Ribociclib + Belinostat for Breast Cancer

(CHARGE Trial)

Recruiting at 1 trial location

Overseen By Janna Espinosa

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Utah

Must not be taking: Valproic acid, UGT1A1 inhibitors

Disqualifiers: Active infection, Uncontrolled arrhythmia, others

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

Compensation: Varies

Number of Visits: Unknown

34 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open-label, multi-center, phase I study designed to assess the maximum tolerated dose of ribociclib and belinostat in combination. The trial will open with a dose escalation followed by an expansion cohort at the identified dose. Dose escalation will be open to the enrollment of patients diagnosed with triple-negative breast cancer or ovarian cancer. Dose expansion will only be open to patients diagnosed with triple-negative breast cancer.

Will I have to stop taking my current medications?

The trial requires stopping certain medications, including those that inhibit UGT1A1, herbal supplements, and medications with a risk of inducing Torsades de Pointes, at least 7 days before starting the study. You should discuss your current medications with the trial team to see if any need to be stopped or adjusted.

What data supports the effectiveness of the drug Ribociclib in combination with Belinostat for breast cancer?

Ribociclib, when used with other drugs like letrozole, has shown to improve progression-free survival (the time during and after treatment that a patient lives with the disease without it getting worse) in patients with hormone receptor-positive, HER2-negative advanced breast cancer. This suggests that Ribociclib can be effective in treating certain types of breast cancer. ^{1 2 3 4 5}

Is the combination of Ribociclib and Belinostat safe for humans?

Ribociclib has been studied in combination with other drugs for breast cancer and is generally considered safe, but it can cause side effects like low white blood cell counts, nausea, and fatigue. It may also affect liver function and heart rhythm, so patients with heart issues should be cautious. There is no specific safety data available for the combination of Ribociclib and Belinostat. ^{1 3 4 6 7}

How is the drug combination of Ribociclib and Belinostat unique for breast cancer treatment?

The combination of Ribociclib and Belinostat is unique because Ribociclib is a CDK 4/6 inhibitor that has shown improved survival in hormone receptor-positive, HER2-negative breast cancer, while Belinostat is a histone deacetylase inhibitor, potentially offering a novel mechanism of action by targeting different pathways in cancer cells. ^{1 3 4 8 9}

Research Team

Theresa Werner, MD

Principal Investigator

Huntsman Cancer Institute

Eligibility Criteria

This trial is for adults with metastatic triple-negative breast cancer or recurrent ovarian cancer. Participants must have good organ function, be able to swallow pills, and not be pregnant. They should agree to use birth control and provide consent. People with certain heart conditions, unresolved diarrhea, active infections, or those who've had recent major treatments are excluded.

Inclusion Criteria

Agrees to continue use of approved birth control for at least 6 months after receiving the last dose of study drugs

I can take care of myself but might not be able to do heavy physical work.

I agree to have up to 3 biopsies on areas where my cancer has spread.

Exclusion Criteria

I am not allergic to belinostat, ribociclib, or their components.

I have brain metastases or leptomeningeal disease but don't need immediate brain-specific treatment.

I am not using herbal supplements or they are approved by the study lead.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Ribociclib and belinostat are given at escalating doses to determine the maximum tolerated dose (MTD)

8 weeks

Multiple visits for dose adjustments and monitoring

Dose Expansion

Participants receive the identified MTD of ribociclib and belinostat to further assess safety and efficacy

36 months

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

36 months

Treatment Details

Interventions

• Belinostat
• Ribociclib

Trial Overview The study tests the combination of two drugs: Ribociclib and Belinostat. It's designed to find the highest dose patients can tolerate without severe side effects. The trial has two parts: first finding the right dose (dose escalation) and then giving that dose to more people (dose expansion).

Participant Groups

Group I: Cohort 2: Dose expansion cohort Experimental Treatment 2 Interventions

Participant will be enrolled in dose expansion cohort at the identified Recommended Phase 2 Dose (RP2D). Dose escalation will be open to the enrollment of patients diagnosed with triple-negative breast cancer or ovarian cancer. However, dose expansion will only be open to the enrollment of patients diagnosed with triple-negative breast cancer

Group II: Cohort 1: Dose Escalation Cohort Experimental Treatment 2 Interventions

Ribociclib and belinostat will be given at escalating doses and on multiple administration schedules throughout the dose escalation component of the study. The MTD identified in the dose escalation component will be used to define the dose and administration schedule used in the dose expansion.

Belinostat is already approved in United States for the following indications:

Approved in United States as Beleodaq for:

• Peripheral T-cell lymphoma (PTCL)

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Acrotech Biopharma

Collaborator

Trials

1

Recruited

30+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

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 early-stage breast cancer, the combination of ribociclib and letrozole was found to activate estrogen-independent resistance pathways, which may affect treatment outcomes.

This finding suggests that while ribociclib and letrozole are used together to target cancer growth, their interaction could lead to challenges in effectively managing breast cancer due to potential resistance mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Resistance Mechanisms to CDK Inhibition plus Endocrine Therapy Identified. [2022]

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, when combined with letrozole or fulvestrant, has shown improved progression-free survival and overall survival in postmenopausal women with hormone receptor-positive breast cancer, based on a Phase III study involving 668 participants.

While ribociclib is effective, it has a higher risk of liver function abnormalities and can cause QTc prolongation, making it less suitable for patients with certain cardiac conditions; alternative CDK 4/6 inhibitors like palbociclib or abemaciclib may be safer options in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib in the Treatment of Hormone-Receptor Positive/HER2-Negative Advanced and Early Breast Cancer: Overview of Clinical Data and Patients Selection. Parati, MC., Pedersini, R., Perego, G., et al.[2022]

In the MONALEESA-2 study involving 213 US patients with hormone receptor-positive, HER2-negative advanced breast cancer, ribociclib combined with letrozole significantly improved progression-free survival (PFS) to 27.6 months compared to 15.0 months with letrozole alone, indicating its efficacy as a first-line treatment.

The most common side effects of ribociclib included neutropenia (72%), nausea (69%), and fatigue (60%), highlighting the importance of monitoring for these adverse events during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Ribociclib With Letrozole in US Patients Enrolled in the MONALEESA-2 Study. Yardley, DA., Hart, L., Favret, A., et al.[2020]

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 has been approved by the FDA for use in male patients with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, showing an overall response rate of 46.9% in a clinical trial with 39 male patients.

The safety profile of ribociclib in male patients is similar to that observed in female patients, indicating that its efficacy and safety are consistent across genders when used in combination with aromatase inhibitors or fulvestrant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer. Gao, JJ., Osgood, CL., Feng, Z., et al.[2023]

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]

The combination of antiestrogen therapy and ribociclib, a CDK4/6 inhibitor, significantly improved progression-free survival in women with metastatic HR-positive, HER2-negative breast cancer compared to letrozole alone.

These findings come from a large phase III trial, which may support FDA approval for this combination treatment, highlighting its potential efficacy in managing this type of breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib Lengthens Breast Cancer Survival. [2018]

References

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

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

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

Resistance Mechanisms to CDK Inhibition plus Endocrine Therapy Identified. [2022]

3. 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]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Ribociclib in the Treatment of Hormone-Receptor Positive/HER2-Negative Advanced and Early Breast Cancer: Overview of Clinical Data and Patients Selection. [2022]

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

Efficacy and Safety of Ribociclib With Letrozole in US Patients Enrolled in the MONALEESA-2 Study. [2020]

6. 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]

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

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer. [2023]

8. 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]

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

Ribociclib Lengthens Breast Cancer Survival. [2018]