Adoptive Cell Transfer + Immunotherapy for Melanoma

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: B-RAF inhibitors

Must not be taking: Steroids, Cytotoxic chemotherapy

Disqualifiers: Pregnancy, Infections, Immunodeficiency, 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

Compensation: Varies

Number of Visits: 6

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatments for melanoma, a type of skin cancer, by testing the effectiveness of different combinations of cell therapies and immunotherapies. The researchers aim to determine if adding dendritic cells (a type of immune cell) to T-cell therapy can enhance the body's ability to fight cancer and how these cells migrate to the tumor site. Participants should have melanoma that has spread to other areas, with measurable disease, and may have tried other treatments without success. The trial also examines the safety and response of these treatments in the body, particularly for those with specific conditions like leptomeningeal disease (cancer spreading to the membranes covering the brain and spinal cord). As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people, offering participants a chance to contribute to potentially groundbreaking advancements in melanoma treatment.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on B-RAF or MEK targeted therapy, you must stop it at least 7 days before starting the trial. Also, if you are on steroid therapy, you must stop it 30 days before starting the trial, unless it's a physiologic dose.

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

Research has shown that the treatments in this trial have promising safety records from past studies. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has proven safe and manageable for patients with advanced melanoma, a serious type of skin cancer. These cells assist the immune system in fighting cancer. Notably, the FDA recently approved TILs for treating metastatic melanoma.

High-dose interleukin-2 (IL-2), used in this trial, has been part of melanoma treatment since 1998. Although it can cause serious side effects, it is considered safe for carefully selected patients and has demonstrated lasting benefits in some cases.

The dendritic cell vaccine has also shown safety and good tolerance in patients with late-stage melanoma. Dendritic cells, a type of immune cell, help boost the body's fight against cancer.

Overall, while these treatments can have side effects, research has found them to be generally well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for melanoma because they use a cutting-edge approach called adoptive cell transfer, which involves boosting the body's own immune system by infusing specially prepared T-cells. Unlike traditional treatments such as surgery, chemotherapy, or targeted therapy, these experimental treatments combine chemotherapy, Interleukin-2 (IL-2), and T-cells, sometimes with a dendritic cell vaccine, to enhance the immune response against cancer cells. This approach targets melanoma more directly and has the potential to improve treatment effectiveness by utilizing the body's natural defenses to fight cancer. By employing a combination of therapies, these treatments might offer a more personalized and potentially more effective option for patients with advanced melanoma.

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

This trial will evaluate various treatment combinations for melanoma, including adoptive cell transfer (ACT) using tumor-infiltrating lymphocytes (TILs), high-dose interleukin-2 (IL-2), and dendritic cell vaccines. Research has shown that ACT with TILs can lead to significant improvements in melanoma patients, with more than 50% experiencing noticeable improvements and about 22% achieving complete cancer disappearance. In this trial, some participants will receive TILs and IL-2, while others will also receive dendritic cell vaccines. High-dose IL-2 alone has shown promise, with about 10% of patients achieving long-lasting cancer-free results and a 5-year survival rate of 15% for those with advanced melanoma. Additionally, dendritic cell vaccines, which help the immune system recognize and attack cancer cells, have been linked to better long-term survival. Medications like cyclophosphamide and fludarabine, used in some trial arms, enhance the effectiveness of TILs by strengthening the immune response against cancer. Overall, these treatments aim to improve outcomes for melanoma patients by enhancing the body's natural ability to fight cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Rodabe N. Amaria

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients over 12 years old with metastatic melanoma, including those who have not responded well to B-RAF inhibitors or have brain lesions. Participants must be in good health overall, with proper kidney function and no severe illnesses affecting the heart, lungs, or immune system. Pregnant women and individuals with rapid disease progression or significant psychiatric conditions are excluded.

Inclusion Criteria

I had a heart stress test within the last 6 months.

I may have small brain lesions (≤1cm) or larger treated ones not considered active.

I can care for myself and am up more than 50% of my waking hours.

Exclusion Criteria

Any active systemic infections requiring intravenous antibiotics, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, such as abnormal stress test and/or abnormal PFT. PI or his designee shall make the final determination regarding appropriateness of enrollment

My doctor has noted a quick worsening of my nerve-related symptoms.

You have a serious mental health condition that could affect your ability to understand the study or make immunotherapy treatment unsafe for you.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy and T-cell Infusion

Participants receive chemotherapy followed by T-cell infusion and IL-2 administration

4 weeks

Multiple visits for chemotherapy and T-cell infusion

Vaccine Administration

Participants receive dendritic cell vaccine after T-cell infusion

3 weeks

Vaccine administration on Day 0 and Day 21

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-12 weeks

Clinical evaluation and CT scan at 6-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Dendritic Cell Immunization
• Fludarabine
• Interleukin-2
• T-Cells

Trial Overview The study tests whether adding dendritic cell immunization to T-cell therapy improves the persistence of infused T cells in fighting melanoma compared to T-cell therapy alone. It also examines if this combination enhances anti-tumor activity and migration of T cells to tumor sites across different cohorts.

How Is the Trial Designed?

Group I: Group E: Chemotherapy + IL-2 plus T-Cells + Vaccine Experimental Treatment 6 Interventions

Chemotherapy and IL-2 plus T-cells and the vaccine of dendritic cells received by vein (IV) about 4 hours after T-cells and again on Day 21 (+/- 7 days). Cyclophosphamide 60 mg/kg/d IV over 2 hours Days -7 and -6 (with Mesna) and Fludarabine 25 mg/m\^2 IV daily Days -5 to -1 before T cell infusion. On Day 0, up to 1.5 x 10\^11 T cells IV infusion over 30-60 minutes. Interleukin-2 12-16 hours after T cell infusion at standard dose of 720,000 IU/kg as intravenous bolus over 15 minute period every 8-16 hours for up to 15 doses on Days 1-5 and 22-26.

Group II: Group D: Leptomeningeal Disease Experimental Treatment 2 Interventions

T-cells: 5.0x109 TIL administered on Day 1 and 10x109 TIL on Day 15. IL-2: 1.2 MIU of IL- 2 on Days 2, 4, 9, 11, 16 and 18 as tolerated. After this period, patient receives twice weekly IL-2 that will be gradually changed to weekly IL-2. After 4-6 weeks, patients switched to IL-2.

Group III: Group C: Prior Treatment with BRAF Inhibitor Experimental Treatment 6 Interventions

Chemotherapy and IL-2 plus T-cells and the vaccine of dendritic cells received by vein (IV) about 4 hours after T-cells and again on Day 21 (+/- 7 days). Cyclophosphamide 60 mg/kg/d IV over 2 hours Days -7 and -6 (with Mesna) and Fludarabine 25 mg/m\^2 IV daily Days -5 to -1 before T cell infusion. On Day 0, up to 1.5 x 10\^11 T cells IV infusion over 30-60 minutes. Interleukin-2 12-16 hours after T cell infusion at standard dose of 720,000 IU/kg as intravenous bolus over 15 minute period every 8-16 hours for up to 15 doses on Days 1-5 and 22-26.

Group IV: Group B: Chemotherapy + IL-2 plus T-Cells + Vaccine Experimental Treatment 6 Interventions

Chemotherapy and IL-2 plus T-cells and the vaccine of dendritic cells received by vein (IV) about 4 hours after T-cells and again on Day 21 (+/- 7 days). Cyclophosphamide 60 mg/kg/d IV over 2 hours Days -7 and -6 (with Mesna) and Fludarabine 25 mg/m\^2 IV daily Days -5 to -1 before T cell infusion. On Day 0, up to 1.5 x 10\^11 T cells IV infusion over 30-60 minutes. Interleukin-2 12-16 hours after T cell infusion at standard dose of 720,000 IU/kg as intravenous bolus over 15 minute period every 8-16 hours for up to 15 doses on Days 1-5 and 22-26.

Group V: Group A: Chemotherapy + IL-2 plus T-cells Experimental Treatment 5 Interventions

Cyclophosphamide 60 mg/kg/d by vein (IV) over 2 hours Days -7 and -6 (with Mesna) and Fludarabine 25 mg/m\^2 IV daily Days -5 to -1 before T cell infusion. On Day 0, up to 1.5 x 10\^11 T cells IV infusion over 30-60 minutes. Interleukin-2 12-16 hours after T cell infusion at standard dose of 720,000 IU/kg as intravenous bolus over 15 minute period every 8-16 hours for up to 15 doses on Days 1-5 and 22-26. Group A has been closed to new patient entry as of January 14, 2016.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

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+

Key Biologics, LLC

Industry Sponsor

Trials

2

Recruited

1,300+

Prometheus Laboratories

Industry Sponsor

Trials

27

Recruited

4,800+

Adelson Medical Research

Collaborator

Trials

1

Recruited

1,200+

Published Research Related to This Trial

In a study of 89 hematopoietic cell transplantation recipients, higher levels of the active metabolite of cyclophosphamide (PM AUC0-8 hr) were linked to worse nonrelapse mortality and overall survival, indicating that careful monitoring of this metabolite is crucial for patient outcomes.

Patients with low levels of the active metabolite of fludarabine (F-ara-ADay-4) and low PM AUC0-8 hr had significantly lower nonrelapse mortality, suggesting that optimizing drug exposure could improve safety and efficacy in reduced-intensity conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy. Takahashi, T., Scheibner, A., Cao, Q., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3138719/

Randomized Multicenter Trial of the Effects of Melanoma ... This multicenter randomized trial was designed to test whether melanoma-associated helper peptides augment CD8 + T-cell responses to a melanoma vaccine.

2. sciencedirect.com sciencedirect.com/science/article/pii/S266663672400784X

Review The Clinical TIL Experience in Melanoma At 6 years of follow-up, 43% of responders were alive with no documented melanoma progression. Treated patients had a median overall survival (OS) of 13.9 ...

3. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%28197611%2938%3A5%3C1922%3A%3AAID-CNCR2820380509%3E3.0.CO%3B2-2

Cyclophosphamide, vincristine and procarbazine in the ... This study has demonstrated that a combina- tion of cyclophosphamide and vincristine with or without procarbazine given in three weekly cycles results in ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2628959/

Inhibitors of melanogenesis increase toxicity ... Pigmented melanoma cells were significantly less sensitive to cyclophosphamide and to killing action of IL-2-activated peripheral blood lymphocytes.

5. ascopubs.org ascopubs.org/doi/10.1200/jco.2014.32.15_suppl.e20025

Phase II study of low-dose cyclophosphamide and ... Results: Six pts completed all 4 cycles of induction, and 4 pts received at least 2- 3 cycles. At Wk 24, 4 pts had stable disease, and 6 pts had progression of ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4514042/

Novel dendritic cell-based vaccination in late stage ... Overall, data from the above trials in late stage melanoma patients showed the safety of a dentritoma vaccine itself as well as increased survival when ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2352304225004027

Dendritic cell vaccines: Current research progress ... This review examines the advancements in cancer immunotherapies, particularly focusing on dendritic cell (DC)-based vaccines developed ...

8. translational-medicine.biomedcentral.com translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06403-8

Adjuvant dendritic cell-based immunotherapy in melanoma Our findings support the safety and tolerability of DC vaccination as an adjuvant treatment for melanoma, demonstrating significant immune modulation.

9. clinicaltrials.gov clinicaltrials.gov/study/NCT03092453

Study Details | NCT03092453 | Dendritic Cell Vaccination ... This is a single arm open label trial that will assess the safety and tolerability of mature dendritic cell (mDC3/8) vaccine (primer and booster) in subjects ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4902323/

Immune-related Adverse Events of Dendritic Cell ... In conclusion, DC vaccination is safe and tolerable in both stage III and IV melanoma patients and naturally circulating DCs induce less immune ...