Azenosertib + Carboplatin + Pembrolizumab for Breast Cancer

Overseen By Filipa Lynce, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Filipa Lynce, MD

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Untreated brain metastases, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: 25

78 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new drug, Azenosertib, in combination with carboplatin (a chemotherapy drug) and pembrolizumab (an immunotherapy drug), to determine its safety and effectiveness for individuals with metastatic triple-negative breast cancer. The trial will assess how well these drugs work together in combating cancer that has spread and is difficult to treat. Eligible participants should have metastatic triple-negative breast cancer and have undergone specific prior treatments without recent progression on platinum-based chemotherapy. As a Phase 1 trial, this research seeks to understand how the treatment functions in people, offering participants the opportunity to be among the first to receive this new drug.

Do I need to stop my current medications to join the trial?

The trial requires that you stop any prior cytotoxic chemotherapy and biologic therapy at least 14 days before starting the study treatment. Additionally, you must not take any medications that are strong or moderate inhibitors or inducers of certain liver enzymes (CYP3A4/CYP3A5) and P-gp inhibitors, and these should be stopped before the trial as specified. Please consult with the trial team for specific guidance on your current medications.

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

Previous studies found Azenosertib to be safe and well-tolerated when used alone. Patients with various solid tumors responded positively to the drug, even after multiple prior treatments. When combined with carboplatin (a chemotherapy drug) and pembrolizumab (an immune therapy), patients with breast cancer showed promising results, including a high survival rate for those who completed treatment.

These findings suggest that these drugs can be safely used together, although some side effects may still occur. Azenosertib has been tested with these other drugs before, and the safety results are encouraging. Participants in the current study will help further confirm the effectiveness and safety of this combination. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Azenosertib, Carboplatin, and Pembrolizumab for breast cancer because it offers a novel approach to treatment. Azenosertib is unique as it targets a specific pathway in cancer cells that helps them survive and grow, potentially leading to more effective results. Unlike standard treatments that typically involve chemotherapy or hormone therapy, this combination includes Pembrolizumab, an immunotherapy that helps the body's immune system recognize and attack cancer cells. Additionally, the use of Carboplatin, a well-known chemotherapy drug, complements these mechanisms by directly damaging the DNA of cancer cells. This multi-pronged approach could lead to improved outcomes for patients by tackling cancer from different angles simultaneously.

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

Research has shown that Azenosertib alone has reduced tumors in 34.9% of patients with certain hard-to-treat cancers, indicating its potential effectiveness in some cases. In this trial, participants in the Phase 1 Dose Escalation Arm will receive Azenosertib with carboplatin and pembrolizumab to establish a Maximum Tolerated Dose. Early studies suggest this combination could be effective for advanced triple-negative breast cancer, but more data is needed. Carboplatin damages cancer cells' DNA, while pembrolizumab helps the immune system fight cancer. Together, they aim to be more effective by attacking the cancer in different ways. ^{1 3 5 6 7}

Who Is on the Research Team?

Filipa Lynce, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for patients with metastatic triple-negative breast cancer. Participants should meet specific health criteria not detailed here.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document.

I can take care of myself but might not be able to do heavy physical work.

I can swallow pills.

Exclusion Criteria

My cancer has worsened despite having platinum-based chemotherapy.

Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.

I do not have any uncontrolled illnesses.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Phase 1: Dose Escalation

Participants are enrolled in a 3+3 dose-escalation scheme to establish the Maximum Tolerated Dose (MTD) of Azenosertib

Up to 27 weeks

CT or MRI scan every 9 weeks until 27 weeks

Phase 2: Treatment

Participants receive Azenosertib, Carboplatin, and Pembrolizumab with regular CT or MRI scans and tumor biopsies

Up to 48 months

CT or MRI scan every 9 weeks until 27 weeks, then every 12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 6 months

Follow-up visits every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Azenosertib
• Carboplatin
• Pembrolizumab

Trial Overview The study tests the safety and effectiveness of Azenosertib combined with Carboplatin and Pembrolizumab in treating metastatic triple-negative breast cancer.

How Is the Trial Designed?

Group I: Phase 2: AZENOSERTIB + PEMBROLIZUMAB + CARBOPLATIN Experimental Treatment 3 Interventions

Participants will complete: * Baseline visit with CT or MRI scan and tumor biopsy. * CT or MRI scan every 9 weeks until 27 weeks then every 12 weeks. * Cycle 1 through End of Treatment: * Days 1 through 5, 8 through 12, and 15 through 19 of 21 Day Cycle: Predetermined dose of Azenosertib 1x daily. * Day 1 of 21 Day Cycle: Predetermined dose of Pembrolizumab 1x daily. * Days 1 and 8 of 21 Day Cycle: Predetermined dose of Carboplatin 1x daily. * Tumor biopsy during Cycle 2. * End of Treatment visit * Follow up: every 6 months

Group II: Phase 1: Dose Escalation Arm Experimental Treatment 3 Interventions

Participants will be enrolled in a standard 3+3 dose-escalation scheme to establish a Maximum Tolerated dose (MTD) of Azenosertib, starting at Dose Level 0, de-escalating to Dose Level -1, and escalating to Dose Levels 1 and 2. * Baseline visit with CT or MRI scan. * CT or MRI scan every 9 weeks until 27 weeks then every 12 weeks. * Cycle 1 through End of Treatment: * Days 1 through 5, 8 through 12, and 15 through 19 of 21 Day Cycle: Predetermined dose of Azenosertib 1 x daily. * Day 1 of 21 Day Cycle: Predetermined dose of Pembrolizumab 1x daily. * Days 1 and 8 of 21 Day Cycle: Predetermined dose of Carboplatin 1x daily. * End of Treatment visit * Follow up: every 6 months * Dose de-escalation and escalation will follow dose-limiting toxicities specifications (DLTs) per the protocol. The MTD is the highest dose level with ≤1 DLT in a cohort of 6 participants and the study will proceed to Phase 2.

Who Is Running the Clinical Trial?

Filipa Lynce, MD

Lead Sponsor

Trials

2

Recruited

140+

Zentalis Pharmaceuticals

Collaborator

Trials

2

Recruited

80+

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

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]

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]

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]

The combination of pemetrexed, platinum, and pembrolizumab shows manageable toxicity, with most severe adverse events occurring early in treatment and resolving within two weeks, indicating a favorable safety profile for long-term use.

While there was a slightly higher incidence of renal toxicity in patients receiving the pembrolizumab combination compared to those on pemetrexed alone, this did not increase with longer treatment durations, supporting the regimen's safety in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of pemetrexed plus platinum in combination with pembrolizumab for metastatic nonsquamous non-small cell lung cancer: A post hoc analysis of KEYNOTE-189. Garon, EB., Aerts, J., Kim, JS., 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 50 patients with locally advanced or metastatic breast cancer, the combination of pemetrexed and carboplatin showed a promising overall response rate of 54%, with a median response duration of 11.1 months.

The treatment was associated with manageable safety concerns, primarily hematologic toxicities, including grade 3/4 neutropenia in 58% of patients, but no severe non-hematologic toxicities were reported, indicating an acceptable safety profile for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of pemetrexed and carboplatin in patients with locally advanced or metastatic breast cancer. Garin, A., Manikhas, A., Biakhov, M., et al.[2015]

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 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]

Pembrolizumab (Keytruda) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

In a study of 167 patients with recurrent/metastatic squamous cell carcinoma of the head and neck treated with pembrolizumab, the median overall survival was 22.7 months and progression-free survival was 5.1 months for those receiving pembrolizumab alone, indicating significant efficacy.

The presence of immune-related adverse events (irAEs) was associated with better progression-free survival, suggesting that these side effects may serve as important prognostic factors in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Pembrolizumab in Recurrent/Metastatic Squamous Cell Head and Neck Carcinoma: A Multicenter Retrospective Study. Okada, T., Fushimi, C., Matsuki, T., et al.[2023]

Adjuvant platinum-based chemotherapy is the standard treatment for patients with resected non-small-cell lung cancer (NSCLC) stage IB to IIIA, but many still face disease recurrence, highlighting the need for more effective therapies.

The ALCHEMIST trial is investigating the efficacy of pembrolizumab, a PD-1 inhibitor, in combination with chemotherapy to potentially improve outcomes compared to standard chemotherapy alone, with the aim of reducing recurrence rates in NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integration of immunotherapy into adjuvant therapy for resected non-small-cell lung cancer: ALCHEMIST chemo-IO (ACCIO). Sands, JM., Mandrekar, SJ., Kozono, D., et al.[2022]

In the KEYNOTE-407 study involving 1107 patients with untreated metastatic squamous non-small-cell lung cancer, the addition of pembrolizumab to chemotherapy significantly improved overall survival and quality of life without increasing severe toxicity.

Patients receiving pembrolizumab reported better health-related quality of life scores at weeks 9 and 18 compared to those receiving placebo, indicating that pembrolizumab enhances patient well-being while maintaining effective cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-Related Quality of Life With Carboplatin-Paclitaxel or nab-Paclitaxel With or Without Pembrolizumab in Patients With Metastatic Squamous Non-Small-Cell Lung Cancer. Mazieres, J., Kowalski, D., Luft, A., et al.[2020]

Citations

1. dana-farber.org dana-farber.org/clinical-trials/24-005

A phase I/II, single-arm trial of Azenosertib (ZN-c3 ... This research is being done to evaluate the safety and effectiveness of a drug currently known as Azenosertib (ZN-C3) in combination with the drugs carboplatin ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.5513

Correlation of cyclin E1 expression and clinical outcomes ... 26.6% had a partial response (PR) and median progression free survival (PFS) = 9.03 mo (95%CI: 5.52-11.01). Azenosertib + PAC demonstrated the ...

3. targetedonc.com targetedonc.com/view/azenosertib-shows-promising-efficacy-in-platinum-resistant-ovarian-cancer

Azenosertib Shows Promising Efficacy in Platinum- ... Azenosertib monotherapy showed a 34.9% overall response rate in heavily pretreated, cyclin E1–positive, platinum-resistant ovarian cancer, ...

4. onclive.com onclive.com/view/azenosertib-monotherapy-appears-safe-and-effective-in-ovarian-cancer

Azenosertib Monotherapy Appears Safe and Effective in ... Azenosertib (ZN-c3) monotherapy elicited an overall response rate (ORR) of 34.9% (95% CI, 21.0%-50.9%) in response-evaluable, ...

5. clin.larvol.com clin.larvol.com/trial-detail/NCT04158336

A Study of ZN-c3 in Participants With Solid Tumors In these patients, an ORR of 34.8% (8/23; 95% CI: 16.4-57.3) and an mDOR of 5.2 months (95% CI: 2.8, 6.9) were observed. Full efficacy results at a total daily ...

6. ir.zentalis.com ir.zentalis.com/news-releases/news-release-details/zentalis-pharmaceuticals-announces-promising-initial-data

Release Details ZN-c3 demonstrated single agent activity, generating Exceptional Responses in a range of heavily pre-treated solid tumors. ZN-c3 was safe and well-tolerated.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05368506

ZN-c3 for the Treatment of Metastatic Triple-Negative ... This early phase I trial tests the safety and side effects of ZN-c3 in treating patients with triple-negative breast cancer or ovarian cancer that have ...