Vaccine + Chemotherapy + Immunotherapy for Breast Cancer

Recruiting at 34 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: CNS disease, Autoimmune, Infection, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 13

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach to treating metastatic triple negative breast cancer. It combines standard chemotherapy with immunotherapy and a personalized vaccine to determine if this combination can more effectively fight cancer. The study includes two groups: one receives chemotherapy and immunotherapy, while the other also receives a personalized vaccine to enhance the immune system's ability to attack cancer cells. Individuals with a confirmed diagnosis of metastatic triple negative breast cancer, who have not received prior treatment for this stage and can provide a biopsy sample, might be suitable candidates. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to potentially groundbreaking cancer treatment advancements.

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.

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

Previous studies have generally found the combination of nab-paclitaxel and durvalumab to be well-tolerated. Some patients experienced side effects like tiredness and nausea, common with many cancer treatments. Research shows that adding a personalized neoantigen vaccine to this treatment has not caused any unexpected safety issues, though the vaccine's safety remains under careful study.

Patients who received nab-paclitaxel with durvalumab reported similar side effects, such as fatigue and low blood cell counts, typical with chemotherapy and immunotherapy. The combination of these treatments with another immunotherapy drug, tremelimumab, is also under testing, and its safety is still under review.

Overall, while side effects occur, many patients have found the treatment combinations manageable. Prospective participants should discuss potential side effects with their healthcare team to ensure the treatment is suitable for them. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for breast cancer because they combine innovative approaches that could enhance the effectiveness of current therapies. Unlike traditional treatments like surgery, radiation, or standard chemotherapy, this approach pairs durvalumab and tremelimumab, which are immunotherapies designed to boost the body's immune response against cancer cells, with nab-paclitaxel, a chemotherapy drug that targets cancer cell growth. The addition of a neoantigen vaccine in one arm aims to train the immune system specifically against the unique features of a patient’s tumor, potentially increasing the precision and effectiveness of the treatment. This combination of therapies not only attacks the cancer through multiple pathways but also holds the promise of more personalized and robust treatment options.

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

Research has shown that combining nab-paclitaxel and durvalumab may help treat triple-negative breast cancer. Nab-paclitaxel stops cancer cells from growing and spreading, while durvalumab, an immunotherapy drug, helps the immune system fight cancer. In this trial, some participants will receive nab-paclitaxel and durvalumab. Others will receive these drugs along with a personalized neoantigen vaccine, which early results suggest could enhance the immune system's ability to target cancer cells. Although more research is needed, these treatments are considered potentially effective for this challenging type of breast cancer. ^{1 5 6 7 8}

Who Is on the Research Team?

William E Gillanders

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab
• Nab-paclitaxel
• Personalized Synthetic Long Peptide Vaccine
• Tremelimumab

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.

How Is the Trial Designed?

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 European Union, United States, Japan for the following indications:

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)

Approved in United States as Imfinzi for:

• Extensive-stage small cell lung cancer (ES-SCLC)
• Limited-stage small cell lung cancer (LS-SCLC)
• Locally advanced or metastatic urothelial carcinoma

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

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. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02250326

NCT02250326 | Safety and Efficacy Study of Nab®- ... This is a Phase 2, open-label, multicenter study to assess the efficacy and safety of second/third-line treatment with nab-paclitaxel in combination with ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11604547/

Molecular adaptation to neoadjuvant immunotherapy in triple ... Durvalumab induces an activation of immune and stromal gene expression as well as a reduction of proliferation-related gene expression. Immune ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02489448

Study Details | NCT02489448 | Neoadjuvant MEDI4736 ... MEDI4736 concomitant with ddAC neoadjuvant chemotherapy will induce higher pathologic complete response (pCR) rate (>55%) in triple negative breast cancer.

4. cancer.osu.edu cancer.osu.edu/for-patients-and-caregivers/learn-about-cancers-and-treatments/innovation-at-the-james/clinical-trials/find-a-clinical-trial/randomized-phase-ii-clinical-trial-of

Randomized Phase II Clinical Trial of Nab-Paclitaxel + ... Randomized Phase II Clinical Trial of Nab-Paclitaxel + Durvalumab (MEDI4736) + Tremelimumab + Neoantigen Vaccine vs. Nab-Paclitaxel + Durvalumab (MEDI4736) ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7870853/

Neoadjuvant durvalumab plus weekly nab-paclitaxel and ... The goal of this Phase I/II trial is to assess the safety and efficacy of administering durvalumab concurrent with weekly nab-paclitaxel and ...

6. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT02250326/

Clinical Trial: NCT02250326 This is a Phase 2, open-label, multicenter study to assess the efficacy and safety of second/third-line treatment with nab-paclitaxel in combination with the ...

7. moffitt.org moffitt.org/clinical-trials-and-studies/clinical-trial-23250/

Clinical Trial 23250 Secondary Objective: The secondary objective is to evaluate the safety of nab-paclitaxel + Durvalumab (MEDI4736) + tremelimumab + neoantigen vaccine vs. nab- ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.572

Safety of MEDI4736 (anti-PD-L1 antibody) administered ... Safety of MEDI4736 (anti-PD-L1 antibody) administered concomitant with weekly nab-paclitaxel and dose dense doxorubicin/cyclophosphamide (ddAC) ...