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

NCT04069026 | Completed Phase 1 FDA Drug

• 3 other identifiers: 202012023-503546-32-002019-000722-22
• Study Type: interventional
• Target: 78
• Locations: 5 countries
• Sites: 17

Brief 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.

Conditions

Advanced Solid Tumors

Keywords

Non-small cell lung cancer (NSCLC); Head and neck squamous cell carcinoma (HNSCC); Advanced cancer; Immunotherapy; Immuno oncology; Aryl Hydrocarbon Receptor inhibitor(AhRi); Aryl Hydrocarbon Receptor

Outcome Measures

Primary Outcomes (6)

• 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

• 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

• 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

• Recommended Phase II dose (RP2D) of BAY2416964

  Integration of all available safety, PK and PD data

  Up to 90 days after end of treatment

• 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

• 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 Outcomes (3)

• 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.

• 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)

• 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)

Study Arms (2)

Dose escalation of BAY2416964

EXPERIMENTAL

Approximately 8 dose levels of BAY2416964 are planned

Drug: BAY2416964

Dose expansion of BAY2416964 in tumor type specific

EXPERIMENTAL

Patients with NSCLC, HNSCC

Drug: BAY2416964

Interventions

BAY2416964 DRUG

Oral application of study drug daily in a predefined dose escalation scheme.

Dose escalation of BAY2416964

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Hepatic:

You may not qualify if:

• 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.

Sponsors & Collaborators

• Bayer: lead

Study Sites (17)

Yale University School of Medicine

New Haven, Connecticut, 06520-8028, United States

Location

Greenville Health System

Greenville, South Carolina, 29605, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

South Texas Accelerated Research Therapeutics | START San Antonio

San Antonio, Texas, 78229-3307, United States

Location

Princess Margaret Hospital-University Health Network

Toronto, Ontario, M5G 2M9, Canada

Location

CHU de Québec-Hôpital de l'Enfant-Jésus

Québec, G1J 1Z4, Canada

Location

Universitätsklinikum Heidelberg

Heidelberg, Baden-Wurttemberg, 69120, Germany

Location

Universitätsklinikum Carl Gustav Carus Dresden

Dresden, Saxony, 01307, Germany

Location

Charité Campus Benjamin Franklin (CBF)

Berlin, 12200, Germany

Location

Institut Català d'Oncologia Hospitalet

L'Hospitalet de Llobregat, Barcelona, 08907, Spain

Location

Hospital Ramón y Cajal | Oncología

Madrid, 28034, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Hospital Universitario Virgen de la Victoria | Cardiology Department

Málaga, 29010, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, 46010, Spain

Location

Royal Marsden NHS Trust (Surrey)

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Beatson West of Scotland Cancer Centre

Glasgow, G12 0YN, United Kingdom

Location

Christie Hospital

Manchester, M20 4BX, United Kingdom

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Squamous Cell Carcinoma of Head and Neck

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Head and Neck Neoplasms

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 9, 2019
• First Posted: August 28, 2019
• Study Start: August 15, 2019
• Primary Completion: January 17, 2024
• Study Completion: January 17, 2024
• Last Updated: March 6, 2024

Record last verified: 2024-03

Locations

DE (3); US (4); GB (3); CA (2); ES (5)