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Testing Cabozantinib in Patients With Advanced Pancreatic Neuroendocrine and Carcinoid Tumors

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.
 
ClinicalTrials.gov Identifier: NCT03375320
Recruitment Status : Recruiting
First Posted : December 18, 2017
Last Update Posted : January 27, 2023
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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Brief 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 may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of 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.

Condition or disease Intervention/treatment Phase
Atypical Carcinoid Tumor Carcinoid Tumor Functioning Pancreatic Neuroendocrine Tumor Intermediate Grade Lung Neuroendocrine Neoplasm Locally Advanced Digestive System Neuroendocrine Neoplasm Locally Advanced Digestive System Neuroendocrine Tumor G1 Locally Advanced 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 Lung Carcinoid Tumor Metastatic Lung Neuroendocrine Neoplasm Metastatic Pancreatic Neuroendocrine Neoplasm Metastatic Pancreatic Neuroendocrine Tumor Metastatic Thymic Neuroendocrine Neoplasm Neuroendocrine Neoplasm Non-Functioning Pancreatic Neuroendocrine Tumor Pancreatic Serotonin-Producing Neuroendocrine Tumor Thymic Carcinoid Tumor Unresectable Digestive System Neuroendocrine Neoplasm Unresectable Digestive System Neuroendocrine Tumor G1 Unresectable Lung Neuroendocrine Neoplasm Unresectable Pancreatic Neuroendocrine Neoplasm Unresectable Thymic Neuroendocrine Neoplasm Drug: Cabozantinib S-malate Procedure: Computed Tomography Other: Placebo Administration Other: Quality-of-Life Assessment Phase 3

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 395 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Randomized, Double-Blinded Phase III Study of Cabozantinib Versus Placebo in Patients With Advanced Neuroendocrine Tumors After Progression on Prior Therapy (CABINET)
Actual Study Start Date : July 18, 2018
Estimated Primary Completion Date : October 1, 2025
Estimated Study Completion Date : October 1, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Carcinoid Tumors

Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm I (cabozantinib S-malate)
Patients receive cabozantinib S-malate PO 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 CT every 3 cycles until progression.
 Drug: Cabozantinib S-malate
Given PO
Other Names:
  • BMS-907351
  • Cabometyx
  • Cometriq
  • XL-184
  • XL184

Procedure: Computed Tomography
Undergo CT
Other Names:
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT
  • CT Scan
  • tomography

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Placebo Comparator: Arm II (placebo)
Patients receive placebo PO 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 CT every 3 cycles until progression.
 Procedure: Computed Tomography
Undergo CT
Other Names:
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT
  • CT Scan
  • tomography

Other: Placebo Administration
Given PO

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


Outcome Measures
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Primary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: From randomization to the first radiographic documentation of disease progression, or death from any cause, assessed for up to 8 years ]
    Will be assessed per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 determined by retrospective independent central review. Will be compared between treatment arms using the stratified log rank test at one-sided level 0.025. The stratification factors will be used for the analysis. The hazard ratio (HR) for PFS will be estimated using a stratified Cox proportional hazards model, and the 95% confidence interval (CI) for the HR will be provided. Results from an unstratified analysis will also be provided. Kaplan-Meier methodology will be used to estimate the median PFS for each treatment arm, and Kaplan-Meier curves will be produced. Brookmeyer Crowley methodology will be used to construct the 95% CI for the median PFS for each treatment arm.


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: From randomization to death, from any cause, assessed for up to 8 years ]
    The analyses for OS will follow intent-to-treat (ITT) principle and will be conducted separately within each cohort (pancreatic neuroendocrine tumor [NET] and carcinoid tumor). The distribution of OS will be estimated using the method of Kaplan-Meier. The median OS, along with the 95% CI, will be estimated by the two treatment groups. Overall survival will be compared between treatment arms using the stratified log-rank test at a one-sided cumulative 2.5% level of significance. The stratified Cox regression will be used to estimate the HR of OS, along with the 95% CI. A hierarchical approach will be used to control for family-wise type-I error rate, therefore OS will be formally statistically tested only if the primary efficacy endpoint, PFS, is statistically significantly different between the two treatment groups.

  2. Incidence of adverse events (AEs) graded according to the Common Terminology Criteria for Adverse Events (CTCAE) and Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) [ Time Frame: Up to 8 years ]
    For CTCAE data, the frequency tables will be reviewed to determine the patterns. The overall adverse event rates will be compared between treatment groups using Chi-square test (or Fisher's exact test if the data in contingency table is sparse). PRO-CTCAE data will, at minimum, be analyzed similarly to CTCAE data. The initial analysis of each PRO-CTCAE item will use all available scores in an analysis which mirrors the approach used for the CTCAE data. Supplemental analysis will use model-based multiple imputation incorporating baseline patient characteristics and physician-rated performance status. CTCAE data may be incorporated as auxiliary data into multiple imputation models for AEs which are captured by both PRO-CTCAE and CTCAE. Results from supplemental analysis will be descriptively compared to the results of the initial analysis to assess the robustness of results to missing data. Additional analyses of PRO-CTCAE data beyond those specified above may be undertaken.

  3. Radiographic response rate [ Time Frame: Up to 8 years ]
    Will be defined as the proportion of patients in each arm whose best response is either complete response (CR) or partial response (PR). Radiographic response rate for both cohorts: the analyses for confirmed radiographic response rate will follow the ITT principle and will be conducted separately within each cohort (pancreatic NET and carcinoid tumor). The proportion of patients with either confirmed CR or confirmed PR as their best response will be estimated using point estimates and 95% confidence intervals. Radiographic response rate will be compared between treatment arms using the 2-sample z-test to compare sample proportion at a one-sided 2.5% level of significance.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

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 without specification of differentiation status, adenocarcinoid tumor, or goblet cell carcinoid tumor are not eligible. Patients with well-differentiated grade 3 neuroendocrine tumor are 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 (i.e., associated with symptoms or clinical syndrome related to hormone secretion by tumor) or nonfunctional tumors are allowed
    • Radiologic Evaluation: Target lesions must have shown evidence of 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, imaging reports, and clinic notes indicating growth of existing lesions, development of new lesions, or treatment changes must be submitted

  • Measurable Disease

    • 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

  • Prior Treatment

    • Patient must have experienced disease progression after receiving 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 must include one of the following: 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 (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
    • 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 myocardial infarction (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 registration on the study

  • 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)
  • Age >= 18 years
  • 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)
  • 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)

    • 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

  • 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 TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible

  • Calcium 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 TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible

  • Magnesium 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 TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible
  • Urine protein to creatinine (UPC) ratio =< 1
  • QT interval corrected for heart rate using Fridericia's formula (QTcF) =< 500 msec

  • TSH 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 TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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 ClinicalTrials.gov identifier (NCT number): NCT03375320


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Jennifer A Chan Alliance for Clinical Trials in Oncology
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03375320    
Other Study ID Numbers: NCI-2017-02297
NCI-2017-02297 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
A021602 ( Other Identifier: Alliance for Clinical Trials in Oncology )
A021602 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
First Posted: December 18, 2017    Key Record Dates
Last Update Posted: January 27, 2023
Last Verified: January 2023

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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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Neuroendocrine Tumors
Neoplasms
Carcinoid Tumor
Adenoma, Islet Cell
Intestinal Neoplasms
Pancreatic Neoplasms
Stomach Neoplasms
Malignant Carcinoid Syndrome
Gastrointestinal Neoplasms
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
 Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Adenoma
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Stomach Diseases