A Study of BI-1206 in Combination with Pembrolizumab in Subjects with Advanced Solid Tumors (KEYNOTE-A04)

Phase 1/2a Clinical Trial of BI-1206, a Monoclonal Antibody to CD32b (FcγRIIB), in Combination with Pembrolizumab in Subjects with Advanced Solid Tumors Previously Treated with Anti-PD-1 or Anti-PD-L1 Antibodies

This is a Phase 1/2a, multicenter, dose-finding, consecutive-cohort, open-label trial of BI-1206 in combination with pembrolizumab in subjects with advanced solid tumors who have previously received treatment with a PD-1/PD-L1 immune checkpoint inhibitor.

The trial will consist of 2 main parts:

Phase 1 with 2 different sets of cohorts assessing IV or SC dosing, with dose escalation of BI-1206 and selection of the RP2D of IV dosing (ivRP2D) and the RP2D of SC dosing (scRP2D).

Phase 2a with 3 expansion cohorts at the scRP2D for all subjects treated with pembrolizumab and BI-1206. Each of the 3 expansion cohorts will comprise a specific subset of subjects with advanced solid tumors (e.g., non-small-cell lung cancer, metastatic melanoma, and other tumor types known to be responsive to PD-1/PD-L1 immune checkpoint inhibition).

Subjects will initially receive 3 cycles of therapy with pembrolizumab in combination with BI-1206, either IV or SC.

Subjects who show clinical benefit (CR, PR, or SD) at the Week 9 Visit may continue on combination therapy (pembrolizumab/BI-1206). Starting at Week 10, these subjects will receive additional cycles of pembrolizumab and BI-1206 every 3 weeks for up to 32 additional cycles or up to 2 years from their first dose of BI-1206 therapy or until progression.

Eligibility Criteria:
Inclusion Criteria:

* Is willing and able to provide written informed consent for the trial.
* Is ≥18 years of age on day of signing informed consent.
* Has a histologically confirmed advanced solid tumor. Subjects must have received at least 2 doses of an approved anti- PD-1/L1 mAb, and have documented progression on or within 12 weeks from the last dose of anti-PD-1/L1 mAb.
* Is intolerant of, refuses, or is not eligible for standard antineoplastic therapy.
* Has at least 1 measurable disease lesion as defined by Response Evaluation Criteria in Solid Tumors.
* Is able to safely undergo a baseline tumor tissue biopsy prior to first dose of BI-1206.
* Has a life expectancy of ≥12 weeks.
* Has an ECOG performance status of 0-1.
* Has adequate organ function as confirmed by laboratory values listed in the main body of the protocol Expansion Cohort

Specific Inclusion Criteria:

In addition to the general inclusion criteria above, subjects must also meet the criteria for the specific cohort.

Cohort 1 (Non-small cell lung cancer):

* For subjects whose tumor has PD-L1 ≥ 50%: Required prior therapies will include anti-PD-1 therapy as monotherapy. Prior standard of care chemotherapy will be allowed but not required.
* For tumors with unknown PD-L1 or PD-L1 \< 50% , required prior therapies will include anti-PD 1/PD-L1 therapy and SOC chemotherapy either combined with anti PD-1/PD-L1 therapy or given separately.
* For subjects with known anaplastic lymphoma kinase, ROS1 or epidermal growth factor receptor (EGFR) sensitizing molecular rearrangements or with BRAF mutations, one line of targeted therapy will be required in addition to anti-PD1/ PD-L1 therapy.

Cohort 2 (Metastatic Melanoma):

* Required prior therapies will include anti-PD-1 therapy either as monotherapy or as part of a combination regimen.
* For subjects with a known BRAF V600-activating mutation combination targeted therapy will be required in addition to anti-PD-1/PD-L1 therapy.

Cohort 3 (Other Tumor Types):

* All subjects will require prior anti-PD-1/PD-L1 therapy.

Exclusion Criteria:

* Needs doses of prednisolone \>10 mg daily (or equipotent doses of other corticosteroids).
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
* Has known or suspected hypersensitivity to pembrolizumab or BI-1206 or any of their excipients.
* Has cardiac or renal amyloid light-chain (AL) amyloidosis.
* Has received the following:

  * Chemotherapy or small molecule products within 4 weeks of first dose of BI 1206.
  * Radiotherapy within 2 weeks of first dose of BI-1206. 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.
  * Immunotherapy within 4 weeks prior to the first dose of BI-1206.
* Has not recovered from AEs to at least Grade 1 by Common Terminology Criteria for Adverse Events v5.0 due to prior anti-cancer therapies.
* Has had Grade ≥3 autoimmune manifestations of previous immune checkpoint inhibitor treatments .
* Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
* Has an active, known or suspected autoimmune disease.
* Is a female subject and has the ability to become pregnant (or already pregnant or lactating/ breastfeeding).
* Is a male subject with partner(s) of child-bearing potential.
* Has had major surgery from which the subject has not yet recovered.
* Is at high medical risk because of non-malignant systemic disease including severe active infections on treatment with antibiotics, antifungals or antivirals.
* Has presence of chronic graft versus host disease.
* Has had an allogenic tissue/solid organ transplant.
* Has known human immunodeficiency virus (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.
* Has a history of active tuberculosis (bacillus tuberculosis).
* Has received a live vaccine within 30 days before the first dose of study treatment.
* Has uncontrolled or significant cardiovascular disease.
* Has a known psychiatric or substance abuse disorder that would interfere with the subject's ability to cooperate with the requirements of the study.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
* 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 drug. Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. Participation in an observational trial is acceptable.
* Has a known additional malignancy of another type.
* Has a diagnosis of primary or acquired immunodeficiency disorder or taking any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.