A Two Arm Trial of Axitinib and Carboplatin/Paclitaxel in Melanoma
Condition: Melanoma
MeSH terms: Melanoma
Intervention: Axitinib; Carboplatin; Paclitaxel
Intervention description: 5mg BID Axitinib Days 1-14 for dual therapy - 5mg BID QD for patients on monotherapy; Day 1 of each 21 day cycle in combination with paclitaxel if patients are in dual therapy phase; Day 1 of each 21 Day cycle in combination with Carboplatin if patients on on dual therapy phase.
Intervention MeSH terms: Paclitaxel; Carboplatin; Axitinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 40.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Melanoma; Axitinib; Carboplatin; Paclitaxel

Summary:

      This is a two arm prospective Phase II pilot trial designed to determine the optimal duration
      of break between axitinib and chemotherapy with carboplatin/paclitaxel in melanoma. In this
      study, 6 patients will be enrolled to Arm A, the FLT PET scan (3'deoxy-3'-18F-Fluorothymidine
      positron emission tomography scans)cohort. 30 patients will be enrolled to Arm B, the
      treatment-only cohort. 36 total patients will be enrolled. The treatment schedule will be the
      same in either cohort, with the exception of the FLT PET scans.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Histologically or cytologically proven melanoma with Stage IV or unresectable stage
             III disease.

          2. Male or female, age ≥ 18 years.

          3. Resolution of all acute toxic effects of prior radiotherapy, chemotherapy or surgical
             procedures to NCI CTCAE Version 4.0 grade ≤1.

          4. May have ≤ 2 prior chemotherapy treatments and any prior immunotherapy treatments.
             These can include dacarbazine and/or temozolomide but not carboplatin or paclitaxel.

          5. At least 2 weeks since the end of prior systemic treatment (4 weeks for
             bevacizumab-containing regimens), radiotherapy, or surgical procedure with resolution
             of all treatment-related toxicity to NCI CTCAE Version 4.0 grade ≤ 1 or back to
             baseline except for alopecia or hypothyroidism.

          6. No evidence of preexisting uncontrolled hypertension. The baseline systolic blood
             pressure readings must be ≤140 mm Hg, and the baseline diastolic blood pressure
             readings must be ≤90 mm Hg. Patients whose hypertension is controlled by
             antihypertensive therapies are eligible.

          7. Adequate organ function as defined by the following criteria:

               1. Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase
                  (SGOT)) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase
                  (SGPT)) ≤ 2.5 x local laboratory upper limit of normal (ULN), or AST and ALT ≤ 5
                  x ULN if liver function abnormalities are due to underlying malignancy

               2. Total serum bilirubin ≤ 1.5 x ULN (Grade 0-1)

               3. Absolute neutrophil count (ANC) ≥ 1500 /ml

               4. Platelets ≥ 100,000/mL

               5. Hemoglobin ≥ 9.0 g/dL (may be transfused or erythropoietin treated)

               6. Serum calcium ≥12.0 mg/dL

               7. Serum creatinine ≤ 1.5 x ULN

          8. Patients with CNS (central nervous system) metastasis must have had either:

               1. Resected CNS metastasis without evidence of recurrence for > 12 weeks, OR

               2. Brain metastasis treated by stereotactic radiosurgery without evidence of
                  recurrence or progression for 12 weeks, OR

               3. Multiple brain lesions treated with whole brain radiation therapy with stable
                  disease off corticosteroids for at least 12 weeks prior to the start of therapy,
                  AND

               4. Without any evidence of leptomeningeal disease, AND

               5. Patients must be neurologically intact.

          9. May have previous adjuvant therapy with interferon, vaccines, or therapy with IL-2 or
             GM-CSF.

         10. Measurable disease by RECIST criteria.

         11. ECOG performance status 0 or 1.

        Exclusion Criteria:

          1. Major surgery within 4 weeks of starting the study treatment.

          2. Radiation therapy within 2 weeks of starting the study treatment. Prior palliative
             radiotherapy to metastatic lesion(s) is permitted, provided there is at least one
             measurable lesion that has not been irradiated.

          3. NCI CTCAE version 4.0 grade 2 or greater hemorrhage within 4 weeks of starting study
             treatment.

          4. History of hemoptysis or bleeding from GI tract.

          5. History of abdominal fistulae or perforation within 6 months prior to starting study
             treatment.

          6. History of or known carcinomatous meningitis, or evidence of symptomatic
             leptomeningeal disease on screening CT or MRI scan.

          7. Any of the following within the 6 months prior to study drug administration:
             myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
             graft, symptomatic congestive heart failure, cerebrovascular accident or transient
             ischemic attack, or pulmonary embolism.

          8. Hypertension that cannot be controlled by medications.

          9. Current use or anticipated need for treatment with drugs that are known potent CYP3A
             inhibitors (grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole,
             erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir,
             nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine).

         10. Current use or anticipated need for treatment with drugs that are known potent CYP3A
             or CYP1A2 inducers (ie, carbamazepine, dexamethasone, felbamate, omeprazole,
             phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and
             St. John's wort).

         11. Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose
             anticoagulants for maintenance of patency of central venous access devise or
             prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular
             weight heparin is allowed.

         12. Active seizure disorder or evidence of brain metastases, spinal cord compression, or
             carcinomatous meningitis.

         13. CNS disease on stable dexamethasone

         14. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
             (AIDS)-related illness or other active infection

         15. Pregnancy or breastfeeding. Female subjects must be surgically sterile or be
             postmenopausal, or must agree to use effective contraception during the period of
             therapy. All female subjects with reproductive potential must have a negative
             pregnancy test (serum or urine) prior to enrollment. Male subjects must be surgically
             sterile or must agree to use effective contraception during the period of therapy. The
             definition of effective contraception will be based on the judgment of the principal
             investigator or a designated associate.

         16. Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or study
             drug administration, or may interfere with the interpretation of study results, and in
             the judgment of the investigator would make the subject inappropriate for entry into
             this study.