A First-in-Humans Dose Finding Study for an Aryl Hydrocarbon Receptor Inhibitor (AhRi) in Patients With Advanced Cancer

Advanced Solid Tumors Clinical Trial

Official title:

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 Aryl Hydrocarbon Receptor Inhibitor (AhRi) BAY 2416964 in Participants With Advanced Solid Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04069026
• Other study ID #: 20201
• Secondary ID: 2023-503546-32-0
• Status: Completed
• Phase: Phase 1
• Start date: August 15, 2019
• Est. completion date: January 17, 2024

Study information

• Verified date: March 2024
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In this study researchers want to gather relevant information regarding the safety of BAY2416964 and how well the drug works in participants with a type of solid tumors that cannot be cured by currently available drugs. Researchers want to find the highest dose of BAY2416964 that participants could take without having too many side effects, how the drug is tolerated and the way the body absorbs, distributes and gets rid of the study dug. BAY2416964 is a small molecule which blocks the Aryl Hydrocarbon Receptor (a protein involved in immune cell reaction to tumor cells) allowing the body to use its immune response against the tumor cells.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 78
• Est. completion date: January 17, 2024
• Est. primary completion date: January 17, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participants 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 clinical benefit, or are intolerant to treatment, or refuse standard treatment.

• Dose Escalation: all solid tumor types

• Tumor type-specific high-dose (MTD or MAD) Expansion cohorts: Will be grouped by tumor type:

• NSCLC

• HNSCC

• NSCLC (TID dosing) expansion cohorts

• Have measurable disease per RECIST 1.1 as assessed by CT/MRI. At least one measurable lesion by RECIST 1.1 is required. Lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are considered measurable if progression has been demonstrated in such lesions.

• Life expectancy at least 12 weeks.

• Eastern Cooperative Oncology Group (ECOG)performance status of 0 to 1.

• Adequate bone marrow and organ function as assessed by the following laboratory tests performed within 7 days before treatment initiation.

• Bone marrow reserve:

• Absolute neutrophil count (ANC) = 1.5 x 10^9/L

• Hemoglobin (Hb) = 9.0g/dL, without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.

• Platelet count = 100 x 10^9/L. Transfusion to meet the inclusion criteria will not be allowed.

• Hepatic:

• Total bilirubin = 1.5 x the upper limit of normal range (ULN). Known Gilbert syndrome is allowed if total bilirubin is = 3 x ULN.

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5 x ULN (= 5 x ULN for participants with liver metastases).

• Albumin > 25 g/L.

• Renal:

--- eGFR = 60 mL/min as calculated using the MDRD equation or creatinine level = 1.5x ULN.

• Lipase and amylase = 1.5 x ULN.

• Coagulation:

• International normalized ratio (INR) OR prothrombin time (PT) AND activated partial thromboplastin time (aPTT) = 1.5 x ULN unless the participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.

• Adequate cardiac function, measured by echocardiography within 28 days before start of study intervention (left ventricular ejection fraction within institutional normal range for age and gender).

Exclusion Criteria:

• Severe (CTCAE v.5 Grade = 3) infections within 4 weeks before the first BAY2416964 administration, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia. Clinically active infections (CTCAE v.5 > Grade 1) within 2 weeks before the first BAY2416964 administration.

• Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) within 1 week before the first dose of study intervention or any other form of immunosuppressive therapy within 2 weeks prior the first dose of study intervention.

• Congestive heart failure New York Heart Association (NYHA) greater than Class I or cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or calcium channel blockers.

• Has active central nervous system (CNS) metastases and/or carcinomatous meningitis.

Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that repeat imaging needs to be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.

• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.

• Significant acute gastrointestinal disorders with diarrhea as a major symptom, e.g. Crohn's disease, malabsorption, or = NCI-CTCAE v. 5.0 Grade 2 diarrhea of any etiology.

• History of organ allograft transplantation, including allogeneic bone marrow transplantation.

• Has received prior radiotherapy within 2 weeks before start of BAY2416964 or received radiation therapy to the lung that is > 30 Gy within 6 months before start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=2 weeks of radiotherapy) to non-CNS disease.

• Treatment with systemic immunosuppressant medications (including but not limited to

• > 10 mg/day prednisone or equivalent within 1 week before the first study intervention administration.

• any other form of immunotherapy, e.g., cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks before the first BAY2416964 administration.

The use of inhaled corticosteroids, or low doses of glucocorticoids (no more than 10 mg/day prednisone or equivalent; if a higher dose would be needed to maintain adrenal function investigator must obtain approval from sponsor), and mineralocorticoids (e.g. fludrocortisone for adrenal insufficiency) is allowed.

Related Conditions & MeSH terms

• Advanced Solid Tumors

Intervention

Drug:
• BAY2416964
Oral application of study drug daily in a predefined dose escalation scheme.
• BAY2416964
Oral application of study drug daily at the dose defined in the dose escalation scheme to determine the recommended phase 2 dose (RP2D).

Locations

Country	Name	City	State
Canada	CHU de Québec-Hôpital de l'Enfant-Jésus	Quebec
Canada	Princess Margaret Hospital-University Health Network	Toronto	Ontario
Germany	Charité Campus Benjamin Franklin (CBF)	Berlin
Germany	Universitätsklinikum Carl Gustav Carus Dresden	Dresden	Sachsen
Germany	Universitätsklinikum Heidelberg	Heidelberg	Baden-Württemberg
Spain	Institut Català d'Oncologia Hospitalet	Hospitalet de Llobregat	Barcelona
Spain	Hospital Ramón y Cajal | Oncología	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Virgen de la Victoria | Cardiology Department	Málaga
Spain	Hospital Clínico Universitario de Valencia	Valencia
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Christie Hospital	Manchester
United Kingdom	Royal Marsden NHS Trust (Surrey)	Sutton	Surrey
United States	Greenville Health System	Greenville	South Carolina
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Yale University School of Medicine	New Haven	Connecticut
United States	South Texas Accelerated Research Therapeutics | START San Antonio	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

United States,  Canada,  Germany,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The incidence of treatment emergent adverse events (TEAEs) including treatment-emergent serious adverse events (TESAEs) and dose-limiting toxicities (DLTs)		Up to 90 days after end of treatment
Primary	Severity of treatment emergent adverse events (TEAEs) including treatment-emergent serious adverse events (TESAEs) and dose-limiting toxicities (DLTs)		Up to 90 days after end of treatment
Primary	Maximum tolerated dose (MTD) or maximum administered dose (MAD) of BAY2416964	MTD:defined as the dose level that can be given such that the estimated Dose limiting toxicity (DLT) probability is closest to approximately 25%.	Cycle 1 (21 days) in dose escalation
Primary	Recommended Phase II dose (RP2D) of BAY2416964	Integration of all available safety, PK and PD data	Up to 90 days after end of treatment
Primary	Maximal plasma exposure (Cmax) for once daily (QD) dosing of BAY2416964 after single-dose and multiple-dose in Cycle 1.		From pre-dose up to 24 hours after administration on Cycle 1 (21 days) Day 1. From pre-dose up to 12 hours after administration on Cycle 1 (21 days) Day 15
Primary	Area under the curve [AUC (0 - t)] (t=6,12 or 24 dependent on the dosing regimen) of BAY2416964 after single and multiple-dose in Cycle 1		From pre-dose up to 6, 12, or 24 hours after administration on Day 1 and/or Day 15 in Cycle 1 (21 days).
Secondary	Objective response rate (ORR) by RECIST 1.1		At the end of Cycle 2 (- 7 days), Cycle 4 (-7 days), every 9 weeks (- 7 days) from Cycle 5 to Cycle 10 and every 4th cycle (- 7 days) from Cycle 11 onwards. Each cycle is 21 days.
Secondary	Change from baseline in AhR target gene expression in whole blood after ex-vivo stimulation		Screening, Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 4 Day 1(each cycle is 21 days)
Secondary	Cytokine measurements, e.g. IL-6 (immunoassay), in whole blood after ex-vivo stimulation.		Screening, Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 4 Day 1(each cycle is 21 days)