NK Cell Therapy + Temozolomide for Melanoma with Brain Metastasis

Overseen By The Ohio State University Comprehensive Cancer Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Kari Kendra

Disqualifiers: Active infection, Hepatic disease, Renal disease, others

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

Compensation: Varies

Number of Visits: 9

Duration: 12 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for individuals with stage IV melanoma that has spread to the brain. It combines Natural Killer Cell Therapy, a type of immune cell therapy that fights cancer, with temozolomide, a drug that slows cancer cell growth. The goal is to determine the optimal dose and assess whether this combination can effectively shrink tumors. This trial may suit those with melanoma that has spread to the brain and shows noticeable tumor growth. Participants should not have received recent cancer treatments and should not require radiation therapy. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the chance to be among the first to receive this novel therapy.

Will I have to stop taking my current medications?

The trial requires that you stop any anticancer treatments at least 4 weeks before joining. If you're taking steroids for brain swelling, you need to be on a stable dose, and higher doses must be approved by the study's principal investigator.

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

In a previous study, most patients tolerated temozolomide well. Only 3% of participants stopped treatment due to side effects, which mainly affected blood cell counts. This suggests that most people manage the drug reasonably well.

Researchers continue to study Natural Killer (NK) cell therapy. Since the trial is in its early stages, complete safety information is not yet available. However, NK cells can find and destroy cancer cells, making them a promising option for cancer treatment.

These treatments are being tested together to determine their effectiveness in treating melanoma that has spread to the brain. While past studies show temozolomide is generally well-tolerated, ongoing research is still exploring the safety of NK cell therapy. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for melanoma with brain metastasis, which often involve surgery, radiation, and traditional chemotherapy, the combination of NK Cell Therapy and Temozolomide offers a novel approach. Natural Killer (NK) Cell Therapy leverages the body's own immune system by using specially engineered cells to target and destroy cancer cells, potentially enhancing precision and reducing side effects compared to conventional methods. Temozolomide complements this by being an oral chemotherapy that can cross the blood-brain barrier, which is crucial for treating brain metastases. Researchers are excited because this dual approach could improve targeting of cancer cells in the brain while minimizing harm to healthy tissue.

What evidence suggests that NK cell therapy and temozolomide could be effective for melanoma with brain metastasis?

Research shows that Natural Killer (NK) cells assist the immune system by locating and destroying cancer cells. This trial will administer a combination of NK cell therapy and the drug temozolomide to participants to evaluate their ability to shrink tumors in stage IV melanoma that has spread to the brain. Temozolomide can slow or stop the growth of cancer cells and has shown some effectiveness in treating cancer that has metastasized to the brain. Studies suggest that combining NK cell therapy with temozolomide might enhance treatment effectiveness for melanoma that has reached the brain. This trial tests whether this combination can improve outcomes for patients with this challenging condition. ^{1 2 3 6 7}

Who Is on the Research Team?

Kari L. Kendra

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with stage IV melanoma that has spread to the brain. Participants must have finished any cancer treatments at least 4 weeks prior, have certain normal organ function tests, and no severe mental status changes or other serious medical conditions. Women of childbearing age and men who can father a child must use effective contraception.

Inclusion Criteria

I am not a candidate for precise, high-dose radiation therapy.

I have at least one brain tumor larger than 10 mm that is growing.

My melanoma is confirmed and has spread to other parts of my body.

Exclusion Criteria

Pregnant women, women who are likely to become pregnant or are breastfeeding

I do not have any severe illnesses like active infections or liver/kidney diseases.

I am mentally capable and have no major obstacles that would prevent me from following the study's requirements.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive UD TGFbetai NK cells intravenously over 30 minutes on day 1 and temozolomide orally daily on days 1-5. Treatment with UD TGFbetai NK cells repeats every 28 days for up to 3 cycles.

12 weeks

3 cycles of treatment, each lasting 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion every 6 months for up to 5 years.

5 years

Follow-up visits every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Natural Killer Cell Therapy
• Temozolomide

Trial Overview

The trial is testing the safety and effectiveness of UD TGFbetai NK cell therapy combined with temozolomide in shrinking brain tumors caused by melanoma. It's exploring the best dose of these therapies in patients whose cancer has advanced despite previous treatments.

How Is the Trial Designed?

Group I: Treatment (UD TGFbetai NK cells, temozolomide) Experimental Treatment 2 Interventions

Patients receive UD TGFbetai NK cells IV over 30 minutes on day 1 and temozolomide PO daily on days 1-5. Treatment with UD TGFbetai NK cells repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Cycles of temozolomide repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

Kari Kendra

Lead Sponsor

Trials

3

Recruited

50+

Published Research Related to This Trial

In a study of 39 patients with CNS metastatic melanoma, the combination of temozolomide, thalidomide, and whole brain radiation therapy resulted in a low response rate of only 7.6% for CNS tumors, indicating limited efficacy of this treatment regimen.

The treatment was associated with significant side effects, including serious complications like deep venous thrombosis and pulmonary embolism, leading to a high rate of hospital admissions (45% of patients), suggesting that alternative therapies may be more suitable for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide, thalidomide, and whole brain radiation therapy for patients with brain metastasis from metastatic melanoma: a phase II Cytokine Working Group study. Atkins, MB., Sosman, JA., Agarwala, S., et al.[2018]

In a phase II study involving 65 patients with advanced metastatic melanoma, the combination of temozolomide and docetaxel resulted in a 27% objective response rate, with a median response duration of 9.5 months, indicating significant efficacy.

The treatment was particularly promising for patients with brain metastases, where 38% showed a partial response, and it was well tolerated, although myelosuppression was noted as the primary side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with docetaxel in patients with advanced melanoma: a phase II study of the Hellenic Cooperative Oncology Group. Bafaloukos, D., Gogas, H., Georgoulias, V., et al.[2018]

The TMZ-resistant glioma cell line SF188/TR showed a 6-fold resistance to temozolomide and cross-resistance to various other anticancer agents, indicating a significant challenge in treating resistant tumors.

Increased activity of the enzyme alkylguanine alkyltransferase (AGT) was identified as a primary mechanism of resistance to TMZ, while changes in the balance of pro-apoptotic and anti-apoptotic proteins contributed to broader cross-resistance to other drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. Ma, J., Murphy, M., O'Dwyer, PJ., et al.[2022]

Temozolomide, an oral chemotherapy drug, was found to be well tolerated in patients with brain metastases from metastatic melanoma, with only 3% of patients discontinuing treatment due to adverse effects.

In a study of 151 patients, temozolomide showed some efficacy, with 7% of previously untreated patients achieving an objective response and 29% having stable disease, although the median overall survival was 3.5 months for untreated patients and 2.2 months for those previously treated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. Agarwala, SS., Kirkwood, JM., Gore, M., et al.[2018]

In a phase II study involving 30 patients with brain metastases from non-small cell lung cancer (NSCLC), temozolomide (TMZ) was found to be an active and safe treatment option, with 10% of patients achieving an objective response, including two complete remissions.

No severe (grade 3 or 4) toxicities were reported, and all treatment-related adverse events were mild to moderate, indicating that TMZ can be administered without significant safety concerns in this heavily pre-treated patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral temozolomide in heavily pre-treated brain metastases from non-small cell lung cancer: phase II study. Giorgio, CG., Giuffrida, D., Pappalardo, A., et al.[2018]

Temozolomide is a chemotherapeutic agent that effectively crosses the blood-brain barrier and has shown a good safety profile in treating brain metastases from solid tumors, with clinical activity observed in heavily pretreated patients.

In a randomized phase II trial, temozolomide combined with radiation therapy resulted in a significantly higher objective response rate (96% vs. 67%) compared to radiation alone, particularly benefiting patients with newly diagnosed brain and lung metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide for treating brain metastases. Abrey, LE., Christodoulou, C.[2019]

Temozolomide (TMZ) and irradiation (IR) significantly increase the expression of NKG2D ligands (NKG2DL) in glioblastoma cells, enhancing their recognition by the immune system, which could improve treatment efficacy.

The survival benefits of TMZ and IR in glioblastoma depend on an intact NKG2D immune pathway, suggesting that combining NKG2D-targeted immunotherapies with these conventional treatments could be a promising strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NKG2D-Dependent Antitumor Effects of Chemotherapy and Radiotherapy against Glioblastoma. Weiss, T., Schneider, H., Silginer, M., et al.[2022]

Temozolomide (TMZ) not only improves survival in glioblastoma patients but also slows glioma cell growth and inhibits their ability to invade surrounding tissues by reducing fascin-1 expression.

TMZ enhances the expression of gBK and HLA-A2, making glioma cells more recognizable and vulnerable to cytolytic T lymphocytes (CTLs), thereby improving the immune response against the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide induces the expression of the glioma Big Potassium (gBK) ion channel, while inhibiting fascin-1 expression: possible targets for glioma therapy. Hoa, NT., Ge, L., Martini, F., et al.[2018]

In a study of 26 patients with brain metastases from malignant melanoma, those treated with whole brain irradiation (WBRT) plus temozolomide (TMZ) had a median survival of 6 months, compared to just 1 month for those receiving WBRT alone.

The addition of TMZ to WBRT significantly improved long-term survival outcomes, indicating that this combination therapy may be more effective for patients with melanoma brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Temozolomide in patients with melanoma brain metastases treated with whole brain irradiation]. Conill, C., Fernández-Ibiza, J., Malvehy, J., et al.[2019]

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