Sorafenib Tosylate in Treating Patients With Progressive Metastatic Neuroendocrine Tumors

A Phase II Trial of Bay 43-9006 in Progressive Metastatic Neuroendocrine Tumors

This phase II trial is studying how well sorafenib tosylate works in treating patients with progressive metastatic neuroendocrine tumors. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Study Overview

• Status: Completed
• Conditions: Neuroendocrine Tumor; Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma; WDHA Syndrome
• Intervention / Treatment: Drug: sorafenib tosylate

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the objective tumor response rate of BAY 43-9006 (sorafenib tosylate) in patients with advanced neuroendocrine tumors.

SECONDARY OBJECTIVES:

I. Adverse event rate(s). II. Progression free survival and time to progression. III. Improvement in circulating hormone levels. IV. Overall survival.

OUTLINE: This is a multicenter study. Patients are grouped into 2 separate analysis Groups according to tumor type (Group A: Carcinoid; Group B: Islet cell/other well-differentiated tumor). Each Group was independently evaluated for all study endpoints.

Patients receive oral sorafenib tosylate twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months until disease progression and then every 6 months for up to 2 years from study entry.

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Criteria:

• Histologically confirmed neuroendocrine tumor:

  • Carcinoid tumor OR islet cell carcinoma/other well-differentiated tumor
  • No anaplastic or high-grade histology
  • Metastatic disease
• Measurable disease
• No thyroid carcinoma of any histology, thymoma, or pheochromocytoma/paraganglioma
• No known brain metastases

• Performance status:

  • Eastern Cooperative Oncology Group (ECOG) 0-2

• Life expectancy:

  • At least 24 weeks

• Hematopoietic:

  • Absolute neutrophil count >= 1,500/mm3
  • Platelet count >= 100,000/mm3
  • No bleeding diathesis

• Hepatic:

  • Bilirubin =< 2 times upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) =< 3 times ULN (5 times ULN if liver metastases are present)
  • International normalized ratio (INR) normal
  • PTT normal

• Renal:

  • Creatinine =< 1.5 times ULN
• Cardiovascular:

No poorly controlled hypertension; No symptoms of congestive heart failure; No unstable angina pectoris; No cardiac arrhythmia

• Gastrointestinal:

  • Able to swallow capsules intact
  • No gastrointestinal tract disease resulting in an inability to take oral medication (e.g., dysphagia)
  • No requirement for IV alimentation
  • No active peptic ulcer disease
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance
• No other invasive malignancy within the past 3 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No other uncontrolled illness
• At least 4 weeks since prior interferon
• No more than 1 prior systemic chemotherapy regimen:

Chemoembolization is not considered systemic chemotherapy

• At least 4 weeks since prior chemoembolization
• At least 3 weeks since prior radiotherapy
• No prior procedures adversely affecting intestinal absorption
• At least 4 weeks since prior hepatic artery embolization
• No other prior systemic therapy
• No other concurrent investigational treatment
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent enzyme-inducing anticonvulsants (e.g., carbamazepine, phenobarbital, or phenytoin)
• No concurrent rifampin
• No concurrent Hypericum perforatum (St. John's wort)
• Prior or concurrent octreotide for symptomatic treatment allowed
• No concurrent therapeutic anticoagulation:

Concurrent prophylactic anticoagulation (i.e., low dose warfarin) of venous or arterial access devices allowed provided requirements for INR or PTT are met

• At least 4 weeks since prior major surgery
• Recovered from all prior therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A (patients with carcinoid tumors); Patients receive 400 mg oral sorafenib twice daily on days 1-28.	Drug: sorafenib tosylate; 400 mg given orally; Other Names: BAY 43-9006; BAY 43-9006 Tosylate Salt; BAY 54-9085; Nexavar; SFN
Experimental: Group B (islet cell and other neuroendocrine tumors); Patients receive 400 mg oral sorafenib twice daily on days 1-28.	Drug: sorafenib tosylate; 400 mg given orally; Other Names: BAY 43-9006; BAY 43-9006 Tosylate Salt; BAY 54-9085; Nexavar; SFN

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed Response Rate	Confirmed response rate was defined using Response Evaluation Criteria In Solid Tumors (RECIST). A confirmed response is defined as a complete response (CR) or partial response (PR) observed on subsequent scans at least 4 weeks apart. Confirmed response rate was estimated by the number of successes divided by the total number of evaluable patients.> > Complete Response (CR) is defined as the disappearance of all target lesions.> Partial Response (PR) is defined as a 30% decrease in sum of longest diameter of target lesions;> > We report the percentage of patients with a confirmed response and a 95% confidence interval estimated by the Duffy and Santner method.	Duration of Treatment (Up to 2 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity	For this secondary endpoint, toxicity is defined as a grade 3 or higher adverse events that is classified as either possibly, probably, or definitely related to study treatment. The assignment of attribution to study treatment and grade (or degree of severity) of the adverse event are classified using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The number of participants reporting a grade 3 or higher toxicity are reported.	Up to 2 years
Overall Survival	Overall survival (OS) was defined as the time from registration to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% CI was estimated using the Kaplan Meier method.	From registration to death (up to 2 years)
Progression Free Survival	Progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST) as a 20% increase in the su of longest diameter of target lesions. Progression free survival (PFS) was defined as the time from registration to progression or death of any cause. Participants who were progression free were censored at the date of their most recent disease assessment. The median PFS with 95% CI was estimated using the Kaplan Meier method.	Time from registration to progression or death (up to 2 years)
Duration of Response	Duration of response (DOR) was defined as the time from attaining a response (PR or CR) to the date of progression. Participants without progression were censored at the date of their most recent disease assessment. The median DOR was estimated using simple summary statistics.	Time from response to progression (up to 2 years)

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Timothy Hobday, Mayo Clinic

Study record dates

Study Major Dates

• Study Start: June 1, 2005
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: August 16, 2005
• First Submitted That Met QC Criteria: August 16, 2005
• First Posted (Estimate): August 19, 2005

Study Record Updates

• Last Update Posted (Estimate): November 17, 2014
• Last Update Submitted That Met QC Criteria: November 14, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Disease Attributes; Digestive System Neoplasms; Gastrointestinal Diseases; Endocrine Gland Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Pancreatic Diseases; Adenoma; Carcinoma, Neuroendocrine; Pancreatic Neoplasms; Adenoma, Islet Cell; Neoplasms; Recurrence; Gastrointestinal Neoplasms; Neuroendocrine Tumors; Carcinoid Tumor; Malignant Carcinoid Syndrome; Carcinoma, Islet Cell; Insulinoma; Gastrinoma; Glucagonoma; Somatostatinoma; Vipoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Sorafenib
• Other Study ID Numbers: NCI-2009-00121; N01CM62205 (U.S. NIH Grant/Contract); 7046; MC044H; CDR0000437792