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Cabozantinib S-malate in Treating Patients With Neuroendocrine Tumors Previously Treated With Everolimus That Are Locally Advanced, Metastatic, or Cannot Be Removed by Surgery

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ClinicalTrials.gov Identifier: NCT03375320
Recruitment Status : Recruiting
First Posted : December 18, 2017
Last Update Posted : December 13, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This randomized phase III trial studies cabozantinib S-malate to see how well it works compared with placebo in treating patients with neuroendocrine tumors previously treated with everolimus that have spread to nearby tissues or lymph nodes, have spread to other places in the body, or cannot be removed by surgery. Cabozantinib S-malate 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 Digestive System Neuroendocrine Neoplasm Enterochromaffin Cell Serotonin-Producing Pancreatic Neuroendocrine Tumor Functional Pancreatic Neuroendocrine Tumor Intermediate Grade Lung Neuroendocrine Neoplasm Low Grade Lung Neuroendocrine Neoplasm Lung Atypical Carcinoid Tumor Lung Carcinoid Tumor Metastatic Digestive System Neuroendocrine Tumor G1 Neuroendocrine Neoplasm Nonfunctional Pancreatic Neuroendocrine Tumor Pancreatic 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 Drug: Cabozantinib S-malate Other: Laboratory Biomarker Analysis Other: Placebo Other: Quality-of-Life Assessment Phase 3

  Show Detailed Description

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 Everolimus (CABINET)
Actual Study Start Date : July 18, 2018
Estimated Primary Completion Date : January 1, 2021
Estimated Study Completion Date : January 1, 2021


Arm Intervention/treatment
Experimental: Arm I (cabozantinib S-malate)
Patients receive cabozantinib S-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Cabozantinib S-malate
Given PO
Other Names:
  • BMS-907351
  • Cabometyx
  • Cometriq
  • XL184

Other: Laboratory Biomarker Analysis
Correlative studies

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. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Other: Placebo
Given PO
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy

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




Primary Outcome Measures :
  1. Progression-free survival (PFS) assessed per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 determined by retrospective independent central review [ 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 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 defined as the proportion of patients in each arm whose best response is either complete response (CR) or partial response (PR) [ Time Frame: Up to 8 years ]
    Radiographic response rate for both cohorts: the analyses for 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 CR or PR as their best response will be estimated using point estimates and 95% confidence intervals according to the methods in Duffy and Santner. 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.



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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, 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, or unknown primary site; GI, lung, 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 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 failed at least one prior systemic therapy that included everolimus; disease progression or treatment intolerance leading to discontinuation is considered treatment failure
    • 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 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 invading the GI tract 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)
  • 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
  • Magnesium WNL
  • Urine protein to creatinine (UPC) ratio =< 1
  • QT interval corrected for heart rate using Fridericia's formula (QTcF) =< 500 msec
  • Thyroid-stimulating hormone (TSH) WNL

    • Supplementation is acceptable to achieve a TSH WNL; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible

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


  Show 249 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Jennifer Chan Alliance for Clinical Trials in Oncology

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03375320     History of Changes
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: December 13, 2018
Last Verified: July 2018

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

Additional relevant MeSH terms:
Neoplasms
Neuroendocrine Tumors
Carcinoid Tumor
Adenoma, Islet Cell
Malignant Carcinoid Syndrome
Gastrointestinal Neoplasms
Pancreatic 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
Everolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs