Triple-Drug Combo for BRCA-Mutated Breast Cancer

Overseen By Alexandra Torres

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: Abramson Cancer Center at Penn Medicine

Must not be taking: CYP3A inhibitors/inducers

Disqualifiers: Other malignancy, Brain metastases, Immunocompromised, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Estimated average of 7 months

54 Participants Needed

Trial Summary

What is the purpose of this trial?

The main purpose of this research study is to learn whether the investigational combination of olaparib, palbociclib, and fulvestrant is safe in patients with estrogen receptor-positive breast cancer and BRCA1 or BRCA2 mutations.

Will I have to stop taking my current medications?

The trial requires participants to stop taking any herbal preparations or medications. Additionally, you cannot take strong or moderate CYP3A inhibitors or inducers while participating in the study.

What data supports the effectiveness of the drug combination for BRCA-mutated breast cancer?

Research shows that olaparib, a part of the drug combination, has been effective in prolonging progression-free survival in patients with advanced breast cancer carrying a BRCA mutation. Additionally, PARP inhibitors like olaparib have shown clinical benefits in improving survival outcomes in BRCA-mutated breast cancer. ^{1 2 3 4 5}

Is the triple-drug combo for BRCA-mutated breast cancer safe for humans?

Olaparib, one of the drugs in the combo, has been studied for safety in breast cancer patients with BRCA mutations. It has shown clinical benefits and is generally considered tolerable, but specific safety data for the triple-drug combination is not provided in the available research. ^{1 2 3 6 7}

What makes the triple-drug combo of Fulvestrant, Olaparib, and Palbociclib unique for BRCA-mutated breast cancer?

This triple-drug combo is unique because it combines Fulvestrant, a hormone therapy, with Olaparib, a PARP inhibitor that targets DNA repair weaknesses in BRCA-mutated cancers, and Palbociclib, a CDK4/6 inhibitor that helps control cell division, offering a multi-faceted approach to treating BRCA-mutated breast cancer. ^{1 2 4 5 7}

Research Team

Payal D. Shah, MD

Principal Investigator

Abramson Cancer Center at Penn Medicine

Eligibility Criteria

This trial is for adults with estrogen receptor-positive, HER2-negative metastatic breast cancer who have a BRCA1 or BRCA2 mutation. They should be relatively healthy and not have had certain treatments recently. Women must use two forms of contraception, and men must also ensure their partners use contraception to prevent pregnancy.

Inclusion Criteria

You have a disease that can be measured or seen on a CT or MRI scan.

My breast cancer is advanced, cannot be surgically removed, and is hormone receptor positive but not HER2 positive.

I have had up to 2 chemotherapy treatments for my advanced breast cancer.

Exclusion Criteria

Involvement in study planning or conduct

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

I have brain metastases that are causing symptoms and are not under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive olaparib, palbociclib, and fulvestrant in 28-day cycles until disease progression or unacceptable toxicity

Estimated average of 7 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Fulvestrant
• Olaparib
• Palbociclib

Trial Overview The HOPE trial is testing the safety of combining three drugs: Olaparib, Palbociclib, and Fulvestrant in patients with specific genetic mutations associated with breast cancer. The goal is to see if this combination works better than current treatments.

Participant Groups

Group I: Phase II Experimental Treatment 3 Interventions

(28-day cycle) Olaparib 300 mg by mouth twice a day, days 1-28; fulvestrant 500 mg intramuscularly once monthly on Day 1 of each cycle + 500 mg intramuscularly on Cycle 1 Day 15; palbociclib dose as per maximum tolerated dose determined during Phase I, by mouth daily, days 1-21 Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-mandated study removal.

Group II: Phase I Level 2 Experimental Treatment 3 Interventions

(28-day cycle) Olaparib 300 mg by mouth twice a day, days 1-28; fulvestrant 500 mg intramuscularly, Day 1 + 500 mg intramuscularly Cycle 0 Day 15; palbociclib 125 mg by mouth daily, days 1-21, beginning at cycle 1 Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-mandated study removal.

Group III: Phase I Level 1 Experimental Treatment 3 Interventions

(28-day cycle) Olaparib 300 mg by mouth twice a day, days 1-28; fulvestrant 500 mg intramuscularly, Day 1 + 500 mg intramuscularly Cycle 0 Day 15; palbociclib 100 mg by mouth daily, days 1-21, beginning at cycle 1 Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-mandated study removal.

Group IV: Phase I Level 0 Experimental Treatment 3 Interventions

(28-day cycle) Olaparib 300 mg by mouth twice a day, days 1-28; fulvestrant 500 mg intramuscularly, Day 1 + 500 mg intramuscularly Cycle 0 Day 15; palbociclib 75 mg by mouth daily, days 1-21, beginning at cycle 1

Fulvestrant is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in United States as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in Canada as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in Japan as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Who Is Running the Clinical Trial?

Abramson Cancer Center at Penn Medicine

Lead Sponsor

Trials

425

Recruited

464,000+

Abramson Cancer Center of the University of Pennsylvania

Lead Sponsor

Trials

360

Recruited

108,000+

Findings from Research

Olaparib, an oral PARP-inhibitor, significantly improves progression-free survival in HER2-negative advanced breast cancer patients with BRCA1/2 mutations compared to standard chemotherapy, based on a randomized Phase III trial.

The trial also indicated an overall survival benefit for patients who had not received prior chemotherapy for metastatic disease, highlighting olaparib's potential as an effective treatment option in this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib for advanced breast cancer. Griguolo, G., Dieci, MV., Miglietta, F., et al.[2021]

In a phase II study involving 80 patients with early-stage triple-negative and BRCA1/2 mutation-associated breast cancer, the combination of iniparib, gemcitabine, and carboplatin resulted in a pathologic complete response rate of 36%, indicating its efficacy as a preoperative treatment.

The study found that higher homologous recombination deficiency loss of heterozygosity (HRD-LOH) scores were associated with better treatment responses, suggesting that this assay could help identify patients likely to benefit from the therapy, even those without BRCA1/2 mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Gemcitabine, Carboplatin, and Iniparib As Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation-Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105. Telli, ML., Jensen, KC., Vinayak, S., et al.[2022]

The combination of olaparib and carboplatin was found to be safe and effective in treating breast and ovarian cancer in patients with germline BRCA1 or BRCA2 mutations, with 50% of patients showing a partial response and one patient achieving a complete response.

Proteomic analysis indicated that high levels of FOXO3a expression before treatment may predict a better response to the therapy, suggesting a potential biomarker for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. Lee, JM., Hays, JL., Annunziata, CM., et al.[2022]

References

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

Update on PARP Inhibitors in Breast Cancer. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Olaparib for advanced breast cancer. [2021]

3. Saudi Arabia pubmed.ncbi.nlm.nih.gov

PARP Inhibitors for the Treatment of BRCA1/2-Mutated Metastatic Breast Cancer: A Systematic Review and Meta-analysis. [2023]

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

Phase II Study of Gemcitabine, Carboplatin, and Iniparib As Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation-Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105. [2022]

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

Medical Management of newly diagnosed breast cancer in a BRCA1/2 mutation carrier. [2021]

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

Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. [2022]

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

Olaparib for metastatic breast cancer in a patient with a germline PALB2 variant. [2023]