ZEN-3694 + Pembrolizumab + Chemotherapy for Breast Cancer

Recruiting at 6 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, Factor Xa inhibitors

Disqualifiers: Autoimmune disease, GI disorder, others

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

Compensation: Varies

Number of Visits: 12

57 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for individuals with advanced triple-negative breast cancer, where the cancer has spread and does not respond to typical hormone therapies. The combination includes an experimental drug called ZEN003694, an immunotherapy drug called pembrolizumab, and a chemotherapy drug called nab-paclitaxel. The researchers aim to determine if this combination is safe and can control cancer more effectively than chemotherapy alone. This trial may suit those diagnosed with advanced triple-negative breast cancer that cannot be surgically removed. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take strong inhibitors or inducers of CYP3A4, Factor Xa inhibitors, or Factor IIa inhibitors. It's important to discuss your current medications with the study team to ensure there are no interactions.

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

Research shows some safety information is available for ZEN-3694, nab-paclitaxel, and pembrolizumab.

ZEN-3694 has undergone safety studies when combined with other cancer drugs. For example, it was tested with talazoparib in patients with a specific type of breast cancer. These studies showed some cancer-fighting effects, but specific safety details in humans are not provided in the sources.

Nab-paclitaxel, a chemotherapy drug used since 2005 for advanced breast cancer, is generally well-tolerated. However, it can cause side effects like low white blood cell counts and liver issues in some people. Its safety is considered good for patients with advanced breast cancer.

Pembrolizumab, an immunotherapy drug, helps the immune system fight cancer. It has improved survival rates when combined with chemotherapy in patients with advanced triple-negative breast cancer. Safety data suggest pembrolizumab is generally well-tolerated, but monitoring for immune-related side effects is important.

Overall, while each treatment has shown some safety in other studies or uses, this specific trial remains in an early stage. Researchers are still determining the best dose and closely monitoring for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ZEN-3694, pembrolizumab, and nab-paclitaxel for treating breast cancer because it offers a unique approach compared to standard therapies like hormone therapy or HER2-targeted treatments. ZEN-3694 is particularly interesting as it targets the BET proteins, which play a role in gene regulation that can drive cancer growth, offering a novel mechanism of action. Combining this with pembrolizumab, an immunotherapy that helps the immune system attack cancer cells, and nab-paclitaxel, a chemotherapy drug, could potentially enhance efficacy by attacking the cancer on multiple fronts. This multifaceted approach is what makes this treatment combination stand out and why researchers are eager to explore its potential benefits.

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

Research has shown that ZEN-3694, one of the treatments in this trial, can help fight cancer in patients with certain types of breast cancer when combined with other treatments. Previous studies combining ZEN-3694 with talazoparib showed positive results in some breast cancer patients. In this trial, ZEN-3694 is combined with nab-paclitaxel and pembrolizumab. Nab-paclitaxel has proven effective on its own for treating various stages of breast cancer, including metastatic cases. Studies have found that nab-paclitaxel is generally well tolerated and can improve patient outcomes. Pembrolizumab, an immunotherapy drug, has been shown to extend survival when used with chemotherapy in advanced breast cancer cases. Together, these treatments in the trial aim to shrink or control cancer more effectively than chemotherapy alone. ^{3 6 7 8 9}

Who Is on the Research Team?

Ana C Garrido-Castro

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with advanced triple-negative breast cancer that's spread and can't be removed by surgery. Participants must have acceptable organ function, no severe prior reactions to similar drugs, and not be on certain medications that affect the study drugs. They should not have had recent chemotherapy or immunotherapy, and women of childbearing age must use contraception.

Inclusion Criteria

I am willing and able to have tumor biopsies before and during treatment.

My kidney function is within the normal range.

I had hepatitis C but have been successfully treated and cured.

Exclusion Criteria

I have a digestive condition that affects how my body absorbs pills.

I have never taken the study drug or any experimental BET inhibitors.

I am currently taking blood thinners that target Factor Xa or IIa.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Patients receive ZEN003694 orally once daily on days 1-21, nab-paclitaxel intravenously on days 1, 8, and 15, and pembrolizumab intravenously every 21 days of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 35 cycles (28 days each)

3 visits per cycle (in-person)

Dose Expansion

Patients receive ZEN003694 orally once daily on days 1-7 prior to combination therapy, then continue with ZEN003694, nab-paclitaxel, and pembrolizumab as in dose escalation. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 35 cycles (28 days each)

3 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs 30 days after the last dose and then every 6 months for up to 3 years or until death.

Up to 3 years

Every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Nab-paclitaxel
• Pembrolizumab
• ZEN-3694

Trial Overview

The trial tests ZEN003694 (a BET protein inhibitor) combined with pembrolizumab (an immunotherapy drug) and nab-paclitaxel (a form of chemotherapy). It aims to see if this combination is safer and more effective than standard treatments in shrinking or stabilizing cancer.

How Is the Trial Designed?

Group I: Dose Expansion (ZEN003694, nab-paclitaxel, pembrolizumab) Experimental Treatment 7 Interventions

Patients receive ZEN003694 PO QD on days 1-7 prior to combination therapy. Patients then receive ZEN003694 PO QD on days 1-21, nab-paclitaxel IV over 30 minutes on days 1, 8, and 15, and pembrolizumab IV over 30 minutes every 21 days of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity with a maximum of 35 doses of pembrolizumab administered. Patients also undergo biopsies on study, and CT or MRI scans and collection of blood samples throughout the trial.

Group II: Dose Escalation (ZEN003694, nab-paclitaxel, pembrolizumab) Experimental Treatment 6 Interventions

Patients receive ZEN003694 PO QD on days 1-21, nab-paclitaxel IV over 30 minutes on day 1, 8, and 15, and pembrolizumab IV over 30 minutes every 21 days of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity with a maximum of 35 doses of pembrolizumab administered. Patients also undergo CT or MRI scan and collection of blood samples throughout the trial.

Nab-paclitaxel is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Abraxane for:

• Metastatic breast cancer
• Non-small cell lung cancer
• Adenocarcinoma of the pancreas

Approved in European Union as Abraxane for:

• Metastatic breast cancer
• Non-small cell lung cancer
• Adenocarcinoma of the pancreas

Approved in Canada as Abraxane for:

• Metastatic breast cancer
• Non-small cell lung cancer
• Adenocarcinoma of the pancreas

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Nab-paclitaxel was well tolerated in pediatric solid tumor models, with a maximum weight loss of about 10% that returned to baseline after treatment, indicating a favorable safety profile.

The treatment showed significant efficacy, improving event-free survival in 19 out of 20 solid tumor xenograft models, particularly demonstrating high activity against Ewing sarcoma and rhabdomyosarcoma, making it a promising candidate for further pediatric evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial testing (stage 1) of the tubulin binding agent nanoparticle albumin-bound (nab) paclitaxel (Abraxane(®)) by the Pediatric Preclinical Testing Program (PPTP). Houghton, PJ., Kurmasheva, RT., Kolb, EA., et al.[2022]

Nab-paclitaxel is a solvent-free formulation of paclitaxel that can be safely administered to breast cancer patients who are eligible for taxane treatments, making it a versatile option for various treatment scenarios.

The review identifies six specific patient profiles where nab-paclitaxel is particularly beneficial, including first-line and second-line treatments for metastatic breast cancer (MBC), and for patients who have had prior exposure to standard taxanes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nab-Paclitaxel in Metastatic Breast Cancer: Defining the Best Patient Profile. González-Martín, A., Alba, E., Ciruelos, E., et al.[2019]

In a study involving 74 patients with metastatic melanoma, nab-Paclitaxel showed a response rate of 21.6% in chemotherapy-naive patients and 2.7% in previously treated patients, indicating better efficacy in those who had not undergone prior treatment.

The treatment was well tolerated, with 78% of previously treated patients and 49% of chemotherapy-naive patients able to complete therapy without dose reductions, suggesting a favorable safety profile compared to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Hersh, EM., O'Day, SJ., Ribas, A., et al.[2020]

In a study of women with metastatic breast cancer treated with nab-paclitaxel, 43% experienced a clinical benefit, with a median survival of 63.6 weeks, indicating its effectiveness as a treatment option.

Nab-paclitaxel was well tolerated, with no severe hypersensitivity reactions reported and mild sensory neuropathy being the most common side effect, suggesting a favorable safety profile compared to traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Retrospective Study of Efficacy and Safety of Albumin-Bound Paclitaxel in Metastatic Breast Cancer. Singh, RK., Pankaj, S., Kumar, S., et al.[2022]

Nab-paclitaxel, a new formulation of paclitaxel, has shown a good safety and efficacy profile for treating metastatic breast cancer (MBC), although there is limited data on its impact on overall survival.

In combination with gemcitabine, nab-paclitaxel significantly improves survival in advanced pancreatic cancer (PC) and demonstrates better results in non-small-cell lung cancer (NSCLC) patients with squamous histology, highlighting its potential as a valuable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy evaluation of albumin-bound paclitaxel. Cecco, S., Aliberti, M., Baldo, P., et al.[2015]

In a study of 364 patients with advanced squamous NSCLC treated with first-line pembrolizumab-chemotherapy, the median time on treatment was 6.5 months, indicating a substantial duration of therapy in a real-world setting.

The median overall survival for these patients was 15.3 months, which aligns closely with results from clinical trials, demonstrating the efficacy of pembrolizumab-chemotherapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Pembrolizumab Plus Chemotherapy for Advanced Squamous NSCLC: Real-World Outcomes at U.S. Oncology Practices. Liu, SV., Rai, P., Wang, D., et al.[2023]

In a study of 81 women with early-stage estrogen receptor-positive breast cancer, nab-Paclitaxel showed significant antitumor activity with a good response rate (RCB 0+I) of 24.7%, indicating its effectiveness as a neoadjuvant treatment despite a higher than expected poor response rate (RCB III) of 28.4%.

The treatment was associated with low rates of severe toxicity, with neutropenia being the most common side effect, and an exploratory analysis suggested that overexpression of the SPARC protein in tumors may predict a complete response, highlighting the need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Therapy with Weekly Nanoparticle Albumin-Bound Paclitaxel for Luminal Early Breast Cancer Patients: Results from the NABRAX Study (GEICAM/2011-02), a Multicenter, Non-Randomized, Phase II Trial, with a Companion Biomarker Analysis. Martín, M., Chacón, JI., Antón, A., et al.[2021]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9016319/

A Real-World Efficacy of Nab-Paclitaxel Monotherapy in ...

In conclusion, this real-world data shows that nab-paclitaxel is an effective treatment option in metastatic breast cancer. Nab-paclitaxel was well tolerated ...

2.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.19.00877

Nab-Paclitaxel: A New Standard of Care in Neoadjuvant ...

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) was approved in 2005 for the treatment of metastatic breast cancer, primarily on the basis of a phase ...

3.

ehoonline.biomedcentral.com

ehoonline.biomedcentral.com/articles/10.1186/s40164-017-0066-5

nab-Paclitaxel for the treatment of breast cancer

Recent clinical data indicate that nab-paclitaxel is effective and safe across all stages of breast cancer. The results from trials in the ...

4.

targetedonc.com

targetedonc.com/view/fiveyear-dosing-efficacy-results-for-nabpaclitaxel-in-tnbc

Five-Year Dosing, Efficacy Results for Nab-Paclitaxel in ...

For OS, ixabepilone was inferior, while nab-paclitaxel trended toward inferior in the HR+ subset, although ixabepilone was quite superior for PFS, at 21 months ...

5.

link.springer.com

link.springer.com/article/10.1007/s00432-025-06246-2

The efficacy and therapy management of nab-paclitaxel in ...

Adverse events occurred in 83.1% of patients, with high-grade adverse events being rare (< 8% of patients). Quality of life did not change under ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8286600/

A systematic review and meta-analysis of nab-paclitaxel mono ...

Approximately one-fourth of patients with early localized breast cancer will eventually develop recurrent or metastatic breast cancer (MBC) [33] ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11599493/

Safety and efficacy of generic nab-paclitaxel-based therapy ...

This study demonstrates a promising safety and efficacy of generic nab-paclitaxel-based regimens for Chinese patients with malignancies in a real-world setting.

8.

clinical-breast-cancer.com

clinical-breast-cancer.com/article/S1526-8209(18)30064-8/fulltext

Final Effectiveness and Safety Results of NABUCCO

The results of the NABUCCO study confirm the clinical trial outcomes and the favorable safety profile of nab-P in patients with metastatic breast cancer in a ...

9.

nature.com

nature.com/articles/s41598-025-16848-y

Distinct safety profiles of albumin-bound nab-paclitaxel and ...

Nab-paclitaxel was associated with a higher frequency of severe hematologic and hepatobiliary events, including neutropenia (ROR 44.63; PRR ...