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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

Tracking Information
First Submitted Date  ICMJE August 9, 2019
First Posted Date  ICMJE August 28, 2019
Last Update Posted Date July 22, 2020
Actual Study Start Date  ICMJE August 15, 2019
Estimated Primary Completion Date February 7, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 23, 2019)
  • 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 ]
  • 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 ]
  • 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%.
  • 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
  • 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 ]
  • 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 ]
  • 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 ]
  • AUC(0-12) after multiple dose [ Time Frame: From pre-dose up to 12 hours after administration on Cycle 1 (21 days) Day 15 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 23, 2019)
  • 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. ]
  • 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) ]
  • 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) ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A First-in-Humans Dose Finding Study for an Aryl Hydrocarbon Receptor Inhibitor (AhRi) in Patients With Advanced Cancer
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Advanced Solid Tumors
Intervention  ICMJE
  • Drug: BAY2416964
    Oral application of study drug daily in a predefined dose escalation scheme.
  • 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).
Study Arms  ICMJE
  • Experimental: Dose escalation of BAY2416964
    Approximately 6 dose levels of BAY2416964 are planned
    Intervention: Drug: BAY2416964
  • Experimental: Dose expansion of BAY2416964 in tumor type specific
    Patients with NSCLC, HNSCC and Colorectal cancer MSS
    Intervention: Drug: BAY2416964
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 23, 2019)
114
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 4, 2023
Estimated Primary Completion Date February 7, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Bayer Clinical Trials Contact (+)1-888-84 22937 clinical-trials-contact@bayer.com
Listed Location Countries  ICMJE Germany,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04069026
Other Study ID Numbers  ICMJE 20201
2019-000722-22 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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.

Responsible Party Bayer
Study Sponsor  ICMJE Bayer
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Bayer
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP