Combination Therapy for Triple Negative Breast Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Gordon Mills, MD, PhD

Must not be taking: Strong CYP3A inhibitors, Strong CYP3A inducers

Disqualifiers: Active CNS metastases, Myelodysplastic syndrome, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: Up to 12 cycles (each cycle is 4 weeks)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining certain drugs can effectively treat metastatic triple-negative breast cancer (TNBC), a type of cancer that has spread and does not respond to hormone therapy. It examines the effects of using olaparib (a PARP inhibitor) with other drugs like durvalumab (an immunotherapy), selumetinib, and capivasertib, or using ceralasertib alone. These drugs either stop cancer cell growth or boost the immune system to fight the cancer. People with TNBC who have tried fewer than three types of chemotherapy for their metastatic cancer might be suitable candidates for this trial. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group of people, offering participants a chance to contribute to important advancements in cancer therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot use strong CYP3A inhibitors or inducers, and there is a required washout period (time without taking certain medications) of 3 to 5 weeks for some drugs before starting the trial. It's best to discuss your current medications with the trial team.

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

Research shows that earlier studies have examined the treatments in this study, providing varying levels of safety information.

For the combination of olaparib and durvalumab, studies have found that most patients tolerate this combo well. Sufficient safety information from other studies suggests that this treatment usually doesn't cause serious side effects for most people.

Olaparib combined with selumetinib is still under investigation. The FDA has already approved olaparib for some other conditions, providing some safety knowledge. However, selumetinib remains under research, so its safety profile is less understood.

The combination of olaparib and capivasertib has also undergone testing. An initial safety study showed it was tolerable, but like many new treatments, more studies are needed to fully understand the long-term effects.

Ceralasertib, when used alone, has shown activity against tumors in models of triple-negative breast cancer (TNBC). However, more studies are needed to assess its long-term safety.

Overall, while promising safety information exists for these treatments, especially for olaparib, it's important to remember that they are still experimental. Participants should be aware of this and discuss any concerns with their healthcare team. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for triple-negative breast cancer because they offer new approaches that differ from the existing standard of care, which includes chemotherapy and targeted therapies like PARP inhibitors. The combination of olaparib with other drugs like durvalumab, capivasertib, and selumetinib introduces new mechanisms of action, such as immune checkpoint inhibition and cell signaling pathway targeting. For instance, durvalumab is an immune checkpoint inhibitor that helps the immune system attack cancer cells, while capivasertib and selumetinib target specific proteins involved in cancer cell growth. These combinations may enhance the effectiveness of olaparib, providing a potentially more powerful treatment option for patients. Additionally, ceralasertib, which targets DNA repair, offers a unique approach that could improve outcomes for patients with this aggressive cancer type.

What evidence suggests that this trial's treatments could be effective for metastatic triple negative breast cancer?

Research has shown that combining the drugs olaparib and durvalumab, which participants in this trial may receive, may help treat metastatic triple negative breast cancer (TNBC). One study found that this combination controlled the disease in 80% of patients who had already received other treatments. Another treatment arm in this trial involves olaparib and capivasertib, which have also been effective in treating breast cancer, with no serious side effects reported. Additionally, the combination of selumetinib and olaparib, tested in a separate arm of this trial, has been studied for its potential to delay disease progression. Ceralasertib, tested in its own arm, targets a specific enzyme and showed complete tumor shrinkage in early lab studies, indicating potential effectiveness. Overall, these treatments either block important enzymes or boost the immune system, offering hope for TNBC patients. ^{1 2 4 6 7}

Who Is on the Research Team?

Gordon Mills, MD, PhD

Principal Investigator

OHSU Knight Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with metastatic triple negative breast cancer who haven't been treated with PARP inhibitors like olaparib. They must be able to consent, have a life expectancy of at least 16 weeks, and agree to biopsies and contraception if applicable. Exclusions include certain medication use, other cancers unless cured over 5 years ago, CNS metastases, major surgery recently, or conditions affecting drug absorption.

Inclusion Criteria

Participants must have certain test results within a certain range.

My breast cancer has spread, is triple-negative, and lacks certain hormone receptors and HER2.

Participants of childbearing potential must have a negative pregnancy test and agree to use adequate contraception

Exclusion Criteria

Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial

I cannot swallow pills or have a stomach condition that affects medication absorption.

Involvement in the planning and/or conduct of the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead-in

Patients with biopsy proven TNBC undergo a pre-treatment biopsy and receive olaparib orally twice daily for one cycle

4 weeks

2 visits (in-person)

Treatment

Patients receive treatment based on assigned arm with olaparib in combination with durvalumab, selumetinib, capivasertib, or ceralasertib monotherapy

Up to 12 cycles (each cycle is 4 weeks)

Monthly visits (in-person)

Follow-up

Participants are monitored for disease and survival outcomes every 6 months up to 1 year

12 months

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Capivasertib
• Ceralasertib
• Durvalumab
• Olaparib
• Selumetinib

Trial Overview The study tests the effectiveness of olaparib combined with durvalumab (a monoclonal antibody), selumetinib (MEK inhibitor), capivasertib (AKT inhibitor) or ceralasertib alone (ATR inhibitor) in treating metastatic triple negative breast cancer. The goal is to see if these combinations can stop tumor growth by blocking enzymes needed for cell growth.

How Is the Trial Designed?

Group I: Arm IV (ceralasertib) Experimental Treatment 3 Interventions

Patients receive ceralasertib PO BID on days 1-14 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.

Group II: Arm III (olaparib, capivasertib) Experimental Treatment 4 Interventions

Patients receive olaparib PO BID on days 1-28 of each cycle and capivasertib PO BID 4 days on and 3 days off of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.

Group III: Arm II (olaparib, selumetinib) Experimental Treatment 4 Interventions

Patients receive olaparib PO BID on days 1-28 of each cycle and selumetinib PO BID on days 1-28 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.

Group IV: Arm I (olaparib, durvalumab) Experimental Treatment 4 Interventions

Patients receive olaparib PO BID on days 1-28 of each cycle and durvalumab intravenously (IV) over 1 hour on day 1 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.

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

Approved in United States as Truqap for:

• Hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations

Approved in European Union as Truqap for:

• Locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN alterations

Who Is Running the Clinical Trial?

Gordon Mills, MD, PhD

Lead Sponsor

OHSU Knight Cancer Institute

Lead Sponsor

Trials

239

Recruited

2,089,000+

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

Oregon Health and Science University

Collaborator

Trials

1,024

Recruited

7,420,000+

Published Research Related to This Trial

The combination of olaparib, a PARP inhibitor, and paclitaxel showed a promising response rate of 37% in patients with metastatic triple-negative breast cancer, indicating potential efficacy despite safety concerns.

Neutropenia was a significant side effect, with high rates observed in both treatment cohorts, leading to dose modifications and the need for prophylactic granulocyte-colony stimulating factor, highlighting the need for careful management of side effects in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer. Dent, RA., Lindeman, GJ., Clemons, M., et al.[2021]

In a phase II clinical trial involving 41 patients with advanced triple-negative breast cancer (TNBC), the small-molecule inhibitor ENMD-2076 showed a 6-month clinical benefit rate of 16.7%, indicating some effectiveness in this challenging cancer subtype.

Treatment with ENMD-2076 was associated with a decrease in cellular proliferation and microvessel density, along with increased expression of p53 and p73, suggesting that the drug may work by promoting apoptosis and inhibiting tumor growth, consistent with preclinical findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer. Diamond, JR., Eckhardt, SG., Pitts, TM., et al.[2020]

Niraparib, a PARP inhibitor, significantly increased median survival and reduced tumor burden in a specific BRCA-mutant TNBC mouse model (MDA-MB-436), demonstrating its potential efficacy against brain metastases of triple-negative breast cancer.

The study found that combining RAD51 inhibition with PARP inhibition could enhance the sensitivity of various TNBC cell lines to treatment, suggesting a promising strategy for improving therapeutic outcomes in this challenging cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and pharmacodynamics of niraparib in BRCA-mutant and wild-type intracranial triple-negative breast cancer murine models. Sambade, MJ., Van Swearingen, AED., McClure, MB., et al.[2022]

AZD5363, a pan-AKT inhibitor, shows promising efficacy in treating triple-negative metastatic breast cancer, especially in patients with specific genetic alterations, as indicated by a study involving 28 patient-derived xenografts (PDXs).

The study identified key biomarkers for sensitivity to AZD5363, such as mutations in PIK3CA/AKT1, and revealed mechanisms of resistance, including cyclin D1 overexpression, which could help tailor more effective treatments for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts. Gris-Oliver, A., Palafox, M., Monserrat, L., et al.[2021]

Metastatic triple-negative breast cancer (mTNBC) has a poor overall survival rate, and treatment primarily aims to relieve symptoms and improve survival.

New FDA-approved treatments, including PARP inhibitors for gBRCA mutation carriers and the combination of atezolizumab with nab-paclitaxel for patients with PD-L1 expression, offer promising options for improving outcomes in mTNBC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic triple-negative breast cancer: Established and emerging treatments. Puri, A., Reddy, TP., Patel, TA., et al.[2021]

In the IMpassion130 trial, the combination of atezolizumab and nab-paclitaxel (A + nP) significantly improved progression-free survival in patients with metastatic triple-negative breast cancer (mTNBC) without negatively impacting their health-related quality of life (HRQoL).

Patient-reported outcomes showed no significant differences in HRQoL or functioning between the A + nP and placebo plus nab-paclitaxel groups, indicating that the treatment did not worsen symptoms like fatigue or nausea, thus maintaining patients' day-to-day functioning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes from the phase III IMpassion130 trial of atezolizumab plus nab-paclitaxel in metastatic triple-negative breast cancer. Adams, S., Diéras, V., Barrios, CH., et al.[2022]

A novel approach identified a combination of three kinase inhibitors—dasatinib, afatinib, and trametinib (DAT)—that effectively inhibited the growth of triple-negative breast cancer (TNBC) cell lines, showing the potential for enhanced treatment options in this aggressive cancer type.

The DAT combination demonstrated the highest cytotoxicity and synergy compared to other two-drug combinations, suggesting it warrants further testing in animal models to evaluate its efficacy in treating TNBC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of a Triple Drug Combination That Is Synergistically Cytotoxic for Triple-Negative Breast Cancer Cells Using a Novel Combination Discovery Approach. Ahmad, S., He, Q., Williams, KP., et al.[2022]

The combination of the PD-L1 inhibitor atezolizumab with standard chemotherapy significantly improves overall survival in patients with metastatic triple-negative breast cancer compared to chemotherapy alone.

This research suggests that adding atezolizumab could provide a new treatment option for patients suffering from this aggressive form of breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-L1 Inhibitor Improves Survival in TNBC. [2019]

In a study testing 128 drugs on triple-negative breast cancer (TNBC) cell lines, several drug combinations, including ABT-263/crizotinib and paclitaxel/JQ1, showed promising synergistic effects that could be translated into clinical treatments.

The combination of ABT-263 and crizotinib demonstrated a mechanism of action involving receptor tyrosine kinase blockade and pro-apoptotic signaling, suggesting a rapid path for clinical application in aggressive TNBC cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer. Wali, VB., Langdon, CG., Held, MA., et al.[2022]

In a multicenter retrospective analysis of early triple-negative breast cancer (eTNBC) patients treated with pembrolizumab and chemotherapy, the incidence of immune-related adverse events (irAEs) was found to be 63.9%, with 20% of patients experiencing severe (grade 3 or higher) irAEs.

The study reported a pathological complete response (pCR) rate of 57.1%, with a significant correlation between the occurrence of irAEs and higher pCR rates (72.2% vs. 30.8%), indicating that while irAEs are common, they may be associated with better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emergence of immune-related adverse events correlates with pathological complete response in patients receiving pembrolizumab for early triple-negative breast cancer. Marhold, M., Udovica, S., Halstead, A., et al.[2023]

In the KEYNOTE-355 trial, patients with previously untreated metastatic triple-negative breast cancer (mTNBC) who received pembrolizumab combined with chemotherapy experienced a significant improvement in quality-adjusted survival, gaining an average of 3.7 months more time without symptoms or treatment toxicity compared to those receiving chemotherapy alone.

The benefits of pembrolizumab plus chemotherapy increased over time, with a 20% relative gain in quality-adjusted survival at a maximum follow-up of 52 months, indicating both efficacy and manageable safety in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Q-TWiST analysis of pembrolizumab combined with chemotherapy as first-line treatment of metastatic triple-negative breast cancer that expresses PD-L1. Huang, M., O'Shaughnessy, J., Haiderali, A., et al.[2023]

In the KEYNOTE-086 study involving 254 patients with metastatic triple-negative breast cancer, several biomarkers such as PD-L1, CD8, stromal tumor-infiltrating lymphocytes (sTILs), tumor mutational burden (TMB), and T-cell-inflamed gene expression profile (TcellinfGEP) were significantly associated with better clinical outcomes when treated with pembrolizumab.

These findings suggest that assessing these biomarkers can help identify which patients are more likely to benefit from pembrolizumab monotherapy, enhancing personalized treatment strategies for metastatic triple-negative breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Biomarkers and Clinical Outcomes of Pembrolizumab Monotherapy in Patients With Metastatic Triple-Negative Breast Cancer: KEYNOTE-086 Exploratory Analysis. Loi, S., Salgado, R., Schmid, P., et al.[2023]

Citations

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Olaparib and Ceralasertib (AZD6738) in Patients with Triple ... This triple-negative breast cancer (TNBC) subgroup has a poor prognosis with overall survival for those patients with metastatic disease of 1 to 2 years (1).

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Olaparib and Ceralasertib (AZD6738) in Patients with ... The response rate to olaparib and ceralasertib did not meet prespecified criteria for activity in the overall evaluable population, ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.1087

Olaparib (O) + ceralasertib (C) in patients (pts) with ... We report an exploratory translational analysis of predictive genomic biomarkers of response to O ± C beyond gBRCAm.

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5. aacrjournals.org aacrjournals.org/cancerres/article/82/6/1140/682067/ATR-Inhibitor-AZD6738-Ceralasertib-Exerts

ATR Inhibitor AZD6738 (Ceralasertib) Exerts Antitumor Activity ... In a BRCA2-mutant patient-derived triple-negative breast cancer (TNBC) xenograft model, complete tumor regression was achieved with 3 to5 days of daily AZD6738 ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S1936523324000196

Small molecule agents for triple negative breast cancer Although clinical trials have shown that uprosertib monotherapy at a daily dose of 75 mg is safe and well tolerated in patients with solid tumors with PIK3CA ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11365631/

Efficacy and safety analysis of AKT inhibitor in triple- ... AKT inhibitors showed slightly better efficacy in the treatment of TNBC. However, further studies are needed to evaluate its long-term safety and optimal ...