ARV-471 + Ribociclib for Advanced Breast Cancer
Recruiting in Palo Alto (17 mi)
+45 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Pfizer
Must be taking: CDK4/6 inhibitors
Must not be taking: CYP3A inhibitors, QT prolongation drugs
Disqualifiers: Visceral crisis, Brain metastases, Cardiovascular diseases, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?The purpose of this clinical trial is to learn about the safety and effects of the study medicine (called ARV-471) when given together with other medicines for the potential treatment of advanced or metastatic breast cancer.
This study is seeking participants who have breast cancer that:
* is advanced, may have spread to other organs (metastatic) and cannot be fully treated by surgery or radiation therapy
* is sensitive to hormonal therapy (it is called estrogen receptor positive); and
* is no longer responding to previous treatments
This study is divided into separate sub-studies.
For Sub-Study B:
All participants will receive ARV-471 and a medicine called ribociclib. ARV-471 and ribociclib will be given at the same time by mouth, at home, 1 time a day.
The experiences of people receiving the study medicine will be examined. This will help determine if the study medicine is safe and effective.
Participants will continue to take ARV-471 and ribociclib until their cancer is no longer responding, or side effects become too severe. They will have visits at the study clinic about every 4 weeks.
Do I need to stop my current medications for the trial?
The trial protocol does not specify if you need to stop your current medications. However, you cannot take medications, foods, or supplements that strongly affect certain liver enzymes (CYP3A) or those that could cause heart rhythm issues.
What data supports the effectiveness of the drug ARV-471 + Ribociclib for advanced breast cancer?
Ribociclib, one of the drugs in the treatment, has been shown to improve progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer when combined with letrozole, as demonstrated in clinical trials.
12345Is the combination of ARV-471 and Ribociclib safe for humans?
Ribociclib, also known as Kisqali, has been studied in combination with other drugs for advanced breast cancer and is generally considered to have a manageable safety profile. Common side effects include low white blood cell counts, nausea, tiredness, diarrhea, hair loss, vomiting, constipation, headache, and back pain.
12346What makes the drug ARV-471 + Ribociclib unique for advanced breast cancer?
The combination of ARV-471 and Ribociclib is unique because it targets specific pathways in cancer cells, potentially offering a new approach for treating advanced breast cancer. ARV-471 is a novel drug that works by degrading estrogen receptors, which are often involved in breast cancer growth, while Ribociclib is a CDK4/6 inhibitor that helps stop cancer cells from dividing.
7891011Eligibility Criteria
This trial is for people with advanced or metastatic breast cancer that's hormone-sensitive and not responding to previous treatments. Participants must have at least one measurable tumor, received up to two prior therapies, and had a CDK4/6 inhibitor regimen. They should be relatively healthy (ECOG PS ≤1) without serious heart issues, other recent cancers (except certain skin cancers or treated cervical carcinoma), active infections, renal or liver problems, brain metastases unless stable and untreated for 14 days.Inclusion Criteria
I am fully active and can carry on all my pre-disease activities without restriction.
You have at least one visible and measurable abnormality according to specific criteria.
I've had up to 2 treatments for advanced cancer, including one with CDK4/6 inhibitors.
+1 more
Exclusion Criteria
I have heart problems or significant heart disease.
I have had lung problems caused by medication before.
I haven't had any cancer except for certain skin cancers or treated cervical cancer in the last 3 years.
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive ARV-471 and ribociclib orally once a day at home. Treatment continues until cancer no longer responds or side effects become too severe.
Until progression or unacceptable toxicity
Visits at the study clinic about every 4 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study tests ARV-471 combined with Ribociclib in patients with estrogen receptor-positive breast cancer that has spread and can't be removed by surgery. Both drugs are taken orally once daily at home. The trial aims to assess the safety and effectiveness of this combination therapy as long as it continues to work without intolerable side effects.
1Treatment groups
Experimental Treatment
Group I: ARV-471 in combination with RibociclibExperimental Treatment2 Interventions
ARV-471 administered orally QD continuously and Ribociclib administered orally QD consecutively for 21 days followed by 7 days off treatment on 28-day cycles
ARV-471 is already approved in United States for the following indications:
🇺🇸 Approved in United States as Vepdegestrant for:
- None approved; under investigation for ER+/HER2- metastatic breast cancer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Sunnybrook Research Institute - Odette Cancer CentreToronto, Canada
Houston Area Locations MDACC League CityLeague City, TX
The Ottawa Hospital - General CampusOttawa, Canada
Moffitt Cancer Center - International PlazaTampa, FL
More Trial Locations
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Who Is Running the Clinical Trial?
PfizerLead Sponsor
Arvinas Estrogen Receptor, Inc.Industry Sponsor
References
Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients. [2020]To review the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of ribociclib (LEE011, Kisqali) in hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) metastatic breast cancer.
Safety and Efficacy of Ribociclib in Combination with Letrozole in Patients with HR+, HER2- Advanced Breast Cancer: Results from the Italian Subpopulation of Phase 3b CompLEEment-1 Study. [2022]Ribociclib plus letrozole demonstrated manageable safety and efficacy profiles in hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) in the Phase 3b CompLEEment-1 trial.
FDA Approval: Ribociclib for the Treatment of Postmenopausal Women with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer. [2019]On March 13, 2017, the FDA approved ribociclib (KISQALI; Novartis Pharmaceuticals Corp.), a cyclin-dependent kinase 4/6 inhibitor, in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer. The approval was based on a randomized, double-blind, placebo-controlled, international clinical trial (MONALEESA-2). A total of 668 patients were randomized to receive either ribociclib plus letrozole (n = 334) or placebo plus letrozole (n = 334). An improvement in progression-free survival (PFS) was observed in patients receiving ribociclib plus letrozole compared with patients receiving placebo plus letrozole [HR = 0.556; 95% confidence interval (CI), 0.429-0.720]. Overall response rate (ORR) in patients with measurable disease was 52.7% (95% CI, 46.6-58.9) in the ribociclib plus letrozole arm and 37.1% (95% CI, 31.1-43.2) in the placebo plus letrozole arm. Overall survival data were immature. The most common adverse reactions observed in 20% or more of patients taking ribociclib were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain. This article summarizes FDA decision-making and data supporting the approval of ribociclib. Clin Cancer Res; 24(13); 2999-3004. ©2018 AACRSee related commentary by Spring and Bardia, p. 2981.
Pharmaceutical Approval Update. [2020]Ribociclib (Kisqali) for HR+/HER2- advanced or metastatic breast cancer in postmenopausal women; safinamide (Xadago) as adjunctive treatment for patients with Parkinson's disease; and avelumab (Bavencio) for metastatic Merkel cell carcinoma.
Anti-hormonal maintenance treatment with the CDK4/6 inhibitor ribociclib after 1st line chemotherapy in hormone receptor positive / HER2 negative metastatic breast cancer: A phase II trial (AMICA). [2023]This phase II study evaluated the impact of adding ribociclib to maintenance endocrine therapy (ET) treatment of physicians' choice following the first palliative chemotherapy in pre- and post-menopausal women with hormone receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (mBC).
MONALEESA clinical program: a review of ribociclib use in different clinical settings. [2020]Ribociclib has received approval in the pre/peri- and postmenopausal disease settings on the basis of the MONALEESA trials. MONALEESA-2 demonstrated that ribociclib plus letrozole significantly improved progression-free survival compared with placebo plus letrozole as first-line therapy in postmenopausal patients with HR-positive, HER2-negative advanced breast cancer. Subsequently, ongoing trials reported significant progression-free survival improvements with ribociclib in combination with either fulvestrant in postmenopausal patients with advanced breast cancer who were either treatment naive or received ≤1 line of prior endocrine therapy in the advanced disease setting (MONALEESA-3) or tamoxifen/nonsteroidal aromatase inhibitor with ovarian function suppression in pre/perimenopausal women (MONALEESA-7). This review summarizes the MONALEESA clinical program. ClinicalTrials.gov identifiers: NCT01958021 (MONALEESA-2), NCT02422615 (MONALEESA-3), NCT02278120 (MONALEESA-7).
[The impact of the androgen receptor splice variant AR-V7 on the prognosis and treatment of advanced prostate cancer]. [2022]A recently discovered mechanism enabling prostate cancer cells to escape the effects of endocrine therapies consists in the synthesis of C-terminally truncated, constitutively active androgen receptor (AR) splice variants (AR-V). Devoid of a functional C-terminal hormone/ligand binding domain, various AR-Vs are insensitive to therapies targeting the androgen/AR signalling axis. Preliminary studies suggest that AR-V7, the most common AR-V, is a promising predictive tumour marker and a relevant selection marker for the treatment of advanced prostate cancer. This review critically outlines recent advances in AR-V7 diagnostics and presents an overview of current AR-V7 targeted therapies.
Current status of androgen receptor-splice variant 7 inhibitor niclosamide in castrate-resistant prostate-cancer. [2019]Castrate-Resistant Prostate-Cancer (CRPC) is one of the most common malignancies occurring in men. Unfortunately, even if several recently approved agents clinically improved the outcome of CRPC patients, none of these is curative especially for a splice version of the Androgen Receptor (AR) AR-V7, which is a variant of the receptor constitutively activated and does not require the presence of androgens for the activation AR down-stream pathways. Since high AR-V7 expression is one of the most common features of CRPC, targeting this receptor variant is considered as one of the most promising strategies for treating this disease. Therefore anti-AR-V7 molecules could lead to a potential shift in paradigm in the treatment of CRPC. Niclosamide, an already FDA-approved anti-helminthic drug, was identified as a potent AR-V7 inhibitor in prostate cancer cells. Due to the recent positive preclinical results, niclosamide may be an interesting and novel type of targeted treatments for CRPC. This mini-review outlines the most recent pre- and clinical- data on the current status of niclosamide in the treatment of ARV7-positive CRPC patients.
[AR-V7 Androgen Receptor Variant as a Predictor of Response to Androgen-receptor Targeting Agents Used to Treat Castration-refractory Metastatic Prostate Cancer]. [2021]Several systemic treatment options are currently available for patients with metastatic castration-refractory prostate cancer (mCRPC), including the androgen-receptor targeting agents (ARTA) enzalutamide and abiraterone, the taxanes docetaxel and cabazitaxel, and the radioisotope drug 223-radium dichloride. In some patients with mCRCP, alternative splicing of androgen receptor (AR) mRNA occurs, resulting in the formation of a truncated AR lacking the androgen-binding domain. These receptors activate downstream signalling pathways even without the ligand. Recent studies show that the presence of the AR-V7 (ARV - AR variants) splicing variant is associated with resistance to ARTA. Bec>ause the presence of AR-V7 does not affect the efficacy of other systemic therapies used in mCRCPs, particularly taxanes, AR-V7 is a candidate predictive biomarker for the individualisation of mCRCP treatment. Two types of assays based on mRNA or abnormal protein detection are used to detect AR-V7 in circulating tumour cells.
High-Content Screening Identifies Src Family Kinases as Potential Regulators of AR-V7 Expression and Androgen-Independent Cell Growth. [2018]AR-V7 is an androgen receptor (AR) splice variant that lacks the ligand-binding domain and is isolated from prostate cancer cell lines. Increased expression of AR-V7 is associated with the transition from hormone-sensitive prostate cancer to more advanced castration-resistant prostate cancer (CRPC). Due to the loss of the ligand-binding domain, AR-V7 is not responsive to traditional AR-targeted therapies, and the mechanisms that regulate AR-V7 are still incompletely understood. Therefore, we aimed to explore existing classes of small molecules that may regulate AR-V7 expression and intracellular localization and their potential therapeutic role in CRPC.
Clinical Utility of CLIA-Grade AR-V7 Testing in Patients With Metastatic Castration-Resistant Prostate Cancer. [2023]A splice variant of the androgen receptor, AR-V7, confers resistance to AR-targeted therapies (ATTs) but not taxane chemotherapies in patients with metastatic castration-resistant prostate cancer. Since August 2015, a clinical-grade assay to detect AR-V7 messenger RNA expression in circulating tumors cells (CTCs) has been available to providers through a Clinical Laboratory Improvement Amendments-certified laboratory at Johns Hopkins University.