First in Human Study of BAY2927088 in Participants Who Have Advanced Non-small Cell Lung Cancer (NSCLC) With Mutations in the Genes of Epidermal Growth Factor Receptor (EGFR) and/or Human Epidermal Growth Factor Receptor 2 (HER2)

Study Overview
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Brief Summary
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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. Two mutations observed in NSCLC are called EGFR- or HER2exon20ins and EGFR C797X. The study treatment, BAY2927088, works by blocking the mutated EGFR protein and also its ex20ins version which are present in NSCLC. It is also believed to work against HER2 and HER2ex20ins mutations. Researchers think this may help stop the further spread of NSCLC cancer. This is the first time that researchers will study BAY2927088 in humans. In this study, the researchers want to learn more about using BAY2927088 in participants who have NSCLC with EGFR and/or HER2 mutations including EGFRex20ins and/or HER2ex20ins mutations. The main aims of this study are to find for BAY2927088 how safe BAY2927088 is how it affects the body (also referred to as tolerability) how BAY2927088 moves into, through and out of the body the maximum amount of BAY2927088 that the participants can take without too many side effects. The researchers will also study the action of BAY2927088 against the cancer. The study will have three parts: Dose Escalation, Backfill, and Dose Expansion. Each participant of the first, so called dose escalation part, will be assigned to one of specific sequential dose groups for BAY2927088. The amount of BAY2927088 that is given increases stepwise from one group to the next. The second may be initiated at any dose that has already been tested during the first part and found to be safe and to have either reached a predicted efficacious exposure range or to have induced an objective response. The first part and second part will run concurrently. The participants of the third, so called dose expansion part, will receive the most appropriate dose of BAY2927088 found in the first and second parts. The third part may be initiated in parallel with the first and second part based on emerging data. During the study, the participants will take the study treatment in 3 week periods called cycles. They will in general take BAY2927088 once daily until their cancer gets worse, until they have medical problems, until they leave the study or until the study is terminated. Participants will have around 5 visits in each cycle. During the study, the study team will: take blood and urine samples take regular CT or MRI scans to check if the participants' cancer has gotten better or worse 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 any medical problem that a participant has during a study. Doctors keep track of all adverse events that happen in studies, even if they do not think the adverse events might be related to the study treatments.

Official Title
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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

Conditions
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Advanced Non-small Cell Lung Cancer, EGFR Mutation, HER2 Mutation

Intervention / Treatment
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* Drug: BAY2927088_formulation A
* Drug: BAY2927088_formulation B_1
* Drug: BAY2927088_formulation B_2


Participation Criteria
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Eligibility Criteria
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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. 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: 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. Platelets ≥ 100 × 10^9 cells/L. 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) > 60 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: 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). 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: 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. 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. 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: 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 Active Hepatitis B infection (positive for Hepatitis B surface antigen [HbsAg]) and Hepatitis B virus [HBV] DNA). 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation<br> | Drug: BAY2927088_formulation A<br>* Oral administration<br>Drug: BAY2927088_formulation B_1<br>* Oral administration<br>Drug: BAY2927088_formulation B_2<br>* Oral administration<br>|
| Experimental: Backfill<br>Dose Escalation and Backfill run concurrently | Drug: BAY2927088_formulation A<br>* Oral administration<br>Drug: BAY2927088_formulation B_1<br>* Oral administration<br>Drug: BAY2927088_formulation B_2<br>* Oral administration<br>|
| Experimental: Dose expansion<br>Dose Expansion is initiated after Dose Escalation and Backfill. | Drug: BAY2927088_formulation B_1<br>* Oral administration<br>Drug: BAY2927088_formulation B_2<br>* Oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-emergent adverse events (TEAEs) |  | Up to 30 days after the last administration of study treatment | 
| Number of participants with treatment-emergent serious adverse events (TESAEs) |  | Up to 30 days after the last administration of study treatment | 
| Severity of TEAEs |  | Up to 30 days after the last administration of study treatment | 
| Severity of TESAEs |  | Up to 30 days after the last administration of study treatment | 
| Number of participants who discontinue study treatment due to an AE |  | About 4 years (Up to the end of study treatment) | 
| Maximum tolerated dose (MTD) or maximum administered dose (MAD) within the DLT observation period | In Dose Escalation (including participants from Backfill) | At the end of Cycle 1 of a 21-day cycle | 
| Number of participants experiencing dose-limiting toxicities (DLTs) at each dose level associated with administration of BAY2927088 | In Dose Escalation (including participants from Backfill) | At the end of Cycle 1 of a 21-day cycle | 
| Cmax of BAY2927088 | Cmax: Maximum/peak concentration | Cycle 1, Day 1 (Cycle duration is 21 days) | 
| AUC(0-24) of BAY2927088 for QD | AUC: Area under the concentration vs. time curve. AUC(0-24): AUC from time 0 to 24 hours post dose. QD: Quaque die (once daily) | Cycle 1, Day 1 (Cycle duration is 21 days) | 
| AUC(0-12) of BAY2927088 for BID | If applicable. AUC(0-12): AUC from time 0 to 12 hours post dose. BID: Bis in die, 2 times daily. | Cycle 1, Day 1 (Cycle duration is 21 days) | 
| Cmax,md of BAY2927088 | Cmax,md: Cmax after multiple dose administrations | Cycle 1, Day 15 (Cycle duration is 21 days) | 
| AUC(0-24)md of BAY2927088 for QD | AUC(0-24)md: AUC(0-24) after multiple dose administrations | Cycle 1, Day 15 (Cycle duration is 21 days) | 
| AUC(0-12)md of BAY2927088 for BID | If applicable AUC(0-12)md: AUC(0-12) after multiple dose administrations | Cycle 1, Day 15 (Cycle duration is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) as per RECIST v1.1 by investigator assessment | RECIST v1.1: Response Evaluation Criteria in Solid Tumors, version 1.1 | About 4 years | 
| Recommended phase II dose (RP2D) of BAY2927088 |  | About 1.5 years |