Clinical trial NCT05099172: First in Human Study of BAY2927088 in Participants Who Have Advanced Non-small Cell Lung Cancer (NSCLC) With Mutations in the Genes of Epidermal Growth Factor Receptor (EGFR) and/or Human Epidermal Growth Factor Receptor 2 (HER2)
Official title: An Open Label, First-in-human Study of BAY 2927088 in Participants With Advanced Non-small Cell Lung Cancer (NSCLC) Harboring an EGFR and/or HER2 Mutation
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Non-small Cell Lung Cancer
EGFR Mutation
HER2 Mutation
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2021-10-29
Enrollment: 370
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: Researchers are looking for a better way to treat people who have advanced non-small cell lung cancer (NSCLC), a group of lung cancers that have spread to nearby tissues or to other parts of the body.

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) are proteins that help cells to grow and divide. A damage (also called mutation) to the building plans (genes) for these proteins in cancer cells leads to a production of abnormal EGFR and/or HER2. These abnormal proteins drive the growth and the spread of the cancer. Several EGFR and/or HER2 mutations exist in the cancer cells. The study treatment, BAY2927088, is expected to block the mutated EGFR and HER2 proteins which may stop the spread of NSCLC.

The main purpose of this study is to learn:

Escalation, Backfill, and Expansion Part:

* How safe is BAY2927088 for the participants?
* What is the highest dose of BAY2927088 that can be tolerated (maximum tolerated dose) by or given to (maximum administered dose) the participants?
* How does BAY2927088 move into, through, and out of the bodies of the participants?

For this, the researchers will measure the followings:

* The number of participants with medical problems, also called adverse events and serious adverse events, and their severity
* The number of participants who discontinue study treatment due to an adverse event.
* The highest dose of BAY2927088 that the participants can take without having adverse events (maximum tolerated dose (MTD)) or the maximum dose that is tested and found to be safe for the participants in case MTD cannot be found out (maximum administered dose (MAD)) of BAY2927088
* Number of participants experiencing adverse events that prevent an increase in the dose of BAY2927088 (dose-limiting toxicities (DLTs)) at each dose level
* The (average) total level of BAY2927088 in the blood (also called AUC) after receiving single or multiple doses of BAY2927088
* The (average) highest level of BAY2927088 in the blood (also called Cmax) after receiving a single or multiple doses of BAY2927088 Extension Part
* How well does BAY2927088 work in participants?

For this, the researchers will measure the following:

• Percentage of participants whose cancer completely disappears (complete response) or reduces by at least 30% (partial response) after taking the treatment (also known as objective response rate (ORR)). This will be assessed by doctors other than the study doctor.

This study has 4 parts:

* The escalation part aims to find the maximum daily amount (dose) of BAY2927088 that participants can receive.
* The backfill part aims to test the doses of BAY2927088 that are considered safe in the escalation part by giving it to more participants. This will help find optimal doses of BAY2927088 that work well and are safe to be tested in the next part.
* The expansion part aims to determine the dose of BAY2927088 to be tested in further studies.
* The extension part aims to determine whether the selected dose of BAY2927088 from the expansion part works well.

The participants in this study will take the study treatment BAY2927088 in 3-week periods called "cycles". They will in general take BAY2927088 once or twice daily as a liquid/tablet by mouth until their cancer gets worse, they have medical problems, they leave the study, or the study is terminated. Participants will have no more than 5 visits per cycle.

During the study, the study team will:

* take blood and urine samples,
* check the status of the cancer by doing computed tomography (CT) or magnetic resonance imaging (MRI) scans,
* check the participants' overall health and heart health,
* ask the participants questions about how they are feeling and what adverse events they are having.

An adverse event is considered "serious" when it leads to death, puts the participant's life at risk, requires hospitalization, causes disability, causes a baby being born with medical problems, or is medically important.


Eligibility criteria: Inclusion Criteria:

* Documented histologically or cytologically confirmed locally advanced NSCLC, not suitable for definitive therapy or recurrent or metastatic NSCLC at screening (small cell or mixed histologies are excluded).
* Documented disease progression after treatment with at least one prior systemic therapy for advanced disease. Participants who do not have standard of care access due to any reason, are intolerant to, or are not eligible for standard treatments, may also be eligible.

Note: Except for participants eligible for one of the groups (Expansion or Extension) who should have received no prior systemic treatment for locally advanced or metastatic disease.

* Adequate archival tumor tissue (ideally taken after last targeted treatment and not older than 6 months) has to be available, either from primary or metastatic sites. If archival material is not available, a fresh tumor biopsy should be performed if feasible and if the procedure poses no significant risk for the participant.
* Measurable disease by RECIST v1.1 with at least one lesion not chosen for biopsy during the screening period (if a biopsy is taken during screening) that can be accurately measured at baseline with computed tomography (CT) or magnetic resonance imaging (MRI) and that is suitable for accurate repeated measurements. A biopsied lesion should not be used as a target lesion for RECIST 1.1 tumor assessments (or, for participants in Expansion Group G, for RANO-BM tumor assessments). Previously irradiated lesions must have shown progression to be considered measurable.
* Documented activating EGFR and/or HER2 mutation assessed by a Clinical Laboratory Improvement Amendments (CLIA)-certified (United States \[US\] sites) or an equally accredited (outside of the US) local laboratory
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
* Minimum life expectancy of 12 weeks.
* Adequate bone marrow function as assessed by the following laboratory tests to be conducted within 7 days before the first dose of study treatment:

  1. Hemoglobin ≥ 9.0 g/dL. Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within 2 weeks prior to testing.
  2. Platelets ≥ 100 × 10\^9 cells/L.
  3. Absolute neutrophil count ≥ 1.5 ×10\^9 cells/L. Criteria must be met without the use of hematopoietic growth factors (e.g., G-CSF) within 2 weeks prior to testing.
* Adequate kidney function as assessed by following laboratory test to be conducted within 7 days before the first dose of study treatment:

  a. Estimated glomerular filtration rate (eGFR) \> 50 mL/min per 1.73 m\^2 according to the Modification of Diet in renal Disease Study Group (MDRD) formula.
* Adequate liver function as assessed by following laboratory tests to be conducted within 7 days before the first dose of study treatment:

  1. Total bilirubin ≤ 1.5 × ULN (or ≤ 3 X ULN for participants with documented Gilbert-Meulengracht Syndrome, or for participants with hyperbilirubinemia considered due to liver metastasis).
  2. Aspartate transaminase and alanine transaminase ≤ 2.5 × ULN (or ≤ 5 × ULN if due to liver involvement by tumor).

Exclusion Criteria:

* Treatment with an EGFR tyrosine kinase inhibitor (TKI) ≤ 8 days or 5x the terminal phase, elimination half-lives, whichever is shorter, prior to the first dose of study drug.
* Treatment with a systemic anti-cancer treatment (excluding EGFR TKIs as described above) ≤ 14 days prior to the first dose of study drug.
* Radiation therapy, stereotactic radiosurgery (SRS) and palliative radiation ≤ 14 days prior to the first dose of study drug.
* Treatment with immunotherapy ≤ 28 days prior to the first dose of study drug.
* Have any unresolved toxicity of Grade ≥ 2 from previous anti-cancer treatment, except for alopecia and skin pigmentation. Participants with chronic, but stable Grade 2 toxicities may be allowed to enroll after agreement between the Investigator and Sponsor.
* Any history of primary brain or leptomeningeal disease (symptomatic or asymptomatic), presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local treatment (such as radiotherapy or surgery).
* History of spinal cord compression or brain metastases with the following exceptions:

  1. Participants with treated brain metastases that are asymptomatic at screening and who are off or receiving low-dose corticosteroids (≤10 mg prednisone or equivalent) for at least 7 days prior to first dose of BAY 2927088 are eligible to enroll in Dose Escalation and Backfill.
  2. Participants with treated brain metastases that are asymptomatic at screening are eligible in Dose Expansion/Extension (with the exception of Group G) if all of the following criteria are met:

     * there is no evidence of progression (new or enlarging brain metastases) for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period.
     * Participants must be off or receiving low-dose corticosteroids (≤10 mg prednisone or equivalent) for 7 days prior to first dose of BAY2927088.
  3. Participants with history of spinal cord compression \>3 months from definitive therapy and stable by imaging (MRI or CT) during the screening period and clinically asymptomatic.
  4. Expansion Group G only: Participants with active (new or progressing) clinically stable brain metastases who do not require immediate CNS-directed treatment as per Investigator's judgement and who are off or receiving low-dose corticosteroids (≤10 mg prednisone or equivalent such as ≤ 1.5 mg/day dexamethasone) in the 7 days prior to first dose of BAY2927088 are eligible.
* History of congestive heart failure (CHF) Class \>II according to the New York Heart Association (NYHA) Functional Classification or serious cardiac arrhythmias requiring treatment (e.g. ventricular arrhythmias, atrial fibrillation) or any clinically important abnormalities in rhythm, conduction or morphology or resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval \>250 msec)
* Participants with:

  1. Known human immunodeficiency virus (HIV), except as noted below: Participants with history of HIV infection are eligible at the Investigator's discretion provided that: • CD4+ T-cell (CD4+) counts are ≥ 350 cells/uL • The participant has been on established antiretroviral therapy (ART) for at least 4 weeks prior to the start of study drug and has an HIV viral load less than 400 copies/mL prior to start of the study treatment • The ART being used does not contain strong inducers or inhibitors of CYP3A4, and is not anticipated to cause overlapping toxicities with study drug • The participant has not had an opportunistic infection within the past 12 months
  2. Active Hepatitis B infection (positive for Hepatitis B surface antigen \[HbsAg\]) and Hepatitis B virus \[HBV\] DNA).
  3. Active Hepatitis C infection (positive anti-HCV Antibody and quantitative HCV RNA results greater than the lower limits of detection of the assay).

     NOTE: Participants with history of chronic HBV or HCV infection are eligible at the Investigator's discretion provided that the disease is stable and sufficiently controlled under treatment.
* Use of strong CYP3A4 inhibitors and inducers from 14 days prior to first administration of study drug. Strong CYP3A4 inhibitors and inducers are prohibited during the study and until Safety FU (follow up) visit.

Primary outcomes:
measure: Number of participants with treatment-emergent adverse events (TEAEs)
timeFrame: Up to 30 days after the last administration of study treatment
measure: Number of participants with treatment-emergent serious adverse events (TESAEs)
timeFrame: Up to 30 days after the last administration of study treatment
measure: Severity of TEAEs
timeFrame: Up to 30 days after the last administration of study treatment
measure: Severity of TESAEs
timeFrame: Up to 30 days after the last administration of study treatment
measure: Number of participants who discontinue study treatment due to an AE
timeFrame: About 4 years (Up to the end of study treatment)
measure: Maximum tolerated dose (MTD) or maximum administered dose (MAD) of BAY2927088 within the DLT observation period in Dose Escalation (including participants from Backfill qualifying for the MTD population)
timeFrame: At the end of Cycle 1 of a 21-day cycle
measure: Number of participants experiencing dose-limiting toxicities (DLTs) at each dose level associated with administration of BAY2927088 in the DLT observation period in Dose Escalation (including participants from Backfill)
timeFrame: At the end of Cycle 1 of a 21-day cycle
measure: Cmax of BAY2927088
timeFrame: Cycle 1, Day 1 (Cycle duration is 21 days)
measure: AUC(0-24) of BAY2927088 for QD
timeFrame: Cycle 1, Day 1 (Cycle duration is 21 days)
measure: AUC(0-12) of BAY2927088 for BID
timeFrame: Cycle 1, Day 1 (Cycle duration is 21 days)
measure: Cmax,md of BAY2927088
timeFrame: Cycle 1, Day 15 (Cycle duration is 21 days)
measure: AUC(0-24)md of BAY2927088 for QD
timeFrame: Cycle 1, Day 15 (Cycle duration is 21 days)
measure: AUC(0-12)md of BAY2927088 for BID
timeFrame: Cycle 1, Day 15 (Cycle duration is 21 days)
measure: Overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central review (BICR) in extension part
timeFrame: From the start of the study treatment up to 12 months
Secondary outcomes:
measure: Overall response rate (ORR) as per RECIST v1.1 by investigator assessment
timeFrame: About 4 years
measure: Recommended phase 2 dose (RP2D) of BAY2927088
timeFrame: About 1.5 years
measure: ORR per RECIST v1.1 by Investigator assessment in extension part
timeFrame: From the start of the study treatment up to 12 months
measure: Disease control rate (DCR) per RECIST v1.1 by Investigator assessment and BICR in extension part
timeFrame: From the start of the study treatment up to 12 months
measure: Duration of response (DOR) per RECIST 1.1 by Investigator assessment and BICR in extension part
timeFrame: From the start of the study treatment up to 12 months
measure: Progression-free survival (PFS) per RECIST 1.1 by Investigator assessment and BICR in extension part
timeFrame: From the start of the study treatment up to 12 months
measure: Overall survival (OS) in extension part
timeFrame: From the start of the study treatment up to 12 months
measure: Number of participants with treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) categorized by severity in extension part
timeFrame: Up to 30 days after the last administration of study treatment
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center at Banner Gateway Medical Center
state: Arizona
city: Duarte
country: United States
facility: City of Hope - Duarte Cancer Center
state: California
city: Atlanta
country: United States
facility: Emory Winship Cancer Institute
state: Georgia
city: Bethesda
country: United States
facility: The Center for Cancer and Blood Disorders
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Brigette Harris Cancer Pavilion at Henry Ford Cancer Center - Detroit
state: Michigan
city: Mineola
country: United States
facility: NYU Langone Hospital - Long Island - Urology
state: New York
city: Nashville
country: United States
facility: Tennessee Oncology - Nashville Centennial Clinic
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg - Pneumology Department
state: Vlaams-Brabant
city: Roeselare
country: Belgium
facility: AZ Delta | Clinical Trial Center - Pneumology
state: West-Flanders
city: Natal
country: Brazil
facility: Liga Norte Riograndense Contra o Cancer | Centro de Pesquisa Clínica
state: Rio Grande Do Norte
city: São José do Rio Preto
country: Brazil
facility: Hospital de Base | Integrated Research Center
state: Sao Paulo
city: Sao Paulo
country: Brazil
facility: Hospital Israelita Albert Einstein | Morumbi - Clinical Research Department
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Beijing
country: China
facility: Beijing Hospital
state: Beijing
city: Fuzhou
country: China
facility: Fujian Cancer Hospital
state: Fujian
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital
state: Heilongjiang
city: Wuhan
country: China
facility: Union Hospi, Tongji Med College, Huazhong Univ. Scien&Tech
state: Hubei
city: Changsha
country: China
facility: Hunan Cancer Hospital
state: Hunan
city: Nanjing
country: China
facility: NJ Drum Tower Hospital, the Affil Hos of NJ Univ Med School
state: Jiangsu
city: Jinan
country: China
facility: Qilu Hosp., Shandong Univ.
state: Shandong
city: Shanghai
country: China
facility: Shanghai Chest Hospital, Shanghai Jiaotong University
state: Shanghai
city: Chengdu
country: China
facility: West China Hospital Sichuan University
state: Sichuan
city: Jinan
country: China
facility: Shandong University - Shandong Cancer Hospital
state: Sichuan
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital, Zhejiang Univ. School of Medicine
state: Zhejiang
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Zhejiang
city: Taizhou
country: China
facility: Zhejiang University School of Medicine - Taizhou Hospital of Zhejiang Province
state: Zhejiang
city: Bordeaux
country: France
facility: Institut Bergonie - Unicancer Nouvelle Aquitaine - Service Oncologie medicale
city: Lyon Cedex 08
country: France
facility: UNICANCER - Centre Leon-Berard (CLB) - Medical oncology
city: Nantes
country: France
facility: Hopital Nord Laennec - Oncologie medicale thoracique et digestive
city: Paris
country: France
facility: Institut Curie - Paris - Oncologie medicale
city: Saint Herblain
country: France
facility: Institut de Cancerologie Ouest - Saint Herblain - Oncologie medicale
city: Villejuif Cedex
country: France
facility: Gustave Roussy - Departement Oncologie-Radiotherapie
city: Hong Kong
country: Hong Kong
facility: Prince of Wales Hospital
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Petach Tikva
country: Israel
facility: Rabin Medical Center | Beilinson Hospital - Internal Medicine C Department
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Parma
country: Italy
facility: Azienda Ospedaliero Universitaria Parma - SC Oncologia Medica
state: Emilia-Romagna
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico di Aviano - Oncologia Medica e dei Tumori Immuno-Correlati
state: Friuli-Venezia Giulia
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS - UOC Fase I
state: Lazio
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori - S. C. Oncologia Medica 1
state: Lombardia
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia s.r.l - Sviluppo di nuovi farmaci per Terapie Innovative
state: Lombardia
city: Rozzano
country: Italy
facility: Humanitas Mirasole S.p.A. - Oncologia Medica ed Ematologia
state: Lombardia
city: Orbassano
country: Italy
facility: Azienda Ospedaliero-Universitaria San Luigi Gonzaga - Oncologia Medica
state: Piemonte
city: Verona
country: Italy
facility: Centro Ricerche Cliniche Di Verona S.r.l. - Oncologia
city: Nagoya
country: Japan
facility: Aichi Cancer Center Hospital
state: Aichi
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Matsuyama
country: Japan
facility: National Hospital Organization Shikoku Cancer Center
state: Ehime
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
state: Hokkaido
city: Yokohama
country: Japan
facility: Kanagawa Cancer Center
state: Kanagawa
city: Osaka-shi
country: Japan
facility: Osaka International Cancer Institute
state: Osaka
city: Osakasayama
country: Japan
facility: Kindai University Hospital
state: Osaka
city: Sunto
country: Japan
facility: Shizuoka Cancer Center
state: Shizuoka
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Yonago
country: Japan
facility: Tottori University Hospital
state: Tottori
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Cheongju-si
country: Korea, Republic of
facility: Chungbuk National University Hospital
state: Chungcheongbugdo
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggido
city: Suwon-si
country: Korea, Republic of
facility: St.Vincent's Hospital
state: Gyeonggido
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Amsterdam
country: Netherlands
facility: Nederlands Kanker Instituut
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center | Research Department - Lung Diseases
city: Porto
country: Portugal
facility: IPO Porto
city: Singapore
country: Singapore
facility: National University Hospital Medical Centre
city: Singapore
country: Singapore
facility: National Cancer Center Singapore
city: Singapore
country: Singapore
facility: Curie Oncology | Mount Elizabeth Novena
city: Barcelona
country: Spain
facility: Institut Catala D'oncologia - Oncologia
state: L Hospitalet De Llobregat
city: Barcelona
country: Spain
facility: Hospital Quiron Dexeus - Oncologia
city: Barcelona
country: Spain
facility: Ciutat Sanitaria i Universitaria de la Vall d'Hebron
city: Madrid
country: Spain
facility: Fundacion Jimenez Diaz (Clinica de la Concepcion)
city: Madrid
country: Spain
facility: Centro Integral Oncológico Clara Campal
city: Valencia
country: Spain
facility: Hospital Universitario Y Politecnico La Fe - Oncologia
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Tainan
country: Taiwan
facility: Chi-Mei Medical Center, Liouyine
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital at Linkou
Study officials:
References: