Clinical trial NCT04489771: A Study of Belzutifan (MK-6482) in Participants With Advanced Renal Cell Carcinoma (MK-6482-013)
Official title: Phase 2 Study of MK-6482 in Participants With Advanced Renal Cell Carcinoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Carcinoma, Renal Cell
Keywords: Hypoxia inducible factor (HIF)
Hypoxia inducible factor 1B (HIF-1B)
Hypoxia inducible factor 2 alpha (HIF-2 alpha)
Hypoxia inducible factor 2α (HIF-2α)
Renal Cell Carcinoma (RCC)
Kidney cancer
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2020-07-28
Enrollment: 154
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: This study will compare the efficacy and safety of two doses of belzutifan in participants with advanced renal cell carcinoma (RCC) with clear cell component after prior therapy.

The primary hypothesis is that the higher dose of belzutifan is superior to the standard dose in terms of objective response rate (ORR).


Eligibility criteria: Inclusion Criteria:

* Has a histologically confirmed diagnosis of locally advanced/metastatic RCC with clear cell component
* Has measurable disease per RECIST 1.1 as assessed by BICR
* Can submit an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
* Has experienced disease progression on or after systemic treatment with an anti-programmed cell death 1 (PD-1)/Ligand 1 (L1) therapy for locally advanced or metastatic RCC. The anti-PD-1/L1 therapy may be monotherapy or in combination with other agent(s) such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or vascular endothelial growth factor (VEGF) targeted- tyrosine kinase inhibitor (TKI). The immediately preceding line of treatment has to have been an anti-PD-1/L1 therapy
* Has received no more than 3 prior systemic regimens for locally advanced or metastatic RCC
* Has received only 1 prior anti-PD-1/L1 therapy for locally advanced or metastatic RCC
* Has recovered from all AEs due to previous therapies to ≤Grade 1 or baseline, with the exception of ≤Grade 2 neuropathy or endocrine-related AEs ≤Grade 2 requiring treatment or hormone replacement
* Has a Karnofsky performance status (KPS) score of at least 70% assessed within 10 days prior to the first dose of study intervention
* A male participant is eligible to participate if he is abstinent from heterosexual intercourse or agrees to use contraception during the intervention period and for at least 7 days after the last dose of study intervention
* A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: Not a (woman of childbearing potential) WOCBP or a WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 30 days after the last dose of study intervention
* A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) within 24 hours before the first dose of study intervention

Exclusion Criteria:

* Has hypoxia (a pulse oximeter reading \<92% at rest), requires intermittent supplemental oxygen, or requires chronic supplemental oxygen
* Has a known additional malignancy that is progressing or has required active treatment within the past 3 years except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ \[e.g., breast carcinoma, cervical cancer in situ\] that have undergone potentially curative therapy
* Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction ≤6 months from Day 1 of study drug administration or New York Heart Association Class III or IV congestive heart failure
* Has moderate to severe hepatic impairment (Child-Pugh B or C)
* Has received colony-stimulating factors (eg, granulocyte colony-stimulating factor \[G-CSF\], granulocyte-macrophage colony-stimulating factor \[GM-CSF\], or recombinant erythropoietin \[EPO\]) ≤28 days prior to the first dose of study intervention
* Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
* Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption)
* Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any component of the study intervention (belzutifan) formulations
* Has received prior treatment with belzutifan or another hypoxia-inducible factor (HIF)-2α inhibitor
* Has received any type of small molecule kinase inhibitor (including investigational kinase inhibitor) ≤2 weeks before randomization
* Has received any type of systemic anticancer antibody (including investigational antibody) ≤4 weeks before randomization
* Has received prior radiotherapy ≤2 weeks prior to first dose of study intervention. Participants must have recovered from all radiation-related toxicities and not require corticosteroids
* Has had major surgery ≤3 weeks prior to first dose of study intervention
* Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (eg, bosentan, efavirenz, modafinil) inducers of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study
* Is currently participating in a study of an investigational agent or is currently using an investigational device
* Has an active infection requiring systemic therapy
* Has active tuberculosis (TB)
* Has a diagnosis of immunodeficiency
* Has a known history of human immunodeficiency virus (HIV) infection
* Has a known history of hepatitis B (HBV) or known active hepatitis C (HCV) infection
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not the best interest of the participant to participate, in the opinion of the treating investigator

Primary outcomes:
measure: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
timeFrame: Up to approximately 27 months
Secondary outcomes:
measure: Progression-Free Survival (PFS) According to RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 27 months
measure: Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 27 months
measure: Clinical Benefit Rate (CBR) Per RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 27 months
measure: Overall Survival (OS)
timeFrame: Up to approximately 27 months
measure: Number of Participants Who Experience One or More Adverse Events (AEs)
timeFrame: Up to approximately 27 months
measure: Number of Participants Who Discontinue Study Treatment Due to an AE
timeFrame: Up to approximately 26 months
measure: Maximum Plasma Concentration (Cmax) of Belzutifan
timeFrame: Weeks 1 and 3 on Day 1: predose and 1, 2, and 4 hours. Week 5 on Day 1: predose only
measure: Trough Plasma Concentration (Ctrough) of Belzutifan
timeFrame: Weeks 1 and 3 on Day 1: predose and 1, 2, and 4 hours. Week 5 on Day 1: predose only
Other outcomes:
Locations:
city: Washington
country: United States
facility: Georgetown University Medical Center ( Site 0002)
state: District of Columbia
city: Miami
country: United States
facility: Univ of Miami- Sylvester Comprehensive Cancer Center ( Site 0023)
state: Florida
city: Louisville
country: United States
facility: Norton Cancer Institute - St. Matthews ( Site 0025)
state: Kentucky
city: Baltimore
country: United States
facility: Weinberg Cancer Institute at Franklin Square ( Site 0007)
state: Maryland
city: Lincoln
country: United States
facility: Cancer Partners of Nebraska ( Site 0003)
state: Nebraska
city: Omaha
country: United States
facility: Oncology Hematology West, PC dba Nebraska Cancer Specialists ( Site 0012)
state: Nebraska
city: Albany
country: United States
facility: New York Oncology Hematology P.C ( Site 0028)
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute ( Site 0038)
state: New York
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center ( Site 0026)
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Sanford Cancer Center Oncology Clinic ( Site 0031)
state: South Dakota
city: Germantown
country: United States
facility: UT West Cancer Center ( Site 0032)
state: Tennessee
city: Nashville
country: United States
facility: Urology Associates ( Site 0015)
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas ( Site 0004)
state: Texas
city: Temple
country: United States
facility: Baylor Scott & White Medical Center - Temple ( Site 0013)
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute ( Site 0037)
state: Utah
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute ( Site 0001)
state: Virginia
city: Roanoke
country: United States
facility: Blue Ridge Cancer Care - Roanoke ( Site 0017)
state: Virginia
city: Kennewick
country: United States
facility: Kadlec Clinic Hematology and Oncology ( Site 0008)
state: Washington
city: Macquarie University
country: Australia
facility: Macquarie University ( Site 1007)
state: New South Wales
city: Box Hill
country: Australia
facility: Eastern Health - Box Hill Hospital ( Site 1003)
state: Victoria
city: Frankston
country: Australia
facility: Peninsula Health Frankston Hospital ( Site 1001)
state: Victoria
city: Wilrijk
country: Belgium
facility: GZA Sint Augustinus ( Site 2003)
state: Antwerpen
city: Charleroi
country: Belgium
facility: Grand Hopital de Charleroi ( Site 2005)
state: Hainaut
city: Liège
country: Belgium
facility: CHU de Liege ( Site 2002)
state: Liege
city: Gent
country: Belgium
facility: UZ Gent ( Site 2004)
state: Oost-Vlaanderen
city: Leuven
country: Belgium
facility: UZ Leuven ( Site 2001)
state: Vlaams-Brabant
city: Athens
country: Greece
facility: General Hospital of Athens "Alexandra" ( Site 1102)
state: Attiki
city: Chaidari
country: Greece
facility: Athens University Hospital ATTIKON ( Site 1100)
state: Attiki
city: Larissa
country: Greece
facility: University General Hospital of Larissa ( Site 1101)
state: Thessalia
city: Cork
country: Ireland
facility: Cork University Hospital ( Site 9053)
city: Dublin
country: Ireland
facility: Tallaght University Hospital ( Site 9051)
city: Beer Sheva
country: Israel
facility: Soroka Medical Center ( Site 4004)
city: Haifa
country: Israel
facility: Rambam Medical Center ( Site 4001)
city: Petach Tikva
country: Israel
facility: Rabin Medical Center ( Site 4002)
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center ( Site 4003)
city: Maastricht
country: Netherlands
facility: Maastricht Universitair Medisch Centrum - MUMC ( Site 5001)
state: Limburg
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek Ziekenhuis ( Site 5003)
state: Noord-Holland
city: Zwolle
country: Netherlands
facility: Isala klinieken ( Site 5002)
state: Overijssel
city: Rotterdam
country: Netherlands
facility: Erasmus MC ( Site 5000)
state: Zuid-Holland
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht ( Site 5004)
city: Moscow
country: Russian Federation
facility: Federal state budgetary institution Russian Research Centre of radiology and nuclear medicine ( Site
state: Moskva
city: Moscow
country: Russian Federation
facility: City Clinical Oncology Hospital No. 1 ( Site 6004)
state: Moskva
city: Saint Petersburg
country: Russian Federation
facility: Russian Scientific Center of Radiology and Surgical Technologies ( Site 6001)
state: Sankt-Peterburg
city: Saint-Petersburg
country: Russian Federation
facility: Clinical Research Center of specialized types medical care-Oncology ( Site 6002)
state: Sankt-Peterburg
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust ( Site 9003)
state: England
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust ( Site 9004)
state: London, City Of
city: Oxford
country: United Kingdom
facility: Churchill Hospital ( Site 9000)
state: Oxfordshire
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust. City Hospital Campus ( Site 9001)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Agarwal N, Brugarolas J, Ghatalia P, George S, Haanen JB, Gurney H, Ravilla R, Van der Veldt A, Beuselinck B, Pokataev I, Suelmann BBM, Tuthill MH, Vaena D, Zagouri F, Wu J, Perini RF, Liu Y, Merchan J, Atkins MB. Randomized phase II dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma. Ann Oncol. 2024 Dec;35(12):1148-1156. doi: 10.1016/j.annonc.2024.08.2338. Epub 2024 Sep 2.