Pazopanib Hydrochloride in Treating Patients With Recurrent or Persistent Uterine Cancer

Phase 2

Completed

Conditions: Recurrent Uterine Corpus Sarcoma
Uterine Carcinosarcoma

Interventions: Drug: Pazopanib Hydrochloride

Registration Number: NCT01247571

Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

Detailed Description: PRIMARY OBJECTIVES:

I. To assess the activity of pazopanib in patients with persistent or recurrent carcinosarcoma of the uterus as measured by the proportion of patients who survive progression-free for at least 6 months and the proportion of patients who have objective tumor response (complete or partial).

SECONDARY OBJECTIVES:

I. To determine the frequency and severity of adverse events as assessed by Common Terminology Criteria of Adverse Events version 4.0 (CTCAE v4.0).

II. To determine the duration of progression-free survival and overall survival.

OUTLINE: This is a multicenter study.

Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 22

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (pazopanib hydrochloride)	Pazopanib Hydrochloride	Patients receive pazopanib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Number of Patients With Grade 3 or Higher Adverse Events	Every cycle while on treatment	Grade 3 or higher adverse events were graded by CTCAE v4.
Objective Tumor Response (Complete or Partial)	CT scan or MRI if used to follow lesion(s) for measurable disease every other cycle for the first 6 mnths; then every 3 mnths thereafter until dx progression is confirmed; also repeat any other time clinically indicated, assessed up to 6 months.	Complete and Partial Tumor Response by RECIST 1.0. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Percentage of Participants With Progression-free Survival (PFS) at 6 Months	6 months	Progression-free survival is the period from study entry until disease progression, death or date of last contact. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0), as a 20 % increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Time from start of treatment to time of death or the date of last contact, assessed up to 5 years	The observed length of life from entry into the study to death or the date of last contact.
Progression-free Survival	From start of treatment to time of progression or death, assessed up to 5 years	Progression-free survival is the period from study entry until disease progression, death or date of last contact

Trial Locations

Locations (41): Oklahoma Cancer Specialists and Research Institute-Tulsa
🇺🇸
Tulsa, Oklahoma, United States
Saint Joseph Mercy Oakland
🇺🇸
Pontiac, Michigan, United States
Saint Mary's of Michigan
🇺🇸
Saginaw, Michigan, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
Lake University Ireland Cancer Center
🇺🇸
Mentor, Ohio, United States
CoxHealth South Hospital
🇺🇸
Springfield, Missouri, United States
Saint John Macomb-Oakland Hospital
🇺🇸
Warren, Michigan, United States
Saint Joseph Mercy Port Huron
🇺🇸
Port Huron, Michigan, United States
Novant Health Presbyterian Medical Center
🇺🇸
Charlotte, North Carolina, United States
Women and Infants Hospital
🇺🇸
Providence, Rhode Island, United States
Abington Memorial Hospital
🇺🇸
Abington, Pennsylvania, United States
Nebraska Methodist Hospital
🇺🇸
Omaha, Nebraska, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸
Charlotte, North Carolina, United States
Cancer Research for the Ozarks NCORP
🇺🇸
Springfield, Missouri, United States
The Hospital of Central Connecticut
🇺🇸
New Britain, Connecticut, United States
Riverside Methodist Hospital
🇺🇸
Columbus, Ohio, United States
Case Western Reserve University
🇺🇸
Cleveland, Ohio, United States
MetroHealth Medical Center
🇺🇸
Cleveland, Ohio, United States
Smilow Cancer Hospital Care Center at Saint Francis
🇺🇸
Hartford, Connecticut, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Sudarshan K Sharma MD Limted-Gynecologic Oncology
🇺🇸
Hinsdale, Illinois, United States
MedStar Franklin Square Medical Center/Weinberg Cancer Institute
🇺🇸
Baltimore, Maryland, United States
Oakwood Hospital and Medical Center
🇺🇸
Dearborn, Michigan, United States
Hurley Medical Center
🇺🇸
Flint, Michigan, United States
Genesys Regional Medical Center-West Flint Campus
🇺🇸
Flint, Michigan, United States
Genesys Regional Medical Center
🇺🇸
Grand Blanc, Michigan, United States
Allegiance Health
🇺🇸
Jackson, Michigan, United States
Sparrow Hospital
🇺🇸
Lansing, Michigan, United States
Saint Mary Mercy Hospital
🇺🇸
Livonia, Michigan, United States
Indiana University/Melvin and Bren Simon Cancer Center
🇺🇸
Indianapolis, Indiana, United States
Saint Vincent Oncology Center
🇺🇸
Indianapolis, Indiana, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
MedStar Washington Hospital Center
🇺🇸
Washington, District of Columbia, United States
Cooper Hospital University Medical Center
🇺🇸
Camden, New Jersey, United States
Saint John Hospital and Medical Center
🇺🇸
Detroit, Michigan, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
University of Colorado Cancer Center - Anschutz Cancer Pavilion
🇺🇸
Aurora, Colorado, United States
Florida Hospital Orlando
🇺🇸
Orlando, Florida, United States
Saint Joseph Mercy Hospital
🇺🇸
Ann Arbor, Michigan, United States
Michigan Cancer Research Consortium CCOP
🇺🇸
Ann Arbor, Michigan, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States