Randomized, Double-Blinded Phase III Study of Cabozantinib Versus Placebo in Patients With Advanced Neuroendocrine Tumors After Progression on Prior Therapy (CABINET)

STATUS

Recruiting
End date

Oct 1, 2025
participants needed

395
sponsor

National Cancer Institute (NCI)

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Updated on 27 October 2022

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Sanford Joe Lueken Cancer Center (0.0 mi away) Contact

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heparin

platelet count

cancer

calcium

tyrosine

sunitinib

minor surgery

measurable disease

carcinoma

everolimus

somatostatin

potassium

investigational drug

gilbert's syndrome

international normalized ratio

metastasis

chemotherapy drug

neutrophil count

cabozantinib

pet scan

solid tumors

dotatate

chemoembolization

metastatic cancer

neuroendocrine carcinoma

neuroendocrine tumor

radionuclide therapy

history of allergic reaction

selective internal radiation therapy

hepatic artery embolization

second malignancy

bland embolization

medications other

thyroid-stimulating hormone

carcinoid tumor

gastroenteropancreatic neuroendocrine tumor

Summary

This phase III trial studies cabozantinib to see how well it works compared with placebo in treating patients with neuroendocrine or carcinoid tumors that have spread to other places in the body (advanced). Cabozantinib is a chemotherapy drug known as a tyrosine kinase inhibitor, and it targets specific tyrosine kinase receptors, that when blocked, may slow tumor growth.

Description

PRIMARY OBJECTIVES:

I. To determine whether cabozantinib S-malate (cabozantinib) can significantly improve progression-free survival (PFS) compared to placebo in patients with advanced pancreatic neuroendocrine tumors (NET) whose disease has progressed after prior therapy.

II. To determine whether cabozantinib can significantly improve progression-free survival (PFS) compared to placebo in patients with advanced carcinoid tumors whose disease has progressed after prior therapy.

SECONDARY OBJECTIVES:

I. To determine whether cabozantinib can significantly improve overall survival (OS) compared to placebo in patients with advanced pancreatic NET whose disease has progressed after prior therapy.

II. To determine whether cabozantinib can significantly improve overall survival (OS) compared to placebo in patients with advanced carcinoid tumors whose disease has progressed after prior therapy.

III. To evaluate safety and tolerability of cabozantinib versus placebo in patients with advanced pancreatic NET using Common Terminology Criteria for Adverse Events (CTCAE) and Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

IV. To evaluate safety and tolerability of cabozantinib versus placebo in patients with advanced carcinoid tumors using CTCAE and PRO-CTCAE.

V. To evaluate the overall radiographic response rate of cabozantinib versus placebo in patients with advanced pancreatic NET whose disease has progressed after prior therapy.

VI. To evaluate the overall radiographic response rate of cabozantinib versus placebo in patients with advanced carcinoid tumors whose disease has progressed after prior therapy.

OTHER OBJECTIVE:

I. Results of the primary analysis will be examined for consistency, while taking into account the stratification factors and/or covariates of baseline quality of life (QOL) and fatigue.

QUALITY OF LIFE SUBSTUDY OBJECTIVE:

I. To compare overall quality of life, disease-related symptoms, and other domains between the two treatment groups (cabozantinib versus [vs.] placebo) within each cohort of patients (pancreatic NET vs. carcinoid tumor). (Quality of Life Substudy Objective - A021602-HO1)

POPULATION PHARMACOKINETICS SUBSTUDY OBJECTIVE:

I. To describe the population pharmacokinetic and exposure-response relationships of cabozantinib in patients with advanced neuroendocrine tumors.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive cabozantinib S-malate orally (PO) once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) every 3 cycles until progression.

ARM II: Patients receive placebo PO QD on days 1-28 of each cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT every 3 cycles until progression.

After completion of study treatment, patients are followed up every 12 weeks until disease progression or start of new anticancer therapy, and then every 6 months until 8 years after registration.

Details

Condition	Atypical Carcinoid Tumor, Carcinoid Tumor, Functioning Pancreatic Neuroendocrine Tumor, Intermediate Grade Lung Neuroendocrine Neoplasm, Locally Advanced Pancreatic Neuroendocrine Tumor, Locally Advanced Unresectable Digestive System Neuroendocrine Neoplasm, Low Grade Lung Neuroendocrine Neoplasm, Lung Atypical Carcinoid Tumor, Lung Carcinoid Tumor, Metastatic Digestive System Neuroendocrine Neoplasm, Metastatic Digestive System Neuroendocrine Tumor G1, Metastatic Pancreatic Neuroendocrine Tumor, Metastatic Thymic Neuroendocrine Neoplasm, Neuroendocrine Neoplasm, Non-Functioning Pancreatic Neuroendocrine Tumor, Pancreatic Serotonin-Producing Neuroendocrine Tumor, Stage IIIA Digestive System Neuroendocrine Tumor AJCC v7, Stage IIIB Digestive System Neuroendocrine Tumor AJCC v7, Stage IV Digestive System Neuroendocrine Tumor AJCC v7, Unresectable Thymic Neuroendocrine Neoplasm
Treatment	laboratory biomarker analysis, quality-of-life assessment, computed tomography, Placebo, Placebo Administration, Cabozantinib S-malate
Clinical Study Identifier	NCT03375320
Sponsor	National Cancer Institute (NCI)
Last Modified on	27 October 2022

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Eligibility		Yes	No	Not Sure
Inclusion Criteria
	Documentation of Disease
	Histologic Documentation: Well- or moderately-differentiated neuroendocrine tumors of pancreatic and non-pancreatic (i.e. carcinoid) origin by local pathology
	The pathology report must state ONE of the following: 1) well- or moderately-differentiated neuroendocrine tumor, 2) low- or intermediate-grade neuroendocrine tumor, or 3) carcinoid tumor or atypical carcinoid tumor; documentation of histology from a primary or metastatic site is allowed
	Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid tumor, or goblet cell carcinoid tumor are not eligible
	Stage: Locally advanced/unresectable or metastatic disease
	Tumor Site: Histological documentation of neuroendocrine tumor of pancreatic, gastrointestinal (GI), lung, thymus, other, or unknown primary site; GI, lung, thymus, other, and unknown primary NETs will enroll in the carcinoid tumor cohort of the study
	Functional (associated with a clinical hormone syndrome) or nonfunctional tumors are allowed
	Radiologic Evaluation: Target lesions must have shown evidence of disease
	Measurable Disease
	progression by Response Evaluation Criteria in Solid Tumors (RECIST) version
	(v)1.1 criteria in the 12 months prior to registration; the radiologic images
	Patients must have measurable disease per RECIST 1.1 by computer tomography (CT) scan or magnetic resonance imaging (MRI)
	Lesions must be accurately measured in at least one dimension (longest diameter to be recorded) as >= 1 cm with CT or MRI (or >= 1.5 cm for lymph nodes); non-measurable disease includes disease smaller than these dimensions or lesions considered truly non-measurable including: leptomeningeal disease, ascites, pleural or pericardial effusion, lymphangitic involvement of skin or lung
	imaging reports, and clinic notes indicating growth of existing lesions
	development of new lesions, or treatment changes must be submitted
	Prior Treatment
	Prior treatment (except somatostatin analogs) with biologic therapy, immunotherapy, chemotherapy, investigational agent for malignancy, and/or radiation must be completed at least 28 days prior to registration
	Prior treatment with somatostatin analogs is allowed, and continuation of treatment with somatostatin analogs while on cabozantinib/placebo is allowed provided that the patient has been on a stable dose for at least two months
	Prior systemic treatment with radionuclide therapy must be completed at least 6 weeks prior to registration
	Patient must have experienced disease progression on or intolerance leading to treatment discontinuation of at least one Food and Drug Administration (FDA)-approved line of therapy (except somatostatin analogs); prior lines of therapy may include: everolimus, sunitinib, or lutetium Lu 177 dotatate in patients with pancreatic NET; everolimus in patients with lung NET; everolimus or lutetium Lu 177 dotatate in patients with gastrointestinal NET
	Prior treatment with hepatic artery embolization (including bland embolization, chemoembolization, and selective internal radiation therapy) or ablative therapies is allowed if measurable disease remains outside of the treated area or if there is documented disease progression in a treated site; prior liver-directed or other ablative treatment must be completed at least 28 days prior to registration
	Prior treatment with cabozantinib is not allowed
	Patients should have resolution of any toxic effects of prior therapy (except alopecia and fatigue) to National Cancer Institute (NCI) CTCAE, version 5.0, grade 1 or less
	Patients must have completed any major surgery at least 12 weeks prior to registration and any minor surgery (including uncomplicated tooth extractions) at least 28 days prior to registration; complete wound healing from major surgery must have occurred at least 28 days prior to registration, and complete wound healing from minor surgery must have occurred at least 10 days prior to registration
	Patient History
	No class III or IV congestive heart failure (CHF) within 6 months of registration
	No clinically significant cardiac arrhythmia within 6 months of registration
	No unstable angina or MI within 6 months of registration
	No thromboembolic events within 6 months of registration (including [incl.] stroke, transient ischemic attack [TIA], deep vein thrombosis [DVT], & pulmonary embolism [PE])
	No known history of congenital long QT syndrome
	No uncontrolled hypertension within 14 days of registration (defined as systolic blood pressure [SBP] >= 150 mmHg and/or diastolic blood pressure [DBP] >= 90 mmHg despite optimal medical management)
	No clinically significant GI bleeding within 6 months of registration
	No clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding within 6 months of registration including, but not limited to: active peptic ulcer, known endoluminal metastatic lesion(s) with history of bleeding, inflammatory bowel disease, or other gastrointestinal conditions with increased risk of perforation
	No GI perforation within 6 months of registration
	No known tumor with invasion into the GI tract from the outside causing increased risk of perforation or bleeding within 28 days of registration
	No radiologic or clinical evidence of pancreatitis
	No known cavitary lung lesions
	No known endobronchial lesions involving the main or lobar bronchi and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage; (CT with contrast is recommended to evaluate such lesions)
	No hemoptysis greater than 1/2 teaspoon (2.5 mL) or any other signs of pulmonary hemorrhage within the 3 months prior to registration
	No known tumor invading or encasing any major blood vessels
	No history of non-healing wounds or ulcers within 28 days of registration
	No history of fracture within 28 days of registration
	No brain metastases or cranial epidural disease unless adequately treated, stable, and off steroid support for at least 4 weeks prior to registration
	No known medical condition causing an inability to swallow oral formulations of agents
	No history of allergic reaction attributed to compounds of similar chemical or biological composition to cabozantinib/placebo
	No "currently active" second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ; patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for >= 3 years
	Concomitant Medications
	Other planned concurrent investigational agents or other tumor directed therapies (chemotherapy, radiation) are not allowed while on this study
	Concurrent use of somatostatin analogs while on cabozantinib/placebo is allowed provided that the patient has been on a stable dose for at least two months
	Full dose oral anticoagulation/antiplatelet therapy is not permitted; low dose aspirin =< 81 mg/day is allowed; anticoagulation with therapeutic doses of low molecular weight heparin (LMWH) is allowed in patients who are on a stable dose of LMWH for at least 6 weeks prior to registration; treatment with warfarin is not allowed; anticoagulation in patients with brain metastases is not permitted
	Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed; patients must discontinue the drug at least 14 days prior to registration on the study
	Chronic concomitant treatment with strong CYP3A4 inducers is not allowed; patients must discontinue the drug at least 14 days prior to the start of study treatment
	Not pregnant and not nursing
	Women of childbearing potential must have a negative pregnancy test done =< 14 days prior to registration
	A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months)
	Eastern Cooperative Oncology Group (ECOG) performance status: 0-2
	Absolute neutrophil count (ANC) >= 1,500/mm^3
	Hemoglobin >= 9 g/dL
	Platelet count >= 100,000/mm^3
	Prothrombin time (PT)/ international normalized ratio (INR), partial thromboplastin time (PTT) < 1.3 x upper limit of normal (ULN)
	Age >= 18 years
	Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) =< 3 x ULN
	Total bilirubin =< 1.5 x ULN
	Except in the case of Gilbert disease, in which case total bilirubin must be =< 3 x ULN
	Creatinine =< 1.5 mg/dL OR creatinine clearance >= 45 mL/min
	Albumin >= 2.8 g/dL
	Potassium within normal limits (WNL)
	Phosphorus WNL
	Calcium WNL Phosphorus WNL
	Supplementation is acceptable to achieve a value WNL; in patients with low albumin levels, a corrected calcium value WNL is acceptable; in patients with abnormal thyroid stimulating hormone (TSH), if free T4 is normal and patient is clinically euthyroid, patient is eligible
	Magnesium WNL
	Urine protein to creatinine (UPC) ratio =< 1
	Supplementation is acceptable to achieve a value WNL; in patients with low albumin levels, a corrected calcium value WNL is acceptable; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible
	QT interval corrected for heart rate using Fridericia's formula (QTcF) =< 500 msec
	Supplementation is acceptable to achieve a value WNL; in patients with low albumin levels, a corrected calcium value WNL is acceptable; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible
	Supplementation is acceptable to achieve a value WNL; in patients with low albumin levels, a corrected calcium value WNL is acceptable; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible
	TSH WNL
	Supplementation is acceptable to achieve a value WNL; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible

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selective internal radiation therapy

hepatic artery embolization

second malignancy

bland embolization

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carcinoid tumor

gastroenteropancreatic neuroendocrine tumor

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Randomized, Double-Blinded Phase III Study of Cabozantinib Versus Placebo in Patients With Advanced Neuroendocrine Tumors After Progression on Prior Therapy (CABINET)

Site Public Contact

Sanford Joe Lueken Cancer Center (0.0 mi away) Contact