Clinical trial NCT03797326: Efficacy and Safety of Pembrolizumab (MK-3475) Plus Lenvatinib (E7080/MK-7902) in Previously Treated Participants With Select Solid Tumors (MK-7902-005/E7080-G000-224/LEAP-005)
Official title: A Multicenter, Open-label Phase 2 Study of Lenvatinib (E7080/MK-7902) Plus Pembrolizumab (MK-3475) in Previously Treated Subjects With Selected Solid Tumors (LEAP-005)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Advanced Solid Tumors
Triple Negative Breast Cancer
Ovarian Cancer
Gastric Cancer
Colorectal Cancer
Glioblastoma
Biliary Tract Cancers
Pancreatic Cancer
Keywords: programmed cell death 1 (PD-1, PD1)
programmed cell death ligand 1 (PD-L1, PDL1)
programmed cell death ligand 2 (PD-L2, PDL2)
tyrosine kinase inhibitor (TKI)
multiple TKI
Vascular Endothelial Growth Factor Receptor (VEFG)
Fibroblast Growth Factor (FGF)
Platelet-Derived Growth Factor (PDGF)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
Collaborators: name: Eisai Inc.
First posted: 2019-01-09
Enrollment: 603
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the safety and efficacy of combination therapy with pembrolizumab (MK-3475) and lenvatinib (E7080/MK-7902) in participants with triple negative breast cancer (TNBC), ovarian cancer, gastric cancer, colorectal cancer (CRC), glioblastoma (GBM), biliary tract cancers (BTC), or pancreatic cancer.


Eligibility criteria: Inclusion Criteria:

* Has a histologically or cytologically-documented, advanced (metastatic and/or unresectable) solid tumor that is incurable and for which prior standard systemic therapy has failed in one of the following cohorts: TNBC, Ovarian Cancer, Gastric Cancer, Colorectal Cancer, GBM, BTC (intrahepatic, extrahepatic cholangiocarcinoma and gall bladder cancer; excludes Ampulla of Vater), Pancreatic Cancer
* Must have progressed on or since the last treatment
* Has measurable disease per RECIST 1.1 (RANO for the GBM cohort) as assessed by the local site investigator/radiology and confirmed by BICR
* Has provided a PD-L1 evaluable archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
* Male participants agree to use approved contraception during the treatment period for at least 7 days after the last dose of lenvatinib, or refrain from heterosexual intercourse during this period
* Female participants are not pregnant or breastfeeding, and are not a woman of childbearing potential (WOCBP), OR are a WOCBP that agrees to use contraception during the treatment period (or 14 days prior to the initiation of study treatment for oral contraception) and for at least 120 days post pembrolizumab, or 30 days post lenvatinib, whichever occurs last
* Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 3 days of study treatment initiation
* Has adequate organ function

For Triple Negative Breast Cancer Participants:

* Has received one or 2 prior lines of therapy
* Has Lactate Dehydrogenase (LDH) \<2.0 x Upper Limit of Normal (ULN)
* Has locally determined results for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 tumor analyses

For Ovarian Cancer Participants:

- Has primary ovarian cancer and has received 3 prior lines of therapy.

For Gastric Cancer Participants:

- Has received 2 prior lines of therapy. Note: Gastric cancer will include participants with both gastric and gastroesophageal junction (GEJ) adenocarcinoma. Participants with squamous cell carcinoma histology are not eligible

For Colorectal Cancer Participants:

- Has received 2 prior lines of therapy

For GBM Participants:

* Has failed initial systemic therapy for newly diagnosed GBM
* Have the following time periods elapsed before the projected start of scheduled study treatment: 1) at least 3 weeks from prior surgical resection, 2) at least 1 week from stereotactic biopsy, 3) at least 6 months from completion of prior radiotherapy, 4) at least 4 weeks (or 5 half-lives, whichever is shorter) from any investigational agent, 5) at least 4 weeks from cytotoxic therapy, 6) at least 6 weeks from antibodies, 7) at least 4 weeks (or 5 half-lives, whichever is shorter) from other antitumor therapies and 1 week for cancer vaccines
* Be neurologically stable (e.g. without a progression of neurologic symptoms or requiring escalating doses of systemic steroid therapy within last 2 weeks) and clinically stable
* Has histologically confirmed World Health Organization (WHO) Grade IV GBM
* Has locally determined result for O\^6-methylguanine-DNA methyltransferase (MGMT) analysis

For Biliary Tract Cancer Participants:

* Has received 1 prior line of therapy
* Child-Pugh Score, Class A: well-compensated disease. Child-Pugh Score of 5-6

For Pancreatic Cancer Participants:

* Has pathologically (histologically or cytologically) confirmed pancreatic ductal adenocarcinoma that is metastatic at enrollment
* Has received one or 2 prior lines of therapy
* Has received prior therapy with at least 1 (platinum-containing regimen or gemcitabine-containing regimen) but no more than 2 prior systemic therapies for unresectable or metastatic pancreatic cancer

Exclusion Criteria:

* Has gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib
* Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment (applies to all cohorts except the ovarian cancer cohort)
* Has radiographic evidence of encasement or invasion of a major blood vessel or of intratumoral cavitation. Participants with portal vein invasion (Vp4), inferior vena cava, or cardiac involvement based on imaging in the BTC cohort are not eligible for enrollment
* Has clinical significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study treatment
* Has significant cardiovascular impairment within 12 months of the first dose of study treatment, such as history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident (CVA), or cardiac arrhythmia associated with hemodynamic instability
* Has a history of arterial thromboembolism within 12 months of start of study treatment
* Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
* Has a serious nonhealing wound, ulcer or bone fracture
* Has had major surgery within 3 weeks prior to first dose of study interventions
* Has biologic response modifiers therapy (e.g. granulocyte colony-stimulating factor) within 4 weeks before study entry
* Has preexisting ≥Grade 3 gastrointestinal (GI) or non-gastrointestinal fistula
* Has received prior therapy with lenvatinib, an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], Tumor necrosis factor receptor superfamily, member 4 \[OX 40\], tumor necrosis factor receptor superfamily member 9 \[CD137\])
* Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to study treatment start
* If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
* Has received prior radiotherapy within 2 weeks of start of study treatment. 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-central nervous system (CNS) disease
* Has received a live vaccine within 30 days prior to the first dose of study treatment
* Has known intolerance to lenvatinib (and/or any of the excipients)
* Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment
* Has known active CNS metastases and/or carcinomatous meningitis
* Has tumors involving the brain stem
* Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
* Has an active autoimmune disease that has required systemic treatment in past 2 years
* Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
* Has an active infection requiring systemic therapy
* Has a known history of human immunodeficiency virus (HIV) infection
* Has a known history of hepatitis B or known active hepatitis C virus infection
* Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
* Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
* Has had an allogenic tissue/solid organ transplant (large organ transplants, stem-cell transplant requiring chronic immunosuppressant therapy necessary to prevent graft rejection)

For GBM Participants:

* Has carcinomatous meningitis
* Has recurrent tumor greater than 6 cm in maximum diameter
* Has tumor primarily localized to the brainstem or spinal cord
* Has presence of multifocal tumor, diffuse leptomeningeal or extracranial disease
* Has evidence of intratumoral or peritumoral hemorrhage on baseline magnetic resonance imaging (MRI) scan other than those that are grade ≤ 1 and either post-operative or stable on at least 2 consecutive MRI scans
* Has received Optune® TTFields within 2 weeks of study intervention

Primary outcomes:
measure: Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) or Response Assessment in Neuro-Oncology (RANO) Criteria for Glioblastoma (GBM) by Investigator Assessment in Initial Cohorts
timeFrame: Up to approximately 72 months
measure: ORR per RECIST 1.1 or RANO (GBM) by Blinded Independent Central Review (BICR) in Expanded Cohorts (Combined with Initial Cohorts)
timeFrame: Up to approximately 72 months
measure: Percentage of Participants Receiving Pembrolizumab Plus Lenvatinib who Experience an Adverse Event (AE)
timeFrame: Up to approximately 72 months
measure: Percentage of Participants Receiving Pembrolizumab Plus Lenvatinib who Discontinue Study Treatment Due to an AE
timeFrame: Up to approximately 72 months
measure: Percentage of Participants Receiving Lenvatinib Monotherapy who Experience an AE
timeFrame: Up to approximately 72 months
measure: Percentage of Participants Receiving Lenvatinib Monotherapy who Discontinue Study Treatment Due to an Adverse Event (AE)
timeFrame: Up to approximately 72 months
Secondary outcomes:
measure: Disease Control Rate (DCR) per RECIST 1.1 by Investigator Assessment in Initial Cohorts
timeFrame: Up to approximately 72 months
measure: Duration of Response (DOR) per RECIST 1.1 or RANO (GBM) by Investigator Assessment in Initial Cohorts
timeFrame: Up to approximately 72 months
measure: Progression Free Survival (PFS) per RECIST 1.1 or RANO (GBM) by Investigator Assessment in Initial Cohorts
timeFrame: Up to approximately 72 months
measure: Overall Survival (OS) in Initial Cohorts
timeFrame: Up to approximately 72 months
measure: DCR per RECIST 1.1 by BICR in Expanded Cohorts (Combined with Initial Cohorts)
timeFrame: Up to approximately 72 months
measure: DOR per RECIST 1.1 or RANO (GBM) by BICR in Expanded Cohorts (Combined with Initial Cohorts)
timeFrame: Up to approximately 72 months
measure: PFS per RECIST 1.1 or RANO (GBM) by BICR in Expanded Cohorts (Combined with Initial Cohorts)
timeFrame: Up to approximately 72 months
measure: OS in Expanded Cohorts (Combined with Initial Cohorts)
timeFrame: Up to approximately 72 months
measure: ORR per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm
timeFrame: Up to approximately 72 months
measure: DCR per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm
timeFrame: Up to approximately 72 months
measure: DOR per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm
timeFrame: Up to approximately 72 months
measure: PFS per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm
timeFrame: Up to approximately 72 months
measure: OS in Lenvatinib Monotherapy Arm
timeFrame: Up to approximately 72 months
measure: Plasma Concentration of Lenvatinib
timeFrame: Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose and 2-12 hours post-dose; Cycle 2 Day 1: pre-dose, 0.5-4 hours, and 6-10 hours post-dose (up to approximately 23 days). Each cycle is 21 days.
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope ( Site 0002)
state: California
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center ( Site 0003)
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center ( Site 0005)
state: California
city: Aurora
country: United States
facility: University of Colorado, Anschutz Cancer Pavilion ( Site 0007)
state: Colorado
city: Orlando
country: United States
facility: University of Florida-Health Cancer Center-Orlando ( Site 0015)
state: Florida
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey ( Site 0009)
state: New Jersey
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center at NYU Langone Health ( Site 0023)
state: New York
city: Fargo
country: United States
facility: Sanford Fargo Medical Center ( Site 0059)
state: North Dakota
city: Allentown
country: United States
facility: Lehigh Valley Hospital- Cedar Crest ( Site 0047)
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Sanford Cancer Center ( Site 0058)
state: South Dakota
city: Germantown
country: United States
facility: West Cancer Center - East Campus ( Site 0018)
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Centers - Medical City Hospital ( Site 0049)
state: Texas
city: Seattle
country: United States
facility: Swedish Medical Center ( Site 0021)
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center ( Site 0017)
state: Wisconsin
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Fundacion Favaloro para la Docencia e Investigacion Medica ( Site 2106)
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Hospital Aleman ( Site 2100)
state: Caba
city: Ciudad de Buenos Aires
country: Argentina
facility: Hospital Britanico de Buenos Aires ( Site 2109)
state: Caba
city: Rosario
country: Argentina
facility: Instituto de Oncologia de Rosario ( Site 2105)
state: Santa Fe
city: Buenos Aires
country: Argentina
facility: CEMIC ( Site 2104)
city: Caba
country: Argentina
facility: IDIM Instituto de Diagnostico e Investigaciones Metabolicas ( Site 2101)
city: Herston
country: Australia
facility: Royal Brisbane and Women s Hospital ( Site 0901)
state: Queensland
city: Melbourne
country: Australia
facility: Alfred Health ( Site 0902)
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital ( Site 0903)
state: Western Australia
city: Abbotsford
country: Canada
facility: BC Cancer - Abbotsford ( Site 0200)
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba ( Site 0201)
state: Manitoba
city: Hamilton
country: Canada
facility: Hamilton Health Sciences-Juravinski Cancer Centre ( Site 0208)
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Research Institute ( Site 0207)
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre ( Site 0202)
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0210)
state: Quebec
city: Quebec
country: Canada
facility: CHU de Quebec Universite de Laval ( Site 0206)
city: Temuco
country: Chile
facility: Centro Investigación del Cáncer James Lind ( Site 1203)
state: Araucania
city: Santiago
country: Chile
facility: Fundacion Arturo Lopez Perez ( Site 1201)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Pontificia Universidad Catolica de Chile ( Site 1202)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Hospital Clinico Universidad de Chile ( Site 1200)
state: Region M. De Santiago
city: Medellin
country: Colombia
facility: Fundacion Colombiana de Cancerologia Clinica Vida ( Site 1105)
state: Antioquia
city: Bogota
country: Colombia
facility: Instituto Nacional de Cancerologia E.S.E ( Site 1102)
state: Distrito Capital De Bogota
city: Pereira
country: Colombia
facility: Oncologos del Occidente S.A. ( Site 1106)
state: Risaralda
city: Cali
country: Colombia
facility: Fundacion Valle del Lili ( Site 1101)
state: Valle Del Cauca
city: Nice
country: France
facility: Centre Antoine Lacassagne ( Site 0404)
state: Alpes-Maritimes
city: Lyon
country: France
facility: Centre Leon Berard ( Site 0405)
state: Auvergne
city: Toulouse
country: France
facility: Institut Claudius Regaud IUCT Oncopole ( Site 0403)
state: Haute-Garonne
city: Lille
country: France
facility: Centre Oscar Lambret ( Site 0401)
state: Nord
city: Saint-Herblain
country: France
facility: Institut de Cancerologie de l Ouest Centre Rene Gauducheau ( Site 0402)
state: Val-de-Marne
city: Villejuif
country: France
facility: Institut Gustave Roussy ( Site 0400)
state: Val-de-Marne
city: Stuttgart
country: Germany
facility: Robert Bosch GmbH ( Site 0307)
state: Baden-Wurttemberg
city: Regensburg
country: Germany
facility: Universitaetsklinikum Regensburg ( Site 0304)
state: Bayern
city: Frankfurt am Main
country: Germany
facility: Universitaetsklinikum Frankfurt ( Site 0306)
state: Hessen
city: Wiesbaden
country: Germany
facility: HELIOS Dr. Horst Schmidt Kliniken Wiesbaden ( Site 0301)
state: Hessen
city: Gera
country: Germany
facility: SRH Wald-Klinikum Gera GmbH ( Site 0309)
state: Thuringen
city: Jena
country: Germany
facility: Universitaetsklinikum Jena ( Site 0302)
state: Thuringen
city: Beer Sheva
country: Israel
facility: Soroka Medical Center ( Site 0601)
city: Haifa
country: Israel
facility: Rambam Medical Center ( Site 0602)
city: Jerusalem
country: Israel
facility: Hadassah Ein Kerem Medical Center ( Site 0604)
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center ( Site 0600)
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center ( Site 0603)
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas Research Hospital ( Site 1402)
state: Milano
city: Siena
country: Italy
facility: Policlinico Le Scotte - A.O. Senese ( Site 1401)
state: Toscana
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Fondazione Pascale ( Site 1400)
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario A. Gemelli ( Site 1403)
city: Songpagu
country: Korea, Republic of
facility: Asan Medical Center ( Site 1002)
state: Seoul
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital ( Site 1000)
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System ( Site 1001)
city: Arkhangelsk
country: Russian Federation
facility: Arkhangelsk Clinical Oncological Dispensary ( Site 1600)
state: Arkhangel Skaya Oblast
city: Moscow
country: Russian Federation
facility: Russian Oncological Research Center n.a. N.N. Blokhin ( Site 1604)
state: Moskva
city: Saint-Petersburg
country: Russian Federation
facility: Leningrad Regional Oncology Center ( Site 1609)
state: Sankt-Peterburg
city: Saint-Petersburg
country: Russian Federation
facility: Scientific Research Oncology Institute n.a. N.N.Petrov ( Site 1610)
state: Sankt-Peterburg
city: Saint-Petersburg
country: Russian Federation
facility: City Clinical Oncology Center ( Site 1608)
state: Sankt-Peterburg
city: Kazan
country: Russian Federation
facility: Republican Clinical Oncology Dispensary of Tatarstan MoH ( Site 1603)
state: Tatarstan, Respublika
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial ( Site 0703)
city: Madrid
country: Spain
facility: Hospital Universitario Gregorio Maranon ( Site 0701)
city: Madrid
country: Spain
facility: Clinica Universitaria de Navarra ( Site 0704)
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal ( Site 0702)
city: Bern
country: Switzerland
facility: Inselspital Universitaetsspital Bern ( Site 1705)
state: Berne
city: Chur
country: Switzerland
facility: Kantonsspital Graubuenden ( Site 1704)
state: Grisons
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen ( Site 1702)
state: Sankt Gallen
city: Bellinzona
country: Switzerland
facility: Ospedale Regionale di Bellinzona e Valli ( Site 1703)
state: Ticino
city: Geneve
country: Switzerland
facility: Hopitaux Universitaires de Geneve HUG ( Site 1701)
city: Zurich
country: Switzerland
facility: Universitaetsspital Zurich ( Site 1700)
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital ( Site 3003)
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital ( Site 3000)
city: Bangkok
country: Thailand
facility: Chulalongkorn University ( Site 5001)
state: Krung Thep Maha Nakhon
city: Bangkok
country: Thailand
facility: Ramathibodi Hospital. ( Site 5002)
state: Krung Thep Maha Nakhon
city: Bangkok
country: Thailand
facility: Siriraj Hospital ( Site 5003)
state: Krung Thep Maha Nakhon
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Trust ( Site 0803)
state: Cambridgeshire
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary. Univ. Hosp. of Leicester NHS Trust ( Site 0804)
state: Leicestershire
city: London
country: United Kingdom
facility: Guy's Hospital ( Site 0806)
state: London, City Of
city: London
country: United Kingdom
facility: Royal Marsden Hospital (Sutton) ( Site 0800)
state: Surrey
city: Manchester
country: United Kingdom
facility: Christie NHS Foundation Trust ( Site 0805)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Gonzalez-Martin A, Chung HC, Saada-Bouzid E, Yanez E, Senellart H, Cassier PA, Basu B, Corr BR, Girda E, Dutcus C, Okpara CE, Ghori R, Jin F, Groisberg R, Lwin Z. Lenvatinib plus pembrolizumab for patients with previously treated advanced ovarian cancer: Results from the phase 2 multicohort LEAP-005 study. Gynecol Oncol. 2024 Jul;186:182-190. doi: 10.1016/j.ygyno.2024.04.011. Epub 2024 May 7.
citation: Chung HC, Saada-Bouzid E, Longo F, Yanez E, Im SA, Castanon E, Desautels DN, Graham DM, Garcia-Corbacho J, Lopez J, Dutcus C, Okpara CE, Ghori R, Jin F, Groisberg R, Korakis I. Lenvatinib plus pembrolizumab for patients with previously treated, advanced, triple-negative breast cancer: Results from the triple-negative breast cancer cohort of the phase 2 LEAP-005 Study. Cancer. 2024 Oct 1;130(19):3278-3288. doi: 10.1002/cncr.35387. Epub 2024 Jun 21.