Regorafenib in Treating Patients With Advanced or Metastatic Neuroendocrine Tumors

• Sponsor: University of Southern California (Other)
• Overall Status: Completed
• CT.gov ID: NCT02259725
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 3
• Locations: 5
• Arm: 1
• Actual Duration (Months): 48.1
• Patients Per Site: 0.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
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	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess progression-free survival (PFS) in advanced/metastatic in patients with carcinoid or pancreatic islet cell tumors.

SECONDARY OBJECTIVES:

1. To assess overall survival and response rate in advanced/metastatic poor prognosis in patients with carcinoid or pancreatic islet cell tumors.

2. 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.

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 Study of Single Agent Regorafenib in Patients With Advanced/Metastatic Neuroendocrine Tumors
• Actual Study Start Date: Aug 16, 2016
• Actual Primary Completion Date: Aug 20, 2020
• Actual Study Completion Date: Aug 20, 2020

Arms and Interventions

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 Names: BAY 73-4506 multikinase inhibitor BAY 73-4506 Stivarga ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. PFS [Time from start of treatment to time of progression or death on study whichever comes first, assessed at 6 months]

   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.

Secondary Outcome Measures

1. Tumor Response Rate, Evaluated Using the New International Criteria Proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [Up to 4 years]

   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.

2. Overall Survival [From start of treatment until death due to any cause, assessed up to 4 years]

   The 95% CIs will be calculated using the Wilson method. Will be analyzed using KM curves.

3. Incidence of Adverse Events, Assessed According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [Up to 4 years]

   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.

Other Outcome Measures

1. Biomarkers Such as Messenger Ribonucleic Acid (mRNA) Levels or Germline Variations of Genes Related to Angiogenesis [Up to 4 years]

   The associations between biomarkers and clinical outcomes (6-month PFS, response, PFS, and overall survival) will be analyzed in univariate analysis first using appropriate methods. Multivariable analyses will be conducted to evaluate the independent effect of a marker on clinical outcome. All tests will be two-sided at a significance level of 0.05. P values will be adjusted for multiple comparisons.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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])

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
2	USC Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
3	Hoag Memorial Hospital Presbyterian	Newport Beach	California	United States	92663
4	USC Norris Oncology Hematology-Newport Beach	Newport Beach	California	United States	92663
5	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109

Sponsors and Collaborators

• University of Southern California
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Syma Iqbal, MD, University of Southern California

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 13, 2018

More Information

Publications

None provided.

• Responsible Party: University of Southern California
• ClinicalTrials.gov Identifier: NCT02259725
• Other Study ID Numbers: 0S-14-3; NCI-2014-01996; HS-14-00583; 0S-14-3; P30CA014089
• First Posted: Oct 8, 2014
• Last Update Posted: Dec 15, 2021
• Last Verified: Nov 1, 2021

• 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; Malignant Carcinoid Syndrome; Gastrointestinal Neoplasms; Insulinoma; Carcinoma, Islet Cell; Gastrinoma; Glucagonoma; Somatostatinoma; Recurrence

Study Results

Participant Flow

Recruitment Details	The study began recruiting in August 2016 and ended in January 2019. All subjects were seen and treated either at USC Norris Comprehensive Cancer Center or at LAC+USC Medical Center.
Pre-assignment Detail	There were no pre-assignment criteria. All subjects were given the same treatment.

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	3
COMPLETED	3
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO laboratory biomarker analysis: Correlative studies
Overall Participants	3
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	3 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	3 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 66.7%
Not Hispanic or Latino	1 33.3%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	3 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%

Outcome Measures

1. Primary Outcome

Title	PFS
Description	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 Frame	Time from start of treatment to time of progression or death on study whichever comes first, assessed at 6 months

Outcome Measure Data

Analysis Population Description

No analysis done. Only 3 subjects were enrolled out of accrual goal of 24 subjects.

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO laboratory biomarker analysis: Correlative studies
Measure Participants	0

2. Secondary Outcome

Title	Tumor Response Rate, Evaluated Using the New International Criteria Proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee
Description	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.
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

No analysis was done. Only 3 subjects were enrolled out of accrual goal of 24 subjects.

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO laboratory biomarker analysis: Correlative studies
Measure Participants	0

3. Secondary Outcome

Title	Overall Survival
Description	The 95% CIs will be calculated using the Wilson method. Will be analyzed using KM curves.
Time Frame	From start of treatment until death due to any cause, assessed up to 4 years

Outcome Measure Data

Analysis Population Description

Due to insufficient accrual (only 3 accrued), no analysis was performed.

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO laboratory biomarker analysis: Correlative studies
Measure Participants	0

4. Secondary Outcome

Title	Incidence of Adverse Events, Assessed According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0
Description	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.
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO laboratory biomarker analysis: Correlative studies
Measure Participants	0

5. Other Pre-specified Outcome

Title	Biomarkers Such as Messenger Ribonucleic Acid (mRNA) Levels or Germline Variations of Genes Related to Angiogenesis
Description	The associations between biomarkers and clinical outcomes (6-month PFS, response, PFS, and overall survival) will be analyzed in univariate analysis first using appropriate methods. Multivariable analyses will be conducted to evaluate the independent effect of a marker on clinical outcome. All tests will be two-sided at a significance level of 0.05. P values will be adjusted for multiple comparisons.
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

Analysis not done. Only 3 subjects were enrolled out of the accrual goal of subjects.

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO laboratory biomarker analysis: Correlative studies
Measure Participants	0

Adverse Events

Time Frame	Adverse events were collected from the time the subject received the initial study drug administration and continued throughout the study until 30 days after the last dose or until resolution of adverse event if beyond 30 days after last dose.
Adverse Event Reporting Description	Adverse events are assessed during regularly scheduled follow up.
Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Treatment (Regorafenib)
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Serious Adverse Events
	Treatment (Regorafenib)
	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)
Gastrointestinal disorders
Constipation	1/3 (33.3%)	1
Diarrhea	1/3 (33.3%)	1
Investigations
Alanine aminotransferase increased	1/3 (33.3%)	1
Aspartate aminotransferase increased	1/3 (33.3%)	1
Blood bilirubin increased	1/3 (33.3%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Regorafenib)
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Blood and lymphatic system disorders
Anemia	1/3 (33.3%)	1
Gastrointestinal disorders
Abdominal pain	1/3 (33.3%)	1
Bloating	1/3 (33.3%)	1
Diarrhea	1/3 (33.3%)	1
Mucositis oral	1/3 (33.3%)	1
Nausea	3/3 (100%)	3
Stomach pain	1/3 (33.3%)	1
Vomiting	1/3 (33.3%)	1
General disorders
Edema limbs	1/3 (33.3%)	1
Fatigue	1/3 (33.3%)	3
Infections and infestations
Paronychia	1/3 (33.3%)	1
Investigations
Alkaline phosphatase increased	1/3 (33.3%)	1
Blood bilirubin increased	1/3 (33.3%)	1
Lipase increased	1/3 (33.3%)	1
Metabolism and nutrition disorders
Dehydration	1/3 (33.3%)	1
Hypercalcemia	1/3 (33.3%)	1
Hyperuricemia	1/3 (33.3%)	1
Hypocalcemia	1/3 (33.3%)	1
Musculoskeletal and connective tissue disorders
Flank pain	1/3 (33.3%)	1
Myalgia	2/3 (66.7%)	3
Pain in extremity	1/3 (33.3%)	3
Nervous system disorders
Dysgeusia	1/3 (33.3%)	1
Reproductive system and breast disorders
Testicular pain	1/3 (33.3%)	1
Hoarseness	2/3 (66.7%)	2
Voice alteration	1/3 (33.3%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/3 (33.3%)	1
Dry skin	1/3 (33.3%)	1
Palmar-plantar erythrodysesthesia syndrome	2/3 (66.7%)	2
Vascular disorders
Hypertension	2/3 (66.7%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.