Bortezomib + Pembrolizumab/Cisplatin for Metastatic Breast Cancer

Overseen By Page Blas, MA

Age: 18+

Sex: Female

Trial Phase: Phase < 1

Sponsor: Baylor Research Institute

Must not be taking: Steroids, Immunosuppressants, Antiepileptics, others

Disqualifiers: Autoimmune, HIV, Hepatitis, Cardiovascular, others

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

Compensation: Varies

Number of Visits: Unknown

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—bortezomib, pembrolizumab, and cisplatin—to determine their effectiveness against metastatic triple-negative breast cancer (TNBC). Researchers aim to discover if bortezomib can increase cancer cells' sensitivity to treatment by affecting their DNA repair process. Women who have previously received certain standard chemotherapy treatments for metastatic TNBC and have manageable, biopsy-accessible disease spread are suitable candidates for this trial. As an Early Phase 1 trial, this research seeks to understand how the treatment works in people, providing participants the chance to contribute to groundbreaking cancer research.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on monoclonal antibody agents, a 4-week period without these medications is required before starting the study treatment.

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

Research has shown that the combination of pembrolizumab and cisplatin has been studied for safety in treating certain cancers. One study found this combination generally safe, though some side effects like nausea and tiredness occurred. Bortezomib, another drug in this trial, already has FDA approval for other uses, indicating it is usually well-tolerated. However, early trial phases often focus on safety, so evidence remains limited. Participants might experience side effects, which helps researchers understand how these drugs work together. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for metastatic breast cancer, which typically involve chemotherapy and hormone therapy, the combination of Bortezomib, Pembrolizumab, and Cisplatin offers a unique approach. Bortezomib is a proteasome inhibitor that disrupts cancer cell growth by interfering with protein degradation. Pembrolizumab, an immune checkpoint inhibitor, enhances the immune system's ability to detect and attack cancer cells. Adding Cisplatin, a platinum-based chemotherapy, maximizes the treatment's impact by damaging cancer cell DNA. Researchers are excited because this multi-faceted approach could potentially improve outcomes by attacking cancer cells from multiple angles, offering hope for patients with limited options.

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

Research has shown that bortezomib might increase cancer cells' sensitivity to other treatments by blocking a repair process within the cells. This trial will investigate the effectiveness of bortezomib followed by the combination of pembrolizumab and cisplatin for metastatic triple-negative breast cancer. Studies have found that combining pembrolizumab with cisplatin can improve outcomes, such as reducing the risk of cancer progression in certain cases. However, some patients may still experience drug resistance or cancer recurrence after treatment. Overall, this combination aims to leverage the strengths of each drug to address difficult-to-treat breast cancer. ^{1 3 4 6 7}

Who Is on the Research Team?

Joyce O'Shaughnessy, MD

Principal Investigator

Texas Oncology

Are You a Good Fit for This Trial?

This trial is for women over 18 with metastatic triple-negative breast cancer (TNBC) that's progressed after standard treatments. They must be in good physical condition, have normal blood, liver, and kidney functions, and not have had more than three prior chemo regimens for metastatic disease. Exclusions include severe health issues, active infections like hepatitis or tuberculosis, recent vaccines or radiotherapy, autoimmune diseases treated within two years, HIV infection or other cancers.

Inclusion Criteria

My blood clotting function is normal.

My cancer has spread to my lungs or liver and can be biopsied with a needle.

I have triple-negative breast cancer treated with specific chemotherapies, except when doxorubicin was not suitable for me.

Exclusion Criteria

I have a history of Hepatitis B or currently have Hepatitis C.

I have not needed treatment for an autoimmune disease in the last 2 years.

I have not received a live vaccine in the last 30 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment with Bortezomib

Participants receive bortezomib until disease progression to inhibit NHEJ in metastatic TNBC

Variable until disease progression

Regular visits for treatment and monitoring

Treatment with Pembrolizumab and Cisplatin

Participants receive pembrolizumab and cisplatin until disease progression or a maximum of 6 cycles

Up to 6 cycles

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

18 months

What Are the Treatments Tested in This Trial?

Interventions

• Bortezomib
• Cisplatin
• Pembrolizumab

Trial Overview The study tests if Bortezomib can make TNBC sensitive to Pembrolizumab and Cisplatin by inhibiting a DNA repair process called NHEJ. Patients' tumor genomes will be analyzed before and after Bortezomib treatment to see changes in HR-deficiency (a state where cells can't properly repair DNA) which could make the cancer more treatable.

How Is the Trial Designed?

Group I: Bortezomib followed by pembro/cis Experimental Treatment 1 Intervention

There is only one arm.

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

Approved in European Union as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in United States as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Canada as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Japan as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

Baylor Research Institute

Lead Sponsor

Trials

210

Recruited

205,000+

Published Research Related to This Trial

A patient with metastatic metaplastic breast cancer showed a remarkable response to treatment with pembrolizumab, an anti-PD-1 therapy, combined with nab-paclitaxel, highlighting a potential effective treatment option for this rare cancer subtype.

The tumor exhibited high levels of programmed death-ligand 1 (PD-L1) expression and significant tumor-infiltrating lymphocytes, suggesting that PD-L1 overexpression may be a key factor in the efficacy of this immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dramatic response of metaplastic breast cancer to chemo-immunotherapy. Adams, S.[2020]

The combination of pemetrexed and bortezomib is feasible and tolerable at standard doses, with specific recommended doses identified for further study: pemetrexed 500 mg/m2 with bortezomib 1.3 mg/m2 twice weekly or 1.6 mg/m2 weekly.

In a group of 16 patients with non-small cell lung cancer, the treatment resulted in a 12.5% partial response rate and a 68.8% disease control rate, suggesting potential efficacy that warrants further investigation in a phase II study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of two different schedules of bortezomib and pemetrexed in advanced solid tumors with emphasis on non-small cell lung cancer. Davies, AM., Ho, C., Metzger, AS., et al.[2015]

In a study of 873 patients with relapsed/refractory multiple myeloma, bortezomib treatment resulted in a high overall response rate of 69%, with a median overall survival of 36.1 months, indicating its effectiveness in real-world clinical practice.

While bortezomib is effective, 51% of patients without prior neuropathy developed new-onset peripheral neuropathy by cycle 8, highlighting the importance of monitoring for adverse effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib-based therapy for relapsed/refractory multiple myeloma in real-world medical practice. Terpos, E., Katodritou, E., de la Rubia, J., et al.[2022]

In a phase II study involving 22 patients with BRCA1/2-related metastatic breast cancer, the combination of pembrolizumab and carboplatin showed an overall response rate (ORR) of 43% and a disease control rate (DCR) of 76%, indicating some level of efficacy, particularly in luminal tumors.

Despite the promising results, the study did not meet its primary aim of achieving an ORR of 70%, leading to its termination; however, the safety profile was acceptable with only 22.7% of patients experiencing grade ≥3 adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of pembrolizumab plus carboplatin in BRCA-related metastatic breast cancer (PEMBRACA). Cortesi, L., Venturelli, M., Cortesi, G., et al.[2023]

In a phase II study involving 130 patients with advanced non-small-cell lung cancer (NSCLC), pemetrexed plus cisplatin showed a median progression-free survival (PFS) of 6.0 months and a median overall survival (OS) of 11.7 months, indicating its efficacy as a first-line treatment.

Pemetrexed plus carboplatin, while effective, resulted in a shorter median PFS of 4.7 months and median OS of 8.9 months, suggesting that pemetrexed plus cisplatin may be the more effective combination for treating advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II study of pemetrexed in combination with cisplatin or carboplatin as first-line therapy for patients with locally advanced or metastatic non-small-cell lung cancer. Schuette, WH., Gröschel, A., Sebastian, M., et al.[2022]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

In a real-life study of 121 patients with advanced non-squamous non-small cell lung cancer, the combination of pembrolizumab and chemotherapy resulted in a median progression-free survival of 9 months and overall survival of 20.6 months, demonstrating its efficacy as a first-line treatment.

The treatment was generally well-tolerated, with manageable side effects; however, 17.5% of patients experienced grade 3-4 adverse events, and there were two treatment-related deaths, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus pemetrexed-carboplatin combination in first-line treatment of advanced non-squamous non-small cell lung cancer: a multicenter real-life study (CAP29). Renaud, E., Ricordel, C., Corre, R., et al.[2023]

In the phase III KEYNOTE-189 study, pembrolizumab combined with pemetrexed and platinum-based chemotherapy significantly improved overall survival (OS) and progression-free survival (PFS) in patients with untreated metastatic nonsquamous non-small-cell lung cancer, with a hazard ratio of 0.56 for OS and 0.49 for PFS after a median follow-up of 31 months.

The treatment was associated with a high objective response rate (ORR) of 48.3% compared to 19.9% for the placebo group, and among patients who completed 35 cycles of pembrolizumab, the ORR was even higher at 85.7%, indicating strong efficacy with manageable toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Rodríguez-Abreu, D., Powell, SF., Hochmair, MJ., et al.[2022]

Bortezomib is the first proteasome inhibitor to reach clinical trials and has shown promise in enhancing the effectiveness of chemotherapy by blocking NF-kappaB activation and promoting apoptosis in various tumor types, including breast and pancreatic cancers.

Early clinical trials indicate that bortezomib can be safely combined with standard chemotherapy agents without significant added toxicity, suggesting it may help overcome resistance to these conventional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical update: proteasome inhibitors in solid tumors. Lenz, HJ.[2019]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Citations

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MTS Trials - BreastCancerTrials.org Purpose: To study the anti-cancer activity, safety, and side effects of first giving bortezomib (Velcade®), then giving pembrolizumab (Keytruda®) and cisplatin ...