Bortezomib + Pembrolizumab/Cisplatin for Metastatic Breast Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Joyce O'Shaughnessy, MD

Age: 18+

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

Sponsor: Baylor Research Institute

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

Disqualifiers: Autoimmune, HIV, Hepatitis, Cardiovascular, others

No Placebo Group

Breakthrough Therapy

Trial Summary

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.

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}

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.

Trial 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 (Proteasome Inhibitor)
• Cisplatin (Platinum-based Chemotherapy)
• Pembrolizumab (Monoclonal Antibodies)

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Baylor University Medical Center, Baylor Charles A Sammons Cancer Center Dallas, TX

Who Is Running the Clinical Trial?

Baylor Research Institute

Lead Sponsor

Trials

210

Patients Recruited

205,000+

References

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

A phase II study of pembrolizumab plus carboplatin in BRCA-related metastatic breast cancer (PEMBRACA). [2023] BRCA1/2-related metastatic breast cancers (mBC) are sensitive to DNA-damage agents and show high tumor-infiltrated lymphocytes. We hypothesized that the association between pembrolizumab and carboplatin could be active in BRCA-related mBC.

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

Dramatic response of metaplastic breast cancer to chemo-immunotherapy. [2020] Frequent overexpression of programmed death-ligand 1 has recently been demonstrated in metaplastic breast cancer, which is a rare breast cancer subtype with limited treatment options. This report describes the clinical course of a patient with metastatic metaplastic breast cancer who had a remarkable response to anti-programmed death-1 therapy with pembrolizumab in combination with nab-paclitaxel. Tissue correlates are presented including tumor-infiltrating lymphocytes and high-programmed death-ligand 1 expression in the tumor.

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

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017] New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit.

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] Pembrolizumab combined with chemotherapy is now first-line standard of care in advanced non-small cell lung cancer. This real-life study aimed to assess efficacy and safety of carboplatin-pemetrexed plus pembrolizumab in advanced non-squamous non-small cell lung cancer.

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] A phase II trial investigating the therapeutic effect of neoadjuvant programmed cell death 1 (PD-1) inhibitor pembrolizumab (MK-3475, KEYTRUDA®) administered prior to surgery for the treatment of non-small cell lung cancer (NSCLC) has been conducted (NCT03197467). We report the first clinical results of a planned interim safety analysis after 15 patients were enrolled.

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

Bortezomib-based therapy for relapsed/refractory multiple myeloma in real-world medical practice. [2022] Label="OBJECTIVE" NlmCategory="OBJECTIVE">The efficacy and safety of bortezomib-based therapy for relapsed/refractory multiple myeloma (RRMM) in clinical trials may differ from the oncology practice experience. The electronic VELCADE&#174; OBservational Study was designed to prospectively evaluate bortezomib for multiple myeloma (MM) in real-world medical practice.

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] Bortezomib and pemetrexed are approved anticancer agents with non-overlapping mechanisms of action and toxicity. We examined the safety and tolerability of pemetrexed in combination with two different schedules of bortezomib in patients with advanced solid tumors.

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

Clinical update: proteasome inhibitors in solid tumors. [2019] The proteasome plays a critical role in regulating the cell cycle, neoplastic growth, and metastasis. Bortezomib (VELCADE; formerly PS-341, LDP-341, MLN341) is a novel dipeptide boronic acid that is the first proteasome inhibitor to have progressed to clinical trials. Preclinical research has shown that through the prevention of IkappaB degradation, bortezomib may block chemotherapy-induced NF-kappaB activation and augment the apoptotic response to chemotherapeutic agents. Bortezomib also appeared to increase the stabilization of p21 and p27, as well as transcription factor p53. In preclinical models of breast, lung, pancreatic, and ovarian tumor types, bortezomib inhibited tumor growth and demonstrated anti-angiogenic properties. Bortezomib exhibited the greatest activity when combined with standard chemotherapeutic agents, such as irinotecan, gemcitabine, and docetaxel, suggesting its potential additive/syngeristic role in overcoming resistance to conventional chemotherapy. Preliminary data from early clinical trials suggest that bortezomib can be given at pharmacologically active doses in combination with standard doses of chemotherapy with manageable toxicities. Responses have been seen and no evidence of additive toxicity has been exhibited in combination agent trials.

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

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023] Pembrolizumab (Keytruda) is a monoclonal antibody against the programmed cell death-1 (PD-1) receptor on lymphocytes, which is one of the immune checkpoint inhibitors (ICIs) approved for multiple solid and hematologic malignancies. Although ICIs have proven to be more effective and less toxic compared to chemotherapy, there are reports of adverse side effects with ICIs. For example, pneumonitis is a potentially lethal side effect occurring in 1%-5% of patients who received ICIs in clinical trials, and there are case reports with clinical and radiological features of checkpoint inhibitor-pneumonitis (CIP).

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] In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab.

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] Pemetrexed plus cisplatin was approved for first-line treatment of non-small-cell lung cancer (NSCLC) in patients with nonsquamous histology after initiation of this study. This phase II study evaluated pemetrexed plus cisplatin and pemetrexed plus carboplatin as first-line treatments for stage IIIB/IV NSCLC.