Olaparib + Vorinostat for Breast Cancer

Overseen By Polly Niravath, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: The Methodist Hospital Research Institute

Must not be taking: CYP3A inhibitors, CYP3A inducers, QT prolongers

Disqualifiers: MDS/AML, Uncontrolled brain metastases, others

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

Compensation: Varies

Number of Visits: Unknown

28 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the safety and preliminary efficacy of olaparib and vorinostat when used together in participants with relapsed/refractory and or metastatic breast cancer.

Do I need to stop taking my current medications to join the trial?

The trial requires that you do not take certain medications that affect liver enzymes (CYP3A inhibitors or inducers) and medications that prolong the QT interval (a heart rhythm measure) for at least 2 weeks before joining. If you're on these medications, you may need to stop or switch them.

What data supports the effectiveness of the drug Olaparib + Vorinostat for breast cancer?

Olaparib has shown effectiveness in improving progression-free survival in patients with BRCA-mutated HER2-negative metastatic breast cancer, especially in triple-negative cases. Vorinostat has been studied in combination with other drugs for metastatic breast cancer, suggesting potential benefits when used with other treatments. ^{1 2 3 4 5}

Is the combination of Olaparib and Vorinostat safe for humans?

Vorinostat, also known as SAHA, has been studied for safety in humans, particularly in patients with advanced cancer. It has been evaluated for its safety and tolerability in various clinical studies, including its effects when taken with food. However, specific safety data for the combination of Olaparib and Vorinostat is not provided in the available research. ^{2 6 7 8 9}

What makes the drug combination of Olaparib and Vorinostat unique for breast cancer treatment?

The combination of Olaparib and Vorinostat is unique because it combines a PARP inhibitor (Olaparib) with a histone deacetylase inhibitor (Vorinostat), which may enhance the effectiveness of treatment by targeting cancer cells in different ways. Vorinostat is already used for T-cell lymphoma and shows potential for breast cancer, making this combination a novel approach for treating breast cancer. ^{2 6 7 8 10}

Research Team

Polly Niravath, M.D.

Principal Investigator

Houston Methodist Cancer Center

Eligibility Criteria

This trial is for adults with relapsed/refractory or metastatic breast cancer, excluding those with HER2-positive type. Participants must have a life expectancy of at least 6 months, good organ and bone marrow function, and be willing to use effective contraception. They should not have pneumonitis, uncontrolled brain metastases, known drug hypersensitivity, recent blood transfusions or chemotherapy, certain heart conditions or infections.

Inclusion Criteria

My breast cancer has returned or spread and is not HER2-positive.

Provision of informed consent prior to any study-specific procedures

I am 18 years old or older.

Exclusion Criteria

I have not had major surgery in the last 4 weeks.

I do not have any severe health issues that could interfere with the study.

Participation in another clinical study with an investigational product during the last 3 months

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Olaparib and vorinostat are administered at various dose levels for 4 cycles of 28 days each to determine the maximum tolerated dose (MTD).

16 weeks

Regular visits for dose administration and monitoring

Phase Ib Treatment

Olaparib and vorinostat are administered at the MTD for 4 cycles of 28 days each to assess response in relapsed/refractory and/or metastatic breast cancer.

16 weeks

Regular visits for dose administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Olaparib
• Vorinostat

Trial Overview The study tests the combination of two drugs: Olaparib and Vorinostat in patients whose breast cancer has returned after treatment or spread elsewhere. It aims to determine the safety and initial effectiveness of this drug duo.

Participant Groups

Group I: Olaparib and Vorinostat Experimental Treatment 2 Interventions

Phase I: Olaparib and vorinostat will be orally administered for 4 28-day cycles. Dose levels (DLs) are as follows: DL -1, 100 mg twice daily (b.i.d.) olaparib and 300 mg for 5 consecutive days per week vorinostat; DL 0 (starting dose), 200 mg twice daily (b.i.d.) olaparib and 300 mg once daily (q.d.) vorinostat; DL 1, 300 mg b.i.d. olaparib and 300 mg q.d. vorinostat; and DL 2, 300 mg b.i.d. olaparib and 400 mg q.d. vorinostat. . Patients who derive clinical benefit (CR, PR, or SD) after 4 cycles of treatment can continue to receive the study treatment until they experience unacceptable AEs or disease progression. Phase Ib: Olaparib and vorinostat will be administered at the maximum tolerated dose (MTD) determined in the Phase I portion of the study for 4 28-day cycles. Participants who derive clinical benefit (complete response, partial response, or stable disease) after 4 cycles will continue to receive study treatment until unacceptable toxicity or disease progression.

Olaparib is already approved in European Union, United States for the following indications:

Approved in European Union as Lynparza for:

• Breast cancer
• Ovarian cancer
• Fallopian tube cancer
• Peritoneal cancer
• Pancreatic cancer
• Prostate cancer
• Endometrial cancer

Approved in United States as Lynparza for:

• Ovarian, fallopian tube, and primary peritoneal cancer
• Breast cancer
• Prostate cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

The Methodist Hospital Research Institute

Lead Sponsor

Trials

299

Recruited

82,500+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

Olaparib (Lynparza) is approved for treating adult patients with high-risk early breast cancer that has a germline BRCA mutation, following chemotherapy treatment.

This approval highlights Olaparib's role as an adjuvant therapy, which means it is used after initial treatments to help prevent cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Treatment for High-Risk Early Breast Cancer. Aschenbrenner, DS.[2022]

The maximum tolerated dose (MTD) for the combination of vorinostat and ixabepilone was established in a Phase IB trial with 37 metastatic breast cancer patients, showing a manageable safety profile with dose-limiting toxicities occurring in 27% of patients on one schedule and none on another.

The combination therapy demonstrated an objective response rate of 22% and 30% for different dosing schedules, with median overall survival times of 14.8 and 17.1 months, suggesting comparable efficacy to existing treatments and warranting further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IB trial of ixabepilone and vorinostat in metastatic breast cancer. Luu, T., Kim, KP., Blanchard, S., et al.[2018]

Olaparib, a PARP inhibitor, has shown significant clinical benefits in improving progression-free survival for patients with BRCA1 or BRCA2 mutated HER2 negative metastatic breast cancer compared to standard chemotherapy.

The drug has a manageable safety profile, making it a promising treatment option, particularly for triple negative breast cancer, although further research is needed to optimize its use with other therapies and identify suitable biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib for the treatment of breast cancer. Griguolo, G., Dieci, MV., Guarneri, V., et al.[2019]

Olaparib is particularly effective for patients with BRCA-mutated ovarian cancer, but it also benefits a subset of patients with BRCA wild-type tumors that have loss-of-function mutations in DNA repair genes, showing similar treatment outcomes.

The study suggests that patients with specific HRR gene mutations, even without BRCA mutations, can be identified as a group that may respond well to olaparib, indicating a potential for broader use of this treatment in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. Hodgson, DR., Dougherty, BA., Lai, Z., et al.[2020]

The OPINION study is evaluating the safety and efficacy of olaparib as a maintenance therapy for women with high-grade serous or endometrioid platinum-sensitive relapsed ovarian cancer who do not have BRCA mutations, involving patients who have undergone at least two prior lines of platinum-based chemotherapy.

The primary goal of the study is to assess progression-free survival, which will help determine how effective olaparib is in delaying cancer progression in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design. Poveda, AM., Davidson, R., Blakeley, C., et al.[2020]

Vorinostat (SAHA) shows varying effectiveness in treating breast cancer, with some tumors and cell lines being resistant due to differences in gene expression related to cell adhesion and glutathione metabolism.

Depleting glutathione with buthionine sulfoximine (BSO) can enhance the effectiveness of SAHA, suggesting that evaluating antioxidant gene expression may help predict which tumors will respond to this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer. Chiaradonna, F., Barozzi, I., Miccolo, C., et al.[2018]

A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed to accurately measure vorinostat and its metabolites in human serum, with a lower limit of quantitation of 3.0 ng/ml for each analyte.

This assay is currently being utilized in at least 12 clinical studies, highlighting its importance in evaluating the pharmacokinetics and therapeutic effects of vorinostat as an antineoplastic agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A liquid chromatography-electrospray ionization tandem mass spectrometric assay for quantitation of the histone deacetylase inhibitor, vorinostat (suberoylanilide hydroxamicacid, SAHA), and its metabolites in human serum. Parise, RA., Holleran, JL., Beumer, JH., et al.[2018]

In a phase I study involving 23 advanced-stage cancer patients, vorinostat was found to be safe and tolerable, with common side effects including mild to moderate nausea and fatigue.

The study revealed that a high-fat meal slightly increased the absorption of vorinostat but did not significantly impact its overall effectiveness, suggesting that vorinostat can be administered with or without food in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A study to determine the effects of food and multiple dosing on the pharmacokinetics of vorinostat given orally to patients with advanced cancer. Rubin, EH., Agrawal, NG., Friedman, EJ., et al.[2018]

Vorinostat, a histone deacetylase inhibitor, did not cause maternal toxicity or major fetal malformations in Sprague-Dawley rats and Dutch Belted rabbits, indicating a relatively safe profile during pregnancy at lower doses.

However, at high doses, vorinostat was associated with developmental toxicity, such as decreased fetal weight and skeletal variations, suggesting that while it is generally safe, caution is needed with higher dosages due to potential adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of developmental toxicity of vorinostat, a histone deacetylase inhibitor, in Sprague-Dawley rats and Dutch Belted rabbits. Wise, LD., Turner, KJ., Kerr, JS.[2018]

The combination of vorinostat and paclitaxel did not show superior effectiveness compared to either drug alone in most ovarian cancer cell lines, indicating that their combined use may not enhance treatment outcomes universally.

In one specific ovarian cancer cell line (2774), the sequence of administration mattered, with paclitaxel followed by low-dose vorinostat being the most effective in inducing apoptosis, highlighting the importance of tailoring treatment strategies based on individual tumor characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro and in vivo histone deacetylase inhibitor therapy with vorinostat and paclitaxel in ovarian cancer models: does timing matter? Modesitt, SC., Parsons, SJ.[2018]

References

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

New Adjuvant Treatment for High-Risk Early Breast Cancer. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Phase IB trial of ixabepilone and vorinostat in metastatic breast cancer. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Olaparib for the treatment of breast cancer. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design. [2020]

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

Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer. [2018]

7. Netherlands pubmed.ncbi.nlm.nih.gov

A liquid chromatography-electrospray ionization tandem mass spectrometric assay for quantitation of the histone deacetylase inhibitor, vorinostat (suberoylanilide hydroxamicacid, SAHA), and its metabolites in human serum. [2018]

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

A study to determine the effects of food and multiple dosing on the pharmacokinetics of vorinostat given orally to patients with advanced cancer. [2018]

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

Assessment of developmental toxicity of vorinostat, a histone deacetylase inhibitor, in Sprague-Dawley rats and Dutch Belted rabbits. [2018]

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

In vitro and in vivo histone deacetylase inhibitor therapy with vorinostat and paclitaxel in ovarian cancer models: does timing matter? [2018]