Clinical Trials /

Cabozantinib S-malate in Treating Patients With Metastatic Pheochromocytomas or Paragangliomas That Cannot Be Removed by Surgery

NCT02302833

Description:

This pilot phase II trial studies how well cabozantinib s-malate works in treating patients with pheochromocytomas or paragangliomas that have spread from the primary site to other places in the body and cannot be removed by surgery. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking the growth of new blood vessels necessary for tumor growth.

Related Conditions:
  • Adrenal Gland Pheochromocytoma
  • Paraganglioma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib S-malate in Treating Patients With Metastatic Pheochromocytomas or Paragangliomas That Cannot Be Removed by Surgery
  • Official Title: A Phase II Study to Evaluate the Effects of Cabozantinib in Patients With Unresectable Metastatic Pheochromocytomas and Paragangliomas

Clinical Trial IDs

  • ORG STUDY ID: 2014-0081
  • SECONDARY ID: NCI-2014-02607
  • SECONDARY ID: 2014-0081
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02302833

Conditions

  • Locally Advanced Paraganglioma
  • Metastatic Adrenal Gland Pheochromocytoma
  • Metastatic Paraganglioma
  • Regional Adrenal Gland Pheochromocytoma
  • Unresectable Adrenal Gland Pheochromocytoma
  • Unresectable Paraganglioma

Interventions

DrugSynonymsArms
Cabozantinib S-malateBMS-907351, Cabometyx, Cometriq, XL-184, XL184Treatment (cabozantinib s-malate)

Purpose

This pilot phase II trial studies how well cabozantinib s-malate works in treating patients with pheochromocytomas or paragangliomas that have spread from the primary site to other places in the body and cannot be removed by surgery. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking the growth of new blood vessels necessary for tumor growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To estimate best overall response rate in patients with measurable disease determined by
      computed tomography (CT) or magnetic resonance imaging (MRI).

      SECONDARY OBJECTIVES:

      I. To estimate progression-free survival at 1-year. II. To correlate blood pressure control
      and change/discontinuation of antihypertensive medications with tumor responses.

      III. To correlate symptomatology evaluation by the MD Anderson Symptom Inventory (MDASI) with
      tumor responses.

      IV. To correlate plasma metanephrines and chromogranin A with tumor responses. V. To
      correlate plasma C-reactive protein and interleukin-6 with symptoms and tumor responses.

      VI. Toxicity assessment by the Common Terminology Criteria for Adverse Events (CTCAE).

      VII. To correlate both c-MET expression by immunohistochemistry (IHC) as well as MET
      amplification by fluorescence in situ hybridization (FISH) in archived samples and correlate
      these biomarkers with overall prognosis and responsiveness to cabozantinib (cabozantinib
      s-malate).

      EXPLORATORY OBJECTIVES:

      I. Best overall response rate in patients with bone metastases only (8 patients) as
      determined by fludeoxyglucose F 18 positron emission tomography/computed tomography
      (FDG-PET/CT).

      II. FDG-PET/CT maximum standard uptake value (SUVmax), advanced volumetric measures including
      peak standard uptake value (SUVpeak), metabolic tumor volume (MTV), and total lesion
      glycolysis (TLG).

      III. Time to skeletal related events. IV. Incidence of skeletal related events at 4 months
      and one year. V. Markers of bone turnover (bone specific alkaline phosphatase and C-terminal
      telopeptide [CTx]).

      OUTLINE:

      Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-28. Courses
      repeat every 4 weeks through week 24 and then every 8 weeks in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30-37 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (cabozantinib s-malate)ExperimentalPatients receive cabozantinib s-malate PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
  • Cabozantinib S-malate

Eligibility Criteria

        Inclusion Criteria:

          -  Histological confirmation of pheochromocytoma (PH)/paraganglioma (PG)

          -  Locally advanced or metastatic disease not amenable to surgery

          -  Patients enrolled in the main branch should have measurable disease; patients with a
             predominance of bone disease who have small, non-measurable or small measurable
             lesions other than bone, may be included per the principal investigator's discretion,
             in the exploratory branch of the study for patients with bone metastases only

          -  Progressive disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as
             determined by the investigator within the 12 months preceding study enrollment

          -  Assessment of all known disease sites, e.g., by CT scan, MRI, bone scan as
             appropriate, and/or FDG-PET scan within 28 days before the first dose of cabozantinib

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Life expectancy of at least 3 months

          -  Absolute neutrophil count (ANC) >= 1500/mm^3 without colony stimulating factor support
             (within 4 days prior to the first dose of cabozantinib)

          -  Platelets >= 100,000/mm^3 (within 4 days prior to the first dose of cabozantinib)

          -  Hemoglobin >= 9 g/dL (within 4 days prior to the first dose of cabozantinib)

          -  Bilirubin =< 1.5 x the upper limit of normal (ULN) (for subjects with known Gilbert's
             disease, bilirubin =< 3.0 mg/dL) (within 4 days prior to the first dose of
             cabozantinib)

          -  Serum albumin >= 2.8 g/dl (within 4 days prior to the first dose of cabozantinib)

          -  Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 50 mL/min (for
             creatinine clearance estimation, the Cockcroft and Gault equation should be used)
             (within 4 days prior to the first dose of cabozantinib)

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN
             (within 4 days prior to the first dose of cabozantinib)

          -  Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis (within 4
             days prior to the first dose of cabozantinib)

          -  Urine protein/creatinine ratio (UPCR) =< 1 (within 4 days prior to the first dose of
             cabozantinib)

          -  Serum phosphorus, calcium, potassium >= lower limit of normal (LLN) (within 4 days
             prior to the first dose of cabozantinib)

          -  Serum magnesium >= 1.2 mg/dL (within 4 days prior to the first dose of cabozantinib)

          -  Capable of understanding and complying with the protocol requirements and has signed
             the informed consent document

          -  Sexually active patients (men and women) must agree to use medically accepted barrier
             methods of contraception (e.g., male or female condom) during the course of the study
             and for 4 months after the last dose of study drug(s), even if oral contraceptives are
             also used; all subjects of reproductive potential must agree to use both a barrier
             method and a second method of birth control during the course of the study and for 4
             months after the last dose of study drug(s)

          -  Women of childbearing potential must have a negative pregnancy test at screening;
             women of childbearing potential include women who have experienced menarche and who
             have not undergone successful surgical sterilization (hysterectomy, bilateral tubal
             ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause is
             defined as amenorrhea >= 12 consecutive months; note: women who have been amenorrheic
             for 12 or more months are still considered to be of childbearing potential if the
             amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression
             or any other reversible reason

        Exclusion Criteria:

          -  Received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or
             biologic agents (e.g., cytokines or antibodies) within 3 weeks, or
             nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment

          -  Prior treatment with cabozantinib

          -  Radiation therapy for bone metastasis within 2 weeks, or any other external radiation
             therapy within 4 weeks before the first dose of study treatment; subjects with
             clinically relevant ongoing complications from prior radiation therapy are not
             eligible

          -  Received radionuclide treatment (i.e. iodine [I]-131 meta-iodo-benzyl guanidine)
             within 6 months of the first dose of study treatment

          -  Receipt of any type of small molecule kinase inhibitor (including investigational
             kinase inhibitor) within 14 days before the first dose of study treatment

          -  Receipt of any other type of investigational agent within 28 days before the first
             dose of study treatment

          -  The subject has not recovered to baseline or CTCAE =< grade 1 from toxicity due to all
             prior therapies except alopecia and other non-clinically significant adverse events
             (AEs)

          -  Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin
             time (PTT) test >= 1.3 x the laboratory ULN within 7 days before the first dose of
             study treatment

          -  The subject requires concomitant treatment, in therapeutic doses, with anticoagulants
             such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa
             inhibitors, or antiplatelet agents (eg, clopidogrel); low dose aspirin (=< 81 mg/day),
             low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight heparin (LMWH)
             are permitted

          -  The subject requires chronic concomitant treatment of strong cytochrome P450 family 3,
             subfamily A, polypeptide 4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin,
             carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort)

          -  The subject has experienced any of the following: a. clinically-significant
             gastrointestinal bleeding within 6 months before the first dose of study treatment, b.
             hemoptysis of >= 0.5 teaspoon (2.5 ml) of red blood within 3 months before the first
             dose of study treatment, c. any other signs indicative of pulmonary hemorrhage within
             3 months before the first dose of study treatment

          -  Radiographic evidence of cavitating pulmonary lesion(s)

          -  Tumor invading or encasing any major blood vessels

          -  Evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small
             or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial
             tumor within 28 days before the first dose of cabozantinib

          -  Uncontrolled, significant intercurrent or recent illness including, but not limited
             to, the following conditions: a. cardiovascular disorders including: i. congestive
             heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class
             IV (severe) at the time of screening, ii. concurrent uncontrolled hypertension defined
             as sustained blood pressure > 150 mm Hg systolic, or > 90 mm Hg diastolic despite
             optimal antihypertensive treatment within 7 days of the first dose of study treatment,
             iii. any history of congenital long QT syndrome, or iv. any of the following within 6
             months before the first dose of study treatment: unstable angina pectoris,
             clinically-significant cardiac arrhythmias, stroke (including transient ischemic
             attack [TIA], or other ischemic event), myocardial infarction, or thromboembolic event
             requiring therapeutic anticoagulation (note: subjects with a venous filter [e.g. vena
             cava filter] are not eligible for this study)

               -  Gastrointestinal disorders, particularly those associated with a high risk of
                  perforation or fistula formation, including: i. any of the following within 28
                  days before the first dose of study treatment: intra-abdominal tumor/metastases
                  invading GI mucosa, active peptic ulcer disease (patients must be completely
                  recovered), inflammatory bowel disease (including ulcerative colitis and Crohn's
                  disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
                  (patient must be completely recovered from these conditions), malabsorption
                  syndrome; ii. any of the following within 6 months before the first dose of study
                  treatment: abdominal fistula, gastrointestinal perforation, bowel obstruction or
                  gastric outlet obstruction, or intra-abdominal abscess (complete resolution of an
                  intra-abdominal abscess must be confirmed prior to initiating treatment with
                  cabozantinib even if the abscess occurred more than 6 months before the first
                  dose of study treatment); c. other disorders associated with a high risk of
                  fistula formation including percutaneous endoscopic gastrostomy (PEG) tube
                  placement within 3 months before the first dose of study therapy, d. other
                  clinically significant disorders such as: i. active infection requiring systemic
                  treatment within 28 days before the first dose of study treatment, ii. serious
                  non-healing wound/ulcer/bone fracture within 28 days before the first dose of
                  study treatment, iii. history of organ transplant, iv. concurrent uncompensated
                  hypothyroidism or thyroid dysfunction within 7 days before the first dose of
                  study treatment, or v. major surgery within 12 weeks before the first dose of
                  study treatment; complete wound healing from major surgery must have occurred 1
                  month before the first dose of study treatment; minor surgery within 28 days
                  before the first dose of study treatment with complete wound healing at least 10
                  days before the first dose of study treatment; subjects with clinically relevant
                  ongoing complications from prior surgery are not eligible

          -  Unable to swallow tablets

          -  A corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28
             days before first dose of study treatment; three electrocardiograms (ECGs) must be
             performed; if the average of these three consecutive results for QTcF is =< 500 msec,
             the subject meets eligibility in this regard

          -  Pregnant or breastfeeding

          -  A previously identified allergy or hypersensitivity to components of the study
             treatment formulation

          -  Unable or unwilling to abide by the study protocol or cooperate fully with the
             investigator or designee

          -  Evidence within 2 years of the start of study treatment of another malignancy which
             required systemic treatment except for cured nonmelanoma skin cancer or cured in situ
             cervical carcinoma

          -  Any other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality which, in the judgment of the investigator, would have made the patient
             inappropriate for entry into this study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best overall response rate
Time Frame:Up to 37 days after completion of study treatment
Safety Issue:
Description:As measured per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Will be determined by computed tomography or magnetic resonance imaging. Response will include complete response, partial response, and stable disease. Response rates and their 95% confidence intervals will be estimated.

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame:At 1 year
Safety Issue:
Description:Kaplan Meier survival curves will be used to estimate survival outcomes. Cox proportional hazards regression analysis may be used to assess the association between survival and covariates of interest.
Measure:Blood pressure control and change/discontinuation of antihypertensive medications
Time Frame:Up to 37 days after completion of study treatment
Safety Issue:
Description:Will be correlated with tumor responses.
Measure:Symptomatology evaluation
Time Frame:Up to 37 days after completion of study treatment
Safety Issue:
Description:Assessed by the MD Anderson Symptom Inventory. Will be correlated with tumor responses.
Measure:Plasma metanephrines and chromogranin A
Time Frame:Up to 37 days after completion of study treatment
Safety Issue:
Description:Will be correlated with tumor responses
Measure:Plasma C-reactive protein and interleukin-6
Time Frame:Up to 37 days after completion of study treatment
Safety Issue:
Description:Will be correlated with symptom and tumor responses.
Measure:Incidence of adverse events (AEs)
Time Frame:Up to 37 days after completion of study treatment
Safety Issue:
Description:Seriousness, severity grade and relationship to study treatment will be assessed by the investigator. Severity grade will be defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0. Listings of AEs will be provided.
Measure:c-MET expression
Time Frame:Baseline
Safety Issue:
Description:Evaluated by immunohistochemistry and MET amplification by fluorescence in situ hybridization in archived samples. Will be correlated with overall prognosis and responsiveness to cabozantinib s-malate.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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