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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination to determine its safety for individuals with estrogen receptor-positive breast cancer and BRCA1 or BRCA2 mutations. The combination includes three drugs: olaparib (a PARP inhibitor), palbociclib (a CDK4/6 inhibitor), and fulvestrant (also known as Faslodex, a hormone therapy). It targets those whose breast cancer cannot be completely removed by surgery and who have undergone up to two chemotherapy treatments for metastatic cancer. Individuals with breast cancer that has spread and specific BRCA mutations might be suitable for this trial. The goal is to assess the safety of this treatment combination. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research is examining the safety of using a combination of three drugs—olaparib, palbociclib, and fulvestrant—for certain types of breast cancer. The FDA has already approved olaparib for some other cancers, indicating its general safety for those uses.

Patients who previously took olaparib and palbociclib together usually tolerated them well, though some experienced side effects like nausea and low blood counts. Fulvestrant, commonly used to treat breast cancer, is generally well-tolerated but can cause side effects like pain at the injection site and tiredness.

This trial is in an early stage, so researchers are primarily focused on how this drug combination affects health. They are monitoring for any serious side effects or toxicities. The current goal is to find a safe dose that patients can take without major side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the triple-drug combo of fulvestrant, olaparib, and palbociclib for BRCA-mutated breast cancer because it offers a unique approach compared to current treatments. While standard treatments often involve hormone therapy or chemotherapy, this combo targets cancer in a multi-faceted way. Olaparib is a PARP inhibitor, which exploits the DNA repair weaknesses in BRCA-mutated cells, while palbociclib inhibits CDK4/6, leading to cell cycle arrest. Fulvestrant works by blocking and degrading estrogen receptors. By combining these mechanisms, the treatment aims to attack cancer cells more effectively and potentially delay progression, offering hope for better outcomes.

What evidence suggests that this trial's treatments could be effective for BRCA-mutated breast cancer?

Research has shown that the combination of olaparib, palbociclib, and fulvestrant may help treat breast cancer in people with BRCA1 or BRCA2 mutations. In this trial, participants will receive this combination therapy at different dosage levels to determine the most effective and tolerable regimen. Olaparib stops a protein that helps cancer cells repair themselves. Palbociclib slows cancer cell growth, and fulvestrant targets estrogen receptors. Studies have found that using palbociclib with fulvestrant can prevent cancer progression for about 24.8 months on average. This suggests that the drug combination might effectively slow the disease. The trial will further study the combination to confirm its benefits and manage any side effects. ^{1 2 5 6 7}

Who Is on the Research Team?

Payal D. Shah, MD

Principal Investigator

Abramson Cancer Center at Penn Medicine

Are You a Good Fit for This Trial?

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

People with weakened immune systems

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.TPS1126

A phase I/II trial of olaparib, palbociclib and fulvestrant in ... A phase I/II trial to evaluate safety and efficacy of O, P and F in pts with g/sBRCA1/2-associated, HR+ MBC.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03685331

Study Details | NCT03685331 | HOPE: Olaparib, ... The main purpose of this research study is to learn whether the investigational combination of olaparib, palbociclib, and fulvestrant is safe in patients with ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2019-04210

Olaparib, Palbociclib, and Fulvestrant in Treating Patients ... This phase I/II trial studies the best dose and side effects of palbociclib when given together with olaparib and fulvestrant, and to see how well they work.

4. esmoopen.com esmoopen.com/article/S2059-7029(25)01178-0/fulltext

Extended follow-up of palbociclib with fulvestrant or ... No significant difference in OS or PFS between fulvestrant and letrozole when combined with palbociclib was observed. Median OS was 61.8 months, and median PFS ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6236629/

Inhibitors targeting CDK4/6, PARP and PI3K in breast cancer The combination of palbociclib plus letrozole resulted in pronounced improvement of PFS (24.8 months) compared with the placebo-letrozole group (14.5 months).

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10898914/

Real-world data in patients with BRCA mutated breast cancer ... Olaparib and talazoparib currently are the only PARPi approved for patients with hormone receptor-positive/HER2-negative advanced breast cancer ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.10616

HOPE: Harnessing olaparib, palbociclib, and endocrine ... A phase I trial to evaluate combination olaparib (O), fulvestrant (F), and palbociclib (P) in patients with BRCA1/2-associated HR+, HER2 negative MBC.