CD8+ Antigen-Specific T Cells, Cyclophosphamide, Aldesleukin, and Ipilimumab in Treating Patients With Metastatic Melanoma

Phase II Study of Cellular Adoptive Immunotherapy Using Autologous CD8+ Antigen-Specific T Cells and Anti-CTLA4 for Patients With Metastatic Melanoma

This phase II trial studies the side effects and how well white blood cells taken from person's own (autologous) cluster of differentiation (CD)8+ antigen-specific T cells, cyclophosphamide, aldesleukin, and ipilimumab work in treating patients with melanoma that has spread to another place in the body. Autologous CD8+ antigen-specific T cells are white blood cells that are designed in the laboratory to find melanoma cells and may kill them. Biological therapies, such as aldesleukin, use substances made from living organisms that may stimulate the immune system in different ways and stop tumor cells from growing. Immunotherapy with monoclonal antibodies, such as ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, 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 autologous CD8+ antigen-specific T cells with cyclophosphamide, aldesleukin, and ipilimumab may be an effective treatment for patients with metastatic melanoma.

Study Overview

• Status: Completed
• Conditions: Metastatic Melanoma; Stage IV Cutaneous Melanoma AJCC v6 and v7
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Biological: Ipilimumab; Drug: Cyclophosphamide; Biological: Aldesleukin; Biological: Autologous CD8+ Melanoma Specific T Cells

Detailed Description

PRIMARY OBJECTIVE:

I. Evaluate the safety and efficacy of adoptively transferred cytotoxic T-lymphocytes (CTL) targeting melanoma tumors combined with anti-CTLA4.

SECONDARY OBJECTIVES:

I. Evaluate the influence of anti-CTLA4 on the duration of in vivo persistence and anti-tumor efficacy achieved following adoptive transfer of antigen-specific CTL.

II. Evaluate the influence of anti-CTLA4 on the induction of T cells to non-targeted tumor-associated antigens (antigen-spreading) following adoptive transfer antigen-specific CTL, and the correlation of these responses with clinical outcome.

OUTLINE:

Beginning 48 to 72 hours prior to T cell infusion, patients receive cyclophosphamide intravenously (IV) over 30-60 minutes. Patients then receive autologous CD8+ melanoma-specific T cells IV over 30-60 minutes on day 0, aldesleukin subcutaneously (SC) twice daily (BID) on days 0-13 and ipilimumab IV over 90 minutes on days 1, 22, 43, and 64 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 5 years.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ELIGIBILITY FOR ENROLLMENT
• Histopathologic documentation of melanoma concurrent with the diagnosis of metastatic disease
• Expression of human leukocyte antigen (HLA)-A2
• Eastern Cooperative Oncology Group (ECOG)/Zubrod performance status of '0-1' at screening visit
• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized; suggested precautions should be used to minimize the risk of pregnancy for at least 1 month before start of therapy, and while women are on study for up to 3 months after T cell infusion, and at least 8 weeks after the study drug is stopped; WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal
• Men must be willing and able to use an acceptable method of birth control, for at least 3 months after completion of the study, if their sexual partners are WOCBP
• Willing and able to give informed consent
• Adequate venous access - consider peripherally inserted central catheter (PICC) or central line
• Evaluation of v-raf murine sarcoma viral oncogene homolog B (BRAF)V600 mutation status
• Measurable tumor (by Response Evaluation Criteria in Solid Tumors [RECIST] criteria)
• Melan-A (MART) 1 or solute carrier family 45, member 2 (SLC45A2) (+) staining results; (if patients have not had staining test in the past, the test will be run after patient consent is obtained, but before enrollment)
• ELIGIBILITY FOR TREATMENT (INCLUDES CYCLOPHOSPHAMIDE, T CELL, ANTI-CTLA4 INFUSIONS AND SC IL-2)
• ECOG/Zubrod performance status of '0-1'
• At least 4 weeks must have elapsed since the last chemotherapy, radiotherapy or major surgery; at least 6 weeks for nitrosoureas, mitomycin C and liposomal doxorubicin; if started before T-cell administration, ipilimumab infusions must be least 21 days apart
• Toxicity related to prior therapy must either have returned to =< grade 1, baseline, or been deemed irreversible
• Persons of reproductive potential must agree to use and utilize an adequate method of contraception throughout treatment and for at least 8 weeks after study drug is stopped
• Willing and able to give informed consent.

Exclusion Criteria:

• EXCLUSION FOR ENROLLMENT
• Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix
• Pregnant women, nursing mothers, men or women of reproductive ability who are unwilling to use effective contraception; women of childbearing potential with a positive pregnancy test within 3 days prior to entry
• Active and untreated central nervous system (CNS) metastasis (including metastasis identified during screening magnetic resonance imaging [MRI] or contrast computed tomography [CT])
• No signs or symptoms of CNS metastases (mets) within the last 30 days (from enrollment evaluation)
• No single lesion larger than 1 cm
• No more than 5 lesions
• Autoimmune disease: patients with a history of inflammatory bowel disease are excluded from this study, as are patients with a history of autoimmune disease (e.g. systemic lupus erythematosus, vasculitis, infiltrating lung disease) whose possible progression during treatment would be considered by the investigator to be unacceptable
• Any underlying medical or psychiatric condition, which in the opinion of the investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea
• Positive screening tests for human immunodeficiency virus (HIV), hepatitis B (hep B), and hepatitis C (hep C) (referencing blood draw at leukapheresis screening); if positive results are not indicative of true active or chronic infection, the patient can be treated
• White blood cells (WBC) =< 1000/uL
• Hematocrit (Hct) =< 24% or hemoglobin (Hb) =< 8 g/dL
• Absolute neutrophil count (ANC) =< 500
• Platelets =< 50,000
• Creatinine >= 3.0 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >= 2.5 x ULN
• Bilirubin >= 3 x ULN
• Steroids are not permitted 3 days prior to T cell infusion and concurrently during therapy
• Any non-oncology vaccine therapy used for the prevention of infectious disease within 1 month before or after any ipilimumab dose
• Patients may not be on any other treatments for their cancer aside from those included in the protocol; patients may not undergo another form of treatment concurrently with this study
• EXCLUSION CRITERIA FOR TREATMENT
• WBC =< 1000/uL (prior to cyclophosphamide and T cell infusions)
• Hct =< 24% or hemoglobin =< 8 g/dL (prior to cyclophosphamide and T cell infusions)
• ANC =< 500 (prior to cyclophosphamide and T cell infusions)
• Platelets =< 50,000 (prior to cyclophosphamide and T cell infusions)
• Creatinine >= 3.0 x ULN (prior to cyclophosphamide and T cell infusions)
• AST/ALT >= 2.5 x ULN (prior to cyclophosphamide and T cell infusions)
• Bilirubin >= 3 x ULN (prior to cyclophosphamide and T cell infusions)
• Pregnant women, nursing mothers, men or women of reproductive ability who are unwilling to use effective contraception; women of childbearing potential with a positive pregnancy test within 3 days prior to entry.
• Steroids are not permitted 3 days prior to T cell infusion and concurrently during therapy.
• Any non-oncology vaccine therapy used for the prevention of infectious disease within 1 month before or after any ipilimumab dose.
• Patients may not be on any other treatments for their cancer aside from those included in the protocol. Patients may not undergo another form of treatment concurrently with this study.

• Active and untreated central nervous system (CNS) metastasis (including metastasis identified during screening MRI or contrast CT):

  • No signs or symptoms of CNS mets within the last 30 days (from enrollment evaluation).
  • No single lesion larger than 1cm
  • No more than 5 lesions

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (T cells, chemo, aldesleukin, ipilimumab); Beginning 48 to 72 hours prior to T cell infusion, patients receive cyclophosphamide IV over 30-60 minutes. Patients then receive autologous CD8+ melanoma-specific T cells IV over 30-60 minutes on day 0, aldesleukin SC BID on days 0-13 and ipilimumab IV over 90 minutes on days 1, 22, 43, and 64 in the absence of disease progression or unacceptable toxicity.

Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Ipilimumab; Given IV; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; Ipilimumab Biosimilar CS1002; MDX-010; MDX-CTLA4; Yervoy; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Biological: Aldesleukin; Given SC; Other Names: Proleukin; 125-L-Serine-2-133-interleukin 2; r-serHuIL-2; Recombinant Human IL-2; Recombinant Human Interleukin-2; Biological: Autologous CD8+ Melanoma Specific T Cells; Given IV; Other Names: Autologous Melanoma Specific Cytotoxic T Lymphocytes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response	Monitored using the Bayesian approach of Thall, Simon, Estey and the extension by Thall and Sung.	Up to 12 weeks
Incidence of toxicity	Monitored using the Bayesian approach of Thall, Simon, Estey and the extension by Thall and Sung.	Up to 5 years

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Adi Diab, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• M D Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2015
• Primary Completion (Actual): April 12, 2024
• Study Completion (Actual): April 12, 2024

Study Registration Dates

• First Submitted: January 2, 2014
• First Submitted That Met QC Criteria: January 3, 2014
• First Posted (Estimated): January 6, 2014

Study Record Updates

• Last Update Posted (Estimated): April 15, 2024
• Last Update Submitted That Met QC Criteria: April 12, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Aldesleukin; Cyclophosphamide; Ipilimumab; Interleukin-2
• Other Study ID Numbers: 2012-1055 (Other Identifier: M D Anderson Cancer Center); P50CA159981 (U.S. NIH Grant/Contract); NCI-2014-01040 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No