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

• Sponsor: SCRI Development Innovations, LLC (Other)
• Overall Status: Completed
• CT.gov ID: NCT00600015
• Collaborator: Bayer (Industry)
• Enrollment: 166
• Locations: 16
• Arms: 2
• Duration (Months): 12
• Patients Per Site: 10.4
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Non-Small Cell Lung Cancer	Drug: Erlotinib + Sorafenib; Drug: Erlotinib + Placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 166 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: Feb 1, 2009
• Actual Study Completion Date: Feb 1, 2009

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Overall Objective Response Rate (ORR) [18 months]

   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)

2. Progression Free Survival (PFS) [18 months]

   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

3. Disease Control Rate (DCR) [18 months]

   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).

Secondary Outcome Measures

1. Duration of Response [18 months]

   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.

2. 6-month PFS [6 months]

   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.

3. Overall Survival (OS) [18 months]

   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.

Eligibility Criteria

Criteria

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

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.

Contacts and Locations

Locations

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

Sponsors and Collaborators

• SCRI Development Innovations, LLC
• Bayer

Investigators

• Study Chair: David Spigel, M.D., SCRI Development Innovations, LLC

Study Documents (Full-Text)

None provided.

More Information

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.

• Responsible Party: SCRI Development Innovations, LLC
• ClinicalTrials.gov Identifier: NCT00600015
• Other Study ID Numbers: SCRI LUN 160
• First Posted: Jan 24, 2008
• Last Update Posted: Mar 10, 2022
• Last Verified: Feb 1, 2022

• Keywords provided by SCRI Development Innovations, LLC: Non-Small Cell Lung Cancer; Advanced; Sorafenib; Erlotinib; Double-blind; Placebo-controlled
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Erlotinib Hydrochloride; Sorafenib

Study Results

Participant Flow

Arm/Group Title	Combination Therapy	Placebo
Arm/Group Description	sorafenib (400 mg orally twice a day) plus erlotinib (150 mg orally daily)	Placebo twice daily orally plus erlotinib (150 mg orally daily)
Period Title: Overall Study
STARTED	111	55
COMPLETED	51	20
NOT COMPLETED	60	35

Baseline Characteristics

Arm/Group Title	Combination Therapy	Placebo	Total
Arm/Group Description	sorafenib (400 mg orally twice a day) plus erlotinib (150 mg orally daily)	Placebo twice daily orally plus erlotinib (150 mg orally daily)	Total of all reporting groups
Overall Participants	111	55	166
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65	65	65
Sex: Female, Male (Count of Participants)
Female	49 44.1%	29 52.7%	78 47%
Male	62 55.9%	26 47.3%	88 53%
Region of Enrollment (participants) [Number]
United States	111 100%	55 100%	166 100%

Outcome Measures

1. Primary Outcome

Title	Overall Objective Response Rate (ORR)
Description	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)
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination Therapy	Placebo
Arm/Group Description	sorafenib (400 mg orally twice a day) plus erlotinib (150 mg orally daily)	Placebo twice daily orally plus erlotinib (150 mg orally daily)
Measure Participants	111	55
Number (95% Confidence Interval) [percentage of participants]	8.1 7.3%	10.9 19.8%

2. Primary Outcome

Title	Progression Free Survival (PFS)
Description	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
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination Therapy	Placebo
Arm/Group Description	sorafenib (400 mg orally twice a day) plus erlotinib (150 mg orally daily)	Placebo twice daily orally plus erlotinib (150 mg orally daily)
Measure Participants	111	55
Median (95% Confidence Interval) [Months]	3.38	1.94

3. Primary Outcome

Title	Disease Control Rate (DCR)
Description	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).
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination Therapy	Placebo
Arm/Group Description	sorafenib (400 mg orally twice a day) plus erlotinib (150 mg orally daily)	Placebo twice daily orally plus erlotinib (150 mg orally daily)
Measure Participants	111	55
Number (95% Confidence Interval) [percentage of participants]	54 48.6%	38 69.1%

4. Secondary Outcome

Title	Duration of Response
Description	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.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination Therapy	Placebo
Arm/Group Description	sorafenib (400 mg orally twice a day) plus erlotinib (150 mg orally daily)	Placebo twice daily orally plus erlotinib (150 mg orally daily)
Measure Participants	111	55
Mean (Standard Error) [months]	4.6430 (1.0048)	5.2234 (0.4571)

5. Secondary Outcome

Title	6-month PFS
Description	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.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination Therapy	Placebo
Arm/Group Description	sorafenib (400 mg orally twice a day) plus erlotinib (150 mg orally daily)	Placebo twice daily orally plus erlotinib (150 mg orally daily)
Measure Participants	111	55
Number [percentage of participants]	29 26.1%	22 40%

6. Secondary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination Therapy	Placebo
Arm/Group Description	Erlotinib + Sorafenib	Erlotinib + Placebo
Measure Participants	111	55
Median (95% Confidence Interval) [Months]	7.62	7.23

Adverse Events

Arm/Group Title	All Study Participants
Arm/Group Description	Reported SAEs and AEs for all study participants - Combination Therapy: Erlotinib + Sorafenib Placebo: Erlotinib + Placebo
All Cause Mortality
	All Study Participants
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Study Participants
	Affected / at Risk (%)	# Events
Total	77/166 (46.4%)
Blood and lymphatic system disorders
Hemorrhage	1/166 (0.6%)	1
Cardiac disorders
Cardiopulmonary Arrest	4/166 (2.4%)	4
Supraventricular Arrhythmia - Atrial Fibrillation	1/166 (0.6%)	1
Supraventricular Arrhythmia - Atrial Tachycardia	2/166 (1.2%)	2
Supraventricular Arrhythmia	1/166 (0.6%)	1
Pericardial Effusion	1/166 (0.6%)	2
Cardiac Troponin I	1/166 (0.6%)	1
Gastrointestinal disorders
Dehydration	2/166 (1.2%)	2
Diarrhea	4/166 (2.4%)	4
Obstruction - Small Bowel	1/166 (0.6%)	2
Fistula - Esophagus	1/166 (0.6%)	1
Perforation - Small Bowel	1/166 (0.6%)	1
Enteritis	2/166 (1.2%)	2
Esophagitis	1/166 (0.6%)	1
Vomiting	1/166 (0.6%)	1
Obstruction - Esophagus	1/166 (0.6%)	1
General disorders
Death	2/166 (1.2%)	2
Hepatobiliary disorders
Liver Dysfunction	1/166 (0.6%)	1
Cholecystitis	1/166 (0.6%)	1
Infections and infestations
Pneumonia	4/166 (2.4%)	6
Sepsis	1/166 (0.6%)	1
Fungal Infection	1/166 (0.6%)	1
Cellulitis	1/166 (0.6%)	1
Metabolism and nutrition disorders
Hyperglycemia	1/166 (0.6%)	1
Failure To Thrive	2/166 (1.2%)	2
Musculoskeletal and connective tissue disorders
Back Pain	2/166 (1.2%)	2
Weakness	2/166 (1.2%)	3
Fracture	1/166 (0.6%)	1
Musculoskeletal - Other	1/166 (0.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Progressive Disease	18/166 (10.8%)	18
Nervous system disorders
Chest Pain	1/166 (0.6%)	1
Pain	9/166 (5.4%)	10
Neurology - Other	1/166 (0.6%)	1
Seizure	1/166 (0.6%)	1
Dizziness	1/166 (0.6%)	1
Mental Status	1/166 (0.6%)	1
Syncope	1/166 (0.6%)	1
CNS Ischemia	1/166 (0.6%)	1
Renal and urinary disorders
Cystitis	1/166 (0.6%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	14/166 (8.4%)	16
ARDS	2/166 (1.2%)	2
Pneumothorax	1/166 (0.6%)	1
Pleural Effusion	1/166 (0.6%)	1
Airway Obstruction - COPD	2/166 (1.2%)	2
Hypoxia	1/166 (0.6%)	1
Pneumonitis	1/166 (0.6%)	1
Pulmonary/Upper Respiratory - Other	1/166 (0.6%)	1
Skin and subcutaneous tissue disorders
Rash	1/166 (0.6%)	1
Vascular disorders
Thrombosis/Thrombis/Embolism	3/166 (1.8%)	3
Other (Not Including Serious) Adverse Events
	All Study Participants
	Affected / at Risk (%)	# Events
Total	141/166 (84.9%)
Blood and lymphatic system disorders
Anemia	141/166 (84.9%)	141
Leukopenia	24/166 (14.5%)	24
Neutropenia	15/166 (9%)	15
Thrombocytopenia	37/166 (22.3%)	37
Cardiac disorders
Hypertension	25/166 (15.1%)	25
Gastrointestinal disorders
Diarrhea	121/166 (72.9%)	121
Anorexia	84/166 (50.6%)	84
General disorders
Fatigue	120/166 (72.3%)	120
Skin and subcutaneous tissue disorders
Rash	109/166 (65.7%)	109
Hand-Foot	43/166 (25.9%)	43

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor can review/embargo results communications prior to public release for a period that is >60 days but ≤180 days from date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish its results until 18 mos. after the trial has been completed at all sites.