Ipilimumab, Combination Chemotherapy, Immunotherapy, and Aldesleukin in Treating Patients With Stage III-IV Melanoma

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Basic Trial Information

PhaseTypeAgeTrial IDs
No phase specifiedTreatment18 and overMCC-17057
NCI-2012-02177, Bristol-Myers Squibb CA184-213, CA184-213, NCT01701674

Trial Description

Summary

This pilot clinical trial studies ipilimumab, combination chemotherapy, immunotherapy, and aldesleukin in treating patients with stage III-IV melanoma. Monoclonal antibodies, such as ipilimumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or tumor-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine phosphate, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Treating white blood cells collected from patients in the laboratory may help the lymphocytes kill more tumor cells when they are put back in the body. Aldesleukin may stimulate lymphocytes to kill melanoma cells. Giving ipilimumab, combination chemotherapy, white blood cells, and aldesleukin may work better in treating melanoma.

Further Study Information

PRIMARY OBJECTIVES:

I. To demonstrate that the addition of ipilimumab in patients undergoing adoptive cell transfer (ACT) is safe, with a 30% or less rate of ipilimumab dose-limiting toxicity.

II. To establish the feasibility of the combination treatment, as shown by the ability to deliver at least 50% of the expected doses of ipilimumab and successfully treat 60% or more of the patients with tumor infiltrating lymphocytes (TIL).

SECONDARY OBJECTIVES:

I. To determine the response rate associated with the treatment regimen.

II. To determine the progression-free survival associated with the treatment regimen.

OUTLINE:

Patients receive ipilimumab intravenously (IV) over 90 minutes on days -56, -35, 13, and 34; cyclophosphamide IV over 2 hours on day -7 and -6; and fludarabine phosphate IV over 30 minutes on days -5 to -1. Patients undergo T cell infusion on day 0. Beginning 12-16 hours after T cell infusion, patients receive aldesleukin IV over 15 minutes every 8-16 hours for up to 15 doses on days 1-5.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2 years, and annually thereafter.

Eligibility Criteria

Inclusion Criteria:

Patients must have a positive screening Epstein Barr virus (EBV) antibody titre on screening test as this is required to protect against EBV infection during the time of lymphodepletion

Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 - 1; ECOG performance status of 0-1 will be inferred if the patient’s level of energy is >= 50% of baseline

Patients may have been previously treated for metastatic disease, or may have not had prior systemic treatment; patients with a V600 BRAF mutated tumor may have previously received a prior BRAF inhibitor

Hemoglobin of 8 gm/dL or more

Residual measurable disease after resection of target lesion(s) for TIL growth

Creatinine of less than or equal to 1.7 gm/dL

Total granulocytes of 1000 per mcL or more

Platelets of 100,000 per mcL or more

Patients with antibiotic allergies per se are not excluded; although the production of TIL for adoptive transfer includes antibiotics, extensive washing after harvest will minimize systemic exposure to antibiotics

At screening, patients with =< 3 untreated central nervous system (CNS) metastases may be included provided none of the untreated lesions are > 1 cm in greatest dimension, and there is no peri-tumoral edema present on brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT] if MRI is contraindicated)

At screening, patients may be included if the largest lesion is > 1 cm or > 3 in number, and there is no evidence of progressive CNS disease on brain imaging at least 90 days after treatment with surgery and/or radiation therapy

White blood cells (WBC) of 3000 per mcL

Women of childbearing potential (defined as having a menstrual cycle within the past 12 months and not having had a surgical procedure to accomplish sterilization) must have a negative serum pregnancy test within seven days of screening

Total bilirubin less than or equal to 2.0 mg/dL, except in patients with Gilbert’s syndrome who must have a total bilirubin less than 3.0 mg/dL

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of less than 3 X institutional upper limit of normal

No evidence of ongoing cardiac dysrhythmia >= grade 2 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], version [v]4.0)

Tumor may have a v-raf murine sarcoma viral oncogene homolog B (B-RAF) V600 mutation or be BRAF wild type, and patients must not have been previously treated with ipilimumab

Patients must have unresectable metastatic stage IV melanoma or stage III intransit or regional nodal disease, and in the opinion of the institutional Principal Investigator (PI) is an acceptable candidate for ACT with high dose IL-2 (aldesleukin)

At screening, patients with CNS metastases treated with either surgical resection and/or radiation therapy may be included; patients may be included if the largest lesion is =< 1 cm, and there is no evidence of progressive CNS disease on brain imaging at least 28 days after treatment

All laboratory and imaging studies must be completed and satisfactory within 30 days of signing the consent document, with the exceptions of: negative serum pregnancy test for women of child-bearing potential which must be negative within 7 days of screening, human leukocyte antigen (HLA)-typing which will not be repeated if performed previously, and pulmonary function tests (PFTs)/cardiac stress tests whose results are valid for 6 months if performed previously

Exclusion Criteria:

Patients with > 3 untreated CNS metastases or evidence of peri-tumoral edema will be excluded

Patients unable to comprehend and give informed consent are excluded

Patients with treated CNS metastases > 1 cm or > 3 in number will be excluded if there is evidence of progressive CNS disease on brain imaging at least 90 days after treatment with surgery and/or radiation therapy

Patients testing positive for human immunodeficiency virus (HIV) titre, hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody, human T-lymphotropic virus (HTLV) I or II antibody, or both rapid plasma reagin (RPR) and fluorescent treponemal antibody (FTA) positive are excluded

Patients who are pregnant or nursing are excluded

Patients needing chronic, immunosuppressive systemic steroids are excluded

Patients with =< 3 untreated CNS metastases but with at least one lesion > 1 cm or peri-tumoral edema will be excluded

Patients with active systemic infections requiring intravenous antibiotics, coagulation disorders or other major medical illness of the cardiovascular, respiratory or immune system, which in the opinion of the PI or treating co-investigator is not acceptable risk for ACT, are excluded

Patients with a history of autoimmune disease that require immunosuppressive medications at the time of screening are excluded

Presence of a significant psychiatric disease, which in the opinion of the principal investigator or his designee, would prevent adequate informed consent or render immunotherapy unsafe or contraindicated

Patients who have received ipilimumab in the past are excluded

Male patients with female partners of childbearing potential who do not agree to use two Food and Drug Administration (FDA)-accepted forms of contraception during sexual intercourse with women of child-bearing potential from the start of ipilimumab and up to at least 6 months after ACT are excluded

Female patients of childbearing potential who do not agree to use two FDA forms of contraception during sexual intercourse from the start of ipilimumab and up to at least 6 months after ACT are excluded

Patients with invasive malignancy other than melanoma at the time of enrollment and within 2 years prior to the first TIL administration are excluded, except for adequately treated (with curative intent) basal or squamous cell carcinoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer or other cancers from which the patient has been disease-free for at least 2 years

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

Moffitt Cancer Center

  • National Cancer Institute
Amod Ashok Sarnaik, Principal Investigator

Trial Sites

U.S.A.

Florida
Tampa

Moffitt Cancer Center

Amod Ashok Sarnaik
Ph: 813-745-8581
Email: amod.sarnaik@moffitt.org

Amod Ashok Sarnaik
Principal Investigator

See All Trial Sites

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01701674

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.