PRIMARY OBJECTIVE:
I. To determine the maximum tolerated dose (MTD) of adoptively transferred SLC45A2-specific
cytotoxic T-lymphocytes (CTL) for the treatment of patients with metastatic uveal melanoma.
SECONDARY OBJECTIVES:
I. To establish the anti-tumor efficacy as measured by immune-related response criteria
(irRC) and duration of response in metastatic uveal melanoma patients receiving autologous
CD8+ T cells against SLC45A2.
II. To assess the safety and tolerability of adoptively transferred SLC45A2-specific CTL in
combination with immune checkpoint blockade in metastatic uveal melanoma patients.
III. To quantify in vivo numeric and functional persistence of transferred CTL, and
development of antigen spreading in metastatic uveal melanoma patients.
IV. To assess overall survival and progression-free survival in metastatic uveal melanoma
patients.
OUTLINE: This is a dose escalation study of autologous CD8+ SLC45A2-specific T lymphocytes.
PREPARATIVE REGIMEN: Patients receive cyclophosphamide intravenously (IV) over 30-60 minutes
on day -2.
T-CELL INFUSION: Patients receive autologous CD8+ SLC45A2-specific T lymphocytes via hepatic
arterial infusion via central catheter over 60 minutes on day 0. Within 6 hours of T-cell
infusion, patients also receive aldesleukin twice daily (BID) subcutaneously (SC) for 14 days
in the absence of disease progression or unacceptable toxicity.
POST T-CELL INFUSION: Patients receive 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 at days 84 and 168, and then
every 3 months for up to 5 years.
Inclusion Criteria:
- PHERESIS (TURNSTILE 1): Histopathologic documentation of melanoma concurrent with the
diagnosis of metastatic disease or high-risk primary uveal melanoma defined as a
recurrence score of > 50% in 5 years. A diagnosis of uveal melanoma can be made
clinically without primary tissue evaluation, based on history and records. A prior
history of brachytherapy to the eye is sufficient clinical support for a diagnosis of
uveal melanoma.
- PHERESIS (TURNSTILE 1): Hematocrit (HCT) >= 24% or hemoglobin (HB) >= 8 g/dL.
- PHERESIS (TURNSTILE 1): Platelets > 50,000.
- PHERESIS (TURNSTILE 1): Expression of human leukocyte antigen (HLA)-A:0201 or
HLA-A:2402.
- PHERESIS (TURNSTILE 1): Eastern Cooperative Oncology Group (ECOG)/ Zubrod performance
status of 0-1.
- PHERESIS (TURNSTILE 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 completion of the study. 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.
- PHERESIS (TURNSTILE 1): Male patients must be willing and able to use an acceptable
method of birth control, during and for at least 3 months after completion of the
study, if their sexual partners are WOCBP.
- PHERESIS (TURNSTILE 1): Willing and able to give informed consent.
- PHERESIS (TURNSTILE 1): Toxicity related to prior therapy must either have returned to
=< grade 1, baseline, or been deemed irreversible. Certain non-serious exceptions
include alopecia, hypothyroidism, neuropathy, nausea, adrenocortical deficiency
requiring physiologic replacement dose of steroids, and other conditions noted and
approved by the principal investigator (PI).
- T CELL INFUSION (INCLUDES CYCLOPHOSPHAMIDE, T CELL, ANTI-CTLA4 INFUSIONS AND SC IL-2)
(TURNSTILE 2): ECOG/Zubrod performance status of 0-1 (evaluate at least 1 week before
T cell infusion).
- T CELL INFUSION (INCLUDES CYCLOPHOSPHAMIDE, T CELL, ANTI-CTLA4 INFUSIONS AND SC IL-2)
(TURNSTILE 2): Bi-dimensionally measurable disease by palpation on clinical exam, or
radiographic imaging per irRC (evaluate at least 1 week before T cell infusion).
- T CELL INFUSION (INCLUDES CYCLOPHOSPHAMIDE, T CELL, ANTI-CTLA4 INFUSIONS AND SC IL-2)
(TURNSTILE 2): At least 4 weeks must have elapsed since the last chemotherapy,
targeted therapy, immunotherapy, radiotherapy, liver-directed therapy, 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
(evaluate at least 1 week before T cell infusion).
- T CELL INFUSION (INCLUDES CYCLOPHOSPHAMIDE, T CELL, ANTI-CTLA4 INFUSIONS AND SC IL-2)
(TURNSTILE 2): For the ipilimumab cohort only: Toxicity related to prior therapy must
either have returned to =< grade 1, baseline, or been deemed irreversible. Certain
non-serious exceptions include alopecia, hypothyroidism, neuropathy, nausea,
adrenocortical deficiency requiring physiologic replacement dose of steroids, and
other conditions noted and approved by the PI (evaluate at least 1 week before T cell
infusion).
- T CELL INFUSION (INCLUDES CYCLOPHOSPHAMIDE, T CELL, ANTI-CTLA4 INFUSIONS AND SC IL-2)
(TURNSTILE 2): Patients must have liver metastasis (evaluate at least 1 week before T
cell infusion).
- T CELL INFUSION (INCLUDES CYCLOPHOSPHAMIDE, T CELL, ANTI-CTLA4 INFUSIONS AND SC IL-2)
(TURNSTILE 2): Persons of reproductive potential must agree to use and utilize an
adequate method of contraception throughout treatment and for at least 3 months after
completion of study (evaluate at least 1 week before T cell infusion).
- T CELL INFUSION (INCLUDES CYCLOPHOSPHAMIDE, T CELL, ANTI-CTLA4 INFUSIONS AND SC IL-2)
(TURNSTILE 2): Willing and able to give informed consent (evaluate at least 1 week
before T cell infusion).
Exclusion Criteria:
- PHERESIS: Secondary malignancy is allowed providing it does not require concurrent
therapy.
- PHERESIS: 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 pheresis.
- PHERESIS: Significant cardiovascular abnormalities as defined by any one of the
following:
- Congestive heart failure
- Clinically significant hypotension
- Symptoms of coronary artery disease (angina, dyspnea)
- Presence of cardiac arrhythmias on electrocardiogram (EKG) requiring drug therapy
- PHERESIS: 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. Acceptable exclusions include: Hashimoto's thyroiditis, type 1 diabetes
mellitus, and other localized or inactive conditions with approval of the PI.
- PHERESIS: 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.
- PHERESIS: Positive screening tests for human immunodeficiency virus (HIV), hepatitis B
virus (Hep B), and hepatitis C virus (Hep C). If positive results are not indicative
of true active or chronic infection, the patient can be treated.
- PHERESIS: Participation in any other immunotherapy treatment, that in the opinion of
the principal investigator would be unsafe to receive further checkpoint blockade
immunotherapy
- White blood cell (WBC) =< 2000/uL (prior to cyclophosphamide and T cell infusions).
- Hct =< 24% or Hb =< 8 g/dL (prior to cyclophosphamide and T cell infusions).
- Absolute neutrophil count (ANC) =< 1000 (prior to cyclophosphamide and T cell
infusions).
- Platelets =< 50,000 (prior to cyclophosphamide and T cell infusions).
- Creatinine >= 3.0 x upper limit of normal (ULN) (prior to cyclophosphamide and T cell
infusions).
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >= 5 x ULN (since all
patients will have liver metastasis) (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.
- 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 diffusing capacity
of the lung for carbon monoxide (DLCO) (corrected [corr] for hemoglobin [Hgb]) < 50%
will be excluded.
- Steroids (at prednisone equivalent doses > 10 mg) are not permitted 3 days prior to T
cell infusion and concurrently during therapy. Exceptions include use of systemic
prednisone equivalent doses =< 10 mg/ day, topical steroids or physiologic replacement
dose of steroids for adrenocortical deficiency.
- 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. Oncology supportive treatments such as growth factors, bone modifying
agents, pain or nausea management are allowed.
