| Eligibility |
Inclusion Criteria:
1. Patients must provide written informed consent prior to performance of study-specific
procedures or assessments, and must be willing to adhere with treatment and followup.
2. Age = 18 years
3. Phase Ia: Patients must have histologically or cytologically documented metastatic
solid tumor malignancies. Phase Ib: Patients must have histologically or cytologically
confirmed locally advanced, solid tumor malignancies of one of the following tumor
types:
1. Renal cell carcinoma (N = 20 patients) (Cohort A)
2. Non-anaplastic thyroid carcinoma (N = 20 patients) (Cohort B) Documentation of
histology from a primary or metastatic site is allowed.
3. Soft tissue sarcoma (N = 20 patients) (Cohort C). Patients must have progressed
in a prior line of therapy.
4. Ovarian carcinoma (N = 20 patients) (Cohort D)
4. Measurable disease by RECIST 1.1
5. Phase Ia: Patients may have de novo metastatic disease, or documented progression
despite any number of prior therapies. Patients must have no curative or other
effective therapeutic options available. Phase Ib: Patients may have had any number of
prior treatments, or prior pazopanib.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
7. Resolution of all chemotherapy or radiation-related toxicities to Grade 1 severity or
lower except for alopecia
8. Patient must be at least 4 weeks or five half-lives (whichever is shorter) from last
standard or experimental therapy, except Patients who have received prior pazopanib
are eligible but must not have received it in the last two weeks.
9. Patients must be at least 28 days from last radiation therapy dose, Peptide Receptor
Radionuclide Therapy (PRRT), surgery, or tumor embolization prior to the first dose of
pazopanib/PCI-24781
10. A female is eligible to enter and participate in this study if she is of:
1. 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 units per millilitre (mIU/mL)
and an estradiol value < 40pg/mL (<140 pmol/L). Subjects using HRT must have
experienced total cessation of menses for >= 1 year and be greater than 45
years of age OR have had documented evidence of menopause based on FSH and
estradiol concentrations prior to initiation of HRT
2. 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. Novartis Pharmaceuticals acceptable contraceptive methods, when
used consistently and in accordance with both the product label and the
instructions of the physician, are as follow:
- 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
- Oral contraceptive, either combined or progestogen alone
- Injectable progestogen
- Estrogenic vaginal ring
- Percutaneous contraceptive patches
- Intrauterine device (IUD) or intrauterine system (IUS) with a documented
failure rate of less than 1% per year
- Male partner sterilization (vasectomy with documentation of azoospermia)
prior to the female subject's entry into the study, and this male is the
sole partner for that subject
- Double barrier method: condom and an occlusive cap (diaphragm or
cervical/vault caps) with a vaginal spermicidal agent
(foam/gel/film/cream/suppository)
- 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.
11. Adequate organ system function as defined below
- Absolute neutrophil count (ANC) 1.5 X 109/L
- Hemoglobin 9 g/dL (5.6 mmol/L)
- Platelets 100 X 109/L
- Prothrombin time (PT) or international normalized ratio (INR) 1.2 X upper limit
of normal (ULN)
- Activated partial thromboplastin time (aPTT) 1.2 X ULN
- Total bilirubin 1.5 X ULN
- Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) 2.5 X ULN
- Serum creatinine <1.5 x ULN Or, if >1.5 mg/dL: Calculated creatinine clearance 50
mL/min Urine Protein to Creatinine Ratio (UPC) e <1
12. Subjects may not have had a transfusion within 7 days of screening assessment.
13. Subjects receiving anticoagulant therapy are eligible if their INR is within the
recommended range for the desired level of anticoagulation.
14. Patients with increased bilirubin due to Gilberts disease will not be excluded, if
increased bilirubin is the only protocol exclusion criteria met.
15. Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of
normal) are not permitted.
16. If UPC =1, then a 24-hour urine protein must be assessed. Subjects must have a 24-hour
urine protein value <1 g to be eligible.
5.1.2 Exclusion Criteria
1. Patients with other primary malignancies receiving active treatment at the time of
study entry, other than carcinoma in situ of the cervix, non-melanoma skin cancer,
nonmuscle invasive bladder cancer.
2. History or clinical evidence of central nervous system (CNS) metastases or
leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS
metastases.
3. Clinically significant gastrointestinal abnormalities that may increase the risk for
gastrointestinal bleeding including, but not limited to:
- Active peptic ulcer disease
- Known intraluminal metastatic lesion/s with risk of bleeding
- Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other
gastrointestinal conditions with increased risk of perforation
- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 28 days prior to beginning study treatment
4. Clinically significant gastrointestinal abnormalities that may affect absorption of
investigational product including, but not limited to:
- Malabsorption syndrome
- Major resection of the stomach or small bowel.
5. Presence of known active hepatitis C viral (HCV) or active hepatitis B viral (HBV)
infection, history of human immunodeficiency virus (HIV), or other uncontrolled
systemic infection
6. Corrected QT interval (QTc) > 480 msecs using Bazett's formula
7. Concurrent use of medications that are known to prolong or cause QT prolongation
8. History of any one or more of the following cardiovascular conditions within the past
6 months:
- Cardiac angioplasty or stenting
- Myocardial infarction
- Unstable angina
- Coronary artery bypass graft surgery
- Symptomatic peripheral vascular disease
9. Class III or IV congestive heart failure, as defined by the New York Heart Association
(NYHA), see Appendix A
10. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of =160 mmHg
or diastolic blood pressure (DBP) of = 100 (mmHg].
Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to
study entry. BP must be re-assessed on two occasions that are separated by a minimum
of 1 hour; on each of these occasions, the mean (of 3 readings) Systolic Blood
Pressure/Diastolic Blood Pressure values from each blood pressure assessment must be
<160/100 mmHg in order for a subject to be eligible for the study.
11. History of cerebrovascular accident, including transient ischemic attack (TIA)
12. History of pulmonary embolism or untreated deep venous thrombosis (DVT) within the
past 6 months Note: Patients with recent DVT who have been treated with therapeutic
anticoagulation including Coumadin or any low molecular weight heparin for at least 6
weeks are eligible
13. Prior major surgery or trauma within 28 days prior to first dose of study drug and/or
presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
placement not considered to be major)
14. Evidence of active bleeding or bleeding diathesis
15. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that
could interfere with subject's safety, provision of informed consent, or compliance
with study procedures
16. Unable or unwilling to discontinue use of prohibited medications for at least 14 days
or five half-lives of a drug (whichever is shorter) prior to the first dose of study
drug and for the duration of the study
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