ARV-471 + Ribociclib for Advanced Breast Cancer

Recruiting at 45 trial locations

Overseen By Pfizer CT.gov Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

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 All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

Duration: Until progression or unacceptable toxicity

47 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 2 3 4 6}

What 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. ^{7 8 9 10 11}

Research Team

Pfizer CT.gov Call Center

Principal Investigator

Pfizer

Eligibility 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.

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.

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

Treatment Details

Interventions

• ARV-471
• Ribociclib

Trial Overview 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.

Participant Groups

Group I: ARV-471 in combination with Ribociclib Experimental Treatment 2 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

Who Is Running the Clinical Trial?

Pfizer

Lead Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Arvinas Estrogen Receptor, Inc.

Industry Sponsor

Trials

19

Recruited

2,400+

Findings from Research

Ribociclib, a CDK 4/6 inhibitor, significantly improves median progression-free survival (PFS) in women with HR+/HER2- metastatic breast cancer when used in combination with endocrine therapy, with PFS ranging from 8 to 13 months across three phase III trials.

The treatment is well tolerated, particularly in elderly patients, and while it has some dose-limiting toxicities like neutropenia and QTc prolongation, it maintains health-related quality of life and reduces pain scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients. Rascon, K., Flajc, G., De Angelis, C., et al.[2020]

In a study of 554 Italian patients with hormone receptor-positive, HER2-negative advanced breast cancer, ribociclib combined with letrozole showed a clinical benefit rate of 71.7% and a median time to progression of 26.7 months, indicating effective treatment outcomes.

The treatment was associated with manageable safety profiles, with 98.9% of patients experiencing all-grade adverse events, primarily neutropenia, but health-related quality of life scores remained stable during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. De Laurentiis, M., Caputo, R., Mazza, M., et al.[2022]

Ribociclib, approved by the FDA for treating advanced breast cancer, significantly improves progression-free survival when combined with letrozole compared to a placebo, as shown in a study of 668 patients.

The overall response rate for patients receiving ribociclib plus letrozole was 52.7%, compared to 37.1% for those on placebo, indicating its efficacy, although common side effects included neutropenia and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval: Ribociclib for the Treatment of Postmenopausal Women with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer. Shah, A., Bloomquist, E., Tang, S., et al.[2019]

Ribociclib (Kisqali) is effective for treating HR+/HER2- advanced or metastatic breast cancer in postmenopausal women, providing a targeted therapy option for this patient group.

Safinamide (Xadago) serves as an adjunctive treatment for patients with Parkinson's disease, enhancing overall management of the condition, while avelumab (Bavencio) is approved for metastatic Merkel cell carcinoma, demonstrating its efficacy in a rare and aggressive skin cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmaceutical Approval Update. Choy, M.[2020]

In a phase II study involving 43 patients with hormone receptor positive metastatic breast cancer, adding ribociclib to maintenance endocrine therapy significantly improved progression-free survival (PFS) to a median of 12.4 months compared to 4.75 months for those receiving endocrine therapy alone.

The study also indicated a promising safety profile, with 65.1% of patients on ribociclib experiencing clinical benefits, although a notable percentage (58.1%) experienced grade 3-4 hematological adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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). Decker, T., Lüdtke-Heckenkamp, K., Melnichuk, L., et al.[2023]

Ribociclib, when combined with letrozole, significantly improves progression-free survival in postmenopausal patients with HR-positive, HER2-negative advanced breast cancer, as shown in the MONALEESA-2 trial.

Ongoing trials (MONALEESA-3 and MONALEESA-7) further support ribociclib's efficacy, demonstrating significant progression-free survival benefits in both treatment-naive and previously treated postmenopausal patients, as well as in pre/perimenopausal women with ovarian function suppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MONALEESA clinical program: a review of ribociclib use in different clinical settings. Yardley, DA.[2020]

Prostate cancer cells can evade endocrine therapies by producing truncated androgen receptor splice variants (AR-Vs), particularly AR-V7, which do not respond to treatments targeting the androgen receptor.

AR-V7 is emerging as a significant predictive biomarker for advanced prostate cancer, guiding treatment decisions and the development of targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The impact of the androgen receptor splice variant AR-V7 on the prognosis and treatment of advanced prostate cancer]. Thelen, P., Taubert, H., Duensing, S., et al.[2022]

Castrate-Resistant Prostate Cancer (CRPC) is challenging to treat, especially due to the presence of the AR-V7 variant of the Androgen Receptor, which is activated without androgens, making it a key target for new therapies.

Niclosamide, an FDA-approved drug, has been identified as a potent inhibitor of the AR-V7 variant in prostate cancer cells, suggesting it could be a promising new treatment option for patients with AR-V7-positive CRPC based on recent preclinical findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current status of androgen receptor-splice variant 7 inhibitor niclosamide in castrate-resistant prostate-cancer. Sobhani, N., Generali, D., D'Angelo, A., et al.[2019]

The presence of the AR-V7 splicing variant in patients with metastatic castration-refractory prostate cancer (mCRPC) is linked to resistance against androgen-receptor targeting agents (ARTA) like enzalutamide and abiraterone, making AR-V7 a potential predictive biomarker for treatment individualization.

In patients who have been treated with ARTA, the prevalence of AR-V7 increases significantly to 19-34%, and those with AR-V7 are unlikely to respond to further ARTA treatment, with only 4.8% showing a response, suggesting that AR-V7 testing could guide treatment decisions effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[AR-V7 Androgen Receptor Variant as a Predictor of Response to Androgen-receptor Targeting Agents Used to Treat Castration-refractory Metastatic Prostate Cancer]. Büchler, T., Bobek, V., Kološtová, K.[2021]

AR-V7, a variant of the androgen receptor linked to advanced prostate cancer, can be regulated by targeting specific protein kinases, particularly Src and Fyn, which may help in managing castration-resistant prostate cancer (CRPC).

The Src-Abl inhibitor PD180970 significantly reduced AR-V7 expression by over 46% and inhibited androgen-independent cell growth, suggesting it could be an effective treatment option for CRPC patients resistant to traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Content Screening Identifies Src Family Kinases as Potential Regulators of AR-V7 Expression and Androgen-Independent Cell Growth. Szafran, AT., Stephan, C., Bolt, M., et al.[2018]

AR-V7 testing significantly influenced clinical decision-making in 53% of patients with metastatic castration-resistant prostate cancer, particularly leading to treatment changes for those with AR-V7+ results.

Patients with AR-V7+ results were often switched from androgen receptor-targeted therapies to taxane chemotherapy or offered clinical trials, resulting in a higher likelihood of achieving a significant decline in prostate-specific antigen levels compared to those who did not change treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Utility of CLIA-Grade AR-V7 Testing in Patients With Metastatic Castration-Resistant Prostate Cancer. Markowski, MC., Silberstein, JL., Eshleman, JR., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients. [2020]

2. France pubmed.ncbi.nlm.nih.gov

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]

3. United States pubmed.ncbi.nlm.nih.gov

FDA Approval: Ribociclib for the Treatment of Postmenopausal Women with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Pharmaceutical Approval Update. [2020]

5. Netherlands pubmed.ncbi.nlm.nih.gov

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]

6. England pubmed.ncbi.nlm.nih.gov

MONALEESA clinical program: a review of ribociclib use in different clinical settings. [2020]

7. Germany pubmed.ncbi.nlm.nih.gov

[The impact of the androgen receptor splice variant AR-V7 on the prognosis and treatment of advanced prostate cancer]. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Current status of androgen receptor-splice variant 7 inhibitor niclosamide in castrate-resistant prostate-cancer. [2019]

9. Czech Republic pubmed.ncbi.nlm.nih.gov

[AR-V7 Androgen Receptor Variant as a Predictor of Response to Androgen-receptor Targeting Agents Used to Treat Castration-refractory Metastatic Prostate Cancer]. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

High-Content Screening Identifies Src Family Kinases as Potential Regulators of AR-V7 Expression and Androgen-Independent Cell Growth. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Clinical Utility of CLIA-Grade AR-V7 Testing in Patients With Metastatic Castration-Resistant Prostate Cancer. [2023]