Gemcitabine and Pazopanib in Chemotherapy Naïve Patients With Advanced/Metastatic Urothelial Carcinoma Ineligible for Cisplatin-based Chemotherapy
Condition: Bladder Cancer
MeSH terms: Carcinoma, Transitional Cell
Intervention: Gemcitabine; Pazopanib
Intervention description: Patients will receive gemcitabine 1200 mg/m2 intravenously on day 1 and day 8 and. Patients will receive 6 cycles of combination therapy (gemcitabine and pazopanib) unless disease progression or unacceptable toxicity occurs. Patients that achieve stable disease, a partial response, or a complete response after completion of 6 cycles, and who are not candidates for consolidation surgery, will be eligible to continue pazopanib monotherapy at the same dose and schedule until disease progression for a maximum of 18 additional cycles.; pazopanib 800 mg orally daily day 1 through day 21 (1 cycle = 21 days) Patients will receive 6 cycles of combination therapy (gemcitabine and pazopanib) unless disease progression or unacceptable toxicity occurs. Patients that achieve stable disease, a partial response, or a complete response after completion of 6 cycles, and who are not candidates for consolidation surgery, will be eligible to continue pazopanib monotherapy at the same dose and schedule until disease progression for a maximum of 18 additional cycles.
Intervention MeSH terms: Gemcitabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: URETER; URINARY BLADDER; renal pelvis; GEMCITABINE; GW786034 (PAZOPANIB); 11-191

Summary:

      Gemcitabine and Cisplatin are standard chemotherapy drugs used to treat advanced urothelial
      cancer. There is no standard chemotherapy for patients who cannot receive Cisplatin. However,
      most patients are treated with the chemotherapy drugs Gemcitabine and Carboplatin.

      In this study, the researchers hope to learn what effects, good and/or bad, the combination
      of Gemcitabine and Pazopanib has on urothelial cancer. Gemcitabine is given intravenously
      (through the veins) and works by killing rapidly dividing cells in the body, including cancer
      cells. Pazopanib is an oral chemotherapy and works by decreasing the blood supply to tumors
      which limits the tumor's source of oxygen and nutrients.

      The combination of Gemcitabine and Pazopanib is being tested in research studies such as this
      one. As of August 2011, more than 18 patients with various types of cancer have received
      treatment with Gemcitabine and Pazopanib. The main goal of this clinical research study is to
      learn if the study drugs Gemcitabine and Pazopanib can shrink or slow the growth of
      urothelial cancer. The safety of this drug will also be studied. The physical state, changes
      in the size of the tumor, and laboratory findings will help us decide if the combination of
      Gemcitabine and Pazopanib is safe and effective.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age ≥ 18 years

          -  Histologically confirmed diagnosis of urothelial carcinoma of the bladder, urethra,
             ureter, or renal pelvis by MSKCC pathology review

          -  Measurable disease as determined by RECIST v1.1 on initial pretreatment staging CT
             scan of the chest, abdomen, and pelvis (or MRI if clinically appropriate). (Note: A
             chest x-ray may be performed as an alternative to a CT scan of the chest.)

          -  Ineligible for cisplatin based on one or more of the following:

               -  Calculated creatinine clearance of < 60 mL/min (but ≥ 30 mL/min)

               -  Karnofsky Performance Status (KPS) 60-70% (ECOG PS 2)

               -  Grade 2 ≥ hearing loss

               -  Grade 2 ≥ peripheral neuropathy

          -  Karnofsky Performance Status ≥ 60%

          -  10 unstained slides or paraffin embedded tissue block obtained from pretreatment tumor
             specimens for immunohistochemistry. (Note: One paraffin block or 10 freshly-prepared
             unstained slides from the most representative single paraffin embedded tumor tissue
             block should be submitted. Slides from the primary tumor are preferred. If both the
             primary and metastatic tumor blocks are available, 10 slides from each of the sites
             should be submitted. If tissue from the primary tumor is not available, a paraffin
             block or unstained slides from a metastatic site are acceptable. Fine needle aspirates
             (FNAs) have insufficient tumor tissue and are not permitted.)

          -  Adequate organ system function as defined:

               -  Absolute neutrophil count (ANC) ≥1.5 X 109/L

               -  Hemoglobin ≥9 g/dL (5.6 mmol/L) (Note: Subjects may not have had a transfusion
                  within 7 days of screening assessment.)

               -  Platelets ≥100 X 109/L

               -  Prothrombin time (PT) or international normalized ratio (INR) ≤1.2 X ULN (Note:
                  Subjects receiving anticoagulant therapy are eligible if their INR is stable and
                  within the recommended range for the desired level of anticoagulation.)

               -  Activated partial thromboplastin time (aPTT) ≤1.2 X ULN

               -  Total bilirubin ≤1.5 X ULN

               -  Alanine amino transferase (ALT) and Aspartate aminotransferase (AST)

                  ≤2.5 X ULN (Note: Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN
                  (upper limit of normal) are not permitted.)

               -  Calculated creatinine clearance (ClCR) ≥30 mL/min using the CKD-EPI equation:
                  eGFR = 141 x min(Scr/k, 1)a x max(Scr/k, 1)-1.209 x 0.993 Age x 1.018 [if female]
                  x 1.159 [if black] Scr is serum creatinine, k is 0.7 for females and 0.9 for
                  males, a is - 0.329 for females and -0.411 for males, min indicates the minimum
                  of Scr/k or 1, and max indicates the maximum of Scr/k or 1

               -  Urine Protein to Creatinine Ratio (UPC)d <1 (Note: 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.)

        Exclusion Criteria:

          -  Prior treatment with systemic chemotherapy (prior intravesical therapy is permitted)

          -  Prior malignancy (Note: Subjects who have had another malignancy and have been
             disease-free for 5 years subjects with a history of completely resected
             non-melanomatous skin carcinoma, subjects with successfully treated in situ carcinoma,
             or subjects who have had adenocarcinoma of the prostate that has been definitively
             treated with a post-treatment PSA that is non-detectable are eligible.)

          -  History or clinical evidence of central nervous system (CNS) metastases or
             leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS
             metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure
             medication for 6 months prior to first dose of study drug. 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.

          -  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 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

          -  Active liver disease such as cirrhosis, chronic active hepatitis, or chronic
             persistent hepatitis

          -  Presence of uncontrolled infection Corrected QT interval (QTc) > 480 msecs using
             Bazett's formula

             o If QTc interval is > 480 msecs, then 2 additional ECGs should be obtained over a
             brief period of time (e.g., within approximately 15-20 minutes) to confirm the
             abnormality. The average QTc interval will be determined from the 3 ECG tracings by
             manual evaluation and will be used to determine if the subject will be excluded from
             the study. If the average QTc interval is >480 msec, then the subject is not eligible
             to participate in the study Previous history of QTc prolongation as a result of other
             medication that required discontinuation of that medication

          -  Congenital long QT syndrome or 1st degree relative with unexplained sudden death under
             40 years of age

          -  Use of any concomitant medication (during treatment with pazopanib or within 14 days
             of starting treatment) that are high risk for QTc prolongation or may induce Torsades
             de Pointes.

          -  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)

          -  Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg
             or diastolic blood pressure (DBP) of ≥ 90mmHg] (Note: Initiation or adjustment of
             antihypertensive medication(s) is permitted prior to study entry. At least 24 hours
             after initiation or adjustment of antihypertensive medication (s), 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 <140/90 mmHg in order for a subject to be eligible for the study.)

          -  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.)

          -  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).

          -  Evidence of active bleeding or bleeding diathesis. Known endobronchial lesions and/or
             lesions infiltrating major pulmonary vessels

          -  Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of
             study drug.

          -  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.

          -  Unable or unwilling to discontinue use of prohibited medications listed in
             (Concomitant Therapy) 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

          -  Treatment with any of the following anti-cancer therapies:

               -  Radiation therapy, surgery or tumor embolization within 14 days prior to the
                  first dose of pazopanib OR

               -  Immunotherapy, biologic therapy, investigational therapy or hormonal therapy
                  within 14 days or five half-lives of a drug (whichever is longer) prior to the
                  first dose of pazopanib Administration of any non-oncologic investigational drug
                  within 30 days or 5 half lives whichever is longer prior to receiving the first
                  dose of study treatment

          -  Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is
             progressing in severity

          -  Women who are pregnant or breast feeding (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.)

          -  Adults of child-bearing potential not employing an effective method of birth control
             for two weeks prior to study start and 21 days after the last dose. All women of
             child-bearing potential must have a negative serum pregnancy test. Women of
             child-bearing potential are defined as sexually mature women who have not undergone a
             hysterectomy, bilateral oophorectomy (ovariectomy), or bilateral tubal ligation OR
             have not experienced total cessation of menses for ≥ 1 year and are older than 45
             years in age, In questionable cases, the patient must have a follicle stimulating
             hormone (FSH) value >40 mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).
             Effective methods of birth control are defined in section 9.9 (Contraception
             Requirements).