Pazopanib and Paclitaxel as First-Line Treatment for Subjects With Unresectable Stage III and Stage IV Melanoma
Condition: Stage III Melanoma; Stage IV Melanoma; Unresectable Melanoma
MeSH terms: Melanoma
Intervention: Pazopanib and Paclitaxel
Intervention description: Paclitaxel will be administered intravenously at a starting dose of 80mg/m2 weekly for 3 weeks followed by a 1-week rest. Pazopanib will be administered orally, in a continuous regimen, with a starting dose of 800mg daily.
Intervention MeSH terms: Paclitaxel
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 60.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: pazopanib; paclitaxel; melanoma

Summary:

      This is a Phase II single-arm, open-label, clinical trial evaluating the efficacy and safety
      of pazopanib in combination with paclitaxel as first line therapy for subjects with
      unresectable Stage III and Stage IV melanoma. Previous cytokine therapy is permitted.
      Subjects must have measurable disease per Response Evaluation Criteria in Solid Tumors
      (RECIST). Subjects who are not candidates for curative intent treatments are eligible for
      this study.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subjects must provide written informed consent prior to performance of study-specific
             procedures or assessments, and must be willing to comply with treatment and follow up.
             Procedures conducted as part of the subject's routine clinical management (e.g., blood
             count, imaging study) and obtained prior to signing of informed consent may be
             utilized for screening or baseline purposes provided these procedures are conducted as
             specified in the protocol. Note: It is not necessary that informed consent be obtained
             within the protocol-specified screening window.

          2. Histologically confirmed cutaneous melanoma with 1) unresectable Stage III disease, or
             2) Stage IV disease by American Joint Committee on Cancer (AJCC) criteria.

          3. Must have measurable disease [i.e. with at least one measurable lesion, per RECIST]. A
             measurable lesion is defined as a lesion that can be accurately measured in at least
             one dimension with the longest diameter ≥20mm using conventional techniques or ≥10mm
             with spiral CT scan.

             Note: Subjects should be excluded if all baseline measurable lesions are within
             previously irradiated areas. Subjects participating in the exploratory analysis shall
             not have the biopsied lesion(s) as the only sites of measurable disease.

          4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          5. Age 18 years old or older

          6. A female is eligible to enter and participate in this study if she is of:

             Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
             including any female who has had:

               -  A hysterectomy

               -  A bilateral oophorectomy (ovariectomy)

               -  A bilateral tubal ligation

               -  Is post-menopausal

             Subjects not using hormone replacement therapy (HRT) must have experienced total
             cessation of menses for ≥1 year and be greater than 45 years in age, OR, in
             questionable cases, have a follicle stimulating hormone (FSH) value >40
             milliinternational unit (mIU)/mL and an estradiol value <40pg/mL (<140 pmol/L).

             Subjects must discontinue HRT prior to study enrollment due to the potential for
             inhibition of Cytochrome P450 (CYP) enzymes that metabolize estrogens and progestins.
             For most forms of HRT, at least 2-4 weeks must elapse between the cessation of HRT and
             determination of menopausal status; length of this interval depends on the type and
             dosage of HRT. If a female subject is determined not to be post-menopausal, they must
             use adequate contraception, as defined immediately below.

             Childbearing potential, including any female who has had a negative serum pregnancy
             test within 2 weeks prior to the first dose of study treatment, preferably as close to
             the first dose as possible, and agrees to use adequate contraception. Acceptable
             contraceptive methods, when used consistently and in accordance with both the product
             label and the instructions of the physician, are as follow:

               -  An intrauterine device with a documented failure rate of less than 1% per year.

               -  Vasectomized partner who is sterile prior to the female subject's entry and is
                  the sole sexual partner for that female.

               -  Complete abstinence from sexual intercourse for 14 days before exposure to
                  investigational product, through the dosing period, and for at least 21 days
                  after the last dose of investigational product.

               -  Double-barrier contraception (condom with spermicidal jelly, foam suppository, or
                  film; diaphragm with spermicide; or male condom and diaphragm with spermicide).

             Note: Oral contraceptives are not reliable due to potential drug drug interactions.

             Female subjects who are lactating should discontinue nursing prior to the first dose
             of study drug and should refrain from nursing throughout the treatment period and for
             14 days following the last dose of study drug.

             A male with a female partner of childbearing potential is eligible to enter and
             participate in the study if he uses a barrier method of contraception or abstinence
             during the study.

          7. Adequate organ system functions as defined below:

             System:Laboratory Values

             Hematologic

               -  Absolute neutrophil count (ANC) >= .5 X 10^9/L

               -  Hemoglobin >= 9 g/dL

               -  International normalized ratio (INR) <= 1.2 X upper limit of normal (ULN)

               -  Partial thromboplastin time (PTT) <= 1.2 X ULN

             Hepatic

               -  Total bilirubin <= 1.5 X ULN

               -  Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <=2.5 x ULN

             Renal

               -  Calculated creatinine clearance >= 30 mL/min Note: Subjects may not have had a
                  transfusion within 7 days of screening assessment.

               -  Platelets >= 100 X 10^9/L

               -  Urine Protein to Creatinine Ratio (UPC) < 1 Note: If UPC is more than 1, then a
                  24-hour urine protein must be assessed. Subjects must have a 24-hour urine
                  protein value <1g to be eligible.

          8. Corrected serum calcium concentration within normal range per local clinical
             laboratory standard.

          9. Left ventricular ejection fraction (LVEF) more or equal lower limit of normal (LLN) as
             assessed by echocardiography or multigated acquisition (MUGA) scan.

        Exclusion Criteria:

          -  Subjects meeting any of the following criteria must not be enrolled in the study:

               1. Prior treatment with cytotoxic anti-cancer therapy. (Previous cytokine or
                  investigational immunotherapy are permitted, but must be completed 28 days prior
                  to first dose of study medication).

               2. Prior use of other investigational or licensed tyrosine kinase inhibitors (TKIs),
                  or agents which target vascular endothelial growth factor (VEGF) or VEGF
                  receptors (ie. bevacizumab, VEGF-Trap).

               3. Known history of dose-limiting hypersensitivity reactions to paclitaxel/Cremophor
                  EL.

               4. Pregnant or lactating female. Female subjects who are lactating are eligible if
                  they discontinue nursing prior to the first dose of study drug and refrain from
                  nursing throughout the treatment period and for 14 days following the last dose
                  of study drug.

               5. Melanoma of ocular origin.

               6. History of another malignancy. Note: Subjects who have had another malignancy and
                  have been disease-free for 3 years, or subjects with a history of completely
                  resected non-melanomatous skin carcinoma or successfully treated in situ
                  carcinoma are eligible.

               7. Life expectancy less than 3 months.

               8. History or clinical evidence of central nervous system (CNS) metastases or
                  leptomeningeal carcinomatosis except for subjects who have previously-treated CNS
                  metastases (surgery with or without radiotherapy, radiosurgery, or gamma knife)
                  and meet all 3 of the following criteria:

                    1. Are asymptomatic

                    2. Have had no evidence of active CNS metastases for more or equal 6 months
                       prior to enrollment

                    3. Have no requirement for steroids or enzyme-inducing anticonvulsants (EIAC)

               9. Clinically significant gastrointestinal abnormalities including, but not limited
                  to:

                    1. Malabsorption syndrome

                    2. Major resection of the stomach or small bowel that could affect the
                       absorption of study drug

                    3. Active peptic ulcer disease

                    4. Inflammatory bowel disease

                    5. Ulcerative colitis, or other gastrointestinal conditions with increased risk
                       of perforation

                    6. History of abdominal fistula, gastrointestinal perforation, or intra
                       abdominal abscess within 28 days prior to beginning study treatment.

              10. Presence of uncontrolled infection.

              11. Prolongation of corrected QT interval (QTc) >480 milliseconds (ms).

              12. History of any one or more of the following cardiovascular conditions within the
                  past 6 months:

                    1. Cardiac angioplasty or stenting

                    2. Myocardial infarction

                    3. Unstable angina

                    4. Symptomatic peripheral vascular disease

                    5. Class III or IV congestive heart failure, as defined by the New York Heart
                       Association (NYHA)

              13. History of cerebrovascular accident, pulmonary embolism or untreated deep venous
                  thrombosis (DVT) within the past 6 months. Subjects with recent DVT who have been
                  treated with therapeutic anti-coagulating agents for at least 6 weeks are
                  eligible.

              14. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥150
                  millimeters of mercury (mmHg)or diastolic blood pressure (DBP) of ≥ 90 mmHg].

                  Note: Initiation or adjustment of antihypertensive medication(s) is permitted
                  prior to study entry. Blood pressure must be re-assessed on two occasions that
                  are separated by a minimum of 24 hours. The mean SBP/DBP values from each blood
                  pressure assessment must be less or equal 150 systolic and 90 diastolic mmHg in
                  order for a subject to be eligible for the study.

              15. Prior major surgery or trauma within 14 days of the first dose of study drug
                  and/or presence of any non-healing wound, fracture, or ulcer.

              16. Evidence of active bleeding or bleeding diathesis

              17. Hemoptysis within 6 weeks of first dose of study drug.

              18. Any serious and/or unstable pre-existing medical, psychiatric, or other
                  conditions that could interfere with subject's safety, obtaining informed consent
                  or compliance to the study.

              19. Use of any prohibited medications within 14 days of the first dose of study
                  medication.

              20. Radiation therapy within 28 days of the first dose of study drug.

              21. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that
                  is progressing in severity.

              22. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
                  chemically related to pazopanib.