Pilot Ipilimumab in Stage IV Melanoma Receiving Palliative Radiation Therapy
Condition: Melanoma
MeSH terms: Melanoma
Intervention: Ipilimumab; Radiation Therapy
Intervention description: Ipilimumab will be administered as a single agent standard of care with base dose of 3 mg/kg iv over approximately 90 minutes every 3 weeks for a total of 4 treatments.; Standard of care palliative radiation therapy will start within 5 days of the first ipilimumab dose. Dose is dependent upon lesion size and is determined by the radiation oncologist.
Intervention MeSH terms: Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      To determine the safety of local palliative radiation therapy used in combination with
      anti-CTLA-4 immunotherapy.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Signed Written Informed Consent

             Before any study procedures are performed, subjects (or their legally acceptable
             representatives) will have the details of the study described to them, and they will
             be given a written informed consent document to read. Then, if subjects consent to
             participate in the study, they will indicate that consent by signing and dating the
             informed consent document in the presence of study personnel.

          2. Target Population

               -  Histologically confirmed Stage IV melanoma.

               -  Must have failed at least one systemic therapy for malignant melanoma or be
                  intolerant to at least one prior systemic treatment.

               -  Subjects with asymptomatic brain metastases are eligible. (Systemic steroids
                  should be avoided if possible, or the subject should be stable on the lowest
                  clinically effective dose, as steroids as they may interfere with the activity of
                  ipilimumab if administered at the time of the first ipilimumab dose.)

               -  Primary ocular and mucosal melanomas are allowed.

               -  Must be at least 28 days since treatment with chemotherapy, biochemotherapy,
                  surgery, radiation, or immunotherapy, and recovered from any clinically
                  significant toxicity experienced during treatment.

               -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

               -  Life expectancy of ≥ 16 weeks.

               -  Subjects must have baseline (screening/baseline) radiographic images, (e.g.
                  brain, chest, abdomen, pelvis, and bone scans with specific imaging tests to be
                  determined by the attending physician) within 6 weeks of initiation of
                  ipilimumab.

               -  Required values for initial laboratory tests:

                    -  White blood cell (WBC) ≥ 2000/uL (~ 2 x 10^9/L)

                    -  Absolute neutrophil count (ANC) ≥ 1000/uL (~ 1 x 10^9/L)

                    -  Platelets ≥ 75 x 10^3/uL (~ 75 x 10^9/L)

                    -  Hemoglobin ≥ 9 g/dL (~ 80 g/L; may be transfused)

                    -  Creatinine ~ 2 x upper limit of normal (ULN)

                    -  Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ~ 2.5 x
                       ULN for subjects without liver metastasis ~ 5 times for liver metastases

               -  Bilirubin: ~ 2.0 x ULN (except for subjects with Gilbert's Syndrome, who must
                  have a total bilirubin of < 3.0 mg/dL)

               -  No active or chronic infection with HIV, Hepatitis B, or Hepatitis C.

               -  Two or more measurable sites of disease (≥ 1.5 cm) which include the disease site
                  that requires palliative radiation therapy as well as ≥ 1 other disease site
                  outside of the planned radiation therapy field.

          3. Age and Sex

               -  Men and women, at least 18 years of age.

               -  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.

               -  WOCBP include any female who has experienced menarche and who has undergone
                  successful surgical sterilization (hysterectomy, bilateral tubal ligation, or
                  bilateral oophorectomy) or is not postmenopausal. Post-menopausal is defined as:

                    -  Amenorrhea ≥ 12 consecutive months without another cause, or

                    -  For women with irregular menstrual periods and on 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 prior to the
                  start of investigational product.

                  c) 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.

        Exclusion Criteria:

          1. Sex and Reproductive Status

               -  WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy
                  for the entire study and for up to 8 weeks after the last dose of investigational
                  product.

               -  WOCBP using a prohibited contraceptive method.

               -  Women who are pregnant or breastfeeding.

               -  Women with a positive pregnancy test on enrollment or before investigational
                  product administration.

          2. Target Disease Exceptions

               -  Subjects on any other systemic therapy for cancer, including any other
                  experimental treatment.

               -  Prior treatment with an anti-CTLA-4 antibody if treatment failure was due to
                  adverse events (AEs). If a subject was discontinued from the prior anti-CTLA-4
                  treatment due to an AE or serious adverse event (SAE), regardless of the type of
                  event, that discontinuation constitutes an exclusion criterion. If AEs were
                  serious enough to require a subject's withdrawal from prior treatment, the
                  subject should be excluded from this study.

               -  A history of AEs with prior IL-2 or Interferon will not preclude subjects from
                  entering the current study.

               -  Subjects who relapsed in study MDX010-16 are not eligible for this study.

          3. Medical History and Concurrent Diseases

               -  Autoimmune disease: subjects with a documented history of inflammatory bowel
                  disease, including ulcerative colitis and Crohn's disease are excluded from this
                  study as are subjects with a history of symptomatic disease (eg, rheumatoid
                  arthritis, systemic progressive sclerosis [scleroderma]; systemic lupus
                  erythematosus (SLE); autoimmune vasculitis [eg, Wegener's Granulomatosis]).
                  Subjects with motor neuropathy considered of autoimmune origin (eg,
                  Guillain-Barre Syndrome and Myasthenia Gravis) are excluded from this study.

               -  Any subject who has a life-threatening condition that requires high-dose
                  immunosuppressant(s)

               -  Presence of known Hepatitis B or Hepatitis C infection, regardless of control on
                  antiviral therapy

               -  Subjects with melanoma who have another active, concurrent, malignant disease are
                  not eligible for the CA184045 study, with the exception of subjects with
                  adequately treated basal or squamous cell skin cancer, superficial bladder
                  cancer, or carcinoma in situ of the cervix.

          4. Medical History and Concurrent Diseases

               -  Prisoners or subjects who are involuntarily incarcerated.

               -  Subjects who are compulsorily detained for treatment of either a psychiatric or
                  physical (eg, infectious disease) illness.

               -  Any underlying medical or psychiatric condition that, in the opinion of the
                  investigator, could make the administration of ipilimumab hazardous or could
                  obscure the interpretation of adverse events.

               -  Any non-oncology vaccine therapy used for prevention of infectious diseases for
                  up to 4 weeks before or after any dose of ipilimumab, with the exceptions of
                  amantadine and flumadine.

               -  Central nervous system (CNS) metastases that require palliative radiation
                  therapy; prior brain irradiation is allowed providing CNS disease is stable.

          5. Additional Concomitant Treatments

               -  Any investigational agents

               -  Any other (non-CA184045 related) CTLA-4 inhibitors or agonists

               -  CD137 agonists

               -  Immunosuppressive agents (unless required for treating potential AEs)

               -  Chronic systemic corticosteroids (unless required for treating treatment emergent
                  AEs or required for management of signs or symptoms due to brain metastases, upon
                  discussion with BMS medical monitor).

        Eligibility criteria for this study have been carefully considered to ensure the safety of
        the study subjects and to ensure that the results of the study can be used. It is
        imperative that subjects fully meet all eligibility criteria.