ASTX727 + Paclitaxel + Pembrolizumab for Breast Cancer

Recruiting at 10 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

Trial Summary

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.

What data supports the effectiveness of the drug pembrolizumab (Keytruda) in treating cancer?

Pembrolizumab has been shown to improve survival and response rates in patients with non-small cell lung cancer and is approved for treating advanced endometrial carcinoma, indicating its potential effectiveness in cancer treatment. ^{1 2 3 4 5}

Is the combination of ASTX727, Paclitaxel, and Pembrolizumab generally safe for humans?

Pembrolizumab, one of the drugs in the combination, has been associated with a rare risk of developing type 1 diabetes in 0.2% of cases. In a study with lung cancer patients, adding pembrolizumab to paclitaxel showed little impact on severe toxicity, suggesting it is generally well-tolerated. ^{1 5 6 7 8}

What makes the drug combination of ASTX727, Paclitaxel, and Pembrolizumab unique for breast cancer treatment?

This drug combination is unique because it includes ASTX727 (Decitabine and Cedazuridine), which is not commonly used in breast cancer treatment, and combines it with Paclitaxel and Pembrolizumab, potentially offering a novel approach by targeting cancer cells in multiple ways, including immune system activation and cell division disruption. ^{1 3 9 10 11}

What is the purpose of this trial?

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 pembrolizumab in patients with triple-negative breast cancer that has spread from where it first started (primary site) to other places in the body (metastatic). The usual approach is defined as care most people get for this type of cancer. The usual approach for patients with metastatic triple negative breast cancer who are not in a study is chemotherapy with drugs like paclitaxel, carboplatin, cisplatin, eribulin, vinorelbine, capecitabine, gemcitabine, doxorubicin or cyclophosphamide. There is a protein called PD-L1 that helps regulate the body's immune system. For patients who have PD-L1+ tumors, immunotherapy (pembrolizumab) is usually added to paclitaxel or carboplatin/gemcitabine as initial treatment. For patients who have PD-L1-negative tumors, chemotherapy alone is used, without immunotherapy. ASTX727 is a combination of two drugs, decitabine and cedazuridine. Cedazuridine is in a class of medications called cytidine deaminase inhibitors. It prevents the breakdown of decitabine, making it more available in the body so that decitabine will have a greater effect. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Paclitaxel is in a class of medications called antimicrotubule agents. It stops tumor cells from growing and dividing and may kill them. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving ASTX727 with usual treatment approach with paclitaxel and pembrolizumab may be able to shrink or stabilize the tumor for longer than the usual approach alone in patients with metastatic triple negative breast cancer.

Research Team

Roberto A Leon-Ferre

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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 (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 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, 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 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 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]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

2. England pubmed.ncbi.nlm.nih.gov

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

3. England 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. [2020]

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

New Approved Use for Keytruda. [2022]

5. England 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. [2023]

6. Ireland 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. [2021]

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

8. United States 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. [2020]

9. France 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. [2015]

10. Denmark pubmed.ncbi.nlm.nih.gov

Atezolizumab and nab-paclitaxel for advanced breast cancer in Danish real-world patients. [2023]

11. Germany 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. [2021]