Pazopanib as Front-Line Therapy in Patients With Non-Resectable or Metastatic Soft Tissue Sarcomas Who Are Not Candidates for Chemotherapy
Condition: Sarcoma, Soft Tissue; Soft Tissue Sarcoma
MeSH terms: Sarcoma
Intervention: Pazopanib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 56.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Pazopanib is FDA approved as a second line and beyond treatment for metastatic soft tissue
      sarcoma. There is a population of elderly and debilitated soft tissue sarcoma patients that
      are not fit for standard first line chemotherapy that is doxorubicin based. As pazopanib is
      well tolerated with minimal side effects, the investigators propose a phase II study to
      evaluate pazopanib as a first-line agent in patients with non-resectable or metastatic
      disease who are not candidates for cytotoxic chemotherapy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed diagnosis of nonresectable or metastatic soft tissue sarcoma.
             The following histologies are excluded: embryonal rhabdomyosarcoma, chondrosarcoma,
             osteosarcoma, Ewing tumors, primitive neuroectodermal tumors, gastrointestinal stromal
             tumors, dermatofibrosarcoma protuberans, inflammatory myofibroblastic sarcoma, and
             mixed mesodermal tumors of the uterus.

          -  Evaluable disease by imaging or physical exam OR measurable disease defined as at
             least one lesion that can be accurately measured in at least one dimension (longest
             diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10
             mm with calipers by clinical exam.

          -  Not a candidate for chemotherapy as determined by treatment physician

          -  Age ≥ 18 years

          -  ECOG performance status ≤ 2

          -  Normal bone marrow and organ function as defined below:

               -  Absolute neutrophil count ≥ 1,500/mcl

               -  Platelets ≥ 100,000/mcl

               -  Hemoglobin ≥ 9.0 g/dL

               -  PT or INR ≤ 1.2 x IULN (if not receiving anticoagulation therapy)

               -  PTT ≤ 1.2 x IULN (if not receiving anticoagulation therapy)

               -  Total bilirubin ≤ 1.5 x IULN or ≤ 3.0 x IULN with normal AST and ALT in patients
                  with Gilbert's disease

               -  AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN

               -  Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 30 mL/min/1.73 m2 for patients
                  with creatinine levels above 1.5 mg/dL

               -  UPC < 1 or, if UPC ≥ 1, 24-hour urine protein < 1 g; use of urine dipstick for
                  renal function assessment is not acceptable.

        Notes:

        Subjects may not have had a transfusion within 7 days of screening assessments. Concomitant
        elevation of bilirubin and AST/ALT above the IULN is not allowed.

        Patients receiving anticoagulation therapy are eligible if their INR is stable and within
        the recommended range for the desired level of anticoagulation.

          -  Ability to swallow and retain oral tablets.

          -  Women of childbearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control, abstinence) prior to study entry and for
             the duration of study participation. Should a woman become pregnant or suspect she is
             pregnant while participating in this study, she must inform her treating physician
             immediately.

          -  Ability to understand and willingness to sign an IRB approved written informed consent
             document.

        Exclusion Criteria:

          -  Eligible for cytotoxic chemotherapy.

          -  Prior systemic therapy for this type of sarcoma. Neoadjuvant or adjuvant therapy more
             than two years prior would not apply.

          -  Prior treatment with any VEGFR tyrosine kinase inhibitor.

          -  Administration of any non-oncologic investigational drug within 30 days or 5
             half-lives (whichever is longer) prior to the first dose of pazopanib.

          -  Use of a strong CYP3A4 inhibitor less than 14 days prior to initiation of study
             treatment

          -  A history of other malignancy ≤ 5 years previous with the exception of basal cell or
             squamous cell carcinoma of the skin which were treated with local resection only or
             carcinoma in situ of the cervix.

          -  Known brain metastases.

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to pazopanib or other agents used in the study.

          -  Any ongoing toxicity from prior anti-cancer therapy that is > grade 1 and/or that is
             progressing in severity (except alopecia).

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, uncontrolled seizure disorder, or psychiatric illness/social situations
             that would limit compliance with study requirements.

          -  Corrected QT interval (QTc) > 480 msecs.

          -  History of any one or more of the following cardiovascular conditions within the past
             6 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina
             pectoris, coronary artery bypass graft surgery, symptomatic peripheral vascular
             disease, class III or IV congestive heart failure as defined by the New York Heart
             Association

          -  Poorly controlled hypertension (defined as systolic blood pressure of ≥ 140 mmHg or
             diastolic blood pressure of ≥ 90 mmHg). Note: initiation or adjustment of
             antihypertensive medication(s) is permitted prior to study entry. Following
             antihypertensive medication initiation or adjustment, blood pressure must be
             reassessed three times at approximately 2-minute intervals. At least 24 hours must
             have elapsed between antihypertensive medication initiation or adjustment and blood
             pressure measurement. These three values should be averaged to obtain the mean
             diastolic and systolic blood pressures, which must be < 140/90 mmHg in order for a
             patient to be eligible for the study.

          -  Clinically significant gastrointestinal abnormalities that may increase the risk for
             gastrointestinal bleeding, including (but not limited to) active peptic ulcer disease,
             known intraluminal metastatic lesions with risk of bleeding, inflammatory bowel
             disease (e.g., ulcerative colitis, Crohn's disease) or other GI conditions with
             increased risk of perforation, history of abdominal fistula or intra-abdominal abscess
             within 28 days prior to beginning study treatment.

          -  Clinically significant gastrointestinal abnormalities that may affect absorption of
             pazopanib, including (but not limited to) malabsorption syndrome or major resection of
             the stomach or small bowel.

          -  History of cerebrovascular accident including transient ischemic attack, pulmonary
             embolism (PE) (including asymptomatic or previously treated PE), or untreated deep
             venous thrombosis within the past 6 months. Patients with DVT who are being treated
             with therapeutic anti-coagulating agents are eligible.

          -  Major surgery or trauma within 28 days prior to first dose of pazopanib and/or
             presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
             placement not considered to be major surgery).

          -  Evidence of active bleeding or bleeding diathesis.

          -  Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that
             increase the risk of pulmonary hemorrhage. Note: lesions infiltrating major pulmonary
             vessels (contiguous tumor and vessels) are excluded; however, the presence of a tumor
             that is touching but not infiltrating (abutting) the vessels is acceptable (CT with
             contrast is strongly recommended to evaluate such lesions). Large protruding
             endobronchial lesions in the mail or lobar bronchi are excluded; however,
             endobronchial lesions in the segmented bronchi are allowed. Lesions extensively
             infiltrating the main or lobar bronchi are excluded; however, minor infiltrations in
             the wall of thee bronchi are allowed.

          -  Recent hemoptysis (≥ ½ teaspoon of red blood within 8 weeks before first dose of
             pazopanib).

          -  Pregnant and/or breastfeeding. Patient must have a negative serum pregnancy test
             within 14 days of study entry.

          -  Known HIV-positivity. Appropriate studies will be undertaken in patients receiving
             combination antiretroviral therapy when indicated.