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JOURNAL ONKOLOGIE – STUDIE

A Study of Belzutifan (MK-6482) Versus Everolimus in Participants With Advanced Renal Cell Carcinoma (MK-6482-005)

Rekrutierend

NCT-Nummer:
NCT04195750

Studienbeginn:
Februar 2020

Letztes Update:
14.01.2021

Wirkstoff:
Everolimus, Belzutifan

Indikation (Clinical Trials):
Carcinoma, Carcinoma, Renal Cell

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
Merck Sharp & Dohme Corp.

Collaborator:
-

Studienleiter

Medical Director
Study Director
Merck Sharp & Dohme Corp.

Kontakt

Studienlocations (3 von 136)

Borsod-Abaúj-Zemplén Megyei Központi Kórház és Egyetemi Okta-Klinikai Onkológiai és Sugárterápiás Ce
3526 Miskolc
HungaryRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +36302780644
» Ansprechpartner anzeigen
SBHI SPb Clinical Research Centre of specialized types of medical care ( Site 1159)
197758 Saint-Petersburg
Russian FederationRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +78125739191
» Ansprechpartner anzeigen
Russian Scientific Center of Radiology and Surgical Technologies ( Site 1153)
197758 St. Petersburg
Russian FederationRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +79219629807
» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

Brief Summary:

The primary objective of this study is to compare belzutifan to everolimus with respect to

progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1

(RECIST 1.1) as assessed by Blinded Independent Central Review (BICR) and to compare

everolimus with respect to overall survival (OS). The hypothesis is that belzutifan is

superior to everolimus with respect to PFS and OS.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Has unresectable, locally advanced or metastatic clear cell renal cell carcinoma (RCC)

- Has had disease progression on or after having received systemic treatment for locally

advanced or metastatic RCC with both Programmed cell death 1 ligand 1 (PD-1/L1)

checkpoint inhibitor and a vascular endothelial growth factor - tyrosine kinase

inhibitor (VEGF-TKI) in sequence or in combination.

- Has received no more than 3 prior systemic regimens for locally advanced or metastatic

RCC.

- 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 5 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 for those randomized to belzutifan and for at least 8 weeks

after the last dose of study intervention for those randomized to everolimus.

- The participant (or legally acceptable representative if applicable) provides written

informed consent for the study.

- Has adequate organ function

Exclusion Criteria:

- Has a known additional malignancy that is progressing or has required active treatment

within the past 3 years. (Participants with 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 are not excluded.)

- Has known central nervous system (CNS) metastases and/or carcinomatous meningitis.

(Participants with previously treated brain metastases may participate provided they

are radiologically stable for at least 4 weeks (28 days) by repeat imaging.)

- Has clinically significant cardiac disease, including unstable angina, acute

myocardial infarction within 6 months from Day 1 of study drug administration, or New

York Heart Association Class III or IV congestive heart failure. (Medically controlled

arrhythmia stable on medication is permitted.)

- Has poorly controlled hypertension defined as systolic blood pressure (SBP) ≥150 mm Hg

and/or diastolic blood pressure (DBP) ≥90 mm Hg.

- Has moderate to severe hepatic impairment (Child-Pugh B or C).

- 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 (e.g., gastrectomy, partial bowel obstruction, malabsorption).

- Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any

component of the study intervention (belzutifan or everolimus) formulations.

- Has received prior treatment with belzutifan or another hypoxia inducible factor 2α

(HIF-2α inhibitor).

- Has received prior treatment with everolimus or any other specific or selective target

of rapamycin complex 1 (TORC1)/ phosphatidylinositol 3-kinase (PI3K)/ protein kinase B

(AKT) inhibitor (e.g., temsirolimus) in the advanced disease setting.

- Has received any type of systemic anticancer antibody (including investigational

antibody) within 4 weeks before randomization.

- Has received prior radiotherapy within 2 weeks prior to randomization.

- Has had major surgery within 3 weeks prior to randomization.

- Has received a live vaccine within 30 days prior to randomization. Examples of live

vaccines include, but are not limited to, the following: measles, mumps, rubella,

varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG),

and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed

virus vaccines and are allowed; however, intranasal influenza vaccines are live

attenuated vaccines and are not allowed.

- Is currently receiving either strong (e.g., itraconazole, telithromycin,

clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,

saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (e.g., ciprofloxacin,

erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 3A4

(CYP3A4) that cannot be discontinued for the duration of the study.

- Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin,

rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or

moderate (e.g., bosentan, efavirenz, modafinil) inducers of CYP3A4 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 bacillus tuberculosis (TB).

- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy

(dosing exceeding 10 mg daily of prednisone equivalent) or any other form of

immunosuppressive therapy within 7 days prior to randomization.

- Has a known history of human immunodeficiency virus (HIV) infection. (Testing for HIV

at screening is only required if mandated by local health authority.

- Has a known history of Hepatitis B virus (HBV) (defined as Hepatitis B surface antigen

[HBsAg] reactive) or known active Hepatitis C virus (HCV) (defined as HCV ribonucleic

acid [RNA] [qualitative] is detected) infection.

Studien-Rationale

Primary outcome:

1. Progression-free Survival (PFS) per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) (Time Frame - Up to approximately 47 months):
PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by blinded independent central review will be presented

2. Overall Survival (OS) (Time Frame - Up to approximately 47 months):
Time from randomization to death due to any cause

Secondary outcome:

1. Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) (Time Frame - Up to approximately 47 months):
ORR is defined as the percentage of participants who have a complete response (CR: Disappearance of all target lesions) or a partial response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage of participants who experience a CR or PR as assessed by blinded independent central review based on RECIST 1.1 will be presented.

2. Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) (Time Frame - Up to approximately 47 months):
For participants who demonstrate a confirmed complete response (CR: Disappearance of all target lesions) or confirmed partial response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death. The DOR as assessed by blinded independent central review will be presented.

3. Number of Participants Who Experience One or More Adverse Events (AEs) (Time Frame - Up to approximately 47 months):
An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.

4. Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) (Time Frame - Up to approximately 47 months):
An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who discontinue study treatment due to an AE will be presented.

5. Time to Deterioration in Health-Related Quality-of-Life (HRQoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Score (Time Frame - Up to approximately 47 months):
Time to Deterioration (TTD) is defined as the time from baseline to the first onset of a ≥10-point negative change (decrease) from baseline in global health status (Item 29) & quality of life (Item 30) combined score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from baseline in global health status and quality of life combined score, will be presented. A longer TTD indicates a better outcome.

6. Time to Deterioration in Physical Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1- 5 Score (Time Frame - Up to approximately 47 months):
TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline in physical functioning (EORTC QLQ-C30 Items 1-5) score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from Baseline in physical functioning score, will be presented.

7. Time to Deterioration in Disease Symptoms Using the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-related Symptoms (FKSI-DRS) Items 1-9 Score (Time Frame - Up to approximately 47 months):
The FKSI-DRS index consists of a 9-item questionnaire that assesses the extent of participant symptoms from kidney cancer over the previous 7 days. Responses are scored on a 5-point scale (0=Not at all to 4=Very much) and summed to generate an index symptom score. These scores can range from 0 to 36, with a higher score indicating more favorable kidney cancer symptom status.

8. Change From Baseline in Health-Related Quality-of-Life (HRQoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Score (Time Frame - Baseline (Day 1) and up to approximately 47 months):
The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses for global health status (Item 29) & quality of life (Item 30) are scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall health status. The change from baseline in EORTC QLQ-C30 Items 29 and 30 scores will be presented.

9. Change From Baseline in Physical Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1- 5 Score (Time Frame - Baseline (Day 1) and up to approximately 47 months):
The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) score will be presented.

10. Change From Baseline in Disease Symptoms Using the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-related Symptoms (FKSI-DRS) Items 1-9 Score (Time Frame - Baseline (Day 1) and up to approximately 47 months):
The FKSI-DRS index consists of a 9-item questionnaire that assesses the extent of participant symptoms from kidney cancer over the previous 7 days. Responses are scored on a 5-point scale (0=Not at all to 4=Very much) and summed to generate an index symptom score. These scores can range from 0 to 36, with a higher score indicating more favorable kidney cancer symptom status.

11. Change from Baseline in European Quality of Life 5 Dimensions, 5-level Questionnaire (EuroQoL EQ-5D-5L) Health Utility Score (Time Frame - Baseline (Day 1) and up to approximately 47 months):
The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/ depression. Each dimension has 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty, which are coded on a scale from 1 (no problems) to 5 (extreme problems). The participant is also asked to indicate his/her current health state by selecting the most appropriate level on a visual analog scale from 0 to 100, with 0 being the worst imaginable health state.

Studien-Arme

  • Experimental: Belzutifan
    Participants receive 120 mg of belzutifan orally once daily (QD)
  • Active Comparator: Everolimus
    Participants receive 10 mg of Everolimus orally once daily (QD)

Geprüfte Regime

  • Belzutifan (MK-6482):
    Oral tablets
  • Everolimus (Afinitor / Afinitor DISPERZ / Zortress / ):
    Oral tablets

Quelle: ClinicalTrials.gov


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