The purpose of this study is to determine the safety profile of intra-arterial temozolomide administration during Isolated Limb Infusion (ILI) by defining the dose limiting toxicities associated with this treatment. This study also aims to determine the maximum tolerated dose of intra-arterial administration of temozolomide during ILI that will be used in a phase II trial.

1. The primary objective of this study is to determine the safety profile of intra-arterial temozolomide administration during Isolated Limb Infusion (ILI) by defining the dose limiting toxicities associated with this treatment and to determine the maximum tolerated dose of intra-arterial administration of temozolomide during ILI that will be used in a phase II efficacy trial.
2. Population will include patients who have undergone a previous Melphalan based regional therapy for which they did not respond optimally and present with persistent, progressive, or recurrent disease. Study activities include tumor tissue sampling, blood sampling, and subjects will undergo an Isolated Limb Infusion.
3. To define both response in-field (area of the limb below the tourniquet) and out-of-field (any area outside the tourniquet) in patients treated with temozolomide based ILI. Response in this trial will be defined by the RECIST criteria (CR, PR, SD, PD at 12 weeks post ILI). A CR rate of 20% would be considered as preliminary evidence of a promising approach in this group of patients that have had a previous melphalan regional treatment. ILI with melphalan has a complete response rate of approximately 35% in naïve patients and 20% in patients who have previously received melphalan based regional therapy.

To assess if the proposed treatment has any effect on quality of life as measured by the Functional Assessment of Cancer Therapy - Melanoma.

Inclusion Criteria:

1. Patient must have undergone a previous Melphalan based regional therapy for which they did not respond optimally and present with persistent, progressive, or recurrent disease.
2. Patient must be 18 years of age or older.
3. Patient must have an ECOG status of 0-1.
4. Patient must have histologically proven primary or recurrent extremity melanoma, stage IIIB, IIIC, or IV
5. Patients with Stage IIIC disease must either have had regional lymph nodes previously removed or will have them removed at the time of regional treatment.
6. Patients with Stage IV disease must have had all distant disease resected at least 30 days prior to regional treatment.
7. Disease to be treated by ILI must be distal to the planned site of tourniquet placement
8. Patient's disease must be bi-dimensionally measurable by caliper or radiological method as defined in the RECIST criteria.
9. Patient must have adequate bone marrow, liver and renal function
10. Patient must have a palpable femoral/radial pulse in the affected extremity.
11. Recovery from relevant toxicity prior to first study drug administration.
12. Patients must have a life expectancy of > 6 months.
13. Ability to read and understand English and the ability to complete paper +/- electronic survey assessments.

Exclusion Criteria:

1. Cardiac disease: Congestive heart failure > class II NYHA.
2. Known brain metastasis.
3. Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.
4. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
5. Active clinically serious infection > CTCAE Grade 2.
6. Thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
7. Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of administration of TMZ
8. Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of administration of TMZ.
9. Serious non-healing wound, ulcer, or bone fracture.
10. Major surgery or significant traumatic injury within 30 days of ILI.
11. Evidence or history of bleeding diathesis or coagulopathy.
12. Antineoplastic therapy, radiotherapy, or any other investigational drug within 30 days prior to first study drug administration.
13. Patients with symptoms or signs of vascular insufficiency. Specifically, patients with any history of blood clots or lifestyle altering ischemic peripheral vascular disease will be excluded.
14. History of allergic reactions and/or hypersensitivity to TMZ.
15. Psychiatric conditions or diminished capacity that could compromise the giving of informed consent, or interfere with study compliance.
16. Pregnant or nursing women are not eligible for this study. Patients of reproductive potential must agree to use an effective method of birth control when undergoing treatments with known or possible mutagenic or teratogenic effects. All female participants of child-bearing potential must have a negative serum pregnancy test within two weeks of patient registration. Please note: use of contraception, including surgical procedures such as vasectomy or tubal ligation DO NOT eliminate the need for administering pregnancy testing.
17. Current treatment, or treatment in the previous 24 months, for another non-melanoma malignancy.
18. Unable to return at the regular required intervals for reassessment, or study drug administration.
19. Patients with known heparin induced thrombocytopenia.