Ribociclib + Belinostat for Breast Cancer

(CHARGE Trial)

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Theresa Werner, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: University of Utah

Must not be taking: Valproic acid, UGT1A1 inhibitors

Disqualifiers: Active infection, Uncontrolled arrhythmia, others

No Placebo Group

Breakthrough Therapy

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.

Trial 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 (Histone Deacetylase Inhibitor)
• Ribociclib (CDK4/6 Inhibitor)

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: Treatment: all patients 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)

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Huntsman Cancer Institute Salt Lake City, UT

Inova Schar Cancer Institute Fairfax, VA

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1169

Patients Recruited

1,623,000+

Acrotech Biopharma

Collaborator

Trials

1

Patients Recruited

30+

Novartis

Industry Sponsor

Trials

1646

Patients Recruited

2,778,000+

References

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

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.

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

Resistance Mechanisms to CDK Inhibition plus Endocrine Therapy Identified. [2022] In early-stage breast cancer, ribociclib plus letrozole led to estrogen-independent resistance pathways.

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] 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.

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] Among pre- and postmenopausal women with hormone receptor-positive (HR+) breast cancer (BC), combinations of an aromatase inhibitor (AI) or fulvestrant with a CDK 4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) have demonstrated improved progression-free survival (PFS) and overall survival (OS) compared to standard single-agent hormone therapy alone as first-line therapy for de novo metastatic disease or relapse during or after adjuvant therapy and no previous therapies in an advanced setting. We here reviewed clinical data about ribociclib in advanced and early BC. Also, we shed light on patient selection and special settings in which medical oncologists urgently await an advance in treatment. Ribociclib was FDA-approved in combination with letrozole based on a Phase III study in which 668 postmenopausal women with HR+, HER2-negative recurrent or metastatic BC were treated with first-line letrozole with or without ribociclib. For patients with metastatic disease at presentation or after a course of AIs, the results of the MONALEESA-3 trial suggest ribociclib's efficacy in combination with fulvestrant, and this combination is FDA-approved for initial- and subsequent-line endocrine therapy for postmenopausal women with metastatic hormone receptor-positive, HER2-negative BC. In adjuvant and neoadjuvant settings, the use of CDK 4/6 inhibitors may be useful to boost outcomes in high-risk patients with HR+ BC, but data contrast with those of a phase III study, which produced positive results. New combinations are being explored in upfront disease (neoadjuvant) or in association with other targeted agents in metastatic disease. Compared to other CDK 4/6 available, ribociclib has a higher incidence of liver function test abnormalities than the other agents and can cause QTc prolongation, and therefore may be prudently avoided in patients with cardiac morbidities or other risk factors for QTc prolongation (drugs, interactions). In these cases, different agents (palbociclib or abemaciclib) may be used. In conclusion, ribociclib with letrozole or with fulvestrant is effective for the entire spectrum of patients with HR+ BC in the advanced setting. Ribociclib has all the characteristics of an innovative drug able to change the clinical practice and most BC patients' prognoses.

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] Label="BACKGROUND">In the Mammary Oncology Assessment of LEE011's (Ribociclib's) Efficacy and Safety (MONALEESA-2) study, combination treatment with the selective inhibitor of cyclin-dependent kinases 4/6 ribociclib with letrozole significantly improved progression-free survival (PFS) versus letrozole alone in postmenopausal women with hormone receptor-positive HR+/HER2- advanced breast cancer (ABC). Herein we present results from the subset of US patients enrolled in MONALEESA-2.

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] 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.

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] On December 10, 2021, the FDA expanded the indications for ribociclib to include male patients for the treatment of hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer. Ribociclib is now indicated in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy in adult patients, or with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy (ET), in postmenopausal women or in men. The efficacy of ribociclib+AI for male patients was primarily based on previous favorable benefit-risk assessments of ribociclib from MONALEESA-2 and MONALEESA-7 trials, and supported by COMPLEEMENT-1, an open-label, single arm, multicenter clinical trial, in which 39 male patients (n=3,246 total patients) received ribociclib+letrozole+goserelin/leuprolide. The ORR based on confirmed responses in male patients with measurable disease at baseline was 46.9% (95% CI: 29.1, 65.3), consistent with an ORR 43.6% (95% CI: 41.5, 45.8) in the overall population. Overall, adverse reactions occurring in male patients were similar to those occurring in female patients treated with ribociclib+ET. The efficacy of ribociclib+fulvestrant for male patients was primarily based on the previous findings of a favorable benefit-risk assessment from the MONALEESA-3 trial, supported by FDA review of clinical data of a limited number of male patients treated in clinical practice receiving ribociclib+fulvestrant. The known mechanism of action, biologic rationale, and clinical information available adequately demonstrate that the efficacy and safety of ribociclib+AI/fulvestrant are similar in male and female patients. This article summarizes the FDA's decision-making and data supporting the approval of ribociclib in male patients with breast cancer, and discusses regulatory insights.

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] 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).

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

Ribociclib Lengthens Breast Cancer Survival. [2018] The combination of antiestrogen therapy and ribociclib, an investigational CDK4/6 inhibitor, led to improved outcomes in women with metastatic HR-positive, HER2-negative breast cancer, according to findings presented at a meeting of the European Society for Medical Oncology. The combination significantly increased progression-free survival compared with letrozole alone in a large phase III trial-data that could lead to FDA approval.