An open label, first-in-human study of BAY 2927088 in participants with advanced non-small cell lung cancer (NSCLC) harboring an EGFR and/or HER2 mutation

Researchers are looking for a better way to treat people who have advanced non-small cell
lung cancer (NSCLC), a group of lung cancers that have spread to nearby tissues or to other
parts of the body.

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2)
are proteins that help cells to grow and divide. A damage (also called mutation) to the
building plans (genes) for these proteins in cancer cells leads to a production of abnormal
EGFR and/or HER2. These abnormal proteins drive the growth and the spread of the cancer.
Several EGFR and/or HER2 mutations exist in the cancer cells. The study treatment,
BAY2927088, is expected to block the mutated EGFR and HER2 proteins which may stop the spread
of NSCLC.

The main purpose of this study is to learn:

Escalation, Backfill, and Expansion Part:

- How safe is BAY2927088 for the participants?

- What is the highest dose of BAY2927088 that can be tolerated (maximum tolerated dose) by
or given to (maximum administered dose) the participants?

- How does BAY2927088 move into, through, and out of the bodies of the participants?

For this, the researchers will measure the followings:

- The number of participants with medical problems, also called adverse events and serious
adverse events, and their severity

- The number of participants who discontinue study treatment due to an adverse event.

- The highest dose of BAY2927088 that the participants can take without having adverse
events (maximum tolerated dose (MTD)) or the maximum dose that is tested and found to be
safe for the participants in case MTD cannot be found out (maximum administered dose
(MAD)) of BAY2927088

- Number of participants experiencing adverse events that prevent an increase in the dose
of BAY2927088 (dose-limiting toxicities (DLTs)) at each dose level

- The (average) total level of BAY2927088 in the blood (also called AUC) after receiving
single or multiple doses of BAY 2927088

- The (average) highest level of BAY 2927088 in the blood (also called Cmax) after
receiving a single or multiple doses of BAY2927088 Extension Part

- How well does BAY 2927088 work in participants?

For this, the researchers will measure the following:

• Percentage of participants whose cancer completely disappears (complete response) or
reduces by at least 30% (partial response) after taking the treatment (also known as
objective response rate (ORR)). This will be assessed by doctors other than the study doctor.

This study has 4 parts:

- The escalation part aims to find the maximum daily amount (dose) of BAY2927088 that
participants can receive.

- The backfill part aims to test the doses of BAY2927088 that are considered safe in the
escalation part by giving it to more participants. This will help find optimal doses of
BAY 2927088 that work well and are safe to be tested in the next part.

- The expansion part aims to determine the dose of BAY2927088 to be tested in further
studies.

- The extension part aims to determine whether the selected dose of BAY2927088 from the
expansion part works well.

The participants in this study will take the study treatment BAY2927088 in 3-week periods
called "cycles". They will in general take BAY2927088 once or twice daily as a liquid/tablet
by mouth until their cancer gets worse, they have medical problems, they leave the study, or
the study is terminated. Participants will have no more than 5 visits per cycle.

During the study, the study team will:

- take blood and urine samples,

- check the status of the cancer by doing computed tomography (CT) or magnetic resonance
imaging (MRI) scans,

- check the participants' overall health and heart health,

- ask the participants questions about how they are feeling and what adverse events they
are having.

An adverse event is considered "serious" when it leads to death, puts the participant's life
at risk, requires hospitalization, causes disability, causes a baby being born with medical
problems, or is medically important.

Inclusion Criteria:

- Documented histologically or cytologically confirmed locally advanced NSCLC, not
suitable for definitive therapy or recurrent or metastatic NSCLC at screening (small
cell or mixed histologies are excluded).

- Documented disease progression after treatment with at least one prior systemic
therapy for advanced disease. Participants who do not have standard of care access due
to any reason, are intolerant to, or are not eligible for standard treatments, may
also be eligible.

Note: Except for participants eligible for one of the groups (Expansion or Extension) who
should have received no prior systemic treatment for locally advanced or metastatic
disease.

- Adequate archival tumor tissue (ideally taken after last targeted treatment and not
older than 6 months) has to be available, either from primary or metastatic sites. If
archival material is not available, a fresh tumor biopsy should be performed if
feasible and if the procedure poses no significant risk for the participant.

- Measurable disease by RECIST v1.1 with at least one lesion not chosen for biopsy
during the screening period (if a biopsy is taken during screening) that can be
accurately measured at baseline with computed tomography (CT) or magnetic resonance
imaging (MRI) and that is suitable for accurate repeated measurements. A biopsied
lesion should not be used as a target lesion for RECIST 1.1 tumor assessments.
Previously irradiated lesions must have shown progression to be considered measurable.

- Documented activating EGFR and/or HER2 mutation assessed by a Clinical Laboratory
Improvement Amendments (CLIA)-certified (United States [US] sites) or an equally
accredited (outside of the US) local laboratory

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

- Minimum life expectancy of 12 weeks.

- Adequate bone marrow function as assessed by the following laboratory tests to be
conducted within 7 days before the first dose of study treatment:

1. Hemoglobin ≥ 9.0 g/dL. Criteria must be met without erythropoietin dependency and
without packed red blood cell (pRBC) transfusion within 2 weeks prior to testing.

2. Platelets ≥ 100 × 10^9 cells/L.

3. Absolute neutrophil count ≥ 1.5 ×10^9 cells/L. Criteria must be met without the
use of hematopoietic growth factors (e.g., G-CSF) within 2 weeks prior to
testing.

- Adequate kidney function as assessed by following laboratory test to be conducted
within 7 days before the first dose of study treatment:

a. Estimated glomerular filtration rate (eGFR) > 50 mL/min per 1.73 m^2 according to
the Modification of Diet in renal Disease Study Group (MDRD) formula.

- Adequate liver function as assessed by following laboratory tests to be conducted
within 7 days before the first dose of study treatment:

1. Total bilirubin ≤ 1.5 × ULN (or ≤ 3 X ULN for participants with documented
Gilbert-Meulengracht Syndrome, or for participants with hyperbilirubinemia
considered due to liver metastasis).

2. Aspartate transaminase and alanine transaminase ≤ 2.5 × ULN (or ≤ 5 × ULN if due
to liver involvement by tumor).

Exclusion Criteria:

- Treatment with an EGFR tyrosine kinase inhibitor (TKI) ≤ 8 days or 5x the terminal
phase, elimination half-lives, whichever is shorter, prior to the first dose of study
drug.

- Treatment with a systemic anti-cancer treatment (excluding EGFR TKIs as described
above) ≤ 14 days prior to the first dose of study drug.

- Radiation therapy, stereotactic radiosurgery (SRS) and palliative radiation ≤ 14 days
prior to the first dose of study drug.

- Treatment with immunotherapy ≤ 28 days prior to the first dose of study drug.

- Have any unresolved toxicity of Grade ≥ 2 from previous anti-cancer treatment, except
for alopecia and skin pigmentation. Participants with chronic, but stable Grade 2
toxicities may be allowed to enroll after agreement between the Investigator and
Sponsor.

- Any history of primary brain or leptomeningeal disease (symptomatic or asymptomatic),
presence of symptomatic central nervous system (CNS) metastases, or CNS metastases
that require local treatment (such as radiotherapy or surgery).

- History of spinal cord compression or brain metastases with the following exceptions:

1. Participants with treated brain metastases that are asymptomatic at screening and
who are off or receiving low-dose of corticosteroids (≤10 mg prednisone or
equivalent) for at least 7 days prior to first dose of BAY 2927088 are eligible
to enroll in Dose Escalation and Backfill.

2. Participants with treated brain metastases that are asymptomatic at screening are
eligible in Dose Expansion if all of the following criteria are met:

- there is no evidence of progression (new or enlarging brain metastases) for
at least 4 weeks after CNS-directed treatment, as ascertained by clinical
examination and brain imaging (MRI or CT) during the screening period.

- Participants must be off or receiving low-dose of corticosteroids (≤10 mg
prednisone or equivalent) for 7 days prior to first dose of BAY2927088.

3. Participants with history of spinal cord compression >3 months from definitive
therapy and stable by imaging (MRI or CT) during the screening period and
clinically asymptomatic.

- History of congestive heart failure (CHF) Class >II according to the New York Heart
Association (NYHA) Functional Classification or serious cardiac arrhythmias requiring
treatment (e.g. ventricular arrhythmias, atrial fibrillation) or any clinically
important abnormalities in rhythm, conduction or morphology or resting ECG (e.g.,
complete left bundle branch block, third degree heart block, second degree heart
block, PR interval >250 msec)

- Participants with:

1. Known human immunodeficiency virus (HIV), except as noted below: Participants
with history of HIV infection are eligible at the Investigator's discretion
provided that: • CD4+ T-cell (CD4+) counts are ≥ 350 cells/uL • The participant
has been on established antiretroviral therapy (ART) for at least 4 weeks prior
to the start of study drug and has an HIV viral load less than 400 copies/mL
prior to start of the study treatment • The ART being used does not contain
strong inducers or inhibitors of CYP3A4, and is not anticipated to cause
overlapping toxicities with study drug • The participant has not had an
opportunistic infection within the past 12 months

2. Active Hepatitis B infection (positive for Hepatitis B surface antigen [HbsAg])
and Hepatitis B virus [HBV] DNA).

3. Active Hepatitis C infection (positive anti-HCV Antibody and quantitative HCV RNA
results greater than the lower limits of detection of the assay).

NOTE: Participants with history of chronic HBV or HCV infection are eligible at
the Investigator's discretion provided that the disease is stable and
sufficiently controlled under treatment.

- Use of strong CYP3A4 inhibitors and inducers from 14 days prior to first
administration of study drug. Strong CYP3A4 inhibitors and inducers are prohibited
during the study and until Safety FU (follow up) visit.