Combination Chemotherapy + Immunotherapy for Breast Cancer

(ToPCourT Trial)

Overseen By Leah Wilson

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Wake Forest University Health Sciences

Must not be taking: Corticosteroids, Immunosuppressive drugs

Disqualifiers: CNS metastases, Active infection, Autoimmune disease, 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: 21

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for patients with advanced triple-negative breast cancer, a challenging cancer to treat due to its resistance to hormonal therapy. The study evaluates the effectiveness and safety of a mix of chemotherapy and immunotherapy drugs, including trilaciclib (a supportive care therapy), pembrolizumab (an immunotherapy drug), gemcitabine, and carboplatin. This treatment is suitable for those with breast cancer that cannot be surgically removed or has metastasized. Participants should not have received more than three previous chemotherapy treatments for this cancer type. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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, there is a requirement to not have had prior systemic anti-cancer therapy within 3 weeks before starting the study treatment.

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

Research shows that this combination of drugs has been tested in other studies. Trilaciclib helps protect the bone marrow during chemotherapy. Studies have shown that trilaciclib, when used with chemotherapy drugs like gemcitabine and carboplatin, can reduce some side effects.

Pembrolizumab, a type of immunotherapy, is already approved for other cancers and is generally well-tolerated. Common side effects might include fatigue or nausea, but serious side effects are less common.

Gemcitabine and carboplatin are traditional chemotherapy drugs that can cause side effects like low blood counts, leading to infections or tiredness. However, trilaciclib may help reduce these effects.

Overall, previous patients have demonstrated that the combination can be managed by the body, though some side effects are possible. These findings come from ongoing research and aim to ensure treatments are as safe as possible for patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination therapy for breast cancer because it uniquely integrates chemotherapy with immunotherapy, offering a potentially more comprehensive attack on cancer cells. Unlike standard treatments that primarily focus on killing cancer cells directly, this regimen includes Pembrolizumab, an immunotherapy drug that helps the immune system identify and attack cancer cells. Additionally, Trilaciclib is used to protect bone marrow from the harsh side effects of chemotherapy, which is not a common feature in standard treatments. This combination could lead to more effective treatment outcomes with potentially fewer side effects.

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

In this trial, participants will receive a combination of Trilaciclib, Pembrolizumab, Gemcitabine, and Carboplatin. Research has shown that Trilaciclib, when used with the chemotherapy drugs Gemcitabine and Carboplatin, does not improve survival rates for patients with advanced triple-negative breast cancer. Trilaciclib aims to protect the bone marrow from chemotherapy side effects, but studies found it did not significantly extend patients' lives with these drugs. Pembrolizumab, an immunotherapy included in this trial, has shown promise in treating various cancers by helping the immune system better target cancer cells. Gemcitabine and Carboplatin are standard chemotherapy treatments that directly attack cancer cells. Although the combination aims to enhance treatment effects, current evidence does not show a clear survival benefit for this specific type of cancer. ^{1 2 3 4 5}

Who Is on the Research Team?

Antoinette Tan, MD

Principal Investigator

Wake Forest University Health Sciences

Are You a Good Fit for This Trial?

This trial is for adults with advanced triple-negative breast cancer that hasn't spread to the brain. Participants must have negative hormone receptor tests, be expected to live at least 12 weeks, and have measurable disease. They should understand the study procedures and agree to provide tissue samples. Women of childbearing age must test negative for pregnancy and use contraception.

Inclusion Criteria

Subject agrees to use contraception

You have a disease that can be measured using specific guidelines for evaluating solid tumors.

I am willing to provide a sample of my tumor for research.

Exclusion Criteria

I am allergic to carboplatin, gemcitabine, mannitol, or pembrolizumab.

You have active hepatitis B.

Pregnant or breastfeeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive trilaciclib, pembrolizumab, gemcitabine, and carboplatin until disease progression, unacceptable toxicity, or withdrawal

Up to 2 years

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Gemcitabine
• Pembrolizumab
• Trilaciclib

Trial Overview The trial is testing a combination of drugs: Trilaciclib, Pembrolizumab (an immunotherapy), Gemcitabine, and Carboplatin in patients with metastatic triple-negative breast cancer. It aims to assess how effective this mix is against cancer and how well patients tolerate it.

How Is the Trial Designed?

Group I: Trilaciclib, Pembrolizumab, Gemcitabine, and Carboplatin Experimental Treatment 4 Interventions

Trilaciclib is an agent that helps protect the bone marrow from the side effects of chemotherapy. It is given as an intravenous (IV) infusion over 30 minutes prior to gemcitabine and carboplatin. Gemcitabine is given IV over 30 minutes. Carboplatin is given over 30 minutes. Trilaciclib, gemcitabine and carboplatin are given on Days 1 and 8 every 21 days. Pembrolizumab is given IV over 30 minutes on Day 1 every 21 days.

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

Wake Forest University Health Sciences

Lead Sponsor

Trials

1,432

Recruited

2,506,000+

G1 Therapeutics, Inc.

Industry Sponsor

Trials

22

Recruited

3,300+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

The combination of pembrolizumab and carboplatin was found to be well-tolerated and showed activity in patients with recurrent platinum-resistant ovarian cancer, with a median overall survival of 11.3 months.

Patients with a higher ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden had significantly longer overall survival, suggesting this ratio could help identify those who may benefit more from this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates. Liao, JB., Gwin, WR., Urban, RR., et al.[2022]

Pembrolizumab (Keytruda) was approved by the FDA for treating metastatic non-small cell lung cancer (mNSCLC) in patients with tumors expressing PD-L1, showing significant improvements in overall survival (OS) and progression-free survival (PFS) in two major clinical trials with thousands of participants.

In the KEYNOTE-024 trial, pembrolizumab demonstrated a 40% reduction in the risk of death compared to chemotherapy, while in the KEYNOTE-010 trial, it also showed a significant survival advantage over chemotherapy in patients who had previously progressed on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Pai-Scherf, L., Blumenthal, GM., Li, H., et al.[2022]

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 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]

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 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 study involving patients with recurrent platinum-resistant ovarian cancer, the combination of pembrolizumab, cisplatin, and gemcitabine resulted in an overall response rate of 60%, but the duration of response was relatively short at 4.9 months.

The addition of pembrolizumab did not show a significant benefit over chemotherapy alone, leading to the decision to close the trial for further accrual after an interim analysis indicated modest outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer. Walsh, CS., Kamrava, M., Rogatko, A., et al.[2022]

In a phase II trial involving 150 women with metastatic breast cancer (MBC), the combination of gemcitabine and carboplatin showed a high overall response rate of 64% in HER2-positive patients, indicating strong efficacy, especially when combined with trastuzumab.

The treatment was also effective in HER2-negative patients, achieving response rates of 27% and 32% regardless of prior taxane therapy, while demonstrating a low frequency of serious toxicities, such as neutropenia and leukopenia, and no significant cardiac toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of gemcitabine/carboplatin (plus trastuzumab in HER2-positive disease) in patients with metastatic breast cancer. Loesch, D., Asmar, L., McIntyre, K., et al.[2022]

In a long-term study of 123 patients with advanced nonsquamous NSCLC, the combination of pembrolizumab with pemetrexed-carboplatin significantly improved the objective response rate (58% vs. 33%) and progression-free survival (24.5 months vs. 9.9 months) compared to chemotherapy alone.

Patients who completed 2 years of pembrolizumab treatment had a remarkable 92% survival rate at the data cutoff, indicating a durable clinical benefit, while the safety profile remained manageable with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC. Awad, MM., Gadgeel, SM., Borghaei, H., et al.[2021]

In a phase II study involving 31 pretreated metastatic triple-negative breast cancer (TNBC) patients, the combination of carboplatin and gemcitabine (CG) showed an overall response rate of 32%, indicating its potential effectiveness in this challenging cancer type.

While the CG treatment was associated with significant hematological toxicities, such as Grade 3/4 neutropenia and thrombocytopenia, non-hematological side effects were manageable, suggesting that CG could be a viable treatment option despite the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and gemcitabine combination in metastatic triple-negative anthracycline- and taxane-pretreated breast cancer patients: a phase II study. Maisano, R., Zavettieri, M., Azzarello, D., et al.[2022]

Citations

1. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-06534

Trilaciclib, Pembrolizumab, Gemcitabine and Carboplatin ... This phase II trial tests how well trilaciclib, pembrolizumab, gemcitabine and carboplatin works in treating patients with triple negative breast cancer.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36135712/

Trilaciclib prior to gemcitabine plus carboplatin for ... Abstract. Triple-negative breast cancer (TNBC) is an aggressive malignancy for which cytotoxic chemotherapy remains the backbone of treatment.

3. aacrjournals.org aacrjournals.org/clincancerres/article/31/12_Supplement/PS2-05/754109/Abstract-PS2-05-PRESERVE-2-A-randomized-phase-3

Abstract PS2-05: PRESERVE 2: A randomized, phase 3 ... Data from PRESERVE 2 show that compared with placebo, administering trilaciclib prior to GCb did not improve survival in pts with mTNBC.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04799249

NCT04799249 | Trilaciclib, a CDK 4/6 Inhibitor, in Patients ... To evaluate the effect of trilaciclib on progression-free survival (PFS) compared with placebo in patients receiving gemcitabine and carboplatin. From date of ...

5. onclive.com onclive.com/view/trilaciclib-before-gemcitabine-carboplatin-misses-os-end-point-in-metastatic-tnbc

Trilaciclib Before Gemcitabine/Carboplatin Misses OS End ... Trilaciclib plus chemotherapy failed to improve overall survival in metastatic triple-negative breast cancer.