A Phase II, Single-Arm Study of Pazopanib and Paclitaxel as First-Line Treatment for Subjects With Unresectable Stage III and Stage IV Melanoma
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 milli-international 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
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 in Table 1. Table 1. Definitions for
Adequate Organ Function
System Laboratory Values
Hematologic Absolute neutrophil count (ANC) more or equal 1.5 X 109/L Hemoglobin1
more or equal 9 g/dL Platelets more or equal
100 X 109/L International normalized ratio less or equal 1.2 X upper limit of normal
(ULN) Partial thromboplastin time less or equal 1.2 X ULN
Hepatic Total bilirubin less or equal 1.5 X ULN Aspartate
aminotransferase (AST) and Alanine aminotransferase (ALT) less or
equal 2.5 x ULN
Renal Calculated creatinine clearance2 more or equal 30 mL/min Urine Protein to
Creatinine Ratio (UPC)3 less than 1
1. Subjects may not have had a transfusion within 7 days of screening assessment.
2. See Section 11.6, Appendix 6
3. 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.
4. ULN (Upper limit of Normal)
8. Corrected serum calcium concentration within normal range per local clinical laboratory
9. Left ventricular ejection fraction (LVEF) more or equal lower limit of normal (LLN) as
assessed by echocardiography or multigated acquisition (MUGA) scan.
- 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
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
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
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
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
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.