NCT07340658 - A Study to Investigate the Efficacy and Safety of Letrozole SIE Compared With Femara® (Both Combined With the CDK4/6 Inhibitor Ribociclib) in Postmenopausal Women With HR-Positive, HER2-Negative, Inoperable Locally Advanced or Metastatic Breast Cancer | Crick

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Female participants with inoperable locally advanced or metastatic breast cancer. * Confirmed diagnosis of HR-positive/HER2-negative breast cancer. * Postmenopausal woman. * Previously untreated with any systemic anticancer therapy for their locoregionally recurrent or metastatic HR-positive disease. Participants may have received cytotoxic chemotherapy within (neo) adjuvant previous treatment of breast cancer but must show progressive disease prior to enrollment. * Have either measurable disease or non-measurable bone-only disease. * ECOG performance status 0-2. * Adequate organ and marrow function. * Resolution of all acute toxic effects of prior anticancer therapy or surgical procedures to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 6.0 Grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the participant at the investigator's discretion). * BMI ≥ 19 and ≤ 39 kg/m2. Exclusion Criteria: * Participants with advanced, symptomatic, visceral spread who are at risk of life-threatening complications in the short term. * Participants with inflammatory breast cancer. * Known uncontrolled or symptomatic central nervous system (CNS) metastases. * Concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated basal or squamous cell carcinoma, non-melanomatous skin cancer, or curatively resected cervical cancer. * Active cardiac disease or documented history of cardiac dysfunction. * Uncontrolled hypertension. * History of symptomatic vertebral fragility fracture or any fragility fracture of the hip, pelvis, wrist, or other location (defined as any fracture without a history of trauma or because of a fall from standing height or less, excluding fingers, toes, face and skull). * Presence of medical conditions associated with low bone mass. * History of ILD/pneumonitis. * Other severe acute or chronic medical or psychiatric condition, including recent or active suicidal ideation/behavior, or laboratory or ECG abnormalities that may increase the risk associated with study participation or study intervention administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study. * Presence of detectable viral infection, including HBV, HCV, and HIV. Screening is not required for enrollment. Note: Participants who have been effectively treated and have a sustained virologic response are eligible for enrollment. * Major surgery, chemotherapy, radiotherapy, any investigational agents, or other anticancer therapy within 14 days (2 weeks) before randomization. Participants who received prior radiotherapy to \> 25% of bone marrow are not eligible independent of when it was received. * Bisphosphonates or receptor activator of nuclear factor kappa-β ligand (RANKL) inhibitors initiated or have their dose changed within 14 days prior to randomization, i.e., participants should be on stable dose treatment for at least 14 days prior to randomization. * Hormonal medications or medications or products known to affect serum LH, FSH (except spironolactone which is allowed if medically indicated), or estrogen/E2 levels within 3 months prior to randomization. This includes, but is not limited to, estrogen or progesterone hormone replacement therapy, oral contraceptives, androgens, LHRH analogs, prolactin inhibitors, or antiandrogens and other medications, herbal remedies, and/or supplements for the treatment of vasomotor hot flush symptoms administered via any route, including topical or intravaginal administration. * Use of the following medications within the 3 previous days or a period of 5 half-lives, (whichever is longer) prior to randomization: 1. Any medications or products including St. John's wort, known to be strong inducers of CYP3A. 2. Any medications or products known to be strong inhibitors of CYP3A (e.g., grapefruit or grapefruit juice). 3. Any medications known to be inducers of CYP2A6. 4. Any medications known to be inhibitors of CYP2A6. * Concurrently use of other anticancer therapy.

Outcomes

Primary Outcomes

Progression Free Survival (PFS)

PFS per Investigator assessment, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS will be assessed via a local radiology assessment according to RECIST v1.1. PFS as assessed through a blinded independent central review will be used for supportive evidence of the primary efficacy endpoint.

Time frame: From the date of randomization to the date of the first documented progression or death due to any cause, assessed according to RECIST version 1.1 (up to approximately 30 months).

Secondary Outcomes

Overall Survival (OS): Primary analysis

OS, defined as the time from the date of randomization to date of death from any cause.

Time frame: From the date of randomization to date of death from any cause (up to approximately 30 months).

Overall Survival (OS): Final analysis

OS, defined as the time from the date of randomization to date of death from any cause.

Time frame: From the date of randomization to date of death from any cause (up to approximately 88 months).

Objective Response Rate (ORR)

ORR, defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR) by Investigator assessment per RECIST v1.1 criteria.

Time frame: From the date of randomization to the date of the first documented progression or death due to any cause, assessed according to RECIST version 1.1 (up to approximately 30 months).

Incidence of arthralgias/arthritis and/or myalgias

To compare the incidence rate of a combined event of arthralgias/arthritis and/or myalgias between Letrozole SIE and Femara®

Time frame: From the date of the first dose of study intervention to the post-discontinuation visit (up to approximately 30 months).

Time to Response (TTR)

TTR, defined for participants with complete response or partial response defined by Investigator assessment per RECIST v1.1 criteria as the interval between randomization and the earliest documentation of response.

Time frame: From the date of randomization to the date of the first documented evidence of complete response or partial response (up to approximately 30 months).

Duration of response (DOR)

DOR, defined for those participants with complete response (CR) or partial response (PR) as the time from first documented evidence of CR or PR until disease progression by Investigator assessment per RECIST v1.1 criteria, or death from any cause, whichever occurs first.

Time frame: From first documented evidence of complete response (CR) or partial response (PR) until disease progression or death from any cause, whichever occurs first (up to approximately 30 months).

Clinical benefit rate (CBR)

CBR, defined as the proportion of participants with complete response (CR), partial response (PR), or stable disease (SD) ≥ 6 months according to Investigator assessment per RECIST v1.1 criteria.

Time frame: From the date of randomization to the date of the first documented progression or death due to any cause, assessed according to RECIST version 1.1 (up to approximately 30 months).

Time to treatment failure (TTF)

TTF, defined as the time from randomization to study intervention discontinuation for any reason.

Time frame: From date of randomization to study intervention discontinuation for any reason (up to approximately 30 months).

Change from baseline in the FACT-G total score

To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using FACT-G questionnaire. FACT is a modular approach to assess participant health-related quality of life using a 'core' set of questions (FACT-G) as well as a cancer site-specific module. The FACT-G is a 27-item compilation of general questions divided into 4 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. For all questions, participants are asked to respond to a five-level scale where 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much.

Time frame: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).

Change from baseline in the FACT-G Physical well-being subscale score

To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using FACT-G subscales.

Time frame: From the date of randomization to the time of disease progression (up to approximately 30 months).

Change from baseline in the FACT-G Social/Familiy well-being subscale score

To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using FACT-G subscales.

Time frame: From the date of randomization to the time of disease progression (up to approximately 30 months).

Change from baseline in the FACT-G Emotional well-being subscale score

To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using FACT-G subscales.

Time frame: From the date of randomization to the time of disease progression (up to approximately 30 months).

Change from baseline in the FACT-G Functional well-being subscale score

To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using FACT-G subscales.

Time frame: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).

Change from baseline in the FACT-B total score

To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using FACT-B questionnaire. FACT is a modular approach to assess participant health-related quality of life using a 'core' set of questions (FACT-G) as well as a cancer site-specific module. The FACT-G is a 27-item compilation of general questions divided into 4 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. The FACT-B consists of the FACT-G and a breast-specific module: a 10-item instrument designed to assess participant concerns relating to breast cancer. For all questions, participants were asked to respond to a five-level scale where 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much.

Time frame: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).

Change from baseline in the FACT-B Breast Cancer subscale score

To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using the FACT-B questionnaire.

Time frame: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).

Change from baseline in the FACT-ES total score

To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using the FACT-ES questionnaire. FACT is a modular approach to assess participant health-related quality of life using a 'core' set of questions (FACT-G) as well as a cancer site-specific module. The FACT-G is a 27-item compilation of general questions divided into 4 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. FACT-ES incorporates 19 additional items that assess endocrine related symptoms in addition to the FACT-G core items. For all questions, participants were asked to respond to a five-level scale where 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much.

Time frame: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).

Change from baseline in the FACT-ES Endocrine Symptoms subscale score

To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using the FACT-ES questionnaire.

Time frame: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).

Time to deterioration in the FACT-G total score

Deterioration will be defined as the time from the date of randomization to the first occurrence of a decrease from baseline of at least 5 points for FACT-G total score.

Time frame: From the date of randomization to to the first occurrence of a decrease from baseline of at least 5 points for FACT-G (up to approximately 30 months).

Time to deterioration in the FACT-B total score

Deterioration will be defined as the time from the date of randomization to the first occurrence of a decrease from baseline of at least 7 points for FACT-B total score.

Time frame: From the date of randomization to to the first occurrence of a decrease from baseline of at least 7 points for FACT-B (up to approximately 30 months).

Time to deterioration in the FACT-ES total score

Deterioration will be defined as the time from the date of randomization to the first occurrence of a decrease from baseline of at least 7 points for FACT-ES total score.

Time frame: From the date of randomization to to the first occurrence of a decrease from baseline of at least 7 points for FACT-ES (up to approximately 30 months).

ESR1 mutation status

Percentage of participants with ESR1 mutations at the time of disease progression among those without ESR1 mutations at baseline.

Time frame: From the date of randomization to the time of disease progression (up to approximately 30 months).

ESR1 mutant allele frequency

ESR1 mutant allele frequency at the time of disease progression.

Time frame: At the time of disease progression (up to approximately 30 months).

Incidence of Adverse Events (AEs)

AEs type, severity, seriousness, and relationship to study intervention, including the incidence of TEAEs, the incidence of serious TEAEs, and the incidence of TEAEs leading to study intervention discontinuation.

Time frame: From the Informed Consent Form signature to the post-discontinuation visit (approximately up to 88 months).

Incidence of injection site reactions

Injection site redness, swelling, and induration will be evaluated before and after Letrozole SIE or injectable placebo administration.

Time frame: From the date of the first dose of study intervention to the post-discontinuation visit (approximately up to 88 months).

Changes in injection-related pain score

Injection site pain, self-assessed by participants using an numeric rating scale (NRS) at the time of Letrozole SIE or injectable placebo administration and for a longer period of time if necessary. The numeric rating scale (NRS) evaluates the intensity of injection-related pain experienced at the time of Letrozole SIE/injectable placebo administration. It is scored from 0 to 10 (0 meaning no pain and 10 meaning the worst possible pain).

Time frame: From the date of the first dose of study intervention to the post-discontinuation visit (approximately up to 88 months).

Change from baseline in Bone mineral density (BMD)

Change from baseline in BMD assessed by DXA

Time frame: From the Informed Consent Form signature to the post-discontinuation visit (approximately up to 30 months).

A Study to Investigate the Efficacy and Safety of Letrozole SIE Compared With Femara® (Both Combined With the CDK4/6 Inhibitor Ribociclib) in Postmenopausal Women With HR-Positive, HER2-Negative, Inoperable Locally Advanced or Metastatic Breast Cancer

Overview

Conditions

Interventions

Eligibility

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts