| Eligibility |
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. Age = 18 years
3. Diagnosis of metastatic/unresectable renal cell carcinoma of the clear cell type or
with a component of clear cell histology
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
5. Measurable disease by RECIST criteria (Version 1.1)
6. Eligible patients must have been treated with sunitinib for a minimum of 12 weeks (2
cycles). Patients must have evidence of progressive disease following treatment with
sunitinib as assessed by the site investigator on the basis of CT scans and other
appropriate clinical documentation. Patients who received sunitinib for 12 weeks
(2cycles) but stopped the drug due to toxicity rather than disease progression are
also eligible for this study.
The Investigator should be aware of the patient's intolerance/toxicity with prior
sunitinib treatment and take this in to account when assessing eligibility for the
pazopanib study.
Patients who have had prior treatment with either temsirolimus or everolimus are also
eligible for the trial.
No other prior treatment with bevacizumab, sorafenib, immunotherapies, chemotherapy,
biologic therapy or investigational therapy is allowed.
Previous radiotherapy (RT) is permissible provided the measurable disease is outside
the RT port. RT must be completed > 2 weeks prior to registration.
7. Adequate organ system function as defined below
Definitions for Adequate Organ Function System Laboratory Values
Hematologic Absolute neutrophil count (ANC) = 1.5 X 109/L Hemoglobina = 9 g/dL (5.6
mmol/L)
Platelets > or = 100 X 10^9/L Prothrombin time (PT) or international normalized ratio
(INR)b < or = 1.2 X ULN Activated partial thromboplastin time (aPTT) < or = 1.2 X ULN
Hepatic Total bilirubin < or = 1.5 X ULN Alanine amino transferase (ALT) and Aspartate
aminotransferase (AST)c < or = 2.5 X ULN Renal Serum creatinine < or = 1.5 mg/dL (133
µmol/L) Or, if >1.5 mg/dL: Calculated creatinine clearance (ClCR) (Appendix F) > or =
50 mL/min Urine Protein to Creatinine Ratio (UPC; Appendix F)d <1
- Subjects may not have had a transfusion within 7 days of screening assessment.
- Subjects receiving anticoagulant therapy are eligible if their INR is stable and
within the recommended range for the desired level of anticoagulation.
- Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of
normal) are not permitted.
- If UPC > or = 1, then a 24-hour urine protein must be assessed. Subjects must
have a 24-hour urine protein value <1 g to be eligible.
8. 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 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
Childbearing potential, including any female who has had a negative serum or urine
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:
- Oral contraceptive, either combined or progestogen alone
- Injectable progestogen
- Implants of levonorgestre
- 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.
9. Left Ventricular Ejection Fraction > or = Lower Limit of Institutional Normal as
assessed by Echocardiograph or MUGA
Exclusion criteria
1. Prior 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.
2. History or clinical evidence of central nervous system (CNS) metastases or
leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS
metastases (surgery plus or minus radiotherapy, radiosurgery, or gamma knife) and meet
all 3 of the following criteria are eligible: a) are asymptomatic, b) have had no
evidence of active CNS metastases for > or = 6 months prior to enrolment, and c) have
no requirement for steroids or Enzyme -inducing anticonvulsants EIACs.
Screening with CNS imaging studies (computed tomography [CT] or magnetic resonance
imaging [MRI]) is required only if clinically indicated or if the subject has a
history of CNS metastases.
3. Clinically significant gastrointestinal abnormalities that may increase the risk for
Gastrointestinal (GI) bleeding including, but not limited to:
- Active peptic ulcer disease
- Known intraluminal metastatic lesion/s with suspected 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 uncontrolled infection.
6. Prolongation of corrected QT interval (QTc) > 480 msecs using Bazett's formula
7. 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
- Class III or IV congestive heart failure, as defined by the New York Heart
Association (NYHA) [http://www.abouthf.org/questions_stages.htm, accessed 8th
December 2009]
- Class III (Moderate): marked limitation of physical activity. Comfortable at
rest, but less than ordinary activity causes fatigue, palpitation, or
dyspnea.
- Class IV (Severe): unable to carry out any physical activity without
discomfort. Symptoms of cardiac insufficiency at rest. If any physical
activity is undertaken, discomfort is increased.
8. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of =150 mmHg
or diastolic blood pressure (DBP) of = 90mmHg].
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) SBP / DBP values from
each BP assessment must be <150/90 mmHg in order for a subject to be eligible for the
study (see Appendix H for details on BP control and re-assessment prior to study
enrollment).
Note: A mean BP in 24 hours of <150/90 mm/Hg is acceptable.
9. History of cerebrovascular accident including transient ischemic attack (TIA),
pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating
agents for at least 6 weeks are eligible
10. 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).
11. Evidence of active bleeding or bleeding diathesis.
12. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
13. Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of
study drug.
14. 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 to
study procedures.
15. Unable or unwilling to discontinue use of prohibited medications list in Section 6.2.4
for at least 14 days or five half-lives of a drug (whichever is longer) prior to the
first dose of study drug and for the duration of the study.
16. Treatment with any of the following anti-cancer therapies:
- Minor surgical procedure or tumor embolization within 14 days prior to the first
dose of pazoapnib
- Previous radiotherapy (RT) is permissible provided the measurable disease is
outside the RT port. RT must be completed > 2 weeks prior to registration.
- sunitinib, everolimus or temsirolimus within 14 days or five half-lives of a drug
(whichever is longer) prior to the first dose of pazopanib Note: No other prior
treatment with bevacizumab, sorafenib, immunotherapies, chemotherapy, biologic
therapy or investigational therapy is allowed.
17. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is
progressing in severity, except alopecia.
18. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to pazopanib
|
