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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04069026
Recruitment Status : Recruiting
First Posted : August 28, 2019
Last Update Posted : July 22, 2020
Sponsor:
Information provided by (Responsible Party):
Bayer

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.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: BAY2416964 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 114 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 15, 2019
Estimated Primary Completion Date : February 7, 2023
Estimated Study Completion Date : May 4, 2023

Arm Intervention/treatment
Experimental: Dose escalation of BAY2416964
Approximately 6 dose levels of BAY2416964 are planned
Drug: BAY2416964
Oral application of study drug daily in a predefined dose escalation scheme.

Experimental: Dose expansion of BAY2416964 in tumor type specific
Patients with NSCLC, HNSCC and Colorectal cancer MSS
Drug: BAY2416964
Oral application of study drug daily at the dose defined in the dose escalation scheme to determine the recommended phase 2 dose (RP2D).




Primary Outcome Measures :
  1. The incidence of treatment emergent adverse events (TEAEs) including treatment-emergent serious adverse events (TESAEs) and and dose-limiting toxicities (DLTs) [ Time Frame: Up to 30 days after end of treatment ]
  2. Severity of treatment emergent adverse events (TEAEs) including treatment-emergent serious adverse events (TESAEs) and dose-limiting toxicities (DLTs) [ Time Frame: Up to 30 days after end of treatment ]
  3. Maximum tolerated dose (MTD) or maximum administered dose (MAD) of BAY2416964 [ Time Frame: Cycle 1 (21 days) in dose escalation ]
    MTD:defined as the dose level that can be given such that the estimated Dose limiting toxicity (DLT) probability is closest to approximately 25%.

  4. Recommended Phase II dose (RP2D) of BAY2416964 [ Time Frame: Up to 30 days after end of treatment ]
    Integration of all available safety, PK and PD data

  5. Maximal plasma exposure (Cmax) for once daily (QD) dosing of BAY 2416964 after single-dose and multiple-dose in Cycle 1. [ Time Frame: 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 ]
  6. Area under the curve [AUC (0 - 24)] for QD dosing of BAY 2416964 after single-dose in Cycle 1. [ Time Frame: From pre-dose up to 24 hours after administration on Cycle 1 (21 days) Day 1 ]
  7. Alternatively AUC(0-12) for 2 times daily (BID) dosing after single dose in cycle 1 (based on outcome of PK decision point) [ Time Frame: From pre-dose up to 12 hours after administration on Cycle 1 (21 days) Day 1 ]
  8. AUC(0-12) after multiple dose [ Time Frame: From pre-dose up to 12 hours after administration on Cycle 1 (21 days) Day 15 ]

Secondary Outcome Measures :
  1. Objective response rate (ORR) by RECIST 1.1 [ Time Frame: At the end of cycle 2 (- 7 days; each cycle is 21 days) and every 6 weeks thereafter, an average of 6 months. ]
  2. Change from baseline in AhR target gene expression in whole blood after ex-vivo stimulation [ Time Frame: Screening, Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 4 Day 1(each cycle is 21 days) ]
  3. Cytokine measurements, e.g. IL-6 (immunoassay), in whole blood after ex-vivo stimulation. [ Time Frame: Screening, Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 4 Day 1(each cycle is 21 days) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 clinical benefit, or are intolerant to treatment, or refuse standard treatment. Note: there is no limit to the number of prior treatment regimens. Immune checkpoint inhibitors are also allowed in pretreatment.

    • Dose Escalation: all solid tumor types
    • Tumor type-specific high-dose (MTD or MAD) Expansion cohorts: Will be grouped by tumor type, but no specific biomarker selection will be applied:

      • NSCLC
      • HNSCC
      • Colorectal cancer MSS
    • Tumor type-specific low-dose Expansion cohort: Any tumor type based on data from dose escalation and expansion indicating pharmacodynamics effect and/or clinical response from the tumor type-specific high-dose(MTD or MAD) expansion.
  • 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 109/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 109/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 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) or any other form of immunosuppressive therapy within 7 days 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.
  • Currently present advanced or metastatic primary brain tumors or untreated brain metastases and/or carcinomatous meningitis.

Participants with previously treated brain metastases may participate if all of the following criteria are met:

  • Must be clinically stable and without requirement of steroid therapy for at least 14 days prior to first dose of study intervention.
  • Participants with neurological symptoms must undergo CT/MRI scan of the brain to exclude new or progressive brain metastases.

    • Interstitial lung disease or chronic obstructive pulmonary disease (COPD) with ongoing signs and symptoms at the time of screening. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
    • 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.
    • Prior radiotherapy within 2 weeks before start of BAY2416964. 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 doses > 10 mg/day prednisone or equivalent, 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04069026


Contacts
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Contact: Bayer Clinical Trials Contact (+)1-888-84 22937 clinical-trials-contact@bayer.com

Locations
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United States, Connecticut
Yale University School of Medicine Recruiting
New Haven, Connecticut, United States, 06520-8028
United States, South Carolina
Greenville Health System Recruiting
Greenville, South Carolina, United States, 29605
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
South Texas Accelerated Research Therapeutics, LLC Recruiting
San Antonio, Texas, United States, 78229-3307
Germany
Universitätsklinikum Heidelberg Not yet recruiting
Heidelberg, Baden-Württemberg, Germany, 69120
Spain
Institut Català d'Oncologia Hospitalet Not yet recruiting
L'Hospitalet de Llobregat, Barcelona, Spain, 08907
Hospital Ramón y Cajal Not yet recruiting
Madrid, Spain, 28034
Hospital Universitario 12 de Octubre Not yet recruiting
Madrid, Spain, 28041
Hospital Clínico Universitario de Valencia Not yet recruiting
Valencia, Spain, 46010
United Kingdom
Royal Marsden NHS Trust (Surrey) Recruiting
Sutton, Surrey, United Kingdom, SM2 5PT
Sponsors and Collaborators
Bayer
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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT04069026    
Other Study ID Numbers: 20201
2019-000722-22 ( EudraCT Number )
First Posted: August 28, 2019    Key Record Dates
Last Update Posted: July 22, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description:

Availability of this study's data will be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access.

As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the Study sponsors section of the portal.


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bayer:
Non-small cell lung cancer (NSCLC)
Head and neck squamous cell carcinoma (HNSCC)
Colorectal cancer microsatellite stable (MSS)
Advanced cancer
Immunotherapy
Immuno oncology
Aryl Hydrocarbon Receptor inhibitor(AhRi)
Aryl Hydrocarbon Receptor