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

Trial Summary

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.

What data supports the effectiveness of the treatment NK Cells + Cyclophosphamide + Etoposide for Solid Tumors?

Research shows that cyclophosphamide can enhance the activity of natural killer (NK) cells, which are immune cells that can attack cancer cells. Additionally, NK cells derived from umbilical cord blood have been effectively expanded and shown to target cancer cells, suggesting potential benefits in cancer treatment. ^{1 2 3 4 5}

Is the combination of NK Cells, Cyclophosphamide, and Etoposide generally safe for humans?

Research shows that high doses of cyclophosphamide and etoposide can be used safely in humans, although they may cause side effects like acute kidney problems. Etoposide has been used safely to treat complications in some patients, and cyclophosphamide has been used in cancer treatments with manageable side effects. ^{6 7 8 9 10}

What makes the NK Cells + Cyclophosphamide + Etoposide treatment unique for solid tumors?

This treatment is unique because it combines cord blood-derived natural killer (NK) cells with cyclophosphamide and etoposide, which enhances the NK cells' ability to attack cancer cells. Cyclophosphamide boosts the activity of NK cells, making them more effective in targeting tumors, while the use of cord blood-derived NK cells helps avoid complications like graft-versus-host disease. ^{1 2 3 4 11}

What is the purpose of this trial?

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) and how well they work when given together with cyclophosphamide and etoposide in treating children and young adults with solid tumors that have come back (relapsed) or that do not respond to treatment (refractory). NK cells, white blood cells important to the immune system, are donated/collected from cord blood collected at birth from healthy babies and grown in the lab. Drugs used in chemotherapy, such as cyclophosphamide and etoposide, 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. Giving NK cells together with cyclophosphamide and etoposide may work better in treating children and young adults with solid tumors.

Research Team

Demetrios Petropoulos

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 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]

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]

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]

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]

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]

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]

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]

References

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

Augmentation of human natural killer cell activity by cyclophosphamide in vitro. [2013]

2. United States 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. [2021]

3. Greece pubmed.ncbi.nlm.nih.gov

Augmentation of IL-2 activated natural killer cell adoptive immunotherapy with cyclophosphamide. [2013]

4. Netherlands 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. [2023]

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

NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: dynamics and clinical implications. [2021]

6. Japan 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]. [2013]

7. Japan 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. [2019]

8. China 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]. [2013]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Increase in peripheral blood megakaryocyte progenitors following cancer therapy with high-dose cyclophosphamide and hematopoietic growth factors. [2013]

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

A dose-escalation study of carboplatin/cyclophosphamide/etoposide along with autologous bone marrow or peripheral blood stem cell rescue. [2018]

11. China pubmed.ncbi.nlm.nih.gov

[Enhanced cytotoxicity against leukemia cells of natural Killer cells from cord blood after expansion in vitro]. [2013]