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Lenvatinib in Treating Patients With Metastatic or Advanced Pheochromocytoma or Paraganglioma That Cannot Be Removed by Surgery

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03008369
Recruitment Status : Recruiting
First Posted : January 2, 2017
Last Update Posted : April 8, 2019
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Brief Summary:
This phase II trial studies how well lenvatinib works in treating patients with pheochromocytoma or paraganglioma that has spread to other places in the body or cannot be removed by surgery. Lenvatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Malignant Adrenal Gland Pheochromocytoma Malignant Paraganglioma Metastatic Adrenal Gland Pheochromocytoma Other: Laboratory Biomarker Analysis Drug: Lenvatinib Other: Quality-of-Life Assessment Phase 2

Detailed Description:


I. To determine the anti-tumor activity of lenvatinib (overall response rate; [ORR]) in patients with metastatic or advanced unresectable pheochromocytomas and paragangliomas.


I. To determine progression-free survival (PFS). II. To determine overall survival (OS). III. To determine duration of tumor response. IV. To determine safety and tolerability of lenvatinib. V. To assess patient reported quality of life using EuroQol Five-Dimensional Five Level Scale Questionnaire (EQ-5D-5L) and Functional Assessment of Cancer Therapy-General (FACT-G).


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

II. For patients with secretory tumors, to examine whether lenvatinib-induced changes in plasma metanephrines and 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 (presence of SDHD, SDHB, RET, VHL, neurofibromatosis type-1).


Patients receive lenvatinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Lenvatinib in Metastatic or Advanced Pheochromocytoma and Paraganglioma
Actual Study Start Date : May 31, 2017
Estimated Primary Completion Date : February 2020
Estimated Study Completion Date : February 2020

Arm Intervention/treatment
Experimental: Treatment (lenvatinib)
Patients receive lenvatinib PO once daily on days 1-28. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Lenvatinib
Given PO
Other Names:
  • E7080
  • ER-203492-00
  • Multi-Kinase Inhibitor E7080

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Primary Outcome Measures :
  1. Confirmed tumor response rate [ Time Frame: Up to 5 years ]
    Will be defined as 100% times the number of eligible patients who has started lenvatinib and whose objective tumor status was a complete response or partial response on 2 consecutive evaluations at least 4 weeks apart (using Response Evaluation Criteria in Solid Tumors version 1.1 criteria) divided by the number of eligible patients who has started lenvatinib. Ninety-five percent confidence intervals for the true response proportion will be calculated according to the approach of Duffy and Santner.

Secondary Outcome Measures :
  1. Duration of tumor response [ Time Frame: Up to 5 years ]
    Will be estimated using the Kaplan-Meier method.

  2. Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ]
    All adverse events will be graded. 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.

  3. Overall survival time [ Time Frame: Time from registration to death due to any cause, assessed up to 5 years ]
    Will be estimated using the Kaplan-Meier method.

  4. Progression-free survival [ Time Frame: Time from registration to documentation of disease progression, assessed up to 5 years ]
    Will be estimated using the Kaplan-Meier method.

  5. Quality of life assessed by EQ-5D and FACT-G [ Time Frame: Up to 5 years ]
    Descriptive statistics, and scatter plots will form the basis of presentation of these data both overall and by other outcomes (toxicity, response and survival measures). Correlations between the quality of life outcomes and other outcome measures will be carried out by standard parametric and nonparametric tests (e.g. Pearson's and Spearman's rho). Comparison between continuous variables will be made with Wilcoxon rank sum tests, Fisher's exact tests will be used to determine differences between categorical variables, and Log-rank test will be used to test differences between time-to-event ou

Other Outcome Measures:
  1. Changes in urinary catecholamine and metanephrine levels [ Time Frame: Up to 5 years ]
    Wilcoxon rank sum tests will be used to examine whether fold changes in a given biomarker during the first cycle of treatment differs between whose tumor responded to treatment and those whose tumor did not. Time series plots will be constructed.

  2. Germline mutational status in peripheral blood mononuclear cells [ Time Frame: Up to 5 years ]
    Will 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 SDHD, SDHB, RET, VHL, neurofibromatosis type-1).

  3. Somatic mutational status in peripheral blood mononuclear cells [ Time Frame: Up to 5 years ]
    Will 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 SDHD, SDHB, RET, VHL, neurofibromatosis type-1).

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
  • Measurable disease
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
  • Life expectancy > 24 weeks
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • White blood cell (WBC) count >= 3,000/mm^3
  • Platelet count >= 100,000/mm^3
  • Hemoglobin >= 9.0 g/dL (5.6 mmol/L); NOTE: transfusions are not allowed =< 7 days prior to registration
  • Total bilirubin =< 1.5 X upper limit of normal (ULN) (or total bilirubin =< 3.0 X ULN with direct bilirubin =< 1.5 X ULN in patients with well-documented Gilbert's Syndrome)
  • Aspartate transaminase (AST/serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 X ULN
  • Creatinine =< 1.5 x ULN
  • Urine protein/creatinine ratio =< 1 OR 24-hour urine protein < 1.5 gram
  • Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
  • Blood pressure (BP) < 150 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 < 150/90 mmHg; NOTE: all patients with secretory pheochromocytoma or paraganglioma are REQUIRED to: 1) be evaluated in consultation by a hypertension specialist with specific 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) receive alpha- and beta-adrenergic blockade for at least 7-14 days prior to initiation of lenvatinib; the hypertension specialist of record for each patient should be committed to closely following the patient during the clinical study with evaluation by said specialist required at cycle 1 and 2 and thereafter on an as needed basis
  • Provide written informed consent
  • Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
  • Ability to complete questionnaire(s) by themselves or with assistance

Exclusion Criteria:

  • Any of the following:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception
  • Chemotherapy/systemic therapy, radiotherapy, immunotherapy or surgery =< 21 days prior to registration or kinase inhibitor therapy =< 14 days prior to registration or failure to recover from toxicities (to grade 1 or below) from treatment; 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
  • Active or uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Receiving any other investigational agent
  • Current use of warfarin for any reason; NOTE: if patient can be safely transitioned to another anticoagulant, they may be eligible provided other criteria are satisfied
  • Any of the following:

    • Correct QT (QTc) prolongation (defined as a QTc interval >= 500 msecs)
    • Left ventricular ejection fraction (LVEF) < institutional lower limits of normal (LLN)
    • Frequent ventricular ectopy
    • Evidence of ongoing myocardial ischemia
  • Receiving any medications or substances with risk of torsades de pointes; NOTE: medications or substances with known risk of torsades de pointes are prohibited; consult pharmacist for review if needed
  • Known active and/or untreated brain metastases
  • Known severe allergic or other prohibitive reactions to other tyrosine kinase inhibitors (TKI)
  • Prior treatment with lenvatinib
  • Any of the following conditions:

    • Active peptic ulcer disease
    • 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; NOTE: 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 =< 6 months prior to registration:

    • Cerebrovascular accident (CVA) or transient ischemic attack (TIA)
    • Serious or unstable cardiac arrhythmia
    • Admission for unstable angina or myocardial infarction
    • 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 =< 30 days
    • Arterial thrombosis
    • Symptomatic peripheral vascular disease
  • Other active malignancy =< 2 years prior to registration; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: if there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer; NOTE: adjuvant anti-estrogen/hormonal therapy for breast cancer is allowed

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03008369

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United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Ashish V. Chintakuntlawar         
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
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Principal Investigator: Ashish Chintakuntlawar Mayo Clinic

Additional Information:
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Responsible Party: Mayo Clinic Identifier: NCT03008369     History of Changes
Other Study ID Numbers: MC1575
NCI-2016-02032 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC1575 ( Other Identifier: Mayo Clinic )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: January 2, 2017    Key Record Dates
Last Update Posted: April 8, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Carotid Body Tumor
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Paraganglioma, Extra-Adrenal
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action