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

• Sponsor: Mayo Clinic (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03008369
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 3
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 78
• Patients Per Site Per Month: 0

Study Details

Study Description

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

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

1. 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).

TERTIARY OBJECTIVES:

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

2. 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.

3. 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).

OUTLINE:

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• 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
• Actual Primary Completion Date: Dec 1, 2020
• Anticipated Study Completion Date: Dec 1, 2023

Arms and Interventions

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 Names: Quality of Life Assessment

Outcome Measures

Primary Outcome Measures

1. Confirmed Tumor Response Rate [Monthly, up to 17 months.]

   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. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: 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

Secondary Outcome Measures

1. Duration of Tumor Response [Every month until off treatment, at off treatment, every 3 months until PD, at PD, every 6 months after PD up to 17 months]

   Will be estimated using the Kaplan-Meier method.

2. Patients Evaluable for Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events Version 4.0 [Monthly, up to 17 months.]

   Adverse Events are fully reported in the adverse event section of the results. 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 [Every month until off treatment, at off treatment, every 3 months until PD, at PD, every 6 months after PD up to 17 months]

   Will be estimated using the Kaplan-Meier method.

4. Progression-free Survival [Every month until off treatment, at off treatment, every 3 months until PD, at PD or up to 17 months]

   Will be estimated using the Kaplan-Meier method.

5. Quality of Life Assessed by EQ-5D and FACT-G [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 [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 [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 [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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ashish Chintakuntlawar, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 18, 2018

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT03008369
• Other Study ID Numbers: MC1575; NCI-2016-02032; MC1575; P30CA015083
• First Posted: Jan 2, 2017
• Last Update Posted: Feb 10, 2022
• Last Verified: Feb 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Pheochromocytoma; Paraganglioma; Lenvatinib

Study Results

Participant Flow

Arm/Group Title	Treatment (Lenvatinib)
Arm/Group Description	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.
Period Title: Overall Study
STARTED	3
COMPLETED	3
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Lenvatinib)
Arm/Group Description	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. Laboratory Biomarker Analysis: Correlative studies Lenvatinib: Given PO Quality-of-Life Assessment: Ancillary studies
Overall Participants	3
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	50
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	3 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	3 100%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Confirmed Tumor Response Rate
Description	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. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: 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
Time Frame	Monthly, up to 17 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Lenvatinib)
Arm/Group Description	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.
Measure Participants	3
Number [participants]	1.0 33.3%

2. Secondary Outcome

Title	Duration of Tumor Response
Description	Will be estimated using the Kaplan-Meier method.
Time Frame	Every month until off treatment, at off treatment, every 3 months until PD, at PD, every 6 months after PD up to 17 months

Outcome Measure Data

Analysis Population Description

All treated patients

Arm/Group Title	Treatment (Lenvatinib)
Arm/Group Description	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.
Measure Participants	3
Median (95% Confidence Interval) [Months]	9.7

3. Secondary Outcome

Title	Patients Evaluable for Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events Version 4.0
Description	Adverse Events are fully reported in the adverse event section of the results. 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.
Time Frame	Monthly, up to 17 months.

Outcome Measure Data

Analysis Population Description

All treated patients

Arm/Group Title	Treatment (Lenvatinib)
Arm/Group Description	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.
Measure Participants	3
Count of Participants [Participants]	3 100%

4. Secondary Outcome

Title	Overall Survival Time
Description	Will be estimated using the Kaplan-Meier method.
Time Frame	Every month until off treatment, at off treatment, every 3 months until PD, at PD, every 6 months after PD up to 17 months

Outcome Measure Data

Analysis Population Description

All treated patients

Arm/Group Title	Treatment (Lenvatinib)
Arm/Group Description	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.
Measure Participants	3
Median (95% Confidence Interval) [Months]	NA

5. Secondary Outcome

Title	Progression-free Survival
Description	Will be estimated using the Kaplan-Meier method.
Time Frame	Every month until off treatment, at off treatment, every 3 months until PD, at PD or up to 17 months

Outcome Measure Data

Analysis Population Description

All treated patients

Arm/Group Title	Treatment (Lenvatinib)
Arm/Group Description	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.
Measure Participants	3
Median (95% Confidence Interval) [Months]	11.5

6. Secondary Outcome

Title	Quality of Life Assessed by EQ-5D and FACT-G
Description	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
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Changes in Urinary Catecholamine and Metanephrine Levels
Description	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.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Germline Mutational Status in Peripheral Blood Mononuclear Cells
Description	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).
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Somatic Mutational Status in Peripheral Blood Mononuclear Cells
Description	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).
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Monthly, up to 17 months.
Adverse Event Reporting Description	Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events Version 4.0
Arm/Group Title	Treatment (Lenvatinib)
Arm/Group Description	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. Laboratory Biomarker Analysis: Correlative studies Lenvatinib: Given PO Quality-of-Life Assessment: Ancillary studies
All Cause Mortality
	Treatment (Lenvatinib)
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Serious Adverse Events
	Treatment (Lenvatinib)
	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)
Gastrointestinal disorders
Gastrointestinal disorders - Oth spec	1/3 (33.3%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Lenvatinib)
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Endocrine disorders
Hyperthyroidism	2/3 (66.7%)	4
Hypothyroidism	1/3 (33.3%)	1
Gastrointestinal disorders
Constipation	1/3 (33.3%)	1
Diarrhea	2/3 (66.7%)	12
Gastroesophageal reflux disease	1/3 (33.3%)	1
Mucositis oral	1/3 (33.3%)	1
Nausea	2/3 (66.7%)	11
Vomiting	1/3 (33.3%)	1
General disorders
Fatigue	3/3 (100%)	19
Investigations
Aspartate aminotransferase increased	1/3 (33.3%)	1
Lymphocyte count decreased	1/3 (33.3%)	1
Weight loss	1/3 (33.3%)	2
Metabolism and nutrition disorders
Anorexia	3/3 (100%)	5
Musculoskeletal and connective tissue disorders
Arthralgia	1/3 (33.3%)	1
Musculoskeletal, conn tissue - Oth spec	1/3 (33.3%)	2
Psychiatric disorders
Anxiety	1/3 (33.3%)	4
Renal and urinary disorders
Proteinuria	3/3 (100%)	15
Skin and subcutaneous tissue disorders
Dry skin	2/3 (66.7%)	4
Palmar-plantar erythrodysesthesia syndrm	1/3 (33.3%)	4
Vascular disorders
Hypertension	2/3 (66.7%)	17

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.