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

Phase 1/Phase 2
18 Years
Open (Enrolling)
Recurrent Melanoma, Stage IV Melanoma

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Trial Information

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


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

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


I. 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.


Patients receive cyclophosphamide intravenously (IV) on day -2, therapeutic allogeneic
cytotoxic T lymphocytes IV over 30-60 minutes on day 0, low-dose 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 periodically.

Inclusion Criteria:

- Histopathologic documentation of melanoma concurrent with the diagnosis of metastatic

- Expression of human leukocyte antigen (HLA)-A2

- Eastern Cooperative Oncology Group (ECOG)/Zubrod performance status of 0-1

- 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
or 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

- Bi-dimensionally measurable disease by palpation on clinical exam, or radiographic
imaging (X-ray, computed tomography [CT] scan)

- 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

- 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

Exclusion Criteria:

- Patients with active infections or oral temperature > 38.2 C within 72 hours prior to
planned leukapheresis; the procedure may be deferred

- Patients with hematocrit (Hct) < 30%, white blood cells (WBC) < 2500/uL and platelets
< 50,000 immediately prior to leukapheresis; the procedure may be deferred

- 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

- White blood cell count (WBC) < 2000/uL

- Hematocrit (Hct) < 24% or hemoglobin (Hb) < 8 g/dL

- Absolute neutrophile count (ANC) < 1000

- Platelets < 50,000

- Creatinine > 3.0 x upper limit normal (ULN)

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2.5 x ULN

- Bilirubin > 3 x ULN

- 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

- Clinically significant pulmonary dysfunction, as determined by medical history and
physical exam; patients so identified will undergo pulmonary functions testing and
those with forced expiratory volume in one second (FEV1) < 2.0 L or diffusion
capacity of carbon monoxide (DLco) (corr for Hgb) < 50% will be excluded

- Significant cardiovascular abnormalities as defined by any one of the following:

- Congestive heart failure

- Clinically significant hypotension

- Symptoms of coronary artery disease

- Presence of cardiac arrhythmias on electrocardiogram (EKG) requiring drug

- Ejection fraction < 50 % (echocardiogram or multi gated acquisition [MUGA] scan)

- Active and untreated central nervous system (CNS) metastasis (including metastasis
identified during screening magnetic resonance imaging [MRI] or contrast CT)

- 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

- 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

- Positive screening tests for human immunodeficiency virus (HIV), hepatitis (Hep) B,
and Hep C; if positive results are not indicative of true active or chronic
infection, the patient can be treated

- Steroids are not permitted 3 days prior to T cell infusion and concurrently during

- No prisoners or children will be enrolled on this study

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Numeric frequency and functional persistence of transferred CTL

Outcome Description:

Determined using peptide major histocompatibility complex (MHC)-tetramer analysis or specific CDR3 T-cell-receptor (TCR) quantitative polymerase chain reaction (PCR) of transferred CTL if necessary. The function of transferred CTL will be determined by intracellular cytokine staining of tetramer+ CD8+ cells following in vitro stimulation.

Outcome Time Frame:

Up to 6 months post-infusion

Safety Issue:


Principal Investigator

Aude Chapuis

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium


United States: Food and Drug Administration

Study ID:




Start Date:

February 2009

Completion Date:

Related Keywords:

  • Recurrent Melanoma
  • Stage IV Melanoma
  • Melanoma



Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109