Combo Immunotherapy for Triple Negative Breast Cancer

Overseen By Shipra Gandhi

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Roswell Park Cancer Institute

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Autoimmune disease, Mood disorders, Cardiac risk, others

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

Compensation: Varies

Number of Visits: 1

Duration: 6-8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs for treating triple negative breast cancer that has spread or cannot be removed by surgery. The treatment combines immunotherapy and chemokine modulation therapy (CKM) to enhance the immune system's ability to fight cancer cells. Participants may receive different combinations or timing of these treatments, including pembrolizumab (an immunotherapy drug), to determine the most effective approach. Individuals with triple negative breast cancer that has spread or cannot be surgically removed, and who have no other treatment options, may be suitable candidates for this trial. As a Phase 1/Phase 2 trial, the research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial requires that you stop any cancer-directed therapy at least 3 weeks before starting the study treatment. If you are on systemic immunosuppressive agents, including certain steroids, you must stop them 3 weeks before joining the trial. Inhaled steroids are allowed.

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

Research shows that a combination of four treatments—rintatolimod, celecoxib, interferon alpha-2b, and pembrolizumab—is being tested for safety in people with advanced or hard-to-remove triple-negative breast cancer. Early results suggest these treatments are generally well-tolerated. Rintatolimod has been used in other studies and appears safe when combined with other treatments. Celecoxib is already approved by the FDA for other uses and is known to be well-tolerated by many patients. Interferon alpha-2b and pembrolizumab are both used in cancer treatments and have proven safety records.

Early studies report common side effects such as tiredness, fever, and reactions at the injection site. Serious side effects are rare but can occur. Since the trial is in its early stages, the main goal is to ensure these treatments are safe and to find the best dosage. Participants in this study will help researchers gather important information about how these treatments might work together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the investigational treatments for triple-negative breast cancer because they explore a novel combination of immunotherapy agents. Unlike standard treatments, which often involve chemotherapy, these investigational treatments combine celecoxib, interferon alpha-2, pembrolizumab, and rintatolimod, aiming to boost the body's immune response against cancer cells. Pembrolizumab, a checkpoint inhibitor, helps the immune system recognize and attack cancer cells more effectively. Meanwhile, rintatolimod is designed to enhance the immune response, potentially increasing the treatment’s overall effectiveness. This innovative approach could improve outcomes for patients with this aggressive form of breast cancer.

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

Research shows that pembrolizumab, a type of immunotherapy, effectively treats advanced triple-negative breast cancer (TNBC). Studies have found it can help patients live longer and slow cancer progression when combined with chemotherapy. In this trial, participants in Cohort I will receive pembrolizumab later in the treatment cycle, while those in Cohort II will receive it earlier. Rintatolimod, included in both cohorts, has shown promise in boosting the immune system in TNBC patients. Interferon Alpha-2b, also part of the treatment for both cohorts, has been linked to better survival and higher cancer response rates. Celecoxib, however, has shown limited benefits in cancer treatment. This combination aims to leverage the strengths of each drug to better fight TNBC. ^{6 7 8 9 10}

Who Is on the Research Team?

Ellis Levine, MD

Principal Investigator

Roswell Park Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with triple negative breast cancer that has spread or can't be surgically removed. They must have normal bilirubin levels, agree to use contraception, and not have had cancer treatment in the last 3 weeks. Patients should be able to take oral meds, have measurable disease, and a performance status indicating they are relatively active.

Inclusion Criteria

My cancer has worsened despite previous treatments.

Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

My kidney function, measured by creatinine levels, is normal or near normal.

Exclusion Criteria

Pregnant or nursing female participants

I have had stomach ulcers, bleeding, or a hole in my stomach in the last 3 years.

I am allergic to NSAIDs or any medication planned for this treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive rintatolimod, celecoxib, and interferon alpha-2b, followed by pembrolizumab. Treatment includes IV and oral administration over a 2-week cycle, with pembrolizumab every 3 weeks.

6-8 weeks

Multiple visits (in-person) for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including CT/MRI scans and blood sample collection.

Up to 2 years

Regular visits (in-person) for imaging and sample collection

Open-label extension (optional)

Participants may opt into continuation of treatment long-term to assess long-term safety and efficacy.

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Celecoxib
• Interferon Alpha-2
• Pembrolizumab
• Rintatolimod

Trial Overview The trial tests chemokine modulation therapy (CKM) - rintatolimod with celecoxib and interferon alpha 2b - combined with pembrolizumab immunotherapy. CKM may modify immune responses and tumor growth while pembrolizumab could help the immune system fight cancer more effectively.

How Is the Trial Designed?

Group I: Cohort II (CMK, early pembrolizumab) Experimental Treatment 8 Interventions

Patients receive rintatolimod IV, celecoxib PO, and interferon alpha-2b IV on days 0, 1, and 2 of week 1 and days 7, 8, and 9 of week 2 on study. Patients receive pembrolizumab IV on day 2 of week 1 and then every 3 weeks beginning in week 4 on study. Patients also undergo CT scan or MRI at screening and follow-up, undergo blood sample collection during screening and on study, and may undergo tumor biopsy at screening and follow-up.

Group II: Cohort I (CKM, pembrolizumab) Experimental Treatment 7 Interventions

Patients receive rintatolimod IV, celecoxib PO, interferon alpha-2b IV on days 0, 1, and 2 of week 1 and days 7, 8, and 9 of week 2 on study. Patients receive pembrolizumab IV on day 9 and then every 3 weeks after that for up to 4 doses on study. Patients also undergo CT scan or MRI at screening and follow-up and undergo blood sample collection during screening and on study.

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

Approved in United States as Celebrex for:

• Pain relief
• Inflammation
• Osteoarthritis
• Rheumatoid arthritis
• Menstrual cramps
• Colorectal polyps prevention

Approved in European Union as Celebrex for:

• Symptomatic relief in osteoarthritis
• Symptomatic relief in rheumatoid arthritis
• Ankylosing spondylitis
• Acute pain
• Primary dysmenorrhea
• Adenomatous polyposis coli

Approved in Canada as Celebrex for:

• Symptomatic relief of osteoarthritis
• Symptomatic relief of rheumatoid arthritis
• Ankylosing spondylitis
• Acute pain
• Primary dysmenorrhea

Who Is Running the Clinical Trial?

Roswell Park Cancer Institute

Lead Sponsor

Trials

427

Recruited

40,500+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Atezolizumab combined with nab-paclitaxel has been approved by the FDA for treating patients with locally advanced or metastatic triple-negative breast cancer that expresses PD-L1.

This combination therapy is significant as it is the first immunotherapy regimen to receive marketing authorization for any form of breast cancer, marking a new treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab Combo Approved for PD-L1-positive TNBC. [2020]

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 a phase II trial involving 50 patients with early triple-negative breast cancer, 66% achieved a pathological complete response (pCR) after treatment with nab-paclitaxel and pembrolizumab, indicating a promising efficacy of this combination therapy.

The treatment was associated with manageable side effects, with fatigue, peripheral sensory neuropathy, and neutropenia being the most common adverse events, suggesting that this regimen could be a viable alternative to platinum-based chemotherapy for patients who cannot tolerate it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in combination with nab-paclitaxel for the treatment of patients with early-stage triple-negative breast cancer - A single-arm phase II trial (NeoImmunoboost, AGO-B-041). Fasching, PA., Hein, A., Kolberg, HC., et al.[2023]

In the phase III KEYNOTE-522 trial, pembrolizumab combined with chemotherapy showed increased effectiveness as a neoadjuvant treatment for triple-negative breast cancer, leading to a higher rate of pathologic complete response compared to chemotherapy alone.

This benefit was observed regardless of the PD-L1 expression levels in patients, suggesting that pembrolizumab may be a broadly effective option for this aggressive cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Pembrolizumab Takes on TNBC. [2020]

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 phase II trial involving patients with metastatic triple-negative breast cancer, administering trilaciclib before chemotherapy (gemcitabine plus carboplatin) improved overall survival and enhanced T-cell activation, particularly in patients with higher immune-related gene expression.

The combination of trilaciclib and chemotherapy resulted in fewer total T cells and CD8+ T cells, but improved T-cell effector function, indicating that trilaciclib may effectively modulate immune responses in this cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigating potential immune mechanisms of trilaciclib administered prior to chemotherapy in patients with metastatic triple-negative breast cancer. Tan, AR., O'Shaughnessy, J., Cao, S., et al.[2023]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

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]

Pembrolizumab, an anti-PD-1 monoclonal antibody, has been shown to significantly improve treatment outcomes for high-risk, early-stage triple-negative breast cancer (TNBC) when combined with standard chemotherapy, leading to a marked increase in pathologic complete response rates and 3-year event-free survival, as demonstrated in the KEYNOTE-522 trial.

The FDA approved pembrolizumab in July 2021, marking a significant shift in the treatment approach for TNBC, which has historically been challenging due to its aggressive nature and limited targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Treatment for High-Risk Early-Stage Triple-Negative Breast Cancer: Spotlight on Pembrolizumab. Bagegni, NA., Davis, AA., Clifton, KK., 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 a phase 3 trial involving 902 patients with metastatic triple-negative breast cancer, the combination of atezolizumab and nab-paclitaxel showed a median overall survival of 21.0 months compared to 18.7 months with placebo, although this difference was not statistically significant in the overall population.

For patients with PD-L1 immune cell-positive tumors, atezolizumab plus nab-paclitaxel demonstrated a significant overall survival benefit, with a median survival of 25.0 months versus 18.0 months for placebo, highlighting its potential as an important treatment option for this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Schmid, P., Rugo, HS., Adams, S., et al.[2020]

Immune checkpoint inhibitors like ipilimumab, nivolumab, and pembrolizumab have shown remarkable efficacy in treating various advanced cancers, representing a significant advancement over traditional chemotherapy.

These treatments can lead to immune-related adverse events (irAEs), which may affect any body system and can be life-threatening, highlighting the importance of prompt recognition and management by oncologists.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing adverse effects of immunotherapy. Gerson, JN., Ramamurthy, C., Borghaei, H.[2018]

Citations

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Rintatolimod, Celecoxib and Interferon Alpha 2b With ... This phase I/IIa trial tests the safety, side effects, and best dose of chemokine modulation therapy (CKM) (rintatolimod, celecoxib, and interferon alpha ...

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Rintatolimod, Celecoxib and Interferon Alpha 2b With ... This phase I/IIa trial tests the safety, side effects, and best dose of chemokine modulation therapy (CKM) (rintatolimod, celecoxib, and ...

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Rintatolimod, Celecoxib and Interferon Alpha 2b With ... It identifies the role of the intervention that participants receive. Types of arms include experimental arm, active comparator arm, placebo comparator arm, ...