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

1230 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment Adoptive Cell Transfer + Immunotherapy for Melanoma?

Research shows that combining cyclophosphamide and interleukin-2 (IL-2) can lead to tumor shrinkage in some melanoma patients, with a 26% response rate in one study. Additionally, IL-2 has been shown to activate T-cells, which can attack melanoma cells, and cyclophosphamide may help by reducing the suppressive effects of certain immune cells. ^{1 2 3 4 5}

Is the combination of adoptive cell transfer and immunotherapy for melanoma safe for humans?

The combination of adoptive cell transfer and immunotherapy, including drugs like cyclophosphamide, fludarabine, and interleukin-2, has been studied in humans and is generally considered safe, though it can cause temporary side effects like low white blood cell counts. These side effects usually resolve on their own, and the treatment has been safely administered in various studies. ^{1 2 6 7 8}

How is the treatment 'Adoptive Cell Transfer + Immunotherapy for Melanoma' different from other treatments for melanoma?

This treatment is unique because it combines adoptive cell transfer (using a patient's own tumor-fighting T-cells) with immunotherapy, following a nonmyeloablative chemotherapy regimen to prepare the body. This approach aims to enhance the body's immune response against melanoma, offering potential for durable responses, unlike standard treatments that often have limited long-term effectiveness. ^{1 9 10 11 12}

What is the purpose of this trial?

Objectives: The primary objective will be to determine whether patients receiving the combination of dendritic cells and high dose IL-2 (Cohort A) have sustained persistence of infused T cells compared to patients treated with T cells and high dose IL-2 alone. Secondary endpoints will include evaluations for tumor response and studies to determine whether dendritic cells enhance the infused T cells in anti-tumor activity and their ability to migrate to the tumor site. In addition, we will evaluate the characteristics of the infused T cells that correspond with effectiveness in vivo. Additionally, secondary objectives will include correlation of clinical parameters with survival (overall survival and progression-free survival) for all cohorts. COHORT C In a separate cohort (Cohort C) the primary endpoint will be the overall response rate of TIL treatment for patients who have not achieved PR or CR or have progressive disease from treatment of the BRAF inhibitor alone. COHORT D The primary objective of Cohort D is to confirm the safety of adoptively transferred, TIL into the CSF. The secondary objective is the evaluation of clinical imaging and CSF response. Correlative objectives will assess if the intrathecally-infused T cells persist in the CSF, assess circulating tumor cells in the CSF, and assess various cytokine and other analyses,as feasible. COHORT E The primary objective of Cohort E is to determine the overall response rate of TIL treatment with cells grown by the TIL 3.0 pre-REP (Turnstile 1) phase of cellular growth.

Research Team

Rodabe N. Amaria

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

References

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

A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. [2022]

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

Phase I study of low-dose interleukin-2, fludarabine, and cyclophosphamide for previously untreated indolent lymphoma and chronic lymphocytic leukemia. [2013]

3. Germany pubmed.ncbi.nlm.nih.gov

[Chemo-/immunotherapy in advanced malignant melanoma: carboplatin and DTIC or cisplatin, dtic, bcnu and tamoxifen followed by immunotherapy with interleukin 2 and interferon alpha-2a]. [2018]

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

Pulse infusion interleukin-2 with famotidine and cyclophosphamide has activity in previously treated metastatic melanoma. [2013]

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

Chemotherapy in combination with biomodulation: a 5-year experience with cyclophosphamide and interleukin-2. [2018]

6. United States 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. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

Immunomodulatory effects of cyclophosphamide and implementations for vaccine design. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Continuous interleukin-2 infusion combined with cyclophosphamide- based combination chemotherapy in the treatment of hemato-oncological malignancies. Results of a phase I-II study. [2018]

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

Adoptive cell transfer for patients with metastatic melanoma: the potential and promise of cancer immunotherapy. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis. [2023]

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

Immunotherapy for advanced melanoma. [2021]

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

Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. [2022]