principal 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.5.1 | Primary 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.5.1.1 | Timepoint(s) of evaluation of this end point |
1 year after start of treatment |
|
E.5.2 | Secondary 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.5.2.1 | Timepoint(s) of evaluation of this end point |
1 year after start of treatment |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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.8.7 | Trial 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.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 17 |
E.8.9.2 | In all countries concerned by the trial years | 6 |