Stereotactic Radiosurgery or Other Local Ablation Then Erlotinib in Epidermal Growth Factor Receptor (EGFR)

• Sponsor: UNC Lineberger Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01573702
• Collaborator: Astellas Pharma Global Development, Inc. (Industry)
• Enrollment: 32
• Locations: 8
• Arm: 1
• Actual Duration (Months): 75.1
• Patients Per Site: 4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

• Progression free survival after locally ablative therapy and erlotinib in EGFR patients progressed after EGFR-TKI therapy

Condition or Disease	Intervention/Treatment	Phase
Non Small Cell Lung Cancer	Procedure: Stereotactic Radiosurgery; Drug: Erlotinib	Phase 2

Detailed Description

Primary Objectives

• To estimate progression free survival (PFS) after locally ablative therapy and erlotinib in EGFR-mutant NSCLC patients who progressed on prior EGFR-TKI therapy

Secondary Objectives

• To evaluate local control of sites previously progressive on erlotinib following stereotactic radiosurgery (SRS) followed by erlotinib

• To estimate overall survival (OS) after locally ablative therapy and erlotinib in EGFR-mutant NSCLC patients who progressed on prior EGFR-TKI therapy

• To characterize the toxicity of SRS

• To characterize the toxicity of erlotinib when preceded by SRS

Exploratory Objectives

• To explore if VeriStrat results at initial progression are associated with longer PFS or OS after study treatment

• To explore if VeriStrat results following completion of SRS are associated with longer PFS or OS after re-initiation of erlotinib

• To explore whether "poor" VeriStrat signatures ever turn to "good" signatures with the study therapy, and to explore PFS and OS of patients whose signature changes

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: For all patients, all sites of progressive disease will be treated with local ablation (primarily stereotactic radiosurgery) followed by the EGFR-TKI erlotinib until disease progression.For all patients, all sites of progressive disease will be treated with local ablation (primarily stereotactic radiosurgery) followed by the EGFR-TKI erlotinib until disease progression.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Stereotactic Radiosurgery or Other Local Ablation Followed by Erlotinib for Patients With Epidermal Growth Factor Receptor(EGFR) Mutation Who Have Previously Progressed on an Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitor (EGFR-TKI)
• Actual Study Start Date: Dec 11, 2012
• Actual Primary Completion Date: Mar 15, 2019
• Actual Study Completion Date: Mar 15, 2019

Arms and Interventions

Arm	Intervention/Treatment
Other: Stereotactic Radiosurgery Followed by Erlotinib Stereotactic Radiosurgery or Other Local Ablation Followed by Erlotinib	Procedure: Stereotactic Radiosurgery; 21 Gy daily for 5 days; Other Names: Cyberknife ; Drug: Erlotinib; 150mg once daily; Other Names: Tarceva

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Progression Free Survival [3 months after Initiation of Stereostatic Radiotherapy]

   Progression free survival (PFS) after locally ablative therapy and erlotinib in EGFR-mutant NSCLC patients who progressed on prior EGFR-tyrosine kinase inhibitor (TKI) therapy reported as percentage of participants who are alive and without progressive disease at 3 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or the appearance of new lesions.

Secondary Outcome Measures

1. Percentage of Participants With Local Control of Sites on Erlotinib Following Stereotactic Radiosurgery (SRS) [Initiation of Stereotactic Radiotherapy every 6 to 12 weeks until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months]

   Count of subjects who had local control of sites previously progressive on erlotinib following SRS followed by erlotinib. Using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), local control is defined as Complete Response (CR), Disappearance of all target lesions; or Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; in sites ablated by SRS.

2. Median Overall Survival [up to 5 years after end of treatment]

   To estimate overall survival (OS) after locally ablative therapy and erlotinib in EGFR-mutant, NSCLC patients who progressed on prior EGFR-TKI therapy measured as length of time from start of treatment until date of death from any cause

3. Toxicity Rate From Stereotactic Radiosurgery (SRS) [From initiation to the end of SRS, up to 15 days]

   Toxicity of SRS will be measured by NCI CTCAE version 4 following completion of SRS, but prior to erlotinib re-initiation. The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.

4. Toxicity Rate Attributed to Erlotinib [from end of SRS to end of erlotinib treatment (median duration of 5.7 months)]

   Toxicity of erlotinib will be graded using the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE version 4) which is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Written informed consent

• 18 years of age or older

• Histologically or cytologically confirmed stge IV EGFR-mutant NSCLC

• History of previous response to EGFR-TKI defined by a RECIST 1.1 criteria

• Progressive disease following EGFR-TKI therapy

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Adequate organ and marrow function

• Negative urine or serum pregnancy test for female patients

• Patients who can have children must agree to adequate contraception

Exclusion Criteria:

• Unresolved chronic toxicities greater than 2, measured by CTCAE v4

• Treatment with any FDA approved or experimental cancer treatment following progression on EGFR-TKI

• Any history of previous greater than grade 3 toxicity attributable to erlotinib

• Pregnant or lactating female

• Any previous radiation to sites of planned Stereostatic Radiosurgery

• History of another malignancy

• Concomitant anticancer therapy, immunotherapy, or radiation therapy (within 4 weeks)

• Evidence of severe or uncontrolled systemic diseases

• Known hypersensitivity reaction or idiosyncrasy to erlotinib

• Psychological, familial, sociological, or geographical conditions

• Any other condition in investigator's opinion jeopardize compliance with protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California at San Francisco	San Francisco	California	United States	94115
2	University of Colorado Cancer Center	Aurora	Colorado	United States	80045
3	Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
4	East Carolina University	Greenville	North Carolina	United States	27834
5	STO Taussig Cancer Center; Cleveland Clinic	Cleveland	Ohio	United States	44195
6	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
7	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15232
8	Swedish Cancer Institute	Seattle	Washington	United States	98104

Sponsors and Collaborators

• UNC Lineberger Comprehensive Cancer Center
• Astellas Pharma Global Development, Inc.

Investigators

• Principal Investigator: Jared Weiss, MD, UNC at Chapel Hill

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 18, 2014

More Information

Publications

None provided.

• Responsible Party: UNC Lineberger Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT01573702
• Other Study ID Numbers: LCCC 1123
• First Posted: Apr 9, 2012
• Last Update Posted: Jan 12, 2021
• Last Verified: Dec 1, 2020

• Keywords provided by UNC Lineberger Comprehensive Cancer Center: Non small cell lung cancer; EGFR mutant; Phase II; erlotinib; tarceva; cyberknife; Lineberger
• Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung; Erlotinib Hydrochloride

Study Results

Participant Flow

Recruitment Details	32 participants were accrued from six institutions between 12/2012 and 6/2016
Pre-assignment Detail	Of the 32 participants who consented to the study, 5 were determined to be not eligible and 2 withdrew consent prior to starting study treatment

Arm/Group Title	Stereotactic Radiosurgery Followed by Erlotinib
Arm/Group Description	Stereotactic Radiosurgery or Other Local Ablation Followed by Erlotinib Stereotactic Radiosurgery: 21 Gy daily for 5 days Erlotinib: 150mg once daily
Period Title: Overall Study
STARTED	25
COMPLETED	25
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Stereotactic Radiosurgery Followed by Erlotinib
Arm/Group Description	Stereotactic Radiosurgery or Other Local Ablation Followed by Erlotinib Stereotactic Radiosurgery: 21 Gy daily for 5 days Erlotinib: 150mg once daily
Overall Participants	25
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64
Sex: Female, Male (Count of Participants)
Female	16 64%
Male	9 36%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	25 100%
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	25 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	25 100%
Smoking status (Count of Participants)
Never smoker	16 64%
Former smoker	7 28%
Unknown	2 8%
Performance status (Count of Participants)
0, Fully active	16 64%
1, Restricted in strenuous activity but ambulatory	9 36%
Mutation type (Count of Participants)
Exon 19	14 56%
Exon 21	7 28%
Exon 19+ ALK rearrangement	1 4%
Exon 18 and Exon 20	1 4%
None proven; met clinical criteria	2 8%
Charlson Co-morbidity Index (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	6

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Progression Free Survival
Description	Progression free survival (PFS) after locally ablative therapy and erlotinib in EGFR-mutant NSCLC patients who progressed on prior EGFR-tyrosine kinase inhibitor (TKI) therapy reported as percentage of participants who are alive and without progressive disease at 3 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or the appearance of new lesions.
Time Frame	3 months after Initiation of Stereostatic Radiotherapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stereotactic Radiosurgery Followed by Erlotinib
Arm/Group Description	Stereotactic Radiosurgery or Other Local Ablation Followed by Erlotinib Stereotactic Radiosurgery: 21 Gy daily for 5 days Erlotinib: 150mg once daily
Measure Participants	25
Number (95% Confidence Interval) [percentage of participants]	64 256%

2. Secondary Outcome

Title	Percentage of Participants With Local Control of Sites on Erlotinib Following Stereotactic Radiosurgery (SRS)
Description	Count of subjects who had local control of sites previously progressive on erlotinib following SRS followed by erlotinib. Using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), local control is defined as Complete Response (CR), Disappearance of all target lesions; or Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; in sites ablated by SRS.
Time Frame	Initiation of Stereotactic Radiotherapy every 6 to 12 weeks until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months

Outcome Measure Data

Analysis Population Description

4 subjects were not evaluable for this outcome due to lack of follow-up measurements on ablated lesions

Arm/Group Title	Stereotactic Radiosurgery Followed by Erlotinib
Arm/Group Description	Stereotactic Radiosurgery or Other Local Ablation Followed by Erlotinib Stereotactic Radiosurgery: 21 Gy daily for 5 days Erlotinib: 150mg once daily
Measure Participants	21
Count of Participants [Participants]	7 28%

3. Secondary Outcome

Title	Median Overall Survival
Description	To estimate overall survival (OS) after locally ablative therapy and erlotinib in EGFR-mutant, NSCLC patients who progressed on prior EGFR-TKI therapy measured as length of time from start of treatment until date of death from any cause
Time Frame	up to 5 years after end of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm Study
Arm/Group Description	Stereotactic Radiosurgery or Other Local Ablation Followed by Erlotinib Stereotactic Radiosurgery: 21 Gy daily for 5 days Erlotinib: 150mg once daily
Measure Participants	25
Median (95% Confidence Interval) [Months]	29

4. Secondary Outcome

Title	Toxicity Rate From Stereotactic Radiosurgery (SRS)
Description	Toxicity of SRS will be measured by NCI CTCAE version 4 following completion of SRS, but prior to erlotinib re-initiation. The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.
Time Frame	From initiation to the end of SRS, up to 15 days

Outcome Measure Data

Analysis Population Description

Toxicities occurring in at least two participants from SRS are reported below

Arm/Group Title	Stereotactic Radiosurgery Followed by Erlotinib
Arm/Group Description	Stereotactic Radiosurgery or Other Local Ablation Followed by Erlotinib Stereotactic Radiosurgery: 21 Gy daily for 5 days Erlotinib: 150mg once daily
Measure Participants	25
Grade 1	4 16%
Grade 2	0 0%
None	21 84%
Grade 1	2 8%
Grade 2	1 4%
None	22 88%
Grade 1	2 8%
Grade 2	0 0%
None	23 92%

5. Secondary Outcome

Title	Toxicity Rate Attributed to Erlotinib
Description	Toxicity of erlotinib will be graded using the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE version 4) which is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.
Time Frame	from end of SRS to end of erlotinib treatment (median duration of 5.7 months)

Outcome Measure Data

Analysis Population Description

Toxicities grade 3 or higher and attributed to erlotinib re-treatment, or toxicities occurring in at least two participants are reported below

Arm/Group Title	Stereotactic Radiosurgery Followed by Erlotinib
Arm/Group Description	Stereotactic Radiosurgery or Other Local Ablation Followed by Erlotinib Stereotactic Radiosurgery: 21 Gy daily for 5 days Erlotinib: 150mg once daily
Measure Participants	25
Grade 1	5 20%
Grade 2	2 8%
Grade 3	2 8%
None	16 64%
Grade 1	2 8%
Grade 2	1 4%
Grade 3	0 0%
None	22 88%
Grade 1	2 8%
Grade 2	1 4%
Grade 3	0 0%
None	22 88%
Grade 1	2 8%
Grade 2	0 0%
Grade 3	0 0%
None	23 92%
Grade 1	2 8%
Grade 2	0 0%
Grade 3	0 0%
None	23 92%
Grade 1	2 8%
Grade 2	0 0%
Grade 3	0 0%
None	23 92%
Grade 1	2 8%
Grade 2	0 0%
Grade 3	0 0%
None	23 92%

Adverse Events

Time Frame	From start of treatment to date of death up to 60 months
Arm/Group Title	Stereotactic Radiosurgery Followed by Erlotinib
Arm/Group Description	Stereotactic Radiosurgery or Other Local Ablation Followed by Erlotinib Stereotactic Radiosurgery: 21 Gy daily for 5 days Erlotinib: 150mg once daily
All Cause Mortality
	Stereotactic Radiosurgery Followed by Erlotinib
	Affected / at Risk (%)	# Events
Total	16/25 (64%)
Serious Adverse Events
	Stereotactic Radiosurgery Followed by Erlotinib
	Affected / at Risk (%)	# Events
Total	1/25 (4%)
Injury, poisoning and procedural complications
Fracture	1/25 (4%)	2
Fall	1/25 (4%)	1
Other (Not Including Serious) Adverse Events
	Stereotactic Radiosurgery Followed by Erlotinib
	Affected / at Risk (%)	# Events
Total	24/25 (96%)
Ear and labyrinth disorders
Ear pain	1/25 (4%)
Eye disorders
Blurred vision	2/25 (8%)
Conjunctivitis	1/25 (4%)
Dry eye	1/25 (4%)
Flashing lights	1/25 (4%)
Watering eyes	2/25 (8%)
Gastrointestinal disorders
Abdominal pain	2/25 (8%)
Diarrhea	3/25 (12%)
Dyspepsia	3/25 (12%)
Dysphagia	1/25 (4%)
Gastroesophageal reflux disease	1/25 (4%)
Nausea	3/25 (12%)
Oral hemorrhage	1/25 (4%)
Vomiting	1/25 (4%)
General disorders
Edema face	1/25 (4%)
Edema limbs	2/25 (8%)
Fatigue	8/25 (32%)
Flu like symptoms	1/25 (4%)
Infusion site extravasation	1/25 (4%)
Non-cardiac chest pain	3/25 (12%)
Pain	3/25 (12%)
Infections and infestations
Papulopustular rash	1/25 (4%)
Paronychia	2/25 (8%)
Skin infection	1/25 (4%)
Upper respiratory infection	1/25 (4%)
Urinary tract infection	1/25 (4%)
Injury, poisoning and procedural complications
Bruising	1/25 (4%)
Investigations
Alkaline phosphatase increased	1/25 (4%)
Aspartate aminotransferase increased	3/25 (12%)
Blood bilirubin increased	1/25 (4%)
Lymphocyte count decreased	7/25 (28%)
Neutrophil count decreased	1/25 (4%)
Platelet count decreased	1/25 (4%)
Weight loss	2/25 (8%)
White blood cell decreased	1/25 (4%)
Metabolism and nutrition disorders
Anorexia	4/25 (16%)
Hyperglycemia	4/25 (16%)
Hyperkalemia	1/25 (4%)
Hypernatremia	1/25 (4%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/25 (8%)
Back pain	5/25 (20%)
Bone pain	1/25 (4%)
Myalgia	2/25 (8%)
Neck pain	1/25 (4%)
Pain in extremity	3/25 (12%)
Nervous system disorders
Dysgeusia	1/25 (4%)
Headache	3/25 (12%)
Lethargy	1/25 (4%)
Psychiatric disorders
Depression	1/25 (4%)
Insomnia	1/25 (4%)
Renal and urinary disorders
Urinary tract pain	2/25 (8%)
Urinary urgency	1/25 (4%)
Respiratory, thoracic and mediastinal disorders
Cough	6/25 (24%)
Epistaxis	1/25 (4%)
Pneumonitis	1/25 (4%)
Sore throat	1/25 (4%)
Wheezing	2/25 (8%)
Skin and subcutaneous tissue disorders
Dry skin	4/25 (16%)
Nail loss	1/25 (4%)
Nail ridging	1/25 (4%)
Pruritus	2/25 (8%)
Rash acneiform	5/25 (20%)
Rash maculo-papular	4/25 (16%)
Skin and subcutaneous tissue disorders - Other, specify	2/25 (8%)
Skin hyperpigmentation	1/25 (4%)
Vascular disorders
Hot flashes	1/25 (4%)

Limitations/Caveats

The study closed early due to poor accrual (enrolling only 25 of 40 expected participants) and the development of second line therapy with osimertinib.

More Information

Certain Agreements

All Principal Investigators ARE 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.