Gemcitabine + NK Cells +/- Naxitamab for Breast Cancer

Overseen By Amanda Kabetso

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Margaret Gatti-Mays

Must not be taking: Systemic steroids

Disqualifiers: Active brain metastases, Autoimmune disease, Uncontrolled illness, others

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

Compensation: Varies

Number of Visits: 3

Duration: Up to 1 year

42 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safety and effectiveness of a combination of treatments for individuals with a specific type of breast cancer that has metastasized. The treatments include gemcitabine, a chemotherapy drug; TGFBi NK cells, immune cells designed to target cancer; and naxitamab, a protein that aids the immune system in recognizing and attacking cancer cells. Suitable candidates for this trial have HER2 negative breast cancer that expresses the GD2 protein, have previously tried at least one other treatment, and have experienced cancer spread. 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 novel combination.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received chemotherapy, investigational agents, or radiation within 3 weeks prior to enrollment, and certain medications like systemic steroids must be discontinued more than 2 weeks before starting the trial.

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

Research shows that gemcitabine, a chemotherapy drug used in cancer treatment for some time, works by stopping cancer cells from making DNA, which they need to grow. Most patients handle gemcitabine well, but it can cause side effects like nausea, low blood counts, and tiredness.

Studies suggest that TGFBi NK cells might help the immune system better find and destroy cancer cells. Safety data for these cells indicate they are generally well-tolerated, with no major safety issues reported in earlier research.

The FDA has already approved naxitamab for other uses, meaning it has passed safety tests for those conditions. It is an antibody that helps the immune system target cancer cells. In past studies, naxitamab has been linked to side effects like pain at the infusion site or allergic reactions, but these are usually manageable.

Overall, earlier research has shown that the treatments in this study are generally safe, but like all treatments, they may have side effects. It is important to weigh the benefits and risks and discuss any concerns with healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine novel approaches with existing chemotherapy to potentially enhance effectiveness against breast cancer. Unlike standard treatments, which often rely solely on chemotherapy or targeted therapies, these investigational treatments incorporate TGF-beta-imprinted NK cells, which are a type of immune cell engineered to better attack cancer cells. Some combinations also include naxitamab, a monoclonal antibody that targets GD2, a molecule found on some cancer cells, adding another layer of precision in targeting the tumor. These unique combinations aim to boost the body's natural immune response to fight cancer more effectively, offering hope for improved outcomes compared to current treatments.

What evidence suggests that this trial's treatments could be effective for metastatic GD2 expressing, HER2 negative breast cancer?

This trial will evaluate different combinations of treatments for metastatic GD2-expressing, HER2-negative breast cancer. Research shows that gemcitabine, a chemotherapy drug, can prevent cancer cells from making DNA, potentially helping to kill them. Participants in this trial may receive gemcitabine alone or with other treatments. TGFBi NK cells, specially designed immune cells, can find and destroy tumor cells by identifying abnormal proteins on them. Evidence from previous patients suggests that these NK cells attack cancer cells more effectively when TGF-beta, a protein that usually weakens them, is controlled. Some participants will receive TGFBi NK cells as part of their treatment. Naxitamab, a type of antibody, targets a protein called GD2 on tumor cells, aiding the immune system in attacking them. In this trial, some participants will receive a combination of gemcitabine, TGFBi NK cells, and naxitamab, which might enhance the ability to kill more tumor cells. ^{1 2 3 4 6}

Who Is on the Research Team?

Margaret E Gatti-Mays, MD MPH

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with metastatic, GD2 expressing, HER2 negative breast cancer who've had at least one prior treatment. They must understand the study and consent to it, have good organ function and performance status, resolved any previous therapy side effects to a mild level, and agree to use effective contraception. Excluded are those with certain allergies, recent other cancers or treatments, brain metastases, severe heart conditions or infections.

Inclusion Criteria

You have enough infection-fighting white blood cells in your body.

You must have at least 100,000 platelets per microliter of blood.

My breast cancer is HER2 negative, possibly GD2 positive, and I have a sample of the tumor.

Exclusion Criteria

Any other condition, which would, in the opinion of the principal investigator the subject is a poor candidate for the clinical trial or would jeopardize the subject or the integrity of the data obtained

I haven't had chemotherapy, investigational drugs, or radiation in the last 3 weeks.

I do not have cancer that has spread to my brain or the membranes around my brain and spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive gemcitabine and TGFBi NK cells with or without naxitamab. Treatment cycles repeat every 28 days for up to 1 year.

Up to 1 year

Multiple visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

1 year

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Gemcitabine
• Naxitamab
• Universal Donor Expanded TGF-beta-imprinted NK Cells

Trial Overview The trial tests gemcitabine (a chemotherapy drug) combined with lab-grown NK cells that boost immune response against cancer cells. It also examines the addition of naxitamab—a monoclonal antibody targeting specific proteins on tumor cells—to this combination in patients whose tumors express a particular protein called GD2.

How Is the Trial Designed?

Group I: Arm IV (Gemcitabine, naxitamab, TGFBi x2) Experimental Treatment 6 Interventions

Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle followed by naxitamab IV over 30-60 minutes on days 1, 4, and 8 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 and 18 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.

Group II: Arm III (Gemcitabine naxitamab, TGFBi) Experimental Treatment 6 Interventions

Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle followed by naxitamab IV over 30-60 minutes on days 1, 4, and 8 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.

Group III: Arm II (Gemcitabine, TGFBi x2) Experimental Treatment 5 Interventions

Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 and 18 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.

Group IV: Arm I (Gemcitabine, TGFBi) Experimental Treatment 5 Interventions

Patients receive gemcitabine intravenously (IV) over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.

Gemcitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in United States as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Canada as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Japan as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Who Is Running the Clinical Trial?

Margaret Gatti-Mays

Lead Sponsor

Trials

1

Recruited

40+

Published Research Related to This Trial

A study involving 23 patients with disseminated carcinomas showed that combining cytokine-activated killer (CAK) cell infusion therapy with gemcitabine resulted in long-term stable disease, indicating potential effectiveness in treating metastatic cancers.

In vitro experiments revealed that gemcitabine treatment increased the expression of NKG2D ligands on cancer cells, enhancing the cytotoxic effect of CAK cells, suggesting a synergistic mechanism that improves treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NKG2D-directed cytokine-activated killer lymphocyte therapy combined with gemcitabine for patients with chemoresistant metastatic solid tumors. Morisaki, T., Hirano, T., Koya, N., et al.[2022]

In a study of 109 patients with advanced non-small cell lung cancer (NSCLC), combining pembrolizumab with allogeneic NK cell therapy resulted in significantly longer overall survival (15.5 months) compared to pembrolizumab alone (13.3 months).

Patients receiving multiple courses of NK cell therapy showed even greater survival benefits, with a median overall survival of 18.5 months, highlighting the potential of NK cell infusion to enhance the efficacy of anti-PD-1 treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus allogeneic NK cells in advanced non-small cell lung cancer patients. Lin, M., Luo, H., Liang, S., et al.[2021]

Immunomodulatory drugs (IMiDs) are effective in treating multiple myeloma and myelodysplastic syndrome, showing benefits such as antitumor and immunostimulating effects, particularly on natural killer (NK) cells.

While some cancer treatments can enhance the immune response against tumors, they may also impair NK cell function depending on the dosage and duration of treatment, highlighting the need for careful management in therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel immune modulators used in hematology: impact on NK cells. Krieg, S., Ullrich, E.[2021]

Tumor-infiltrating NK (TI-NK) cells are strong independent biomarkers for predicting pathologic complete response (pCR) to neoadjuvant anti-HER2 antibody treatment in HER2-positive breast cancer, as shown in two patient cohorts totaling 113 participants.

The presence of TI-NK cells is also associated with longer disease-free survival (DFS), and tumor HLA class I expression can help stratify patients by relapse risk, providing additional prognostic information.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NK Cell Infiltrates and HLA Class I Expression in Primary HER2+ Breast Cancer Predict and Uncouple Pathological Response and Disease-free Survival. Muntasell, A., Rojo, F., Servitja, S., et al.[2021]

The study developed allogeneic CAR-NK cells that target pancreatic ductal adenocarcinoma (PDAC) by enhancing their ability to induce cancer cell death through specific receptors (FRα and DR4), showing improved tumor-selective apoptosis.

This approach suggests that using engineered NK cells could provide a safer and more effective treatment option for solid tumors like PDAC, potentially benefiting a larger number of patients with tailored therapies based on their tumor profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationally designed redirection of natural killer cells anchoring a cytotoxic ligand for pancreatic cancer treatment. Lee, YE., Ju, A., Choi, HW., et al.[2021]

A pilot study demonstrated that reprogramming tumor-sensitized immune cells from breast cancer patients can enhance their ability to fight tumors, particularly against HER-2/neu, by expanding activated CD25+ NKT and NK cells.

The study suggests that using a combination of bryostatin 1, ionomycin, and specific interleukins (IL-2, IL-7, IL-15) can effectively overcome immune suppression caused by myeloid-derived suppressor cells (MDSCs), making this approach a promising strategy for adoptive cellular therapy in breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peripheral blood mononuclear cells of patients with breast cancer can be reprogrammed to enhance anti-HER-2/neu reactivity and overcome myeloid-derived suppressor cells. Payne, KK., Zoon, CK., Wan, W., et al.[2021]

NK-CAR-iPSC-NK cells, engineered with a specific CAR construct, show enhanced anti-tumor activity against ovarian cancer compared to traditional T-CAR-expressing NK cells and non-CAR NK cells, indicating their potential as a more effective immunotherapy.

In an ovarian cancer model, NK-CAR-iPSC-NK cells not only inhibited tumor growth and improved survival rates but also exhibited similar in vivo activity to T-CAR T cells while demonstrating lower toxicity, making them a promising 'off-the-shelf' option for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity. Li, Y., Hermanson, DL., Moriarity, BS., et al.[2019]

The combination of expanded natural killer (NK) cells with IgG1 antibodies in patients with advanced gastric or colorectal cancers was well tolerated, showing no severe adverse events during the trial involving 9 participants.

Preliminary results indicated that this therapy could induce anti-tumor activity, with 4 out of 6 evaluable patients achieving stable disease and some showing a decrease in tumor size, alongside enhanced immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical trial of adoptive transfer of expanded natural killer cells in combination with IgG1 antibody in patients with gastric or colorectal cancer. Ishikawa, T., Okayama, T., Sakamoto, N., et al.[2018]

The study developed a new method to create high-quality natural killer (NK) cells from induced pluripotent stem cells (iPSCs), which can be produced in large quantities and used as an 'off-the-shelf' immunotherapy option.

These iPSC-derived NK cells not only directly kill tumors but also enhance the effectiveness of existing checkpoint inhibitor therapies, like PD-1 blockade, by recruiting T cells and increasing inflammatory responses against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

iPSC-derived NK cells maintain high cytotoxicity and enhance in vivo tumor control in concert with T cells and anti-PD-1 therapy. Cichocki, F., Bjordahl, R., Gaidarova, S., et al.[2022]

In HER2-positive breast cancer patients, combining taxanes like docetaxel with trastuzumab enhances the effectiveness of the treatment by increasing the activity of natural killer (NK) cells, which are crucial for antibody-dependent cellular cytotoxicity (ADCC).

The study found that taxane treatment up-regulates NKG2D receptor expression on NK cells, leading to a 15-40% increase in trastuzumab-mediated ADCC, particularly benefiting patients with lower baseline immune activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Taxanes enhance trastuzumab-mediated ADCC on tumor cells through NKG2D-mediated NK cell recognition. Di Modica, M., Sfondrini, L., Regondi, V., et al.[2022]

Tafasitamab, a monoclonal antibody targeting CD19, effectively induces antitumor activity in non-Hodgkin's lymphoma through antibody-dependent cellular cytotoxicity (ADCC), particularly when combined with immune effector cells like γδ T and MG4101 NK cells.

In preclinical models, combining tafasitamab with allogeneic MG4101 NK cells significantly improved survival rates, showing a 1.7- to 4.1-fold increase in lifespan compared to monotherapy, suggesting that enhancing immune cell presence could boost the efficacy of tafasitamab in treating lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tafasitamab mediates killing of B-cell non-Hodgkin's lymphoma in combination with γδ T cell or allogeneic NK cell therapy. Her, JH., Pretscher, D., Patra-Kneuer, M., et al.[2022]

Infusing expanded autologous NK cells alongside trastuzumab in patients with HER2-positive tumors was well tolerated, with no maximum tolerated dose reached, indicating a favorable safety profile for this combination therapy.

While no objective responses were observed, 6 out of 19 patients experienced stable disease for at least 6 months, suggesting potential antitumor activity, particularly in a patient with a specific CD16 variant who had a partial response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers. Lee, SC., Shimasaki, N., Lim, JSJ., et al.[2021]

The soluble MIC (sMIC) produced by tumors reprograms Natural Killer (NK) cells to secrete pro-tumorigenic cytokines, reducing their ability to kill cancer cells, which contributes to poorer outcomes in cancer patients.

Targeting sMIC with antibodies can restore NK cell function and enhance their anti-tumor effects, suggesting that co-targeting sMIC could improve the effectiveness of NK cell-based cancer immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-derived NKG2D ligand sMIC reprograms NK cells to an inflammatory phenotype through CBM signalosome activation. Dhar, P., Basher, F., Ji, Z., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06026657

Study Details | NCT06026657 | Gemcitabine and Ex Vivo ... Giving gemcitabine and TGFBi NK cells with or without naxitamab may kill more tumor cells in patients with metastatic GD2 expressing, HER2 negative breast ...

2. aacrjournals.org aacrjournals.org/clincancerres/article/31/12_Supplement/P3-12-29/752941/Abstract-P3-12-29-Phase-1b-2-Study-of-Naxitamab?searchresult=1

Abstract P3-12-29: Phase 1b/2 Study of Naxitamab (Danyelza ... We designed a clinical trial to evaluate the stepwise addition of (1) gemcitabine, (2) an off-the-shelf, TGFβ imprinted, IL-21 expanded ...

3. trialx.com trialx.com/clinical-trials/listings/226808/gemcitabine-and-ex-vivo-expanded-allogenic-universal-donor-tgfi-natural-killer-nk-cells-with-or-without-naxitamab-danyelza-for-the-treatment-of-patients-with-metastatic-gd2-expressing-her2-negative-breast-cancer/?&geo_lat=40.1146&geo_lng=-82.9105&radius=10&place=Westerville&user_country=United%20States

Gemcitabine and Ex Vivo Expanded Allogenic Universal Donor ... To evaluate the safety of gemcitabine plus transforming growth factor beta imprinted natural killer (TGFBi NKs) +/- naxitamab in metastatic 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/phase-ibii-study-of-naxitamab-danyelza

Phase Ib/II Study of Naxitamab (Danyelza), Gemcitabine ... Phase Ib/II Study of Naxitamab (Danyelza), Gemcitabine and Ex Vivo Expanded Allogenic Universal Donor, TGFBetai Natural Killer (NK) cells in Advanced ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06026657?term=AREA%5BConditionSearch%5D(%22Breast%20Disease%22)%20AND%20AREA%5BInterventionSearch%5D(%22Antineoplastic%20Agents,%20Immunological%22)&rank=5

Gemcitabine and Ex Vivo Expanded Allogenic Universal ... Available: Expanded access is currently available for this investigational treatment, and patients who are not participants in the clinical study may be able to ...

6. researchgate.net researchgate.net/publication/392687145_Abstract_P3-12-29_Phase_1b2_Study_of_Naxitamab_Danyelza_Gemcitabine_and_Ex_Vivo_Expanded_Allogenic_Universal_Donor_TGFbi_Natural_Killer_NK_cells_in_Advanced_GD2-expressing_Breast_Cancers_DiG_NKs

Abstract P3-12-29: Phase 1b/2 Study of Naxitamab ... We designed a clinical trial to evaluate the stepwise addition of (1) gemcitabine, (2) an off-the-shelf, TGFβ imprinted, IL-21 expanded ...