Vaccine + Chemotherapy + Immunotherapy for Breast Cancer

Recruiting at 28 trial locations

Overseen by William E Gillanders

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: CNS disease, Autoimmune, Infection, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well nab-paclitaxel, durvalumab, and tremelimumab with or without personalized synthetic long peptide vaccine (neoantigen vaccine) works in treating patients with triple negative breast cancer that has spread from where it first started (primary site) to other places in the body (metastatic). Chemotherapy drugs, such as nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Vaccines made from peptides may help the body build an effective immune response to kill tumor cells. It is not yet known whether giving nab-paclitaxel, durvalumab, and tremelimumab with or without neoantigen vaccine will work better in treating patients with triple negative breast cancer.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you cannot participate if you are currently using immunosuppressive medication or have received certain treatments like chemotherapy or investigational agents recently. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drugs used in the Vaccine + Chemotherapy + Immunotherapy for Breast Cancer trial?

Research shows that durvalumab, an immune-boosting drug, has been approved for treating certain cancers like urothelial carcinoma and is being tested in other cancers. Additionally, combining durvalumab with tremelimumab and paclitaxel has been explored in other cancer types, suggesting potential benefits in enhancing the body's ability to fight cancer. ^{1 2 3 4 5}

Is the combination of durvalumab, tremelimumab, and paclitaxel generally safe in humans?

The combination of durvalumab and tremelimumab has been studied for safety in various cancers, showing that serious side effects occurred in about 32.6% of patients, compared to 23.8% with durvalumab alone. Common side effects included reduced appetite and diarrhea. Paclitaxel has been safely combined with immune therapies in other cancers. ^{1 2 6 7 8}

What makes the drug combination of Durvalumab, Nab-paclitaxel, and Tremelimumab unique for breast cancer treatment?

This drug combination is unique because it combines immunotherapy (Durvalumab and Tremelimumab) with chemotherapy (Nab-paclitaxel), potentially enhancing the immune system's ability to fight cancer while directly targeting cancer cells. Durvalumab and Tremelimumab work by blocking proteins that prevent the immune system from attacking cancer cells, while Nab-paclitaxel is a solvent-free chemotherapy that may have fewer side effects than traditional formulations. ^{2 4 5 9 10}

Research Team

William E Gillanders

Principal Investigator

Yale University Cancer Center LAO

Eligibility Criteria

This trial is for adults with metastatic triple negative breast cancer. Participants must have a specific tumor profile (PD-L1 negative, HER2 negative, ER and PR less than Allred score of 3 or <1% positive staining), adequate organ function, no prior therapy for metastatic TNBC unless there's been a disease-free interval post-taxane therapy, and an ECOG performance status <=1. Pregnant women and those with certain medical conditions or treatments are excluded.

Inclusion Criteria

Your hemoglobin level is at least 9.0 grams per deciliter.

Your bilirubin levels in the blood should not be higher than 1.5 times the upper limit of normal.

I can provide a biopsy sample from my advanced or relapsed cancer.

Exclusion Criteria

I do not have brain metastases or any known central nervous system disease.

I haven't taken immunosuppressive drugs in the last 14 days.

Patients who are receiving any other investigational agents or who have received an investigational agent within the last 30 days.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part A

Patients receive gemcitabine hydrochloride and carboplatin intravenously on days 1 and 8 of each cycle. Treatment repeats every 21 days for up to 18 weeks.

18 weeks

6 cycles, each with 2 visits (in-person)

Treatment Part B

Patients are randomized to receive either the neoantigen vaccine with durvalumab, tremelimumab, and nab-paclitaxel or just durvalumab, tremelimumab, and nab-paclitaxel. Cycles repeat every 28 days.

Up to 52 weeks

4 cycles, each with multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 3 months for 1 year, then annually.

Up to 1 year

Every 3 months for 1 year, then annually

Treatment Details

Interventions

• Durvalumab (Checkpoint Inhibitor)
• Nab-paclitaxel (Chemotherapy)
• Personalized Synthetic Long Peptide Vaccine (Cancer Vaccine)
• Tremelimumab (Checkpoint Inhibitor)

Trial Overview The study tests if adding a personalized vaccine to chemotherapy drugs nab-paclitaxel and carboplatin along with immunotherapy agents durvalumab and tremelimumab improves outcomes in patients with advanced triple-negative breast cancer. It compares the effects of this combination treatment both with and without the experimental neoantigen vaccine.

Participant Groups

Group I: Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel) Experimental Treatment 12 Interventions

See Detailed Description.

Group II: Arm II (durvalumab, nab-paclitaxel) Active Control 10 Interventions

See Detailed Description.

Durvalumab is already approved in Japan for the following indications:

Approved in Japan as Imfinzi for:

• Not specified in provided sources

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

Durvalumab is an FDA-approved monoclonal antibody that enhances T-cell responses against cancer by blocking the PD-L1 pathway, specifically for patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy.

The drug is currently being tested in phase III trials for various cancers, including lung and head and neck cancers, indicating its potential broad application in oncology beyond urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. Syed, YY.[2022]

In the safety run-in of the IMMUNOBIL PRODIGE 57 trial involving 20 patients, the combination of durvalumab and tremelimumab with paclitaxel resulted in a high rate of dose-limiting toxicities (50%), including serious anaphylactic reactions and other severe adverse events.

Due to the safety concerns raised by the combination therapy, the trial will proceed with only the durvalumab and tremelimumab combination, indicating that the addition of paclitaxel may not be safe for patients with advanced biliary tract carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triplet combination of durvalumab, tremelimumab, and paclitaxel in biliary tract carcinomas: Safety run-in results of the randomized IMMUNOBIL PRODIGE 57 phase II trial. Boilève, A., Hilmi, M., Gougis, P., et al.[2021]

Tremelimumab shows linear pharmacokinetics with a two-compartment model, and its clearance varies depending on whether it is used as monotherapy or in combination with durvalumab, with a 16% increase in clearance for monotherapy and a 17% decrease for combination therapy over one year.

Factors like higher body weight and lower albumin levels lead to higher drug clearance, but no dosage adjustments are needed, as a flat dose of 75 mg provides similar exposure to the weight-based dosing of 1 mg/kg in adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic modelling of tremelimumab in patients with advanced solid tumours and the impact of disease status on time-varying clearance. Hwang, M., Chia, YL., Zheng, Y., et al.[2023]

The combination of durvalumab and tremelimumab was studied in 19 articles involving 2052 patients with solid tumors, showing some benefits over traditional chemotherapy in certain tumor types.

However, this combination did not consistently outperform durvalumab alone, indicating that while it may have potential, further research with larger and better-designed studies is needed to clarify its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab Plus Tremelimumab in Solid Tumors: A Systematic Review. Arru, C., De Miglio, MR., Cossu, A., et al.[2023]

The combination of MEDI0680 and durvalumab was found to be safe and tolerable in patients with advanced clear-cell renal cell carcinoma, but it did not show improved efficacy compared to nivolumab alone, with objective response rates of 16.7% for the combination and 23.8% for nivolumab.

Both treatment groups had a median progression-free survival of 3.6 months, and a notable percentage of patients (23.8% in the combination group) discontinued treatment due to adverse events, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma. Voss, MH., Azad, AA., Hansen, AR., et al.[2023]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

Tremelimumab, a CTLA-4 blocking antibody, was approved in the USA in October 2022 for treating unresectable hepatocellular carcinoma (uHCC) in combination with durvalumab, marking a significant advancement in cancer therapy.

In November 2022, tremelimumab was also approved for metastatic non-small cell lung cancer (mNSCLC) when combined with durvalumab and platinum-based chemotherapy, indicating its broad potential in treating various malignant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tremelimumab: First Approval. Keam, SJ.[2023]

ABI-007, a novel nanoparticle formulation of paclitaxel, demonstrated a significant overall response rate of 48% in treating metastatic breast cancer, with even higher rates of 64% for first-line therapy, indicating its efficacy in this patient population.

The treatment was well-tolerated, with no severe hypersensitivity reactions reported despite the absence of premedication, and typical toxicities associated with paclitaxel, such as neutropenia and sensory neuropathy, were observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. Ibrahim, NK., Samuels, B., Page, R., et al.[2022]

ABI-007, a solvent-free albumin-bound paclitaxel, showed significantly higher response rates (33% vs. 19%) and longer time to tumor progression (23.0 weeks vs. 16.9 weeks) compared to standard paclitaxel in a phase III study with 454 patients.

ABI-007 had a lower incidence of severe neutropenia (9% vs. 22%) and did not require premedication, indicating a better safety profile, although it was associated with a higher rate of manageable sensory neuropathy (10% vs. 2%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. Gradishar, WJ., Tjulandin, S., Davidson, N., et al.[2023]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. [2022]

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

Triplet combination of durvalumab, tremelimumab, and paclitaxel in biliary tract carcinomas: Safety run-in results of the randomized IMMUNOBIL PRODIGE 57 phase II trial. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic modelling of tremelimumab in patients with advanced solid tumours and the impact of disease status on time-varying clearance. [2023]

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

Durvalumab Plus Tremelimumab in Solid Tumors: A Systematic Review. [2023]

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

A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma. [2023]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. [2023]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Tremelimumab: First Approval. [2023]

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

Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. [2022]

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

Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. [2023]