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

Trial Summary

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.

What data supports the effectiveness of the drug combination Bortezomib, Pembrolizumab, and Cisplatin for metastatic breast cancer?

Research shows that pembrolizumab, a part of this drug combination, has been effective in treating various cancers, including breast cancer and lung cancer, when combined with other chemotherapy drugs. Specifically, pembrolizumab has shown promising results in treating metastatic breast cancer and other solid tumors by enhancing the immune system's ability to fight cancer cells. ^{1 2 3 4 5}

Is the combination of Bortezomib, Pembrolizumab, and Cisplatin safe for humans?

Bortezomib has been shown to be safe in combination with other chemotherapy drugs, with manageable side effects. Pembrolizumab, while generally less toxic than traditional chemotherapy, can cause serious side effects like pneumonitis (lung inflammation) in a small percentage of patients. ^{5 6 7 8 9}

What makes the drug combination of Bortezomib, Pembrolizumab, and Cisplatin unique for treating metastatic breast cancer?

This drug combination is unique because it combines Bortezomib, which disrupts cancer cell protein breakdown, with Pembrolizumab, an immunotherapy that helps the immune system attack cancer cells, and Cisplatin, a chemotherapy that damages cancer cell DNA. This multi-faceted approach targets cancer cells in different ways, potentially offering a novel treatment option for metastatic breast cancer. ^{1 2 4 10 11}

What is the purpose of this trial?

The hypothesis of this pilot trial is that administration of bortezomib will inhibit NHEJ in metastatic TNBC leading at the time of disease progression to metastases that are HR-deficient and sensitive to pembrolizumab and cisplatin therapy. The trial will include in depth analysis of the patients' TNBC genome and phosphoproteome to evaluate HR-proficiency and deficiency, and nuclear proteins that drive NHEJ, before and upon progression with bortezomib therapy.

Research Team

Joyce O'Shaughnessy, MD

Principal Investigator

Texas Oncology

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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 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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

A phase II study of pembrolizumab plus carboplatin in BRCA-related metastatic breast cancer (PEMBRACA). [2023]

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

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

3. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

4. China 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). [2023]

5. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Bortezomib-based therapy for relapsed/refractory multiple myeloma in real-world medical practice. [2022]

7. United States 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. [2015]

8. Netherlands pubmed.ncbi.nlm.nih.gov

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

9. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

10. England 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. [2022]

11. United States 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. [2022]