A Two Arm Trial of Axitinib and Carboplatin/Paclitaxel in Melanoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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 (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 and dose will be the same in either cohort, with the exception of the FLT PET scans. We are enrolling only 6 patients to Arm A, the FLT-PET cohort, because of study financial considerations. Patients will be enrolled in Arm A first, the FLT-PET cohort, to accommodate the radiological manufacture of the FLT-PET scan dye. It is expensive to manufacture and it is not usable forever. However if a patient is unable to participate in Arm A because of logistical issues, i.e. not being able to travel to UCSF for FLT-PET scans we will offer them participation in Arm B so that they can receive treatment that is not available off study. Each treatment cycle will last for 21days. During Cycle 1, patients will be treated with: Days 1-14: axitinib 5 mg PO twice daily Days 15-21: break from treatment In all cycles after Cycle 1, patients will be treated with: Day 1: paclitaxel 175 mg/m2 over 3 hours followed by carboplatin AUC 5 (AUC 5 is a term used to describe the dosing of carboplatin based on a patient's height, weight and kidney function) over 45 minutes Days 1-14: axitinib 5 mg PO twice daily Days 15-21: break from treatment Arm A: FLT PET cohort subjects will have FLT PET scans up to 2 weeks prior to day 1 and on days 14, 17, and 21 of cycle 1. Arm B: Treatment-only patients will receive administration of axitinib and carboplatin/paclitaxel on the same schedule and dose as Arm A but will not have FLT PET scans. Patients in Arm B will have standard tumor assessment with FDG PET-CT scans (F18-deoxyglucose positron emission tomography scans), CT Scans, and MRI's.

Official Title
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A Two Arm Phase II Trial of Sequential Axitinib and Carboplatin/Paclitaxel in Melanoma With Correlative FLT PET Scans (3'Deoxy-3'-18F-Fluorothymidine Positron Emission Tomography Scans)(CC# 10852)

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Axitinib
* Drug: Carboplatin
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven melanoma with Stage IV or unresectable stage III disease. Male or female, age ≥ 18 years. Resolution of all acute toxic effects of prior radiotherapy, chemotherapy or surgical procedures to NCI CTCAE Version 4.0 grade ≤1. May have ≤ 2 prior chemotherapy treatments and any prior immunotherapy treatments. These can include dacarbazine and/or temozolomide but not carboplatin or paclitaxel. 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. 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. Adequate organ function as defined by the following criteria: 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 Total serum bilirubin ≤ 1.5 x ULN (Grade 0-1) Absolute neutrophil count (ANC) ≥ 1500 /ml Platelets ≥ 100,000/mL Hemoglobin ≥ 9.0 g/dL (may be transfused or erythropoietin treated) Serum calcium ≥12.0 mg/dL Serum creatinine ≤ 1.5 x ULN Patients with CNS (central nervous system) metastasis must have had either: Resected CNS metastasis without evidence of recurrence for > 12 weeks, OR Brain metastasis treated by stereotactic radiosurgery without evidence of recurrence or progression for 12 weeks, OR 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 Without any evidence of leptomeningeal disease, AND Patients must be neurologically intact. May have previous adjuvant therapy with interferon, vaccines, or therapy with IL-2 or GM-CSF. Measurable disease by RECIST criteria. ECOG performance status 0 or 1. Exclusion Criteria: Major surgery within 4 weeks of starting the study treatment. 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. NCI CTCAE version 4.0 grade 2 or greater hemorrhage within 4 weeks of starting study treatment. History of hemoptysis or bleeding from GI tract. History of abdominal fistulae or perforation within 6 months prior to starting study treatment. History of or known carcinomatous meningitis, or evidence of symptomatic leptomeningeal disease on screening CT or MRI scan. 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. Hypertension that cannot be controlled by medications. 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). 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). 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. Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis. CNS disease on stable dexamethasone Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness or other active infection 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Patients enrolled in Arm A and Arm B will receive the same treatment with study drugs axitinib, carboplatin, and paclitaxel. Patients enrolled in Arm A and Arm B will have tumor imaging assessments: PET-CT, CT Scan, and/or MRI. In addition patients enrolled in Arm A will also have FLT-PET scans. | Drug: Axitinib<br>* 5mg BID Axitinib Days 1-14 for dual therapy - 5mg BID QD for patients on monotherapy<br>Drug: Carboplatin<br>* Day 1 of each 21 day cycle in combination with paclitaxel if patients are in dual therapy phase<br>Drug: Paclitaxel<br>* Day 1 of each 21 Day cycle in combination with Carboplatin if patients on on dual therapy phase.<br>|
| Experimental: Arm B<br>Patients enrolled in Arm A and Arm B will receive the same treatment with study drugs axitinib, carboplatin, and paclitaxel. Patients enrolled in Arm A and Arm B will have tumor imaging assessments: PET-CT, CT Scan, and/or MRI. Patients enrolled in Arm B will not have FLT-PET scans. | Drug: Axitinib<br>* 5mg BID Axitinib Days 1-14 for dual therapy - 5mg BID QD for patients on monotherapy<br>Drug: Carboplatin<br>* Day 1 of each 21 day cycle in combination with paclitaxel if patients are in dual therapy phase<br>Drug: Paclitaxel<br>* Day 1 of each 21 Day cycle in combination with Carboplatin if patients on on dual therapy phase.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the percentage of patients with tumor size reduction, i.e. the sum of partial responses plus complete responses. Radiographic response was evaluated using RECIST criteria during every 21-day cycle of treatment. | Monthly during study treatment, up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Optimal Interval Between the End of Axitinib Therapy and Initiation of Chemotherapy | Optimal interval between the end of axitinib therapy and initiation of chemotherapy, as determined using FLT PET as a Radiological Biomarker information of Resumption of DNA Synthesis Following Axitinib Therapy. | Days 1, 14, 17, and 20 of cycle 1 | 
| Overall Survival (OS) | Overall survival is the duration from first dose of study medication to death. For participants who are alive, overall survival is censored at the last contact. | Baseline until death or up to 24 months | 
| Time to Progression (TTP) |  | within 7 days of odd cycles after cycle 1 for the duration of treatment, up to 12 cycles | 
| Increase From Nadir in the Sum of Maximum (18)F-FLT Uptake Values After Treatment Holiday | (18)F-FLT uptake values following a 7-day treatment holiday compared to the lower of Baseline or Day 14 value. | Baseline, Day 14, Day 20 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, Axitinib, Carboplatin, Paclitaxel