ASTX727 + Paclitaxel + Pembrolizumab for Breast Cancer

Recruiting at 11 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Immunodeficiency, Active malignancy, Autoimmune, others

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

Compensation: Varies

Number of Visits: 22

32 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest and most effective dose of a new drug combination for treating triple-negative breast cancer that has metastasized. The treatment combines ASTX727 (a combination of decitabine and cedazuridine, which helps the body produce normal blood cells and fight cancer) with standard treatments like the chemotherapy drug paclitaxel and the immunotherapy drug pembrolizumab. Researchers hope this combination can shrink or stabilize tumors more effectively than current treatments alone. The trial seeks participants with metastatic triple-negative breast cancer. 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 treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on other cancer treatments or certain immunosuppressive therapies. It's best to discuss your specific medications with the trial team.

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

Research has shown that the combination of decitabine and cedazuridine, known as ASTX727, has a safety profile similar to the approved drug intravenous decitabine, indicating that ASTX727 is generally well-tolerated by patients.

Studies have found that paclitaxel, a chemotherapy drug, can cause side effects like nerve damage, but these effects are usually manageable and tend to improve over time.

For pembrolizumab, an immunotherapy drug, research suggests it improves survival rates when used with chemotherapy. However, it can cause a high rate of serious side effects, some of which may persist.

In summary, while each treatment can have side effects, evidence suggests they are generally manageable and similar to those of other known treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination treatment of ASTX727, paclitaxel, and pembrolizumab for breast cancer because it introduces a unique mechanism by combining a DNA hypomethylating agent (ASTX727) with chemotherapy (paclitaxel) and immunotherapy (pembrolizumab). Unlike traditional options that often use just chemotherapy or hormone therapy, this combination aims to enhance the effectiveness of the immune system while directly attacking cancer cells. ASTX727 includes decitabine and cedazuridine, which work together to inhibit DNA methylation, potentially making cancer cells more susceptible to treatment. Pembrolizumab, an immune checkpoint inhibitor, helps the immune system recognize and target cancer cells more effectively. This multi-pronged approach could offer new hope for patients with advanced breast cancer by potentially improving treatment outcomes.

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

Research has shown that the combination of decitabine and cedazuridine (ASTX727), which participants in this trial will receive, has been effective in treating other cancers, achieving a 70% success rate in myelodysplastic syndromes, a type of blood cancer. This suggests potential effectiveness for breast cancer as well. Paclitaxel, another treatment in this trial, is a common chemotherapy drug that has successfully treated advanced breast cancer, often leading to better patient outcomes. Pembrolizumab, also part of this trial, is an immunotherapy drug that significantly extended survival when used with chemotherapy for advanced triple-negative breast cancer. Together, these treatments aim to enhance the body's ability to fight cancer, potentially improving outcomes for patients with advanced triple-negative breast cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Roberto A Leon-Ferre

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Are You a Good Fit for This Trial?

Adults with metastatic triple-negative breast cancer can join this trial. They should have normal organ function, no severe neuropathy, and be in good physical condition. Prior treatments for cancer are okay if they've recovered from the side effects. People with certain viral infections must have them under control.

Inclusion Criteria

I agree to provide tumor biopsies and my cancer can be measured by scans.

Your AST and ALT levels should not be more than three times the normal limit.

Your platelet count should be at least 100,000 per cubic millimeter within 14 days of joining the study.

Exclusion Criteria

You are currently taking any other experimental medications.

I have been treated for an autoimmune disease in the last 2 years.

I have an active case of tuberculosis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Dose Finding Phase

Determine the recommended phase 2 dose (RP2D) of ASTX727 with paclitaxel and pembrolizumab

28 days

Weekly visits for treatment administration

Dose Expansion Phase

Further describe the adverse event profile and observe anti-tumor activity

Up to 4 years

Every 21 or 28 days for treatment, every 6 weeks for pembrolizumab

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 6 months for 3 years

Bi-annual visits

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine and Cedazuridine
• Paclitaxel
• Pembrolizumab

Trial Overview The trial is testing ASTX727 (a combo of decitabine and cedazuridine) added to standard chemotherapy (paclitaxel) and immunotherapy (pembrolizumab). It aims to find a safe dose that might help shrink or stabilize cancer better than the usual treatment alone.

How Is the Trial Designed?

Group I: Treatment (ASTX727, paclitaxel, pembrolizumab) Experimental Treatment 7 Interventions

Patients receive ASTX727 PO on days 1-5, 1-4, 1-3, or days 1, 3, and 5 of each cycle, and paclitaxel IV over 1 hour on days 1, 8, and 15 of each 28-day cycle or days 1 and 8 of each 21-day cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes every 6 weeks (treatment day varies in 28-day cycles; day 1 of every odd 21-day cycle) in the absence of disease progression or unacceptable toxicity. Patients undergo collection of blood samples and CT and/or MRI throughout the trial. Patients in the dose-expansion phase also undergo a tumor biopsy during screening and day 1 of the treatment cycle 2 of the study.

Decitabine and Cedazuridine is already approved in European Union, United States for the following indications:

Approved in European Union as Inaqovi for:

• Acute myeloid leukemia (AML) in adults who are ineligible for standard induction chemotherapy

Approved in United States as ASTX727 for:

• Adult patients with newly diagnosed acute myeloid leukemia (AML) who are 75 years or older, or who have comorbidities precluding intensive induction chemotherapy

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

In a study of 40 patients with HER2-positive metastatic breast cancer, the combination of trastuzumab, paclitaxel, and capecitabine resulted in a high overall response rate of 81.1%, with 24.3% achieving complete responses and 56.8% partial responses.

The treatment was well-tolerated, with manageable grade 3 adverse events, indicating that this combination therapy is both effective and safe for first-line treatment in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and toxicity of Trastuzumab and Paclitaxel plus Capecitabine in the first-line treatment of HER2-positive metastatic breast cancer. Tonyali, O., Benekli, M., Berk, V., et al.[2021]

In the phase 3 DESTINY-Breast02 trial involving 608 patients with HER2-positive metastatic breast cancer, trastuzumab deruxtecan significantly improved median progression-free survival to 17.8 months compared to 6.9 months for treatment of physician's choice, demonstrating its efficacy in a population with limited treatment options.

While trastuzumab deruxtecan had a higher incidence of treatment-emergent adverse events, including nausea and interstitial lung disease, it still showed a favorable benefit-risk profile, indicating its potential as a viable treatment option for patients resistant to previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. André, F., Hee Park, Y., Kim, SB., et al.[2023]

In the KEYNOTE-189 study, patients with non-squamous non-small cell lung cancer who received the combination of pembrolizumab, pemetrexed, and platinum had a median progression-free survival (PFS) of 9.3 months, significantly longer than the 6.6 months observed in the placebo group, indicating enhanced efficacy of the treatment.

The objective response rate was also higher in the pembrolizumab group (58.7%) compared to the placebo group (28.9%), while the incidence of severe treatment-emergent adverse events (grade ≥3) was similar across both treatment arms, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed maintenance with or without pembrolizumab in non-squamous non-small cell lung cancer: A cross-trial comparison of KEYNOTE-189 versus PARAMOUNT, PRONOUNCE, and JVBL. Garon, EB., Kim, JS., Govindan, R.[2021]

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 case series of 19 patients with previously treated HER2-positive metastatic breast cancer, the combination of pertuzumab, trastuzumab, and taxane therapy resulted in a median progression-free survival of 4.1 months.

The treatment was associated with minimal adverse effects, showing only a slight decrease in left ventricular ejection fraction (-1%) and no occurrences of neutropenic fever, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination pertuzumab, trastuzumab, and taxane for metastatic breast cancer after first progression: a single institution's experience. Dao, BD., Ho, H., Quintal, LN.[2016]

In a case series of 15 patients with metastatic non-squamous cell lung carcinoma, the combination of paclitaxel and bevacizumab showed a partial response rate of 44% based on CT scans and 65% based on PET scans, indicating potential efficacy in this patient population.

No major toxicity was observed in the treatment, and the median progression-free survival was 4.6 months, suggesting that this regimen is safe and may improve patient outcomes, warranting further investigation in a randomized clinical trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of paclitaxel and bevacizumab in heavily pre-treated non-small-cell lung cancer (NSCLC) patients: a case series study on 15 patients. Le Moulec, S., Hadoux, J., Gontier, E., et al.[2015]

In a retrospective study of 74 patients with advanced breast cancer, the combination of atezolizumab and nab-paclitaxel resulted in a median progression-free survival (PFS) of 6.0 months and a median overall survival (OS) of 14.3 months, indicating its effectiveness in a real-world setting.

While the survival outcomes were lower than those reported in the phase III Impassion130 trial, the results still met the efficacy standards observed in similar real-world studies, highlighting the need for careful patient selection for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab and nab-paclitaxel for advanced breast cancer in Danish real-world patients. Garly, R., Knoop, A., Jensen, MB., et al.[2023]

In the KEYNOTE-189 study involving 616 patients with metastatic non-squamous non-small-cell lung cancer, the combination of pembrolizumab and pemetrexed-platinum significantly maintained quality of life (GHS/QOL) scores compared to placebo, with a notable improvement at week 21.

Patients receiving pembrolizumab also experienced a longer median time to deterioration in symptoms like cough and chest pain, although this result was not statistically significant, indicating potential benefits in symptom management with this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Garassino, MC., Gadgeel, S., Esteban, E., et al.[2020]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., 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]

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]

Citations

1. inqovi.com inqovi.com/hcp/efficacy-and-safety

Efficacy & Safety | INQOVI® (decitabine and cedazuridine) ... 70 percent. 70% of MDS patients experienced a clinical response, showing improvements like complete or partial response, complete marrow response, and ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40051275/

A plain language summary of the ASCERTAIN trial What do the results mean?Oral DEC-C was as effective, and had similar side effects, as treatment with intravenous decitabine. Although the trial ...

3. astx.com astx.com/astex-pharmaceuticals-presents-overall-survival-data-from-ascertain-phase-3-study-of-oral-hypomethylating-agent-inqovi-decitabine-and-cedazuridine-in-mds-and-cmml-at-international-congress-on/

Study achieved median overall survival of 31.7 months Study achieved median overall survival of 31.7 months; Updated efficacy data demonstrated an overall response rate of 62%, ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05673200?cond=TNBC

Testing the Addition of an Anti-cancer Drug, ASTX727 ... This phase I trial tests the safety, side effects, and best dose of ASTX727 when given in combination with a usual approach of treatment with paclitaxel and ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6551

Phase II trial of 10-day ASTX727 (decitabine/cedazuridine ... In this prospective clinical trial, we investigate the efficacy of a novel 10-day induction regimen with fully oral combination therapy for pts with R/R AML.

6. taihooncology.com taihooncology.com/us/news/2021-09-23_astex_press_release_astx727_mos_data_presented_at_mds_international_symposium/

Astex Pharmaceuticals Presents Overall Survival Data ... Study achieved median overall survival of 31.7 months; Updated efficacy data demonstrated an overall response rate of 62%, ...

7. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-10810

Testing the Addition of an Anti-cancer Drug, ASTX727 ... This phase I trial tests the safety, side effects, and best dose of ASTX727 when given in combination with a usual approach of treatment with paclitaxel and ...

8. prnewswire.com prnewswire.com/news-releases/taiho-oncology-announces-publication-of-final-results-of-the-phase-3-ascertain-clinical-trial-of-oral-decitabine-and-cedazuridine-fixed-dose-combination-inqovi-in-patients-with-mds-and-cmml-302041085.html

Taiho Oncology Announces Publication of Final Results ... Safety findings from the study were comparable with those previously observed with IV decitabine. ... 2 Oral decitabine and cedazuridine (ASTX727) ...