Pharmacokinetics and Pharmacogenomics of Ribociclib in Race-based Cohorts

NCT04657679 | Terminated Phase 4 Results DMC FDA Drug

• 1 other identifier: STUDY00003100
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 3

Brief Summary

The aim is to determine the pharmacological and biochemical association between ribociclib exposure and CYP3A variants in African American/Blacks and Non-Hispanic White patients. The investigators hypothesize that patients treated with ribociclib who are CYP3A5 poor metabolizers may be exposed to higher levels of ribociclib than CYP3A5 intermediate or normal metabolizers. The findings could allow clinicians to tailor treatments to maintain therapeutic doses while limiting toxicities.

Conditions

Breast Cancer

Keywords

HR-positive/HER2-negative metastatic breast cancer

Outcome Measures

Primary Outcomes (1)

• Ribociclib Area-under-the-curve (AUC)

  Compare the exposure (i.e., AUC) of ribociclib at steady-state between CYP3A5 poor metabolizers (PM) and CYP3A5 intermediate or normal metabolizers (IM/NM) in each independent race-based cohort of women with advance breast cancer

  On day 8-16 of cycle 1 (each cycle is 28 days)

Secondary Outcomes (9)

• Ribociclib Pharmacokinetic Properties - Maximum Concentration (Cmax)

  On day 8-16 of cycle 1 (each cycle is 28 days)

• Ribociclib Pharmacokinetic Properties - the Time to Reach Cmax (Tmax)

  On day 8-16 of cycle 1 (each cycle is 28 days)

• Ribociclib Pharmacokinetic Properties - Clearance

  On day 8-16 of cycle 1 (each cycle is 28 days)

• Ribociclib Pharmacokinetic Properties - Volume of Distribution(vd)

  days 8-16 of cycle 1 (28 day cycle)

• Ribociclib Pharmacokinetic Properties - Elimination Half-life

  On day 8-16 of cycle 1 (each cycle is 28 days)

Study Arms (2)

African American/Black

ACTIVE COMPARATOR

Subject who self identify as African American or Black with metastatic HR+/HER2- advanced breast cancer (estimate 3 participants who are CYP3A5 poor metabolizers and approximately 15 participants who are CYP3A5 intermediate or normal metabolizers)

Drug: Ribociclib

Non-Hispanic White

ACTIVE COMPARATOR

Subjects who self-identify as non-Hispanic White with metastatic HR+/HER2- advanced breast cancer (estimate 3 participants who are CYP3A5 poor metabolizers and approximately 15 participants who are CYP3A5 intermediate or normal metabolizers)

Drug: Ribociclib

Interventions

Ribociclib DRUG

Patients will receive ribociclib 600 mg oral (PO) daily for 21 consecutive days of 28-day cycles and endocrine therapy with either letrozole or fulvestrant. Fulvestrant 500 mg intramuscular (IM) will be administered on days 1, 15, 29 of cycle one, and then monthly. Letrozole 2.5 mg oral daily continuously. If premenopausal women have not undergone bilateral salpingo- oophorectomy, they will receive a luteinizing hormone-releasing hormone (LHRH) agonist (e.g., goserelin leuprolide) for ovarian suppression in combination with fulvestrant or letrozole and ribociclib.

Also known as: KISQALI

African American/Black; Non-Hispanic White

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent must be obtained prior to any screening procedures.
• Female ≥18 years old at the time of informed consent
• Those who self-identify as African American or Black are eligible for that respective cohort
• Those who self-identify as non-Hispanic White are eligible for that respective cohort
• Postmenopausal or premenopausal. Patient has a known menopausal status at the time of the informed consent form signature. The patient is considered postmenopausal if: i) she has had prior bilateral oophorectomy; ii) is age ≥ 60 years; iii) is age \<60 years and has had amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range per local normal ranges. All other patients who do not meet the criteria for postmenopausal status are considered premenopausal and will receive goserelin or leuprolide for ovarian suppression
• Each race-based cohort has a predetermined number of patients with each CYP3A5 phenotype per the sample size calculation (section 9.1). Patients will be screen for CYP3A5: - African American or Black (At least 3 participants who are CYP3A5 poor metabolizers, No more than 15 participants who are CYP3A5 intermediate or normal metabolizers); - Non-Hispanic White (At least 3 participants who are CYP3A5 intermediate or normal metabolizers, No more than 15 participants who are CYP3A5 poor metabolizers)
• Patient has advanced (loco-regionally recurrent or metastatic) breast cancer not amenable to curative therapy
• Treated, stable and asymptomatic brain metastases are permitted
• ECOG performance status 0-3
• Documentation of estrogen receptor (ER) positive and/or progesterone receptor (PR) positive tumor (≥1% positive stained cells) based on most recent tumor biopsy (discuss with the Principal Investigator if results in different biopsies are discordant in terms of hormone receptor positivity) utilizing an assay consistent with local standards.
• Documented HER2-negative tumor based on local testing on most recent tumor biopsy: HER2-negative tumor is determined as immunohistochemistry score 0/1+ or negative by in situ hybridization (FISH/CISH/SISH) defined by current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines. Patients with equivocal HER2 in situ hybridization results according to current ASCO/CAP guidelines are eligible, as long as they have not received and are not scheduled to receive anti-HER2 treatment.
• Must be capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent, approved by the IRB, prior to the initiation of any screening or study-specific procedures.
• Patient must be able to swallow ribociclib tablets.
• Patient must be able to communicate with the investigator and comply with the requirements of the study procedures.
• Patient has adequate bone marrow and organ function as defined by the following laboratory values:

You may not qualify if:

• Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's judgment.
• Patient currently prescribed a CDK4/6 inhibitor (e.g., ribociclib, abemaciclib, or palbociclib).
• Patients with central nervous system (CNS) symptomatic or untreated metastases
• History of liver transplant or allogeneic bone marrow transplantation
• Patient with a known hypersensitivity to any of the excipients of ribociclib (e.g. ribociclib tablets coating contains soya lecithin, and therefore should not be taken by patients who are allergic to peanuts or soya) or of fulvestrant.
• Patient is concurrently using other anti-cancer therapy besides those in the study protocol (e.g., letrozole, fulvestrant, goserelin, leuprolide). Any other prior neo-/adjuvant anti-cancer therapy must be stopped at least 5 half-lives or 7 days, whichever is longer, before the date of ribociclib initiation.
• Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major toxicities
• Patient has not recovered from acute clinical and laboratory toxicities related to prior anticancer therapies to NCI CTCAE v5.0 grade ≤ 1 (except for alopecia, neuropathy, and amenorrhea or other toxicities not considered a safety risk for the patient at investigator's discretion).
• Patient has received extended-field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior to ribociclib initiation and has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).
• Patient has a concurrent malignancy, with the exception of adequately treated basal or squamous cell skin carcinoma, stage 1 melanoma, or curatively resected cervical carcinoma in situ. Patients may still enroll with a concurrent malignancy after receiving approval from the study PI.
• Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drug (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
• Patient has any other concurrent severe and/or uncontrolled medical condition that would in the investigator's judgment, cause unacceptable safety risks to the patient, contraindicate patient participation in the clinical study, or compromise compliance with the protocol.
• Patient has clinically significant, uncontrolled heart disease or who are at significant risk of developing QT prolongation, including any of the following:
• Documented myocardial infarction (MI), angina pectoris, coronary artery intervention, or pericarditis within 6 months prior to study entry
• Documented cardiomyopathy, congestive heart failure, valvular heart disease, congenital heart disease, or prior cardiac surgery

Sponsors & Collaborators

• Georgetown University: lead
• Medstar Health Research Institute: collaborator
• Breast Cancer Research Foundation: collaborator
• Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS): collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (3)

MedStar Georgetown University Hospital

Washington D.C., District of Columbia, 20007, United States

Location

Medstar Washington Hospital Center

Washington D.C., District of Columbia, 20010, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

ribociclib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Sandra Swain, MD,
• Organization: Georgetown University

sandra.swain@georgetown.edu

(202) 687-8487

Study Officials

• Sandra Swain, MD

  Georgetown University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 20, 2020
• First Posted: December 8, 2020
• Study Start: May 20, 2021
• Primary Completion: October 30, 2023
• Study Completion: October 30, 2023
• Last Updated: November 26, 2024
• Results First Posted: November 26, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)