| Eligibility |
Inclusion Criteria:
1. Willing and able to give written informed consent;
2. Accessible for treatment and follow-up;
3. Histologically confirmed malignant melanoma; primary melanoma of the skin, or unknown
primary site (patients with primary mucosa or uveal melanoma are not eligible).
4. Measurable melanoma, as per irRC criteria;
5. AJCC Stage III (unresectable) or Stage IV melanoma;
6. Patient must have demonstrated one of the following in response to treatment with at
least one prior regimen (non-experimental or experimental) with the exception of a
CD137 agonist or PD-1 or CTLA-4 inhibitor or agonist:
- relapse following an objective response of PR or CR; or
- failed to demonstrate an objective response of PR or CR based on an assessment
period of at least 12 weeks from prior regimen start; or
- inability to tolerate treatment due to toxicity;
7. Have a complete set of baseline (i.e., Screening) digital images of lesions and
radiographic images, including, but not limited to: brain, bone, chest, abdomen and
pelvis.
8. Required values for initial laboratory tests:
WBC > 2500/mm³ ANC > 1500/ mm³ Platelets > 75 x 103/uL Hemoglobin > 9 g/dL (may be
transfused) Creatinine < 2.0 x ULN AST/ALT < 2.5 x ULN for patients without liver
metastasis, < 5 times for liver metastases Bilirubin < 2.0 x ULN, (except patients
with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
9. No active or chronic infection with HIV, Hepatitis B, or Hepatitis C.
10. ECOG performance status of 0 or 1;
11. Life expectancy of > 16 weeks;
12. Men and women, >= 18 years of age. The following paragraphs are mandatory when the
protocol includes Women of Childbearing Potential.
13. Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 26 weeks after the
last dose of investigational product, in such a manner that the risk of pregnancy is
minimized. In general, the decision for appropriate methods to prevent pregnancy
should be determined by discussions between the investigator and the study subject.
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 post-menopausal. Post-menopause is defined as:
- Amenorrhea > 12 consecutive months without another cause, or
- For women with irregular menstrual periods and taking hormone replacement therapy
(HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL.
Women who are using oral contraceptives, other hormonal contraceptives (vaginal
products, skin patches, or implanted or injectable products), or mechanical products
such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to
prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg,
vasectomy) should be considered to be of childbearing potential.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L
or equivalent units of HCG) within 72 hours before the start of ipilimumab.
Men of fathering potential must be using an adequate method of contraception to avoid
conception throughout the study [and for up to 26 weeks after the last dose of
investigational product] in such a manner that the risk of pregnancy is minimized.
14. Adequate venous access allowing for a leukapheresis procedure.
Exclusion Criteria:
1. Evidence of brain metastases on brain imaging (i.e., MRI or contrast CT);
2. Primary ocular or mucosal melanoma;
3. Any other malignancy form 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 or carcinoma in situ of the cervix.
4. Autoimmune disease: Patients with a history of inflammatory bowel disease, including
ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients
with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive
sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg,
Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g.
Guillain-Barre Syndrome and Myasthenia Gravis).
5. Any underlying medical or psychiatric condition, which in the opinion of the
investigator will make the administration of ipilimumab hazardous or obscure the
interpretation of AEs, such as a condition associated with frequent diarrhea.
6. Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to
1 month before or after any dose of ipilimumab).
7. A history of prior treatment with ipilimumab or prior CD137 agonist or CTLA 4
inhibitor or agonist, or PD-1 antagonist;.
8. Concomitant therapy with any of the following: IL 2, interferon, or other non-study
immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other
investigation therapies; or chronic use of systemic corticosteroids (used in the
management of cancer or non-cancer-related illnesses);
9. Concomitant therapy with and need of uninterrupted therapeutic anticoagulation (e.g.
because of a recent thrombo-embolic event or cardiac valve prothesis).
10. Previous treatment with other investigational products, including cancer
immunotherapy, within 30 days preceding study recruitment;
11. Previous treatment in another ipilimumab clinical trial or prior treatment with a
CD137 agonist, CTLA-4 inhibitor or agonist;
12. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or physical (eg, infectious) illness.
13. Women of childbearing potential (WOCBP), defined above in Section 4.1, who:
- are unwilling or unable to use an acceptable method of contraception to avoid
pregnancy for their entire study period and for at least 8 weeks after cessation
of study drug, or
- have a positive pregnancy test at baseline, or
- are pregnant or breastfeeding. Sexually active WOCBP must use an effective method
of birth control during the course of the study, in a manner such that risk of
failure is minimized. Before study enrollment, WOCBP must be advised of the
importance of avoiding pregnancy during study participation and the potential
risk factors for an unintentional pregnancy. All WOCBP MUST have a negative
pregnancy test before first receiving ipilimumab. If the pregnancy test is
positive, the patient must not receive ipilimumab and must not be enrolled in the
study.
14. Persons of reproductive potential must agree to use an adequate method of
contraception throughout treatment and for at least 8 weeks after ipilimumab is
stopped.
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