Combination Therapy for Triple Negative Breast Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: OHSU Knight Cancer Institute

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)

27 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II study assesses the efficacy of the combination of olaparib with durvalumab, selumetinib, or capivasertib or ceralasertib alone in the treatment of patients with metastatic triple negative breast cancer (TNBC). Olaparib may stop growth of tumor cells by inhibiting some of the enzymes (ADP ribose polymerase \[PARP\]) needed for cell growth. Durvalumab, a monoclonal antibody, inhibits the growth and spread of tumors by stimulating the patient's antitumor immune response. Selumetinib, capivasertib, and ceralasertib are inhibitor drugs that may stop the growth of tumor cells by blocking some of the enzymes (MEK, AKT, ATR) needed for cell growth. Giving olaparib together with durvalumab, selumetinib, or capivasertib or giving ceralasertib alone may provide an effective method to treat patients with metastatic triple negative breast cancer.

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.

What data supports the effectiveness of the drug combination therapy for triple-negative breast cancer?

Research shows that AZD5363 (capivasertib), a component of the combination therapy, has promising activity in combination with paclitaxel for treating triple-negative metastatic breast cancer with specific genetic alterations. Additionally, combining PD-L1 inhibitors like atezolizumab with chemotherapy has improved survival in patients with this type of cancer. ^{1 2 3 4 5}

What safety data exists for the combination therapy involving Olaparib for triple-negative breast cancer?

A Phase I study evaluated the safety of Olaparib, a type of drug that blocks certain enzymes involved in cancer cell repair, in combination with another drug called paclitaxel for treating metastatic triple-negative breast cancer. This study focused on understanding how well patients could tolerate this combination. ^{2 6 7 8 9}

What makes the combination therapy for triple-negative breast cancer unique?

This combination therapy is unique because it includes multiple drugs that target different pathways involved in cancer growth, such as the PI3K/AKT pathway, and combines them with immune checkpoint inhibitors like Durvalumab, potentially offering a more comprehensive approach to treating triple-negative breast cancer, which currently lacks effective targeted therapies. ^{2 3 10 11 12}

Research Team

Alexandra Zimmer, M.D.

Principal Investigator

OHSU Knight Cancer Institute

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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?

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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 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 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]

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]

References

1. United States 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. [2023]

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

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

3. United States 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. [2021]

4. England 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. [2022]

5. United States 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. [2022]

6. United States 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. [2023]

7. England 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. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy and pharmacodynamics of niraparib in BRCA-mutant and wild-type intracranial triple-negative breast cancer murine models. [2022]

9. England 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. [2021]

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

Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer. [2022]

11. England 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. [2020]

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

Metastatic triple-negative breast cancer: Established and emerging treatments. [2021]