Regorafenib In Treating Patients With Advanced Or Metastatic Neuroendocrine Tumors

Study Overview

Regorafenib in Treating Patients With Advanced or Metastatic Neuroendocrine Tumors

This phase II trial studies regorafenib in treating patients with neuroendocrine tumors that have spread from the primary site (place where it started) to other places in the body. Regorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES: I. To assess progression-free survival (PFS) in advanced/metastatic in patients with carcinoid or pancreatic islet cell tumors. SECONDARY OBJECTIVES: I. To assess overall survival and response rate in advanced/metastatic poor prognosis in patients with carcinoid or pancreatic islet cell tumors. II. To assess the toxicity of patients treated with regorafenib. III. To explore markers of angiogenesis as they relate to outcome in carcinoid and pancreatic islet cell tumors. OUTLINE: Patients receive regorafenib orally (PO) once daily (QD) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months.

Gastrinoma
Glucagonoma
Insulinoma
Metastatic Gastrointestinal Carcinoid Tumor
Pancreatic Polypeptide Tumor
Pulmonary Carcinoid Tumor
Recurrent Gastrointestinal Carcinoid Tumor
Recurrent Islet Cell Carcinoma
Somatostatinoma

DRUG: regorafenib
OTHER: laboratory biomarker analysis

0S-14-3
NCI-2014-01996 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
HS-14-00583
0S-14-3 (OTHER Identifier) (OTHER: USC Norris Comprehensive Cancer Center)
P30CA014089 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2014-10-03	Results First Submitted 2021-11-15	Last Update Submitted that met QC Criteria 2021-11-15
First Submitted that Met QC Criteria 2014-10-03	Results First Submitted that Met QC Criteria 2021-11-15	Last Update Posted (ACTUAL) 2021-12-15
First Posted (ACTUAL) 2014-10-08	Results First Posted 2021-12-15	Last Verified 2021-11

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Treatment (regorafenib) Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	DRUG: regorafenib Given PO OTHER: laboratory biomarker analysis Correlative studies

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Treatment (regorafenib)

Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

DRUG: regorafenib

Given PO

OTHER: laboratory biomarker analysis

Correlative studies

Primary Outcome Measures	Measure Description	Time Frame
PFS	Two parallel Simon's 2-stage phase II trials will be conducted to evaluate the efficacy of regorafenib in patients with advanced carcinoid (cohort A) or pancreatic islet cell tumors (cohort B). Will be summarized as a proportion of patients who are alive and progression-free among all patients in the primary data analysis set. The 95% confidence intervals (CIs) will be calculated using the Wilson method. Will be analyzed using Kaplan-Meier (KM) curves. The median PFS and 95% CIs will be calculated. The probability of 6-month PFS will be estimated from the KM curve too.	Time from start of treatment to time of progression or death on study whichever comes first, assessed at 6 months

Secondary Outcome Measures	Measure Description	Time Frame
Tumor Response Rate, Evaluated Using the New International Criteria Proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee	Will be calculated as a proportion of patients who have either a complete or partial response among all patients in the primary data analysis set. The 95% CIs will be given.	Up to 4 years
Overall Survival	The 95% CIs will be calculated using the Wilson method. Will be analyzed using KM curves.	From start of treatment until death due to any cause, assessed up to 4 years
Incidence of Adverse Events, Assessed According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0	Toxicity profile will be summarized by attribution: regorafenib-related and all reported, course: course 1 and all courses, type, and grade: grade 1-2, 3-4, and 5.	Up to 4 years

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Advanced metastatic, progressing carcinoid or pancreatic islet cell cancers
No prior targeted treatment (tx) or anti-angiogenic therapy; patients may have received one line of prior therapy with octreotide, locoregional therapy; continuation of concurrent octreotide is allowed; patients will be maintained on octreotide (sandostatin) for the duration of their treatment
Life expectancy of at least 12 weeks (3 months)
Subjects must be able to understand and be willing to sign the written informed consent form (ICF); a signed ICF must be appropriately obtained prior to the conduct of any trial-specific procedure
All acute toxic effects of any prior treatment have resolved to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v)4.0 grade 1 or less at the time of signing the informed consent form (ICF); exceptions to this include alopecia
Total bilirubin =< 1.5 x the upper limits of normal (ULN)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer)
Alkaline phosphastase limit =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer)
Lipase =< 1.5 x the ULN
Amylase =< 1.5 x the ULN
Serum creatinine =< 1.5 x the ULN
International normalized ratio (INR)/ partial thromboplastin time (PTT) < 1.5 x ULN; (subjects who are treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists; close monitoring [day 5 of cycle 1 and day 1 of each cycle] is mandatory) will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care)
Platelet count >= 100,000 /mm^3
Hemoglobin (Hb) >= 9 g/dL
Absolute neutrophil count (ANC) >= 1,500/mm^3; blood transfusion to meet the inclusion criteria will not be allowed
Glomerular filtration rate (GFR) >= 30 ml/min/1.73 m^2 according to the Modified Diet in Renal Disease (MDRD) abbreviated formula
Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study drug; post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test; the definition of adequate contraception will be based on the judgement of the investigator
Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until at least 3 months after the last dose of study drug; the definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate
Subject must be able to swallow and retain oral medication
Southwest Oncology Group (SWOG) performance status 0-1
Patients must have measurable disease

Previous assignment to treatment during this study; subjects permanently withdrawn from study participation will not be allowed to re-enter study
Uncontrolled hypertension (systolic pressure > 140 mm Hg or diastolic pressure > 90 mm Hg [NCI-CTCAE v4.0] on repeated measurement) despite optimal medical management
Active or clinically significant cardiac disease including:

Congestive heart failure - New York Heart Association (NYHA) > class II
Active coronary artery disease
Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin
Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomization
Evidence or history of bleeding diathesis or coagulopathy
Any hemorrhage or bleeding event >= NCI-CTCAE grade 3 within 4 weeks prior to start of study medication
Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis or pulmonary embolism within 6 months of start of study treatment
Subjects with any previously untreated or concurrent cancer that is distinct in primary site or histology from carcinoid or pancreatic islet cancer except cervical cancer in-situ, treated basal cell carcinoma, or superficial bladder tumor; subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before randomization are allowed; all cancer treatments must be completed at least 3 years prior to study entry (i.e., signature date of the informed consent form)
Patients with pheochromocytoma
Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection requiring treatment with antiviral therapy
Ongoing infection > grade 2 NCI-CTCAE v4.0
Presence of a non-healing wound, non-healing ulcer, or bone fracture
Renal failure requiring hemo-or peritoneal dialysis
Dehydration grade >= 1 NCI-CTCAE v4.0
Patients with seizure disorder requiring medication
Persistent proteinuria >= grade 3 NCI-CTCAE v4.0 (> 3.5 g/24 hrs, measured by urine protein:creatinine ratio on a random urine sample)
Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
Pleural effusion or ascites that causes respiratory compromise (>= NCI-CTCAE version 4.0 grade 2 dyspnea)
History of organ allograft (including corneal transplant)
Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulations given during the course of this trial
Any malabsorption condition
Women who are pregnant or breast-feeding
Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation
Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results
Patients with known brain metastases should be excluded from this clinical trial
History of allergic reactions attributed to compounds of similar chemical or biologic composition to regorafenib or other agents used in study
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
Excluded therapies and medications, previous and concomitant

Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other than study treatment (regorafenib)
Prior use of regorafenib
Concurrent use of chemotherapy, radiotherapy or another investigational drug or device therapy (i.e., outside of study treatment) during, or within 4 weeks of trial entry (signing of the ICF)
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication
Use of any herbal remedy (e.g. St. John's wort [Hypericum perforatum])

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

National Cancer Institute (NCI)

Investigators

PRINCIPAL_INVESTIGATOR: Syma Iqbal, MD, University of Southern California

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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Clinical Trial Record