## Protocol Section
### Identification Module
**NCT ID:** NCT06428396

**Brief Title:** Study of Belzutifan (MK-6482) Plus Fulvestrant for ER+/HER2- Metastatic Breast Cancer (MK-6482-029/LITESPARK-029)

**Official Title:** A Phase 2, Randomized, Active-controlled, Open-label, Multicenter Study of Belzutifan Plus Fulvestrant in Participants With Estrogen Receptor Positive, HER2 Negative Unresectable Locally Advanced or Metastic Breast Cancer After Progression on Previous Endocrine Therapy (LITESPARK-029)

#### Organization Study ID Info
**ID:** 6482-029
#### Organization
**Class:** INDUSTRY
**Full Name:** Merck Sharp & Dohme LLC
#### Secondary ID Infos
**Domain:** Merck
**ID:** MK-6482-029
**Type:** OTHER
**Domain:** Merck
**ID:** LITESPARK-029
**Type:** OTHER
### Status Module
#### Completion Date
**Date:** 2028-05-24

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-24

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-20

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2027-06-24

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-06-26

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-24
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-20
**Study First Submit QC Date:** 2024-05-20
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** INDUSTRY

**Name:** Merck Sharp & Dohme LLC

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** The purpose of this study is to assess the efficacy and safety of belzutifan (MK-6482) plus fulvestrant compared to everolimus plus endocrine therapy (ET) (investigator's choice of fulvestrant or exemestane) in adults with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) unresectable metastatic breast cancer. There is no formal hypothesis testing in this study.

### Conditions Module

**Conditions:**

- Metastatic Breast Cancer

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 120

**Type:** ESTIMATED

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Participants will receive belzutifan 120 mg orally once daily (QD) PLUS fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until progressive disease or discontinuation.

**Intervention Names:**

- Drug: Belzutifan

- Drug: Fulvestrant

**Label:** Belzutifan + Fulvestrant

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Participants will receive everolimus 10 mg orally QD PLUS investigator's choice of fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter OR exemestane 25 mg orally QD until progressive disease or discontinuation.

**Intervention Names:**

- Drug: Fulvestrant

- Drug: Everolimus

- Drug: Exemestane

**Label:** Everolimus + ET (fulvestrant or exemestane)

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Belzutifan + Fulvestrant

**Description:** Belzutifan 120 mg administered QD as an oral tablet.

**Name:** Belzutifan

**Other Names:**

- MK-6482

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Belzutifan + Fulvestrant

- Everolimus + ET (fulvestrant or exemestane)

**Description:** Fulvestrant 500 mg administered as an IM injection.

**Name:** Fulvestrant

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- Everolimus + ET (fulvestrant or exemestane)

**Description:** Administered at 10mg via oral tablets QD.

**Name:** Everolimus

**Type:** DRUG

#### Intervention 4

**Arm Group Labels:**

- Everolimus + ET (fulvestrant or exemestane)

**Description:** Administered at 25 mg via oral tablets QD.

**Name:** Exemestane

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** PFS is defined as the time from randomization to the first documented disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) based on blinded independent central review (BICR) or death due to any cause, whichever occurs first.

**Measure:** Progression-free Survival (PFS)

**Time Frame:** Up to Approximately 30 months

#### Secondary Outcomes

**Description:** PFS data will be cumulated to a certain cut-off date and the analysis will be performed via Kaplan-Meier approach to estimate the PFS rate at 6 months using the entire PFS data up to the cut-off date. The cut-off date is event-driven and estimated to be approximately 30 months.

**Measure:** Progression-free Survival (PFS) at 6 months

**Time Frame:** Up to Approximately 30 months

**Description:** PFS data will be cumulated to a certain cut-off date and the analysis will be performed via Kaplan-Meier approach to estimate the PFS rate at 12 months using the entire PFS data up to the cut-off date. The cut-off date is event-driven and estimated to be approximately 30 months.

**Measure:** Progression-free Survival (PFS) at 12 months

**Time Frame:** Up to Approximately 30 months

**Description:** OS is defined as the time from randomization to death due to any cause.

**Measure:** Overall Survival (OS)

**Time Frame:** Up to Approximately 30 months

**Description:** ORR is defined as the percentage of participants who have achieved confirmed 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 as assessed by BICR.

**Measure:** Objective Response Rate (ORR)

**Time Frame:** Up to Approximately 30 months

**Description:** CBR is defined as the percentage of participants who have CR: Disappearance of all target lesions, PR: At least a 30% decrease in the sum of diameters of target lesions, or stable disease (SD: Neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study) for ≥24 weeks per RECIST 1.1 as assessed by BICR.

**Measure:** Clinical Benefit Rate (CBR)

**Time Frame:** Up to Approximately 30 months

**Description:** An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.

**Measure:** Number of Participants Who Experience an Adverse Event (AE)

**Time Frame:** Up to Approximately 46 months

**Description:** An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.

**Measure:** Number of Participants Who Discontinue Study Treatment Due To an AE

**Time Frame:** Up to Approximately 46 months

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Has a diagnosis of estrogen receptor positive (ER+)/human epidermal growth factor receptor negative (HER2-) invasive breast carcinoma that is either locally advanced disease not amenable to resection or metastatic disease not treatable with curative intent
* Has documented radiographic confirmation of disease progression during or after the last administered endocrine therapy (ET)
* Provides a new or the most recently obtained core biopsy, taken from a locally advanced unresectable or from a metastatic lesion
* Has received ET in the noncurative setting and has 1) Radiographic disease progression on 12 months or more of ET in combination with CDK4/6 inhibitor in the noncurative setting or 2) Received at least 2 lines of ET in the noncurative setting including CDK4/6 inhibitor where the CDK 4/6 inhibitor was discontinued due to intolerance
* Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days of randomization
* Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have ≤Grade 2 neuropathy are eligible
* Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks prior to the first dose of study intervention and have undetectable HBV viral load prior to randomization

Exclusion Criteria:

* Has Breast cancer amenable to treatment with curative intent
* Is unable to receive any of the endocrine therapies (ETs) (ie, fulvestrant or exemestane)
* Has known difficulty in tolerating oral medications, unable to swallow orally administered medication, or conditions which would impair absorption of oral medications such as uncontrolled nausea or vomiting (ie, CTCAE =Grade 3 despite antiemetic therapy), ongoing gastrointestinal obstruction, motility disorder, malabsorption syndrome, or prior gastric bypass
* Has advanced/metastatic, symptomatic visceral spread at risk of rapidly evolving into life-threatening complications
* Has active, bleeding diathesis, or on oral anti-vitamin K medication
* Has history of noninfectious pneumonitis/interstitial lung disease including radiation pneumonitis that required steroids or has current pneumonitis/interstitial lung disease
* Has uncontrolled diabetes as defined as fasting serum glucose \>1.5 × upper limit of normal (ULN)
* Has a known germline BRCA mutation (deleterious or suspected deleterious) and has received previous treatment with poly-ADP ribose polymerase (PARP) inhibition either in the adjuvant or metastatic setting
* Has received prior fulvestrant in the adjuvant, unresectable locally advanced, or metastatic setting
* Has received any line of cytotoxic chemotherapy or PARP inhibitor in the unresectable or noncurative advanced/metastatic setting
* Has received prior radiotherapy for non-central nervous system (CNS) disease or required corticosteroids for radiation-related toxicities including radiation pneumonitis, within 14 days of the first dose of study intervention
* Is currently receiving strong inducers of CYP3A4 that cannot be discontinued for the duration of the study
* Has received prior systemic anticancer therapy including investigational agents within 4 weeks before randomization
* Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
* Has active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed
* Has concurrent active Hepatitis B and Hepatitis C virus infection
* Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study medication administration, or New York Heart Association Class III or Class IV congestive heart failure
* Has not adequately recovered from major surgery or have ongoing surgical complications

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Overall Officials

**Official 1:**

**Affiliation:** Merck Sharp & Dohme LLC

**Name:** Medical Director

**Role:** STUDY_DIRECTOR

### IPD Sharing Statement Module

**Description:** http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

**IPD Sharing:** YES

**URL:** http://engagezone.msd.com/ds_documentation.php

### References Module

#### See Also Links

**Label:** Merck Clinical Trials Information

**URL:** https://www.merckclinicaltrials.com/

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000009369

- Term: Neoplasms

- ID: D000001941

- Term: Breast Diseases

- ID: D000012871

- Term: Skin Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BC17

- Name: Skin and Connective Tissue Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC23

- Name: Symptoms and General Pathology

### Condition Browse Module - Browse Leaves

- ID: M5220

- Name: Breast Neoplasms

- Relevance: HIGH

- As Found: Breast Cancer

- ID: M20559

- Name: Disease Progression

- Relevance: LOW

- As Found: Unknown

- ID: M5218

- Name: Breast Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M15674

- Name: Skin Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000001943

- Term: Breast Neoplasms

### Intervention Browse Module - Ancestors

- ID: D000091203

- Term: MTOR Inhibitors

- ID: D000047428

- Term: Protein Kinase Inhibitors

- ID: D000004791

- Term: Enzyme Inhibitors

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000007166

- Term: Immunosuppressive Agents

- ID: D000007155

- Term: Immunologic Factors

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000000970

- Term: Antineoplastic Agents

- ID: D000018931

- Term: Antineoplastic Agents, Hormonal

- ID: D000065171

- Term: Estrogen Receptor Antagonists

- ID: D000004965

- Term: Estrogen Antagonists

- ID: D000006727

- Term: Hormone Antagonists

- ID: D000006730

- Term: Hormones, Hormone Substitutes, and Hormone Antagonists

- ID: D000047072

- Term: Aromatase Inhibitors

- ID: D000065088

- Term: Steroid Synthesis Inhibitors

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: Infe

- Name: Anti-Infective Agents

### Intervention Browse Module - Browse Leaves

- ID: M255

- Name: Everolimus

- Relevance: HIGH

- As Found: Criteria

- ID: M1723

- Name: Fulvestrant

- Relevance: HIGH

- As Found: Probe

- ID: M247237

- Name: Exemestane

- Relevance: HIGH

- As Found: Filled

- ID: M348353

- Name: Belzutifan

- Relevance: HIGH

- As Found: Multiple System Atrophy

- ID: M8116

- Name: Estrogens

- Relevance: LOW

- As Found: Unknown

- ID: M21960

- Name: Sirolimus

- Relevance: LOW

- As Found: Unknown

- ID: M353695

- Name: Temsirolimus

- Relevance: LOW

- As Found: Unknown

- ID: M2827

- Name: MTOR Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M25820

- Name: Protein Kinase Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M7951

- Name: Enzyme Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M10212

- Name: Immunosuppressive Agents

- Relevance: LOW

- As Found: Unknown

- ID: M10201

- Name: Immunologic Factors

- Relevance: LOW

- As Found: Unknown

- ID: M20966

- Name: Antineoplastic Agents, Hormonal

- Relevance: LOW

- As Found: Unknown

- ID: M8114

- Name: Estrogen Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M30483

- Name: Estrogen Receptor Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M9789

- Name: Hormones

- Relevance: LOW

- As Found: Unknown

- ID: M9788

- Name: Hormone Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M25769

- Name: Aromatase Inhibitors

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000068338

- Term: Everolimus

- ID: D000077267

- Term: Fulvestrant

- ID: C000056516

- Term: Exemestane

- ID: C000720612

- Term: Belzutifan

### Misc Info Module

- Version Holder: 2024-05-31
