Sorafenib/Erlotinib Versus Erlotinib Alone in Previously Treated Advanced Non-Small-Cell Lung Cancer (NSCLC)

A Randomized Double-Blind Placebo-Controlled Phase II Trial of Sorafenib and Erlotinib or Erlotinib Alone in Previously Treated Advanced Non-Small Cell Lung Cancer

This trial will investigate the use of the newer targeted agents erlotinib and sorafenib in patients with stage IIIB or stage IV NSCLC who have received 1-2 prior chemotherapy regimens. Patients will be randomized to receive erlotinib (150 mg/day) and sorafenib (400 mg twice daily), or erlotinib (150 mg/day) and a placebo.

Study Overview

• Status: Completed
• Conditions: Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: Erlotinib + Sorafenib; Drug: Erlotinib + Placebo

Detailed Description

The rationale of this study is to combine two distinct kinase inhibitors to evaluate synergistic inhibition of angiogenesis and epidermal growth factor receptor (EGFR) signaling. Erlotinib is a oral tyrosine kinase inhibitor that targets EGFR. Sorafenib is a oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor beta, Raf-1, Flt-3, and C-kit. These agents also do not exhibit overlapping adverse event profiles which provided additional support for studying this combination therapy.

• Study Type: Interventional
• Enrollment (Actual): 166
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists
  • Georgia
    • Gainesville, Georgia, United States, 30501
      • Northeast Georgia Medical Center
    • Marietta, Georgia, United States, 30060
      • Wellstar Cancer Research
  • Kansas
    • Overland Park, Kansas, United States, 66210
      • Kansas City Cancer Centers
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Center for Cancer and Blood Disorders
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Grand Rapids Clinical Oncology Program
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Methodist Cancer Center
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Cancer Care of Western North Carolina
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care
    • Columbus, Ohio, United States, 43219
      • Mid Ohio Oncology/Hematology, Inc./ The Mark H. Zangmeister Center
  • South Carolina
    • Columbia, South Carolina, United States, 29210
      • South Carolina Oncology Associates, PA
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Oncology Hematology Associates
    • Collierville, Tennessee, United States, 38017
      • Family Cancer Center
    • Nashville, Tennessee, United States, 37023
      • Tennessee Oncology, PLLC
  • Texas
    • Corpus Christi, Texas, United States, 78463
      • Coastal Bend Cancer Center
  • Virginia
    • Richmond, Virginia, United States, 23235
      • Virginia Cancer Institute

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

Inclusion Criteria:

• Histologically confirmed locally advanced or metastatic NSCLC (unresectable stage IIIB or stage IV). Eligible histologies include adenocarcinoma and squamous cell carcinoma. Patients with recurrent disease after treatment for localized NSCLC are also eligible. Cytologic specimens obtained by brushings, washings, or needle aspiration are acceptable.
• At least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques, or as >= 10 mm with spiral computerized tomography (CT) scan according to the Response Evaluation Criteria in Solid Tumors (RECIST).
• Failure of at least one, and no more than two prior cytotoxic chemotherapy regimens for advanced disease (either due to progressive disease or toxicity).
• Recovery from any toxic effects of prior therapy to <= grade 1.
• Completion of radiation therapy at least 28 days prior to the start of study treatment (not including palliative local radiation). Previously irradiated lesions in the advanced setting cannot be included as target lesions unless clear tumor progression has been observed since the end of radiation.
• An ECOG performance status of 0-2.
• Absolute neutrophil count (ANC) >= 1,500, platelets >= 75,000.
• Hemoglobin >= 9 g/dL (within 7 days prior to study treatment).
• International normalized ratio (INR) <= 1.5 or prothrombin time (PT)/partial thromboplastin time (PTT) within normal limits (WNL) of the institution
• Serum creatinine <= 1.5 x institutional upper limit of normal (ULN) within 7 days prior to study treatment.
• Transaminases <= 3 x institutional ULN
• Agreement of female patients of childbearing potential and male patients who have partners of childbearing potential to use an effective form of contraception to prevent pregnancy during treatment, and for a minimum of 90 days thereafter.
• Patients who have treated brain metastases >= 4 weeks out (with surgery and/or radiation therapy) and no evidence of CNS progression.

Exclusion Criteria:

• Past or current history of neoplasm (other than the entry diagnosis), with the exception of treated non-melanoma skin cancer or carcinoma in-situ of the cervix, or other cancers cured by local therapy alone, and a disease-free survival (DFS) >= 3 years.
• Patients who have mixed tumors with small-cell elements are ineligible.
• Pregnancy or lactation.
• Prior treatment with EGFR TKIs or VEGFR TKIs for NSCLC. [NOTE: prior cetuximab and/or bevacizumab use is permitted].
• Significant cardiac disease within 90 days of starting study treatment
• Myocardial infarction within 6 months prior to initiation of study treatment.
• Cardiomegaly on chest imaging or ventricular hypertrophy on electrocardiogram (ECG)
• Poorly controlled hypertension
• Unstable angina (anginal symptoms at rest).
• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
• Presence of cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmia.
• A serious underlying medical condition that would impair the ability of the patient to receive protocol treatment.
• A major surgical procedure, open biopsy, or significant traumatic injury within 28 days of beginning treatment, or anticipation of the need for major surgery during the course of the study.
• Stroke or transient ischemic attack (TIA) within the past 6 months.
• Any prior history of hypertensive crisis or hypertensive encephalopathy.
• Pulmonary hemorrhage/bleeding event >= grade 2 within 28 days of study treatment.
• Any other non-pulmonary hemorrhage/bleeding event >= grade 3 within 28 days of study treatment.
• Evidence or history of bleeding diathesis or coagulopathy.
• Serious non-healing wound, ulcer, or bone fracture.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combination Therapy; Erlotinib + Sorafenib	Drug: Erlotinib + Sorafenib; Patients who are randomized to Cohort A will take sorafenib 400 mg (2 x 200-mg tablets) orally twice a day, and erlotinib 150 mg orally once a day.; Other Names: Tarceva; Nexavar
Placebo Comparator: Placebo; Erlotinib + Placebo	Drug: Erlotinib + Placebo; Patients who are randomized to Cohort B will take erlotinib 150 mg orally once a day and placebo orally twice a day.; Other Names: Tarceva

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Objective Response Rate (ORR)	Overall response rate (ORR) is defined as the percentage of patients who have a partial or complete response to therapy. Responses were assessed by the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.0). Complete Response: Disappearance of all target lesions, and disappearance of all non-target lesions. Partial Response: At least a 30% decrease in the sum of the longest diameter of target lesions (taking as reference the baseline sum of longest diameters)	18 months
Progression Free Survival (PFS)	Progression-free survival is defined as the time from the first day of treatment until the day tumor progression was documented. Response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST). Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions	18 months
Disease Control Rate (DCR)	Disease Control Rate (DCR) is defined as the percentage of patients who have a partial/complete/stable response to therapy. Responses were assessed by the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.0). Complete Response: Disappearance of all target lesions, and disappearance of all non-target lesions. Partial Response: At least a 30% decrease in the sum of the longest diameter of target lesions (taking as reference the baseline sum of longest diameters) Stable Response: Neither sufficient shrinkage to qualify for partial response, nor sufficient increase to qualify for progressive disease (taking as reference the smallest sum of diameters since the treatment started).	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response	Duration of response is defined as the time from when objective response is realized until time to first documented disease progression. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Objective Response = CR + PR. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions.	18 months
6-month PFS	Progression free survival is defined as the time from the first day of treatment until the day tumor progression was documented. Response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST). Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions (1). Percentage of participants who were progression free at 6 month from the start of treatment is reported here.	6 months
Overall Survival (OS)	OS is defined as the time from the first treatment until date of death due to any cause. In the absence of confirmation of death or lack of data beyond follow-up period, the survival time was censored to last date the participant was known to be alive.	18 months

Collaborators and Investigators

• Sponsor: SCRI Development Innovations, LLC
• Collaborators: Bayer
• Investigators: Study Chair: David Spigel, M.D., SCRI Development Innovations, LLC

Publications and helpful links

General Publications

• Spigel DR, Burris HA 3rd, Greco FA, Shipley DL, Friedman EK, Waterhouse DM, Whorf RC, Mitchell RB, Daniel DB, Zangmeister J, Bass JD, Hainsworth JD. Randomized, double-blind, placebo-controlled, phase II trial of sorafenib and erlotinib or erlotinib alone in previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2011 Jun 20;29(18):2582-9. doi: 10.1200/JCO.2010.30.7678. Epub 2011 May 16.

Study record dates

Study Major Dates

• Study Start: February 1, 2008
• Primary Completion (Actual): February 1, 2009
• Study Completion (Actual): February 1, 2009

Study Registration Dates

• First Submitted: December 26, 2007
• First Submitted That Met QC Criteria: January 23, 2008
• First Posted (Estimate): January 24, 2008

Study Record Updates

• Last Update Posted (Actual): March 10, 2022
• Last Update Submitted That Met QC Criteria: February 15, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Sorafenib; Non-Small Cell Lung Cancer; Placebo-controlled; Double-blind; Erlotinib; Advanced
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride; Sorafenib
• Other Study ID Numbers: SCRI LUN 160