BI-1910 as a Single Agent and in Combination With Pembrolizumab for the Treatment of Advanced Solid Tumors

The goal of this first in human clinical trial is to test BI-1910 administered as single agent and in combination with pembrolizumab in subjects with advanced/metastatic solid tumors whose disease has progressed after standard therapy.

The main questions it aims to answer are:

* how safe and tolerable is BI-1910
* what is maximum tolerated or administrated dose
* to determine recommended dose for further clinical trials

Participants will receive infusions of BI-1910 alone or combination with pembrolizumab every 3 weeks.

This is a Phase 1/2a, open-label, dose-escalation, multicenter, FIH, consecutive-cohort, clinical trial of BI-1910, as a single agent and in combination with pembrolizumab, in subjects with advanced/metastatic solid tumors whose disease has progressed after standard therapy.

The trial comprises 2 phases: a Phase 1 with Parts A and B, and a Phase 2a with Parts A and B.

Phase 1 Part A consists of a dose escalation of BI-1910 as a single agent to evaluate safety and tolerability and to determine the RP2D as a single agent (sRP2D) in subjects with advanced/metastatic solid tumors whose disease has progressed after standard therapy.

Phase 1 Part B consists of a dose escalation of BI-1910 in combination with pembrolizumab to evaluate the safety and tolerability of the combination treatment and to allow selection of the RP2D for BI-1910 in combination with pembrolizumab (cRP2D) in subjects with advanced/metastatic solid tumors whose disease has progressed after standard therapy.

Phase 2a will assess BI-1910 administered as a single agent (Part A) and in combination with pembrolizumab (Part B) at the respective hypothesized RP2D(s) determined in Phase 1. Phase 2a expansion will be conducted in indication specific cohorts of subjects. The aim of the Phase 2a is to urther assess the safety and tolerability of BI-1910 as a single agent (Part A) and in combination with pembrolizumab (Part B), characterize its PK and pharmacodynamics, and assess preliminary antitumor activity by ORR, DoR, and progression-free survival (PFS), as measured by RECIST v1.1 and iRECIST.

Eligibility Criteria:
Inclusion Criteria:

1. Is willing and able to provide signed informed consent for the trial.
2. Is ≥18 years of age on the day of signing the informed consent form.
3. Has a histologically-confirmed advanced/metastatic solid tumor.
4. Has received standard of care and progressed or is intolerant of, or is not eligible to receive standard of care antineoplastic therapy.
5. Has at least 1 measurable disease lesion as defined by RECIST v1.1.
6. Must be willing to provide tumor biopsies as specified in the schedule of assessments
7. Has a life expectancy of ≥12 weeks.
8. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
9. Has adequate organ function as confirmed by laboratory values.

Exclusion Criteria:

1. Needs doses of prednisolone \>10 mg daily (or equipotent doses of other corticosteroids) while on the trial other than as premedication.
2. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
3. Has known or suspected hypersensitivity to BI-1910 or pembrolizumab.
4. Has cardiac or renal amyloid light-chain amyloidosis.
5. Has received the following:

   1. Chemotherapy or small molecule anti-cancer therapy products within 4 weeks, or 5 half-lives of the respective drug whichever is longer, of first dose of BI-1910.
   2. Radiotherapy within 2 weeks of first dose of BI-1910. 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.
   3. Immunotherapy within 4 weeks prior to the first dose of BI-1910.
6. Has not recovered from AEs to at least Grade 1 by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v5.0 or higher).
7. Has had Grade ≥3 autoimmune manifestations of previous immune checkpoint inhibitor treatments (e.g., 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.
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 are considered eligible.
11. Is a male subject with partner(s) of childbearing potential (unless he agrees to use a barrier method of contraception \[condom plus spermicidal gel\] with the female partner(s) who are using one highly effective method of contraception during the trial and for 12 months after completing treatment).
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 other than the ones considered adequate for treatment of HBV.
14. Has presence of chronic graft versus host disease.
15. Has had an allogenic tissue/solid organ transplant.
16. Is positive for Human Immunodeficiency Virus (HIV).
17. Has history of chronic HBV or HCV infections.
18. Has a history of active tuberculosis (Bacillus tuberculosis).
19. Has received a live vaccine within 30 days before the first dose of study treatment.
20. Has uncontrolled or significant cardiovascular disease.
21. Has a known psychiatric or substance abuse disorder that would interfere with the subject's ability to cooperate with the requirements of the trial.
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
23. Is participating or planning to participate in another interventional clinical trial or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to first dose of study treatment.
24. Has a known additional malignancy of another type, with the exception of adequately treated cone-biopsied carcinoma in situ and basal or squamous cell carcinoma of the skin. Male subjects with asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for \>1 year prior to start of study treatment are eligible.
25. Has a confirmed diagnosis of primary immunodeficiency or an acquired condition that leads to an immunodeficiency disorder or taking any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment.