ZEN-3694 + Pembrolizumab + Chemotherapy for Breast Cancer

Recruiting at 4 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

Trial Summary

What is the purpose of this trial?

This phase Ib trial tests the safety and tolerability of ZEN003694 in combination with an immunotherapy drug called pembrolizumab and the usual chemotherapy approach with nab-paclitaxel for the treatment of patients with triple negative-negative breast cancer that has spread to other parts of the body (advanced). Paclitaxel is in a class of medications called antimicrotubule agents. It stops cancer cells from growing and dividing and may kill them. Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of paclitaxel which may have fewer side effects and work better than other forms of paclitaxel. Immunotherapy with monoclonal antibodies, such as pembrolizumab may help the body's immune system attach the cancer and may interfere with the ability of tumor cells to grow and spread. ZEN003694 is an inhibitor of a family of proteins called the bromodomain and extra-terminal (BET). It may prevent the growth of tumor cells that over produce BET protein. Combination therapy with ZEN003694 pembrolizumab immunotherapy and nab-paclitaxel chemotherapy may help shrink or stabilize cancer for longer than chemotherapy alone.

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 the combination of ZEN-3694, Pembrolizumab, and nab-paclitaxel safe for humans?

Nab-paclitaxel, a component of the treatment, is generally considered safe and is approved for use in several cancers, including breast cancer, with known side effects. It was developed to avoid certain toxicities associated with older formulations. However, specific safety data for the combination with ZEN-3694 and Pembrolizumab is not provided in the available research. ^{1 2 3 4 5}

What makes the drug combination of ZEN-3694, Pembrolizumab, and Nab-paclitaxel unique for breast cancer treatment?

This drug combination is unique because it combines ZEN-3694, a novel drug, with Pembrolizumab, an immune therapy, and Nab-paclitaxel, a chemotherapy that avoids certain toxicities, offering a potentially more effective and safer treatment option for breast cancer patients. ^{1 2 5 6 7}

Research Team

Ana C Garrido-Castro

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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, 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]

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]

References

1. England 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. [2021]

2. Canada pubmed.ncbi.nlm.nih.gov

A Retrospective Study of Efficacy and Safety of Albumin-Bound Paclitaxel in Metastatic Breast Cancer. [2022]

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

A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. [2020]

4. United States 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). [2022]

5. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy evaluation of albumin-bound paclitaxel. [2015]

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

First-Line Pembrolizumab Plus Chemotherapy for Advanced Squamous NSCLC: Real-World Outcomes at U.S. Oncology Practices. [2023]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Nab-Paclitaxel in Metastatic Breast Cancer: Defining the Best Patient Profile. [2019]