A First-in-human Study to Learn How Safe the Study Treatment BAY2862789 is, to Find the Best Dose, How it Affects the Body, What Maximum Amount Can be Given, How it Moves Into, Through and Out of the Body, and How it Acts on Different Tumors in Participants With Advanced Solid Tumors

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 solid tumors including a specific kind of lung cancer (non-small cell lung cancer, NSCLC). Advanced solid tumors are types of cancer that have spread to nearby tissue, lymph nodes, and/or to distant parts of the body and that are unlikely to be cured or controlled with currently available treatments. BAY2862789 works by blocking an enzyme in T-cells, thereby activating them. T-cells are a type of immune cell that are known to have an anti-cancer effect. The main purpose of this first-in-human study is to learn: how safe different doses of BAY2862789 are, the degree to which medical problems caused by BAY2862789 can be tolerated (also called tolerability), what maximum amount (dose) can be given, and how BAY2862789 moves into, through and out of the body. To answer this, the researchers will look at: the number and severity of medical problems participants have after taking BAY2862789 for each dose level. These medical problems are also referred to as adverse events. An adverse event is considered serious when it leads to death, puts the participants' lives at risk, requires hospitalization, causes disability, causes a baby being born with medical problems or is otherwise medically important. the (average) total level of BAY2862789 in the blood (also called AUC) after intake of single and multiple doses. the (average) highest level of BAY2862789 in the blood (also called Cmax) after intake of single and multiple doses. Doctors and their team keep track of all medical problems that participants have during the study, even if they do not think the medical problem might be related to the study treatment. In addition, the researchers want to know if and how the participants' tumors change after taking BAY2862789. The study will have two parts. The first part, called dose escalation, is done to find the most appropriate dose that can be given in the second part of the study. For this, each participant will receive one of the increasing doses of BAY2862789. All participants in the second part of the study, called dose expansion, will receive the most appropriate dose identified from the first part of the study, as tablet by mouth. Participants in both parts of the study, will take the study treatment until their tumor gets worse (also known as 'disease progression'), until they have medical problems, until they leave the study, or until the study is terminated. Each participant will be in the study for several months, including a test (screening) phase of up to 28 days, few months of treatment depending on the participant's benefit, and a follow up phase after the end of treatment. The following approximate numbers of visits to the study site are planned: two during the screening phase, six in the first treatment month, one to three per month in the following periods. During the study, the study team will: take blood and urine samples do physical examinations check vital signs such as blood pressure, heart rate, body temperature examine heart health using ECG (electrocardiogram) check cancer status using CT (computed tomography) or MRI (magnetic resonance imaging) and, if needed, bone scans take tumor samples (if required) pregnancy test The treatment period ends with a visit no later than 7 days after the last BAY2862789 dose. The study doctors and their team will check the participants' health and any changes in cancer about 30 and 90 days after the last dose and every 12 weeks thereafter. This follow-up period ends if the cancer worsens, if a new anti-cancer treatment is started, or until the participant leaves the study. In addition, the study doctors and their team will contact the participant every 12 weeks to learn about the participant's survival. This ends no later than 12 months after the last participant started treatment or by the end of the study, whichever comes first. If the study participant benefits from treatment, continuation of treatment with BAY2862789 beyond the duration of this study might be possible.

Official Title
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An Open-label, Phase 1, First-in-human, Dose Escalation and Expansion Study to Evaluate the Safety, Tolerability, Maximum Tolerated or Administered Dose, Pharmacokinetics, Pharmacodynamics, and Tumor Response Profile of the Diacylglycerol Kinase Alpha Inhibitor (DGKαi) BAY 2862789 in Participants With Advanced Solid Tumors

Conditions
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Advanced Solid Tumors, Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: BAY2862789


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving signed informed consent Be ≥18 years of age on day of signing informed consent. Have measurable disease per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) as assessed by the local site investigator. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Participants with a histologically confirmed diagnosis of a solid tumor that have exhausted available treatments known to be beneficial for this tumor type or for whom these treatments are not acceptable and for whom this trial is a reasonable option for them, will be enrolled onto this study. Appropriate molecular profiling of tumors should have been performed according to local national guidelines prior to trial entry. Specifications for the different parts of the study are below: -- Dose escalation: All solid cancers, except primary central nervous system cancers. Non-small cell lung cancer (NSCLC): Patients with NSCLC must have received an approved PD1/L-1 containing regimen and platinum chemotherapy Patients with known targetable genomic aberrations should also have received available targeted drugs deemed appropriate by the investigator. NSCLC Participants with endothelial growth factor receptor (EGFR) or alkaline phosphatase (ALK) mutations will not be eligible for expansion cohorts. Provision of archival tumor sample at baseline is mandatory for all participants in escalation, and expansion cohorts. Participants recruited to expansion cohorts must be willing to undergo mandatory paired biopsies of tumor (re and on treatment). Have adequate organ function. Agree to use contraception during the treatment period and for at least 6 months after the last dose of study treatment. Exclusion Criteria: Had an allogeneic tissue/solid organ transplant. Previous therapy with a diacylglycerol kinase (DGK) inhibitor Has received a prior therapeutic regimen containing an anti-programmed cell death protein 1 (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), or anti-programmed cell death 1 ligand 2 (anti PD-L2) agent or an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX 40, CD137) and was discontinued from that treatment regimen due to a Grade 3 or higher immune related adverse event (irAE) or any toxicity that was life-threatening. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks or 5 half-lives, whatever is shorter, prior to treatment. Growth factor treatments such as granulocyte colony-stimulating factor (G-CSF) must have been discontinued 4 weeks prior to entering the study. Participants must have recovered from previous radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. Participants cannot have had a blood transfusion within 2 weeks of starting therapy. Has received a live vaccine within 30 days prior to the first dose of study drug. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 14 days prior to the first dose of study drug. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Participants with new brain metastases on screening brain magnetic resonance imaging/computed tomography (MRI/CT). Primary central nervous system malignancy or presence of leptomeningeal disease. Participants with gastrointestinal conditions that may compromise oral absorption such as short bowel syndrome or active tumor-related bowel obstruction with ongoing symptoms compromising absorption over last 6 months. Has an active autoimmune disease including inflammatory bowel disease that has required systemic treatment in past 2 years. Current pneumonitis / interstitial lung disease. Has an active infection requiring systemic therapy.

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: Basic Science
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Participants will take BAY2862789 oral doses. | Drug: BAY2862789<br>* Oral administration, solution or tablets<br>|
| Experimental: Dose Expansion<br>Participants will take BAY2862789 oral doses. Dose Expansion starts after Dose Escalation. | Drug: BAY2862789<br>* Oral administration, solution or tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number and severity of treatment-emergent adverse events (TEAEs) | Adverse events (AEs) will be considered treatment-emergent if they have started or worsened after first administration of study treatment up to 90 days after the last administration of study treatment. | Up to 90 days after the last administration of the study treatment | 
| Number of participants experiencing dose-limiting toxicities (DLTs) at each dose level in the Dose Escalation part of the study |  | Up to 21 days after the first administration of the study treatment | 
| Recommended phase 2 dose (RP2D) | The RP2D will be defined in the expansion part based on multiple parameters (i.e., safety, tolerability, pharmacokinetics, pharmacodynamics, efficacy). The final decision about the RP2D will be made by the Sponsor in consultation with the Investigators at the end of the expansion part. | Up to 2 years | 
| Maximum concentration (Cmax) BAY2862789 after single-dose |  | Pre-dose and 1-4 hours post-dose on Day 1 in each cycle from Cycle 2 | 
| Maximum concentration (Cmax) BAY2862789 after multiple-dose |  | Pre-dose and up to 24 hours after Day 16 in Cycle 1 | 
| Area under the curve (AUC) BAY2862789 after single-dose |  | Pre-dose and 1-4 hours post-dose on Day 1 in each cycle from Cycle 2 | 
| Area under the curve (AUC) BAY2862789 after multiple-dose |  | Pre-dose and up to 24 hours after Day 16 in Cycle 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | ORR is defined as the proportion of participants whose best overall response is either a confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) (investigator assessed). | Up to 2 years | 
| Disease control rate (DCR) | DCR is defined as the percentage of participants whose best overall response was either CR, PR, or SD, considering the requirement for confirmation of CR and PR. CR stands for complete response. PR stands for partial response. SD stands for stable disease. | Up to 2 years | 
| Duration of response (DOR) | DOR is defined as the time from the first documented objective response of PR or CR, whichever occurs earlier, to disease progression or death (if death occurs before progression is documented). PR stands for partial response. CR stands for complete response. | Up to 2 years | 
| Progression-free survival (PFS) at 6 months | PFS is defined as the time from the start of study treatment to the date of first observed disease progression by investigator assessment or death due to any cause, if death occurs before progression is documented. | Up to 6 months | 
| Overall survival (OS) at 12 months | OS is defined as the time from the start of study treatment to death due to any cause. | Up to 12 months | 
| Activation of effector T memory cells |  | Up to 2 years | 
| Ex vivo stimulated short-term activation of Interleukin 2 (IL2) and interferon-gamma |  | Up to 2 years |