Clinical trial NCT04069026: A First-in-Humans Dose Finding Study for an Aryl Hydrocarbon Receptor Inhibitor (AhRi) in Patients With Advanced Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2019-08-28
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: The incidence of treatment emergent adverse events (TEAEs) including treatment-emergent serious adverse events (TESAEs) and dose-limiting toxicities (DLTs)
timeFrame: Up to 90 days after end of treatment
measure: Severity of treatment emergent adverse events (TEAEs) including treatment-emergent serious adverse events (TESAEs) and dose-limiting toxicities (DLTs)
timeFrame: Up to 90 days after end of treatment
measure: Maximum tolerated dose (MTD) or maximum administered dose (MAD) of BAY2416964
timeFrame: Cycle 1 (21 days) in dose escalation
measure: Recommended Phase II dose (RP2D) of BAY2416964
timeFrame: Up to 90 days after end of treatment
measure: Maximal plasma exposure (Cmax) for once daily (QD) dosing of BAY2416964 after single-dose and multiple-dose in Cycle 1.
timeFrame: 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
measure: 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
timeFrame: 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:
measure: Objective response rate (ORR) by RECIST 1.1
timeFrame: 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.
measure: Change from baseline in AhR target gene expression in whole blood after ex-vivo stimulation
timeFrame: Screening, Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 4 Day 1(each cycle is 21 days)
measure: Cytokine measurements, e.g. IL-6 (immunoassay), in whole blood after ex-vivo stimulation.
timeFrame: Screening, Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 4 Day 1(each cycle is 21 days)
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Greenville
country: United States
facility: Greenville Health System
state: South Carolina
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: South Texas Accelerated Research Therapeutics | START San Antonio
state: Texas
city: Toronto
country: Canada
facility: Princess Margaret Hospital-University Health Network
state: Ontario
city: Quebec
country: Canada
facility: CHU de Québec-Hôpital de l'Enfant-Jésus
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
state: Baden-Württemberg
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Dresden
state: Sachsen
city: Berlin
country: Germany
facility: Charité Campus Benjamin Franklin (CBF)
city: Hospitalet de Llobregat
country: Spain
facility: Institut Català d'Oncologia Hospitalet
state: Barcelona
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal | Oncología
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria | Cardiology Department
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Trust (Surrey)
state: Surrey
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Manchester
country: United Kingdom
facility: Christie Hospital
Study officials:
References: