Safety and Efficacy of Combination HDI and Anti-CTLA4 for Recurrent Inoperable Stage III or Stage IV Melanoma
Condition: Melanoma
MeSH terms: Melanoma
Intervention: Anti-CTLA4 monoclonal antibody and HDI
Intervention description: One course of therapy consists of three cycles (1 cycle=28days). Anti-CTLA4 monoclonal antibody (15 mg/kg i.v.) will be given during the first cycle only. HDI will be given all three cycles - cycle 1: 20 MU/m2 i.v. on days 0, 1, 2, 3, 4 a week (MTWRF) for 4 weeks; cycle 2: 10 MU/m2 s.c. 3 days a week (MWF) for 4 weeks; and cycle 3: 10 MU/m2 s.c. 3 days a week (MWF) for 4 weeks.
Response assessment will be carried out at day 56 and day 84. Every patient will receive 3 cycles regardless of response status after the first 2 cycles. However, a patient may be taken off therapy in the event of clinical progression at the discretion of the treating physician.
Patients without evidence for disease progression after 3 cycles may be offered additional cycles two weeks after completion of the third cycle. Therapy will continue for a maximum of 12 months.
Intervention MeSH terms: Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Other
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 37.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      To determine the safety and efficacy of the combination of HDI and anti-CTLA-4 monoclonal
      antibody for patients with recurrent inoperable stage III or stage IV melanoma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have a written informed consent obtained prior to the initiation of
             study procedures.

          -  Male and female subjects greater than or equal to 18 years of age.

          -  Patients must have histologically confirmed recurrent stage III or stage IV melanoma
             (AJCC 6th edition classification). Cutaneous melanoma, ocular or mucosal melanoma will
             be eligible.

          -  Patients must have measurable disease as defined by the Response Evaluation Criteria
             in Solid Tumors (RECIST). Baseline measurements must be obtained within 4 weeks prior
             to initiating therapy.

          -  Patients must have adequate hematologic, renal, and liver function as evidenced by the
             following (within 4 weeks prior to starting the study drugs):

          -  WBC greater than or equal to 3,000/mm3

          -  Lymphocytes greater than or equal to 1,000/mm3

          -  Platelets greater than or equal to 100,000/mm3

          -  Serum Creatinine less than or equal to 1.5 x upper limit of normal (ULN)

          -  Serum Bilirubin less than or equal to 1.5 x ULN

          -  Serum AST/ALT less than or equal to 2.5 x ULN

          -  Serum LDH less than or equal to 2.0 x ULN

          -  APTT less than < 40 s

          -  Patients must have fully recovered from any effects of major surgery, and be free of
             significant detectable infection.

          -  Patients must not have received any chemotherapy, hormonal therapy, radiotherapy, or
             biological therapy within the preceding 4 weeks.

          -  Patients must not have previous therapy with Anti-CTLA4 monoclonal antibodies
             (including CP-675,206 and MDX-010). Previous therapy with Interferon-alfa 2b in the
             adjuvant or metastatic setting is allowed. Previous therapy with other biological
             agents (including vaccines and GM-CSF) is allowed.

          -  Patients must have ECOG performance status of 0 or 1.

          -  Patients must not have autoimmune disorders (except vitiligo). Patients with positive
             titers for autoimmune antibodies are allowed on the study in the absence of history of
             clinical manifestations of autoimmune disease.

          -  Patients must not have conditions of immunosuppression or chronic requirement for
             treatment with systemic steroids, including oral steroids, continuous use of topical
             steroid creams or ointments, or any inhaled steroid containing inhalers. Patients who
             discontinue use of these classes of medication for at least 2 weeks are eligible.
             Treatment with steroids or other immunosuppressant medications is allowed during the
             study if clinically required to treat side effects related to autoimmunity that may
             develop secondary to the study agents.

          -  Patients must be free of brain metastasis by contrast-enhanced CT/MRI scans within 4
             weeks prior to starting the study drugs. If known to have prior brain metastases, must
             not have evidence of active brain disease on two successive MRI evaluations at least 3
             months apart (one of which is £ 4 weeks prior to starting the study drugs).

          -  Female patients of child bearing potential must have a negative pregnancy test, and
             must not be breast feeding.

          -  Patients must agree to use effective contraception (both males and females).

        Exclusion Criteria

          -  Serious illnesses, such as: cardiovascular disease (uncontrolled congestive heart
             failure, hypertension, cardiac ischemia, myocardial infarction, severe cardiac
             arrhythmia), bleeding disorders, autoimmune diseases, severe obstructive or
             restrictive pulmonary diseases, active systemic infections, and inflammatory bowel
             disorders.

          -  Treatment with mitomycin C or nitrosureas within six weeks prior to study entry.

          -  Any significant psychiatric disease, medical intervention, or other condition, which
             in the opinion of the principal investigator, could prevent adequate informed consent
             or compromise participation in the clinical trial.

          -  Active infection or antibiotics within one-week prior to study, including unexplained
             fever (temp > 38.1°C).

          -  Treatment with anticoagulants, except to keep an indwelling line patent.

          -  Systemic steroid or other immunosuppressive therapy within 4 weeks of starting the
             study.

          -  Treatment with any investigational product within 28 days of registration.

          -  History of inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis),
             celiac disease, or other chronic gastrointestinal conditions associated with diarrhea,
             or current acute colitis of any origin, or any history of diverticulitis (even a
             single episode) or evidence of diverticulitis at baseline, including evidence limited
             to CT-scan only.

          -  Patients who did not tolerate high-dose interferon-α therapy in the adjuvant setting
             will be excluded.