A First-in-human Study to Learn How Safe the Study Drug BAY2965501 is, Find the Best Dose (Single Drug & Combination), How it Affects the Body, What Maximum Amount Can be Given, How it Moves Into, Through and Out of the Body, 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. Advanced solid tumors are types of cancer that may 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. This study focuses on certain types of skin cancer, kidney cancer, stomach cancer, and lung cancer. The study treatment BAY2965501 is currently under development as monotherapy or in combination with a drug named pembrolizumab for the treatment of people with advanced solid tumors. BAY2965501 blocks an enzyme in T-cells to activate them. T-cells are a type of immune cell that are known to have an anti-cancer effect and BAY2965501 is a potential new immunotherapy. The main purpose of this first-in-human study is to learn: how safe different doses of BAY2965501 are when given as a single drug or in combination, the degree to which medical problems caused by BAY2965501 when given as a single drug or in combination, can be tolerated (also called tolerability), what maximum amount can be given as a single drug or in combination, and how it moves into, through and out of the body as a single drug or in combination. To answer this, researchers will look at: the number and severity of medical problems participants have after taking BAY2965501 as a single drug or in combination for each dose level. These medical problems are also referred to as adverse events. the (average) total level of BAY2965501 in the blood (also called AUC) after intake of single and multiple doses the (average) highest level of BAY2965501 in the blood (also called Cmax) after intake of single and multiple doses Doctors 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 BAY2965501. 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. For this, participants will be assigned to receive one of the planned doses and schedules of BAY2965501 as single drug or participants will be assigned to one of the increasing doses of BAY2965501 in combination with 200mg pembrolizumab. All participants will take BAY2965501 by mouth. Additionally, in the combination group, pembrozilumab will be given. In the second part, called dose expansion, all participants in the single drug group will receive up to 2 of the most appropriate doses of BAY2965501 from the 1st part as tablet by mouth. The participants in the combination group will receive the most appropriate dose of BAY2965501 from the first part. Participants in both parts of the study, will take the study treatment until the tumor gets worse (also known as 'disease progression'), or until the participants have medical problems. In general, the study treatment is planned for a maximum of 35 cycles. Each participant will be in the study for several months, including a 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. Participants in part two will be assigned to one of 3 groups depending on cancer characteristics. Study procedures described below may vary between these groups. 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 if the participants' cancer has grown and/or spread using CT (computed tomography) or MRI (magnetic resonance imaging) and, if needed, bone scan take tumor samples (if required) The treatment period ends with a visit no later than 7 days after the last BAY2965501 dose in the single drug and combination group. About 30 and 90 days after the last dose and every 12 weeks thereafter, the study team will check the participants' health and any changes in cancer. This follow-up period ends with worsening of the cancer, start of new anti-cancer therapy, 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.

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 Zeta Inhibitor (DGKzi) BAY 2965501 as Monotherapy, and in Combination, in Participants With Advanced Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: BAY2965501
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have measurable disease per Response evaluation criteria in solid tumors 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 histologically confirmed diagnosis of a solid tumor (specifications for the different parts of the study below) will be enrolled onto this study: • Dose escalation: All solid cancers, except primary central nervous system cancers The following tumor types will be recruited to the monotherapy expansion cohorts: Non-small cell lung cancer (NSCLC) Gastric/Gastroesophageal Junction (GEJ) adenocarcinoma The following tumor types will be recruited to the BAY 2965501 and pembrolizumab combination expansion cohorts: NSCLC: participants with tumors that are TPS score ≥50% PDL-1 high (based on local historical testing) and are eligible for standard of care anti-PD(L)-1 monotherapy in the first line incurable treatment setting. NSCLC Gastric/GEJ adenocarcinoma Exclusion Criteria: Previous therapy with a DGK inhibitor is prohibited for monotherapy cohorts (participants previously treated with BAY 2965501 or BAY 2862789 must have progressed on that DGK inhibitor (and not discontinued for toxicity) to be eligible for combination). Has received a prior therapeutic regimen containing an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher infusion-related adverse event (irAE). Participants with new brain metastases on screening brain MRI/CT. Previously treated brain metastases that are progressive at screening compared to a brain MRI/CT at least 6 weeks earlier are also excluded. Participants with known previously treated brain metastases, which are radiologically stable compared to a CT/MRI scan at least 6 weeks earlier, clinically stable and without the requirement of steroid treatment for at least 14 days prior to the first dose of study treatment may be eligible. Primary central nervous system malignancy or presence of leptomeningeal disease (i.e., positive cerebrospinal fluid cytology or unequivocal radiological or clinical evidence of leptomeningeal involvement). 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.

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: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation of BAY2965501<br>For escalation part, different dose levels of BAY2965501 are planned. | Drug: BAY2965501<br>* Daily oral application<br>|
| Experimental: Dose expansion of BAY2965501<br>For expansion part, specific tumor types are recruited (non-small cell lung cancer (NSCLC) and gastric/gastroesophageal junction (GEJ) adenocarcinoma). | Drug: BAY2965501<br>* Daily oral application<br>|
| Experimental: Dose escalation of BAY2965501+pembrolizumab<br>For escalation part different dose levels of BAY2965501 are planned in combination with 200mg pembrolizumab. BAY2965501 will be taken daily in combination with 200mg pembrolizumab every 3 weeks. | Drug: Pembrolizumab<br>* In combination group 200mg as infusion every 3 weeks<br>|
| Experimental: Dose expansion of BAY2965501 +pembrolizumab<br>For expansion part, specific tumor types are recruited (non-small cell lung cancer (NSCLC) and gastric/gastroesophageal junction (GEJ) adenocarcinoma). BAY2965501 will be taken daily in combination with 200mg pembrolizumab every 3 weeks. | Drug: Pembrolizumab<br>* In combination group 200mg as infusion every 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The frequency and severity of treatment-emergent adverse events (TEAEs) including treatment-emergent serious adverse events (TESAEs) |  | Up to 90 days after the last administration of study treatment | 
| Maximum Tolerated Dose (MTD)/ Maximum Administered Dose (MAD): Number of participants experiencing dose-limiting toxicities (DLTs) at each dose level in the dose escalation part of the study |  | From first dose of study treatment to the end of Cycle 1 (each cycle is 21 days) | 
| Recommended Phase 2 dose (RP2D) as determined by safety, tolerability, PK, PD, and efficacy data from BAY 2965501 dose(s) at the end of Phase 1 |  | Up to 90 days after the last administration of study treatment | 
| Maximum concentration (Cmax) of the respective dosing interval of BAY2965501 after single dose and multiple-dose |  | From pre-dose up to 24 hours after administration on Cycle 1 Day 1 (each cycle is 21 days) | 
| Area under the curve [AUC (0 - 24)] of the respective dosing interval of BAY 2965501 after single-dose and multiple-dose | If AUC(0-24) cannot be calculated reliably, it might become necessary to appoint the additional parameter AUC(0-tlast) as primary variable. | From pre-dose up to 24 hours after administration on Cycle 1 Day 1 (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Investigator assessment using Response Evaluation Criteria in Solid Tumours version (RECIST 1.1) | Approximately 6 months | 
| Disease control rate (DCR) | Investigator assessment using Response Evaluation Criteria in Solid Tumours version (RECIST 1.1) | Approximately 6 months | 
| Duration of response (DOR) | Investigator assessment using Response Evaluation Criteria in Solid Tumours version (RECIST 1.1) | Approximately 6 months | 
| Progression-free survival (PFS) rate | Investigator assessment using Response Evaluation Criteria in Solid Tumours version (RECIST 1.1) | At 6 months | 
| Overall survival (OS) rate |  | At 12 months | 
| Change from baseline in peripheral activation of effector T memory cells as assessed by flow cytometry |  | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months | 
| Change from baseline in interleukin 2 and interferon-gamma levels after ex-vivo stimulation |  | Screening, Cycle 1: Day 1, Day 8 (each cycle is 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RCC, Solid tumors, Non-small cell lung cancer, NSCLC, Gastroesophageal junction adenocarcinoma, GEJ adenocarcinoma, Renal cell carcinoma, Melanoma