NK Cells + Cyclophosphamide + Etoposide for Solid Tumors

Overseen By Demetrios Petropoulos, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Corticosteroids

Disqualifiers: CNS tumors, Uncontrolled arrhythmias, others

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

Compensation: Varies

Number of Visits: 6

38 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for children and young adults with solid tumors that have returned or aren't responding to existing treatments. Researchers are testing the side effects and optimal dose of NK cells (a type of immune cell from donated cord blood) combined with two chemotherapy drugs, cyclophosphamide and etoposide, to determine if this mix can more effectively fight cancer. Suitable candidates have solid tumors that have relapsed or are resistant to treatment, with no other known effective therapies available. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on chronic corticosteroids and cannot stop them, you may not be eligible for the trial.

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

Research has shown that using special immune cells from cord blood, known as natural killer (NK) cells, is a promising approach. Various studies have tested these NK cells, and early results suggest they are generally safe for patients. No major safety issues have been reported, making them a potential option for treating certain cancers.

Cyclophosphamide and etoposide, well-known chemotherapy drugs, have treated different types of cancer for many years. They can cause side effects like nausea and hair loss, but these are usually manageable and expected with chemotherapy.

This trial explores new ways to treat difficult tumors by combining NK cells with cyclophosphamide and etoposide. The initial safety data for NK cells is reassuring, but like any treatment, monitoring for side effects remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using cord blood-derived expanded allogeneic Natural Killer (NK) cells for solid tumors because these cells have the unique ability to target and destroy cancer cells without harming normal cells. Unlike traditional chemotherapy, which often affects healthy tissue, NK cells offer a more precise approach by enhancing the body's natural immune response to cancer. Additionally, combining NK cells with cyclophosphamide and etoposide may improve the overall effectiveness of the treatment, potentially leading to better outcomes for patients. This innovative approach represents a promising shift from conventional treatments, which typically rely on broad-spectrum chemotherapies.

What evidence suggests that this trial's treatments could be effective for solid tumors?

Research has shown that using special immune cells from cord blood, known as natural killer (NK) cells, is safe and may aid in treating solid tumors. In past studies, children with advanced solid tumors responded well to these NK cells. NK cells, a type of white blood cell, help the body fight cancer. This trial will administer a combination of NK cells, Cyclophosphamide, and Etoposide to participants. Cyclophosphamide and Etoposide are chemotherapy drugs that stop cancer cells from growing and spreading. Combining NK cells with these drugs might enhance the treatment's effectiveness against tumors. Early studies suggest this combination could be a promising option for children and young adults whose tumors have returned or are not responding to other treatments. ^{2 4 6 7 8}

Who Is on the Research Team?

Demetrios Petropoulos

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for children and young adults with relapsed or refractory solid tumors. Participants must have a certain level of physical function, measurable disease, adequate kidney and liver function, controlled pulmonary symptoms, and no severe treatment-related toxicities. They should not be pregnant, dependent on steroids, or have primary brain tumors or uncontrolled infections.

Inclusion Criteria

If you are over 21 years old, you should have a type of solid tumor that is typically found in children, as determined by the study doctor.

You need to be able to perform daily activities without much help, like going to school or work.

There are documented signs of the disease that can be measured or evaluated.

Exclusion Criteria

Determined by study doctor that patient is unlikely to meet inclusion criteria after screening

You have a tumor in your brain or spinal cord.

You are dependent on corticosteroid medication and cannot stop using it.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy

Participants receive cyclophosphamide and etoposide intravenously once daily over 5 days

1 week

5 visits (in-person)

NK Cell Infusion

Participants receive cord blood-derived allogeneic NK cells intravenously on day 8

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Weekly visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Cord Blood-derived Expanded Allogeneic Natural Killer Cells
• Cyclophosphamide
• Etoposide

Trial Overview The trial tests the safety and effectiveness of donor NK cells from cord blood combined with chemotherapy drugs cyclophosphamide and etoposide in treating solid tumors that are resistant to standard treatments. It aims to find the best dose while assessing how well these therapies work together.

How Is the Trial Designed?

Group I: Treatment (cyclophosphamide, etoposide, NK cells) Experimental Treatment 3 Interventions

Patients receive cyclophosphamide IV QD over 30 minutes and etoposide IV QD over 60 minutes on days 1-5 in the absence of unacceptable toxicity. Patients then receive cord blood derived allogeneic NK cells IV on day 8.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Natural Killer (NK) cells from cord blood, when expanded in vitro for 21 days, showed significantly increased expression of activated receptors, enhancing their ability to kill leukemia cells compared to fresh NK cells.

The expanded NK cells demonstrated higher cytotoxicity against leukemia cell lines, indicating their potential effectiveness in cell therapy for tumors, while maintaining specificity for their target ligands.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Enhanced cytotoxicity against leukemia cells of natural Killer cells from cord blood after expansion in vitro]. Zhou, F., Han, WM., Jia, ZX., et al.[2013]

Cyclophosphamide (CY) significantly enhances the activity of natural killer (NK) cells, showing an increase in cytotoxicity by 154 to 333% in lymphocytes cultured with CY compared to those without it, based on a study involving lymphocytes from six normal volunteers.

In children with acute leukemia in remission, CY treatment enabled lymphocytes from 8 out of 15 patients to develop cytotoxicity against their own leukemia cells, indicating CY's potential to boost immune responses in cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Augmentation of human natural killer cell activity by cyclophosphamide in vitro. Sharma, B., Vaziri, ND.[2013]

A 56-year-old man with acute myeloid leukemia underwent reduced-intensity cord blood transplantation (RIC-CBT) after failing multiple chemotherapy regimens, and despite complications, he achieved complete remission after treatment.

The administration of low-dose etoposide was effective in resolving hemophagocytic syndrome (HPS), a serious complication that can hinder engraftment, suggesting it may be a safe and effective treatment option in similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Successful treatment with low-dose etoposide for hemophagocytic syndrome following reduced-intensity conditioning for cord blood transplantation in a patient with acute myelgenous leukemia]. Tokushige, J., Ueki, T., Sato, K., et al.[2013]

In a study of 16 patients with acute leukemia undergoing allogeneic bone marrow transplantation, 14 achieved complete and sustained engraftment using a preparatory regimen of fractionated total body irradiation and high-dose etoposide.

However, two patients experienced graft rejection, suggesting that etoposide may be less effective than cyclophosphamide in preventing graft rejection, indicating a potential risk when using etoposide as an immunosuppressive agent in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Graft rejection and recovery of host-derived hematopoiesis after allogeneic bone marrow transplantation: relation to conditioning with high dose etoposide and total body irradiation. Hara, M., Shinagawa, K., Omoto, E., et al.[2019]

In a study involving 20 patients who received a high-dose chemotherapy regimen, the maximum tolerated doses were established for cyclophosphamide, etoposide, and carboplatin, with acute renal failure identified as the main dose-limiting toxicity.

The treatment showed a promising overall response rate of 70% in patients with various solid and hematologic cancers, indicating its potential efficacy despite some risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A dose-escalation study of carboplatin/cyclophosphamide/etoposide along with autologous bone marrow or peripheral blood stem cell rescue. Shea, TC., Storniolo, AM., Mason, JR., et al.[2018]

In a study involving seven cancer patients undergoing high-dose cyclophosphamide (HD-CTX) treatment, there was a significant increase in megakaryocyte progenitors (BFU-Meg and CFU-Meg) in the recovery phase, indicating a robust response to chemotherapy and growth factors used.

The study found that the recovery-phase progenitors had faster duplication times and a higher ratio of CFU-Meg to BFU-Meg compared to steady-state values, which may explain the rapid recovery of platelets after treatment, enhancing our understanding of hematopoietic recovery post-chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increase in peripheral blood megakaryocyte progenitors following cancer therapy with high-dose cyclophosphamide and hematopoietic growth factors. Siena, S., Bregni, M., Bonsi, L., et al.[2013]

The study successfully developed a feeder-free expansion system that produces large quantities of highly purified and cytotoxic natural killer cells (NKCs) from cord blood, which could be used for cancer immunotherapy.

Expanded cord blood NKCs demonstrated significant cytotoxicity against glioblastoma cells, indicating their potential effectiveness in treating certain cancers, although their cytotoxicity decreased with longer expansion periods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An efficient feeder-free and chemically-defined expansion strategy for highly purified natural killer cells derived from human cord blood. Nakazawa, T., Maeoka, R., Morimoto, T., et al.[2023]

Combining cyclophosphamide with adoptively transferred IL-2 activated natural killer (A-NK) cells significantly enhances the therapeutic efficacy against pulmonary metastases in melanoma and lung cancer models, leading to greater reductions in both the size and number of metastatic colonies.

While A-NK cell therapy alone resulted in only a 30% reduction in metastases, the addition of cyclophosphamide consistently improved outcomes, indicating that this combination therapy may be a more effective treatment strategy for established pulmonary metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Augmentation of IL-2 activated natural killer cell adoptive immunotherapy with cyclophosphamide. Goldfarb, RH., Ohashi, M., Brunson, KW., et al.[2013]

The combination of etoposide (Vp-16) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) is a safe and effective method for mobilizing autologous peripheral blood stem cells (APBSC) in patients with malignant tumors, as shown in a study of 30 patients.

Both doses of Vp-16 (1000 mg/m² and 1500 mg/m²) demonstrated similar efficacy and side effects in mobilizing APBSC, indicating that the lower dose may be sufficient for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Mobilization of autologous peripheral blood stem cells with etoposide and recombinant human granulocyte colony stimulating factor in malignant tumor patients]. Shi, YK., He, XH., Han, XH., et al.[2013]

A new cytokine-based culture system allows for the efficient expansion of natural killer (NK) cells from umbilical cord blood, achieving over 15,000-fold expansion with nearly 100% purity, making it suitable for cancer immunotherapy.

The expanded NK cells effectively target and kill myeloid leukemia and melanoma cells, demonstrating their potential as a powerful treatment option for these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High log-scale expansion of functional human natural killer cells from umbilical cord blood CD34-positive cells for adoptive cancer immunotherapy. Spanholtz, J., Tordoir, M., Eissens, D., et al.[2021]

Posttransplant cyclophosphamide (PT-Cy) effectively reduces proliferating NK cells after haploidentical hematopoietic stem cell transplantation (HSCT), which helps prevent graft-versus-host disease (GVHD) by selectively eliminating alloreactive T cells and NK cells.

In a study of 99 patients, PT-Cy administration resulted in no significant difference in progression-free survival between patients with or without predicted NK alloreactivity, indicating that PT-Cy blunts NK cell alloreactivity and enhances the safety of unmanipulated grafts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: dynamics and clinical implications. Russo, A., Oliveira, G., Berglund, S., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04991870

NCT04991870 | Phase I CB-NK-TGF-ßR2-/NR3C1- in rGBM This phase I trial is to find out the best dose, possible benefits and/or side effects of engineered natural killer (NK) cells containing deleted TGF-betaR2 ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.2546

A phase 1 dose escalation trial of ex-vivo expanded ... Allogeneic ex-vivo expanded NK cells immunotherapy demonstrated favorable safety profile in patients with advanced pediatric solid tumors.

3. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/cord-blood-derived-expanded-allogeneic-natural-killer-cells?pn=1

Clinical Trials Using Cord Blood-derived Expanded ... Review the clinical trials studying cord blood-derived expanded allogeneic natural killer cells on this list and use the filters to refine the results by ...

4. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2020-0960.html

A Phase I clinical trial with a window-of-opportunity ... This phase I trial is to find out the best dose, possible benefits and/or side effects of engineered natural killer (NK) cells containing deleted TGF-betaR2 ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03420963

Study Details | NCT03420963 | Donor Natural Killer Cells ... This phase I trial studies the side effects and best dose of cord blood-derived expanded allogeneic natural killer cells (donor natural killer [NK] cells) ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04991870

NCT04991870 | Phase I CB-NK-TGF-ßR2-/NR3C1- in rGBM This phase I trial is to find out the best dose, possible benefits and/or side effects of engineered natural killer (NK) cells containing deleted TGF-betaR2 ...

7. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04991870/

Clinical Trial: NCT04991870 This phase I trial is to find out the best dose, possible benefits and/or side effects of engineered natural killer (NK) cells containing ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10348479/

Case Report: Cord blood-derived natural killer cells as new ... This clinical work suggests that CB-NK cell immunotherapy holds promise as a therapeutic approach for endometrial cancer.