Pazopanib Hydrochloride in Treating Patients With Advanced or Progressive Malignant Pheochromocytoma or Paraganglioma

This study has suspended participant recruitment.
(Slow Accrual - Adverse Event Assessment)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01340794
First received: April 21, 2011
Last updated: September 23, 2014
Last verified: August 2014

April 21, 2011
September 23, 2014
May 2011
February 2015   (final data collection date for primary outcome measure)
Response rate (RR) (complete response [CR] or partial response [PR]) using RECIST version 1.1 [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
Ninety-five percent confidence intervals for the true response proportion will be calculated according to the approach of Duffy and Santner.
Proportion of patients who have achieved an objective response (partial or complete response [PR or CR]) to pazopanib hydrochloride as defined by RECIST criteria [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01340794 on ClinicalTrials.gov Archive Site
  • Safety profile of pazopanib hydrochloride graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    For each type of adverse event classified as either possibly, probably, or definitely related to study treatment, the proportion of patients experiencing a severe (grade 3 or higher) adverse event will be noted per cycle. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns.
  • Duration of tumor response [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Defined for all patients whose tumor met the criteria of CR or PR (using the RECIST criteria) as the date at which the patient's objective status is first noted to be either a CR or PR to the date progression is documented.
  • Time to treatment failure [ Time Frame: The time from the date of registration to the date at which the patient is removed from treatment due to progression, toxicity, or refusal, assessed up to 5 years ] [ Designated as safety issue: No ]
  • Progression-free survival time [ Time Frame: The time from registration to documentation of disease progression, assessed up to 5 years ] [ Designated as safety issue: No ]
  • Overall survival time [ Time Frame: The time from registration to death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
  • Proportion of patients who have achieved a CR, PR, or stable disease and who have remained on treatment for at least 6 months [ Designated as safety issue: No ]
  • TTP and PFS of patients treated with pazopanib hydrochloride [ Designated as safety issue: No ]
  • Correlation of the % drop in urinary catecholamines/metanephrines in patients with secretory tumors [ Designated as safety issue: No ]
  • CYP isoform levels [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Baseline CYP isoforms will be associated to maximum pazopanib plasma levels during first course of treatment.
  • Maximum pazopanib hydrochloride plasma level achieved [ Time Frame: Baseline and 14 days (first course of treatment) ] [ Designated as safety issue: No ]
    A plot of maximum pazopanib plasma level achieved during first course of treatment will be plotted against baseline CYP isoform to visually assess variability within and between CYP isoforms
  • Tumor response associated with plasma pazopanib hydrochloride levels achieved [ Time Frame: 14 days ] [ Designated as safety issue: No ]
    A two sample Wilcoxon rank sum test will be used to assess whether the peak plasma concentration levels of pazopanib during the first course of treatment differs among those who have a documented tumor response and those who do not.
  • Severe toxicities leading to pazopanib hydrochloride dose reductions [ Time Frame: Up to 14 days ] [ Designated as safety issue: Yes ]
    Severe toxicities leading to pazopanib hydrochloride dose will be associated to maximum pazopanib hydrochloride level achieved during first course of treatment or baseline CYP isoforms. A two sample Wilcoxon rank sum test will be used.
  • Changes in urinary catecholamine and metanephrine levels [ Time Frame: Baseline to up to 5 years ] [ Designated as safety issue: No ]
    Time series plots of urinary catecholamine and metanephrine levels will be constructed to visually assess trends prior to treatment discontinuation within and between chemistries as well as different in trends between those whose tumor responded to treatment and those whose tumor did not.
  • Changes in urinary catecholamine and/or metanephrine levels [ Time Frame: Baseline to up to 14 days ] [ Designated as safety issue: No ]
    Pazopanib hydrochloride-induced changes in urinary catecholamine and/or metanephrine levels during the first course will be associated with objective tumor response. For each biomarker, a plot of the fold change versus response status will be constructed to visually assess differences between those whose tumor responded to treatment and those whose tumor did not.
  • Change in somatic mutational status in archived tumor or in peripheral blood mononuclear cells [ Time Frame: Baseline to up to 5 years ] [ Designated as safety issue: No ]
    A 95% confidence interval for the difference in proportion of patients who have documented tumor response among those with that particular biomarker present and proportion of patients who have a documented tumor response among those without that particular biomarker.
  • Tumor expression levels of HIF-1a, VEGF-R (total and phospho-) assessed via immunohistochemistry [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    A 95% confidence interval for the difference in proportion of patients who have a documented tumor response among those with moderate to strong expression of that particular biomarker and proportion of patients who have a documented tumor response among those with week expression of that particular biomarker present.
  • Tumor microvessel density assessed using MECA-32 immunohistochemical staining [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    A 95% confidence interval for the difference in proportion of patients who have a documented tumor response among those with moderate to strong expression of that particular biomarker and proportion of patients who have a documented tumor response among those with week expression of that particular biomarker present.
Not Provided
 
Pazopanib Hydrochloride in Treating Patients With Advanced or Progressive Malignant Pheochromocytoma or Paraganglioma
A Phase 2 Study of Pazopanib (GW786034) in Patients With Advanced and Progressive Malignant Pheochromocytoma or Paraganglioma

This phase II trial studies how well pazopanib hydrochloride works in treating patients with advanced or progressive malignant pheochromocytoma or paraganglioma. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PRIMARY OBJECTIVES:

I. To assess the anti-tumor activity (in terms of the tumor response rate using the Response Evaluation Criteria in Solid Tumors [RECIST] criteria) of pazopanib (pazopanib hydrochloride) (GW786034) in patients with advanced malignant pheochromocytomas and paragangliomas.

SECONDARY OBJEC TIVES:

I. To assess safety profile of pazopanib. II. To assess duration of tumor response. III. To assess time to treatment failure. IV. To assess progression-free survival time. V. To assess overall survival time.

TERTIARY OBJECTIVES:

I. For patients with secretory tumors, to examine changes in urinary catecholamine and/or metanephrine levels.

II. For patients with secretory tumors, to examine whether pazopanib-induced changes in urinary catecholamine and/or metanephrine levels during the first cycle of treatment may be associated with objective tumor response.

III. To examine associations between tumor response and somatic mutational status in archived tumors, or germline mutational status in patient's peripheral blood mononuclear cells, (presence of succinate dehydrogenase complex subunit D [SDHD], succinate dehydrogenase complex subunit B [SDHB], ret proto-oncogene [RET], von Hippel-Lindau tumor suppressor [VHL], neurofibromatosis type-1).

IV. To examine associations between tumor response and tumor expression levels of angiogenic and vascular markers including hypoxia inducible factor 1, alpha (HIF-1a), vascular endothelial growth factor receptor (VEGF-R) (total and phospho-) and microvessel density in archival tumor tissue.

IV. To examine whether the extent of tumor response/regression may be correlated with plasma pazopanib (GW786034) concentration achieved after the third cycle (first cycle after run-in cycles) of pazopanib (GW786034) therapy.

OUTLINE:

Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28 (days 1-14 of courses 1 and 2). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo urine and blood sample collection at baseline and periodically during study for correlative studies.

After completion of study therapy, patients are followed up every 3-6 months for up to 5 years.

Interventional
Phase 2
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Extra-adrenal Paraganglioma
  • Metastatic Pheochromocytoma
  • Paraganglioma
  • Recurrent Pheochromocytoma
  • Drug: pazopanib hydrochloride
    Given PO
    Other Names:
    • GW786034B
    • Votrient
  • Other: laboratory biomarker analysis
    Correlative studies
Experimental: Treatment (pazopanib hydrochloride)
Patients receive pazopanib hydrochloride PO QD on days 1-28 (days 1-14 of courses 1 and 2). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: pazopanib hydrochloride
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Suspended
38
Not Provided
February 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Histologically or cytologically confirmed malignant secretory or non-secretory pheochromocytoma or paraganglioma that is unresectable and deemed inappropriate for alternative local regional therapeutic approaches
  • Objective evidence of tumor progression =< 185 days prior to registration as assessed by:

    • Unequivocal progression of objectively measured disease on successive appropriate imaging (e.g. computed tomography [CT] scan); in cases of uncertainty of tumor progression, the principal investigator of the study will be available to assist in decisions
  • Measurable disease defined as:

    • At least one non-nodal lesion whose longest diameter can be accurately measured as >= 2.0 cm with chest x-ray, or as >= 1.0 cm with CT scan, CT component of a positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI); and/or
    • A lymph node whose short axis must be > 1.5 cm when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm)
    • Note: Tumor lesions in a previously irradiated area are not considered measurable disease
  • Life expectancy > 24 weeks
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Leukocytes >= 3,000/uL
  • Absolute neutrophil count >= 1,500/uL
  • Platelets >= 100,000/uL
  • Hemoglobin >= 9 g/dL (5.6 mmol/L); transfusions not permitted =< 7 days of registration
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (except in cases of Gilbert's syndrome, where indirect bilirubin may be elevated, but the direct bilirubin remains within 1.5 x ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
  • NOTE: Subjects who have both bilirubin > ULN and AST/ALT > ULN are not eligible
  • Alkaline phosphatase =< 2.5 x ULN
  • Creatinine =< 1.5 mg/dL (133 umol/L) or within normal institutional limits OR creatinine clearance >= 50 mL/min/1.73m^2 for subjects with creatinine levels about institutional normal
  • Urine protein/creatinine ratio =< 1 OR 24-hour urine < 1 gram
  • Prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time (PTT) =< 1.2 x ULN unless a subject is receiving Coumadin and has stable INR which is in range for the desired level of anticoagulation
  • Blood pressure (BP) < 140 mmHg (systolic) and < 90 mmHg (diastolic); initiation or adjustment of BP medication is permitted prior to registration provided that the average of three BP readings at a visit prior to registration is < 140/90 mmHg

    • NOTE: All patients with secretory pheochromocytomas or paragangliomas are required to: 1) be evaluated in consultation by a hypertension specialist (at the registering institution) with experience in the management of hypertension in the setting of catecholamine-secreting tumors (usually an endocrinologist, nephrologist, or a cardiologist), and in the setting of hormone-associated hypertension 2) receive alpha- and beta-adrenergic blockade for at least 7 days prior to initiation of pazopanib (GW786034); the hypertension specialist of record for each patient should be committed to following the patient during the clinical study with evaluation by said specialist required at all run-in cycle evaluations (cycles 1 and 2) and also after the first continuous dosing cycle (cycle 3) and thereafter on an as needed basis
  • Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
  • Ability to understand and the willingness to sign a written informed consent document
  • Willingness to donate blood and tissue for correlative marker studies

Exclusion Criteria:

  • Any of the following:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception NOTE: breastfeeding should be discontinued if the mother is treated with pazopanib (GW786034)
  • Any of the following:

    • Chemotherapy/systemic therapy =< 4 weeks prior to registration
    • Radiotherapy =< 4 weeks prior to registration
    • Surgery =< 4 weeks prior to registration
    • Nitrosoureas or mitomycin C =< 6 weeks prior to registration
    • Those who have not recovered from adverse events due to agents administered more than 4 weeks earlier NOTE: Concurrent therapy with octreotide is allowed providing that tumor progression on this therapy has been demonstrated; concurrent therapy with bisphosphonates (e.g. zoledronic acid) or denosumab is also allowed.

NOTE: An unlimited number of prior chemotherapeutic or biologic therapies for malignant pheochromocytoma or paraganglioma is permitted; this includes prior anti-angiogenesis therapies such as tyrosine kinase inhibitors

  • Any other ongoing investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to pazopanib (GW786034) or other agents used in the study
  • Any of the following:

    • Corrected QT (QTc) prolongation (defined as a QTc interval >= 500 msecs)
    • Left ventricular ejection fraction (LVEF) < institutional lower limit of normal (LLN)
    • Frequent ventricular ectopy
    • Evidence of ongoing myocardial ischemia
  • Receiving prohibited cytochrome P450 (CYP) interactive concomitant medications within 7 days prior to registration
  • Any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain pazopanib (GW786034)
  • Receiving any medications or substances with risk of torsades de pointes; note: medications or substances with risk of torsades de pointes are prohibited; medications or substances with possible or conditional risk of torsades de pointes may be used while on study with extreme caution and careful monitoring; patients receiving these later cautionary agents must be monitored serially with electrocardiogram (ECG) weekly during the run-in and first cycle of therapy and at each evaluation thereafter NOTE: These medications should be discontinued or replaced with drugs that do not carry these risks, if possible
  • Any of the following conditions:

    • Active peptic ulcer disease
    • Known intraluminal bowel metastatic lesions
    • Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or other gastrointestinal conditions which increase the risk of perforation
    • History of new abdominal fistula, gastrointestinal perforation or intra-abdominal abscess =< 84 days prior to registration; enrollment of patients with chronic/canalized fistulous tracts (present for > 84 days) is allowed
    • Serious or non-healing wound, ulcer, or bone fracture
    • History of familial QTc prolongation syndrome
  • Any of the following conditions =< 185 days prior to registration:

    • Cerebrovascular accident (CVA) or transient ischemic attack (TIA)
    • Cardiac arrhythmia
    • Admission for unstable angina
    • Cardiac angioplasty or stenting
    • Coronary artery bypass graft surgery
    • Pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT which has been treated with therapeutic anticoagulation < 42 days
    • Arterial thrombosis
    • Symptomatic peripheral vascular disease
    • Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
  • Hemoptysis in excess of 2.5 mL (1/2 teaspoon) =< 60 days prior to registration
  • Any of the following:

    • Known active and/or untreated brain metastases
    • Brain metastases requiring ongoing therapy (e.g. corticosteroids)
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy
  • Require heparin other than low-molecular weight heparin
  • Prior use of pazopanib (GW786034)
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
China,   United States,   Singapore
 
NCT01340794
NCI-2011-02588, NCI-2011-02588, CDR0000699430, MAYO-MC107B, MC107B, 8783, N01CM62205, N01CM00099, N01CM00071, N01CM00039, P30CA015083
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Keith Bible Mayo Phase 2 Consortium
National Cancer Institute (NCI)
August 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP