A Study to Learn How Safe the Study Drug BAY 2416964 (AhR Inhibitor) in Combination With the Treatment Pembrolizumab is, How This Combination Affects the Body, the Maximum Amount That Can be Given, How it Moves Into, Through and Out of the Body and Its Action Against Advanced Solid Cancers in Adults

Study Overview
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Brief Summary
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Researchers are looking for a better way to treat advanced solid cancers including head and neck cancer, lung cancer and bladder cancer. In some people with cancer a protein called Aryl Hydrocarbon Receptor (AhR) can prevent immune cells from fighting tumor cells. The study drug, BAY 2416964, is a small molecule which blocks the AhR allowing the body to use its immune response against the cancer cells. Researchers think that BAY 2416964 given together with a cancer treatment called pembrolizumab may help shrink tumors in people with cancer. The main aims of this study are to find for BAY 2416964 in combination with pembrolizumab, how safe this drug combination is how it affects the body (also referred to as tolerability) the highest amount of BAY 2416964 that can be given in combination with pembrolizumab without too many side effects. The researchers will also study the action of BAY 2416964 in combination with pembrolizumab against the cancer. The participants in this study will get BAY 2416964 and pembrolizumab. BAY 2416964 will be given by mouth. Pembrolizumab will be given as an intravenous (IV) infusion. An IV infusion is given through a needle into a vein. This study will have two parts. The first part will help find the most appropriate dose that can be given in the second part. Each participant of the first, so called dose escalation part, will be assigned to one specific dose group for BAY 2416964. The amount of BAY 2416964 that is given changes step-wise from one group to the next. The dose of pembrolizumab will always be the same. The participants of the second, so called dose expansion part, will receive the most appropriate dose of BAY 2416964 found in the first part. During the study, the participants will receive the treatment in 3-week periods called cycles. In each cycle, the participants will in general get pembrolizumab once and BAY 2416964 in a daily schedule. These 3-week cycles will be repeated throughout the trial. The participants can take the study treatment until their cancer gets worse, until they have medical problems, or until they leave the trial. Participants will have around 4 visits in each cycle. Some of the visits can also be done via phone. During the study, the study doctors and their team will: take blood and urine samples check if the participants' cancer has changed in size using computed tomography scans or magnetic resonance imaging scans of the participants' tumors check the participants' overall 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, Phase 1b, Dose Escalation and Expansion Study to Evaluate the Safety, Tolerability, Maximum Tolerated or Administered Dose, Pharmacokinetics, Pharmacodynamics and Efficacy of the Aryl Hydrocarbon Receptor Inhibitor (AhRi) BAY 2416964 in Combination With Pembrolizumab in Participants With Advanced Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: BAY2416964
* Drug: BAY2416964
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be ≥18 years of age inclusive, at the time of signing the informed consent. Participants with following histologically or cytologically confirmed advanced solid tumors that have progressed after treatment with all available therapies for metastatic disease that are known to confer clinically meaningful benefit, or are intolerant to treatment, or refuse standard treatment. Dose Escalation: all solid tumor types Tumor type-specific Expansion cohorts: NSCLC HNSCC with primary location in oropharynx, oral cavity, hypopharynx or larynx Urothelial Cancer Participants must have progressed on treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. Have measurable disease per RECIST 1.1 Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Exclusion Criteria: Severe (Common terminology criteria for adverse events (CTCAE) v.5 Grade ≥ 3) infections within 4 weeks before the first study intervention administration Active autoimmune disease that has required systemic treatment in past 2 years Has a diagnosis of immunodeficiency or is receiving immunosuppressive therapy Has active Central nervous system (CNS) metastases and/or carcinomatous meningitis. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. Cardiac disease as specified in the protocol

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 of BAY2416964<br>Six dose levels of BAY 2416964 (as determined in the first in human mono-therapy study of BAY2416964) are planned in combination with standard dose Pembrolizumab. | Drug: BAY2416964<br>* Oral, twice or three times daily<br>Drug: Pembrolizumab<br>* Administered as a dose of 200 mg using a 30-minute IV infusion every 3 weeks<br>|
| Experimental: Dose expansion of BAY2416964 in tumor type specific cohort<br>To determine the RP2D of BAY2416964 in combination therapy with pembrolizumab. Participants will be enrolled in up to 3 tumor type-specific cohorts including relapsed/refractory non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) and urothelial cancer. | Drug: BAY2416964<br>* The highest dose determined safe in combination with pembrolizumab in the dose escalation part or a lower dose. More than one dose may be explored in the dose expansion.<br>Drug: Pembrolizumab<br>* Administered as a dose of 200 mg using a 30-minute IV infusion every 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of TEAEs including TESAEs | TEAEs: treatment-emergent adverse events TESAEs: treatment-emergent serious adverse events | After first administration of BAY2416964 in combination with pembrolizumab up to 90 days after the last dose of BAY2416964 in combination with pembrolizumab | 
| The severity of TEAEs including TESAEs |  | After first administration of BAY2416964 in combination with pembrolizumab up to 90 days after the last dose of BAY2416964 in combination with pembrolizumab | 
| Maximum tolerated dose (MTD) or maximum administered dose (MAD) of BAY2416964 | The MTD/MAD is the dose level that can be safely given, defined as the occurrence of dose-limiting toxicities (DLTs) below a certain threshold. | Cycle 1 (21 days) in dose escalation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of BAY2416964 after single-dose in Cycle 1 |  | Cycle 1 Day 1 (1 cycle is 21 days) | 
| Cmax of BAY2416964 after multiple-dose in Cycle 1 |  | Cycle 1 Day 15 (1 cycle is 21 days) | 
| AUC(0-t) (t depend on the dosing regimen) of BAY2416964 after single-dose in Cycle 1 |  | Cycle 1 Day 1 (1 cycle is 21 days) | 
| AUC(0-t) (t depend on the dosing regimen) of BAY2416964 after multiple-dose in Cycle 1 |  | Cycle 1 Day 15 (1 cycle is 21 days) | 
| Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) | ORR will be evaluated using RECIST 1.1 by investigator assessment. | At the end of Cycle 2 (-7 days, each cycle is 21 days), Cycle 4 (-7 days) and at the end of every third cycle (-7 days) from Cycle 5 onwards | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immuno oncology, Aryl Hydrocarbon Receptor inhibitor(AhRi), Non-small cell lung cancer (NSCLC), Head and neck squamous cell carcinoma (HNSCC), Urothelial Cancer, Advanced cancer, Immunotherapy, Aryl Hydrocarbon Receptor, Pembrolizumab, aPD1, Checkpoint inhibitor