Pazopanib Hydrochloride in Treating Patients With Recurrent or Persistent Uterine Cancer
Condition: Recurrent Uterine Corpus Sarcoma; Uterine Carcinosarcoma
MeSH terms: Carcinosarcoma; Mixed Tumor, Mullerian; Recurrence
Intervention: Pazopanib Hydrochloride
Intervention description: Given PO
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 22.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well pazopanib hydrochloride works in treating patients with
      uterine cancer that has come back or has not responded to treatment. Pazopanib hydrochloride
      may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
      Pazopanib hydrochloride may also stop the growth of uterine cancer by blocking blood flow to
      the tumor.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have histologically confirmed uterine carcinosarcoma which is persistent
             or recurrent; acceptable histological type is defined as carcinosarcoma (malignant
             mixed müllerian tumor), homologous or heterologous type

          -  Patients must have measurable disease

               -  Measurable disease is defined by Response Evaluation Criteria in Solid Tumors
                  (RECIST) (version 1.1)

               -  Measurable disease is defined as at least one lesion that can be accurately
                  measured in at least one dimension (longest diameter to be recorded)

               -  Each lesion must be greater than or equal to 10 mm when measured by computed
                  tomography (CT), magnetic resonance imaging (MRI), or caliper measurement by
                  clinical exam or greater than or equal to 20 mm when measured by chest x-ray

               -  Lymph nodes must be greater than or equal to 15 mm in short axis when measured by
                  CT or MRI

          -  Patients must have at least one "target lesion" to be used to assess response on this
             protocol as defined by RECIST version 1.1

               -  Tumors within a previously irradiated field will be designated as "non-target"
                  lesions unless progression is documented or a biopsy is obtained to confirm
                  persistence at least 90 days following completion of radiation therapy

          -  Patients must not be eligible for a higher priority Gynecologic Oncology Group (GOG)
             protocol, if one exists

               -  In general, this would refer to any active GOG phase III protocol or rare tumor
                  protocol for the same patient population

          -  Patients must have a GOG performance status of 0, 1, or 2

          -  Recovery from effects of recent surgery, radiotherapy, or chemotherapy

               -  Patients should be free of active infection requiring antibiotics (with the
                  exception of uncomplicated urinary tract infection [UTI])

               -  Any hormonal therapy directed at the malignant tumor must be discontinued at
                  least one week prior to registration

               -  Any other prior therapy (chemotherapy) directed at the malignant tumor, must be
                  discontinued at least three weeks prior to registration

               -  At least 4 weeks must have elapsed since the patient underwent any major surgery
                  (e.g., major: hysterectomy, resection of a lung nodule - minor: central venous
                  access catheter placement)

          -  Patients must have had one prior chemotherapeutic regimen for management of
             carcinosarcoma; initial treatment may include chemotherapy, chemotherapy and radiation
             therapy, and/or consolidation/maintenance therapy; chemotherapy administered in
             conjunction with primary radiation as a radio-sensitizer WILL be counted as a systemic
             chemotherapy regimen

          -  Patients are allowed to receive, but are not required to receive, one additional
             cytotoxic regimen for management of recurrent or persistent disease according to the
             following definition:

               -  Cytotoxic regimens include any agent that targets the genetic and/or mitotic
                  apparatus of dividing cells, resulting in dose-limiting toxicity to the bone
                  marrow and/or gastrointestinal mucosa

               -  Note: patients on this non-cytotoxic study are allowed to receive one additional
                  cytotoxic chemotherapy regimen for management of recurrent or persistent disease,
                  as defined above; however, due to the novel nature of biologic compounds,
                  patients are encouraged to enroll on second-line non-cytotoxic studies prior to
                  receiving additional cytotoxic therapy

               -  Patients must have NOT received any non-cytotoxic chemotherapy for management of
                  recurrent or persistent disease; prior hormonal therapy is permitted

          -  Absolute neutrophil count (ANC) greater than or equal to 1,500/mcL

          -  Platelets greater than or equal to 100,000/mcL

          -  Hemoglobin level greater than or equal to 9 g/dL

          -  Creatinine less than or equal to 1.5 x institutional upper limit of normal (ULN)

          -  Urine protein/creatinine ratio (UPCR) must be less than 1 (or urinary protein less
             than 1.0 g/24 hours)

          -  Bilirubin less than or equal to 1.5 x ULN (subjects with Gilbert syndrome and
             elevations of indirect bilirubin only are eligible)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal
             to 2.5 x ULN

          -  Alkaline phosphatase less than or equal to 2.5 x ULN

          -  Subjects who have BOTH bilirubin greater than ULN and AST/ALT greater than ULN are not
             eligible

               -  Specifically, if bilirubin is greater than 1 x ULN but less than or equal to 1.5
                  x ULN, THEN the AST and ALT must be less than or equal to ULN for patient to be
                  eligible; if AST and/or ALT are greater than 1 x ULN but less than or equal to
                  2.5 x ULN, THEN the bilirubin must be less than or equal to ULN for patient to be
                  eligible

          -  Prothrombin time (PT) such that international normalized ratio (INR) is less than or
             equal to 1.5 x ULN (or an in-range INR, usually between 2 and 3, if a patient is on a
             stable dose of therapeutic warfarin) and a partial thromboplastin time (PTT) less than
             or equal to 1.5 x ULN

          -  Patients with a history of hypothyroidism/hyperthyroidism must have had stable
             well-controlled thyroid function for a minimum of 2 months as a condition for
             eligibility and that all other patients must have normal baseline thyroid function
             tests (thyroid stimulating hormone [TSH], triiodothyronine [T]3, T4)

          -  Patients must have the ability to understand and sign an approved informed consent and
             authorization permitting release of personal health information

          -  Patients who have met the pre-entry requirements

          -  Patients must be capable of taking and absorbing oral medications; a patient must be
             clear of the following:

               -  Any lesion, whether induced by tumor, radiation or other conditions, which makes
                  it difficult to swallow tablets

               -  Prior surgical procedures affecting absorption including, but not limited to
                  major resection of stomach or small bowel

               -  Active peptic ulcer disease

               -  Malabsorption syndrome

          -  Patients must be capable of taking and absorbing oral medications

          -  A patient must be clear of the following:

               -  Any lesion, whether induced by tumor, radiation, or other conditions, which makes
                  it difficult to swallow tablets

               -  Prior surgical procedures affecting absorption including, but not limited to,
                  major resection of stomach or small bowel

               -  Active peptic ulcer disease

               -  Malabsorption syndrome

          -  Any concomitant medications that are associated with a risk of corrected QC (QTc)
             prolongation and/or Torsades de pointes should be discontinued or replaced with drugs
             that do not carry these risks, if possible; patients who must take medication with a
             risk of possible risk of Torsades de pointes should be watched carefully for symptoms
             of QTc prolongation, such as syncope

               -  Patients with personal or family history of congenital long QTc syndrome are NOT
                  eligible

          -  Strong inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)
             are prohibited; grapefruit juice is also an inhibitor of CYP450 and should not be
             taken with pazopanib; CYP3A4 Inducers: strong inducers of CYP3A4 are prohibited;
             cytochrome P450 (CYP) substrates: concomitant use of agents with narrow therapeutic
             windows that are metabolized by CYP3A4, cytochrome P450, family 2, subfamily D,
             polypeptide 6 (CYP2D6), or cytochrome P450, family 2, subfamily C, poly peptide 8
             (CYP2C8) is not recommended

          -  Patients of childbearing potential must have a negative pregnancy test prior to the
             study treatment and agree to be practicing an effective form of contraception
             throughout study treatment; pregnant women are excluded from this study

        Exclusion Criteria:

          -  Patients who have had prior therapy with pazopanib

          -  Patients with other invasive malignancies, with the exception of non-melanoma skin
             cancer, are excluded if there is any evidence of other malignancy being present within
             the last three years; patients are also excluded if their previous cancer treatment
             contraindicates this protocol therapy

          -  Patients who have received prior radiotherapy to any portion of the abdominal cavity
             or pelvis OTHER THAN for the treatment of uterine carcinosarcoma within the last three
             years are excluded; prior radiation for localized cancer of the breast, head and neck,
             or skin is permitted, provided that it was completed more than three years prior to
             registration, and the patient remains free of recurrent or metastatic disease

          -  Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER
             THAN for the treatment of uterine carcinosarcoma within the last three years are
             excluded; patients may have received prior adjuvant chemotherapy for localized breast
             cancer, provided that it was completed more than three years prior to registration,
             and that the patient remains free of recurrent or metastatic disease

          -  Patients with clinically significant cardiovascular disease; this includes:

               -  Patients must have blood pressure (BP) no greater than 140 mmHg (systolic) and 90
                  mmHg (diastolic) for eligibility

               -  Myocardial infarction or unstable angina within 6 months of the first date of
                  pazopanib therapy

               -  New York Heart Association (NYHA) class II or greater congestive heart failure

               -  History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
                  ventricular fibrillation) or cardiac arrhythmias requiring anti-arrhythmic
                  medications; this does not include asymptomatic, atrial fibrillation with
                  controlled ventricular rate

               -  Women who have received prior anthracycline (e.g., doxorubicin and/or liposomal
                  doxorubicin) and who have an ejection fraction less than the institutional lower
                  limit of normal will be excluded from the study; patients with a prior life time
                  exposure to doxorubicin (or liposomal doxorubicin) of greater than 300 mg/m^2 are
                  NOT eligible

               -  CTCAE grade 2 or greater peripheral vascular disease

               -  History of cerebrovascular accident (CVA, stroke), transient ischemic attack
                  (TIA) or subarachnoid hemorrhage within six months of the first date of pazopanib
                  therapy

               -  Women with a baseline QTc >= 480 milliseconds

               -  History of cardiac angioplasty or stenting within 6 months prior to registration;
                  history of coronary artery bypass graft surgery within 6 months prior to
                  registration

               -  A patient with arterial thrombosis within 6 months prior to enrollment

          -  Patients with history or evidence upon physical examination of central nervous system
             (CNS) disease, including primary brain tumor, seizures not controlled with standard
             medical therapy or any brain metastases

          -  Patients with active bleeding or pathologic conditions that carry high risk of
             bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major
             vessels

          -  Patients with serious, non-healing wound, ulcer, or bone fracture; this includes
             history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
             within 28 days prior to the first date of pazopanib therapy; patients with underlying
             lesions that caused the fistula or perforation in the past that have not been
             corrected

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to pazopanib

          -  Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral
             therapy are ineligible

          -  Patients who are nursing; patients 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

          -  Patients with any condition that may increase the risk of gastrointestinal bleeding or
             gastrointestinal perforation, including:

               -  Active peptic ulcer disease

               -  Known gastrointestinal intraluminal metastatic lesions (gastrointestinal serosa
                  metastatic lesion are permitted)

               -  Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease)

          -  History of hemoptysis in excess of 2.5 mL (1/2 teaspoon) within 8 weeks prior to first
             dose of pazopanib

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection or psychiatric illness/social situations that would limit compliance with
             study requirements