CTLA-4 Blockade and Low Dose Cyclophosphamide in Patients With Advanced Malignant Melanoma
Condition: Melanoma
MeSH terms: Melanoma
Intervention: Cyclophosphamide
Intervention description: This study consists of a Treatment Period, D1 Zofran 8mg pre-Cyclophosphamide 300mg/mg2 po and D3 Ipilimumab 10mg/kg iv wks 1,4,7 and 10; Tumor assessment at week 12; Follow-Up period weeks 13,16,and 20 with no treatment; Maintenance Period, D1 10mg/kg iv wks 24,36,48 and 60. Week 40=end of treatment; week 60=end of study
Intervention MeSH terms: Cyclophosphamide; Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Melanoma; Advanced Malignant Melanoma; Anti CTLA4 Blockade; Progression Free Survival; Interventional Therapy; Phase II Clinical Trial; Immunotherapy; T Cell Activation

Summary:

      The purpose of this study is to see whether the combination of low-dose Cyclophosphamide and
      Anti-CTLA4 (Ipilimumab) will stop tumor growth in patients with advanced skin cancer. The
      investigators expect to see an increase in response rate of the combination over Anti-CTLA-4
      alone and estimate a response rate of approximately 20 % in the proposed population.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Men & women, ages ≥18

          2. Willing/able to give written informed consent.

          3. Histologic diagnosis of unresectable AJCC Stage III/IV malignant melanoma

          4. At least 2wks must have elapsed since last chemotherapy, immunotherapy, hormonal
             therapy, radiotherapy or major surgery & beginning of protocol therapy. At least 6wks
             for nitrosoureas, mitomycin C, & liposomal doxorubicin

          5. Toxicity related to prior therapy must either have returned to ≤ grade 1 or baseline.

          6. Two punch tumor biopsy at Screening and Wk12 (4mm diameter) must be provided for
             immune analysis/staining if patients have accessible disease. Biopsies are optional
             during the Maintenance Period.Site of tumor biopsy s/n be only site of measurable
             disease. Minimum of 5 out of 1st 10 patients in stage I of the protocol must have
             biopsy accessible disease.

          7. Patients must have measurable disease defined as @ least 1 lesion that can be
             accurately measured in @ least 1 dimension (longest diameter to be recorded) as >20 mm
             with conventional techniques or as >10 mm with spiral CT scan.

          8. Required values for initial laboratory tests:

               1. WBC ≥ 2000/uL

               2. ANC ≥ 1000/uL

               3. Platelets ≥ 50 x 103/uL

               4. Hemoglobin ≥ 9.5 g/dL

               5. Creatinine ≤ 3.0 x ULN

               6. AST/ALT ≤ 2.5 x ULN for patients without liver metastasis, ≤ 5 x ULN for patients
                  with liver metastasis

               7. Bilirubin ≤ 3.0 x ULN, (except patients with Gilbert's Syndrome, who must have a
                  total bilirubin less than 3.0 mg/dL)

          9. Life expectancy of at least 4mos

         10. Patients w/stable, treated central nervous system (CNS) metastasis are eligible

         11. ECOG Performance Status Score 0-1

         12. Women of childbearing potential (WOCBP) must be using an adequate method of
             contraception to avoid pregnancy throughout study & for up to 26wks 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 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 w/o another cause, or

               -  For women with irregular menstrual periods and taking hormone replacement therapy
                  (HRT), documented serum follicle-stimulating hormone (FSH) level ≥ 35 mIU/mL.

               -  Women who are using oral contraceptives, other hormonal contraceptives (vaginal
                  products/skin patches/implanted/injectable products), mechanical products such as
                  an intrauterine device or barrier methods (diaphragm/condoms/ spermicides) to
                  prevent pregnancy,are practicing abstinence or where their partner is sterile (eg
                  vasectomy) should be considered to be of childbearing potential.

               -  WOCBP must have a negative urine or serum pregnancy test (minimum sensitivity 25
                  IU/L or equivalent units of HCG) w/in 72hrs before the start of ipilimumab.

         13. Men of fathering potential must be using an adequate method of contraception to avoid
             conception throughout the study [and up to 26wks after last dose of investigational
             product] in a way that risk of pregnancy is minimized.

        Exclusion Criteria:

          1. Any other malignancy from which patient has been disease-free for less than 5yrs, with
             the exception of adequately treated & cured basal or squamous cell skin cancer,
             superficial bladder cancer or carcinoma in situ of the cervix.

          2. 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 (eg
             Guillain-Barre Syndrome and Myasthenia Gravis).

          3. Any underlying medical or psychiatric condition, which in the opinion of investigator
             will make administration of ipilimumab hazardous or obscure interpretation of AEs,
             like a condition associated with frequent diarrhea.

          4. Uncontrolled or significant cardiovascular disease

          5. Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to
             1mo before/after any dose of ipilimumab).

          6. History of prior treatment with ipilimumab or prior CD137 agonist or CTLA 4 inhibitor
             or agonist.

          7. Concomitant therapy with any of following: IL 2, interferon, other non-study
             immunotherapy regimens; immunosuppressive agents; other investigation therapies; or
             chronic use of systemic corticosteroids (>60mg prednisone/day).

          8. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
             treatment of either a psychiatric or physical (eg infectious) illness.

          9. Women of childbearing potential (WOCBP), defined above who:

               1. are unwilling/unable to use an acceptable method of contraception to avoid
                  pregnancy for their entire study period and for at least 26wks after cessation of
                  study drug, or

               2. have a positive pregnancy test at baseline, or

               3. are pregnant or breastfeeding.

         10. Persons of reproductive potential who are unwilling to use an adequate method of
             contraception throughout treatment & for at least 26wks after ipilimumab is stopped.