Randomized, Double-Blind Trial of Erlotinib/Pazopanib or Erlotinib/Placebo in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer

• Sponsor: SCRI Development Innovations, LLC (Other)
• Overall Status: Completed
• CT.gov ID: NCT01027598
• Collaborator: GlaxoSmithKline (Industry), OSI Pharmaceuticals (Industry)
• Enrollment: 202
• Locations: 8
• Arms: 2
• Duration (Months): 53
• Patients Per Site: 25.3
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This randomized, placebo-controlled, Phase II trial will compare the combination of erlotinib with pazopanib (providing concurrent EGFR and VEGFR inhibition) with erlotinib alone in the second- or third-line treatment of patients with advanced NSCLC. This study will be conducted though the Sarah Cannon Research Consortium, a community-based clinical trial network.

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

Detailed Description

Erlotinib is the current treatment standard for second- or third-line therapy of advanced NSCLC. Since angiogenesis inhibitors have also shown activity in NSCLC, the simultaneous inhibition of the EGFR and VEGF pathway may improve the efficacy of therapy. In a recently reported Phase III trial (Hainsworth et al. 2008), the combination of bevacizumab and erlotinib improved the Progression- Free-Survival (PFS) vs. erlotinib alone when given as second-line therapy in NSCLC (3.4 months vs. 1.7 months, respectively; HR 0.63). Pazopanib also inhibits the angiogenesis pathway, and may have advantages over bevacizumab including: (1) inhibition of other potentially important targets, including PDGFR; and (2) more convenient oral administration.

Study Design

• Study Type: Interventional
• Actual Enrollment: 202 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Double-Blind Trial of Erlotinib and Pazopanib, or Erlotinib and Placebo in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer (NSCLC)
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Apr 1, 2014
• Actual Study Completion Date: Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Erlotinib + Pazopanib Erlotinib: 150 mg orally daily Pazopanib: 600 mg orally daily	Drug: Pazopanib; Pazopanib: 600 mg orally daily; Other Names: Votrient ; Drug: Erlotinib; Erlotinib: 150 mg orally daily; Other Names: Tarceva
Placebo Comparator: Erlotinib + Placebo Erlotinib: 150 mg orally daily Placebo: orally daily	Drug: Erlotinib; Erlotinib: 150 mg orally daily; Other Names: Tarceva

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [14 months]

   The length of time, in months, that patients were alive from first date of protocol treatment until worsening of 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.

Secondary Outcome Measures

1. Overall Survival [18 months]

   The length of time, in months, that patients were alive from first date of protocol treatment until death.

2. Objective Response Rate (ORR) [18 Months]

   The percentage of patients having an objective benefit from treatment 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; Objective Response (OR) = CR + PR.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Pathologic confirmation of stage IIIB/IV NSCLC (squamous carcinoma, adenocarcinoma, or large cell carcinoma) per the American Joint Committee on Cancer Cancer Staging Manual, 6th edition. Patients with mixed tumors with small- cell elements are ineligible.

2. 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 scan according to the Response Evaluation Criteria in Solid Tumors version 1.1 (Eisenhauer et al. 2009)

3. Failure of at least 1, and no more than 2, prior chemotherapy regimens for advanced disease (either due to progressive disease or toxicity).

4. Recovery from any toxic effects of prior therapy to ≤ grade 1 per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).

5. 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.

6. ECOG Performance Status of 0-2.

7. Adequate hematologic, hepatic and renal function.

8. A female is eligible to enter and participate in this study if she is of:

• non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had hysterectomy, bilateral oophorectomy (ovariectomy), bilateral tubal ligation, is post-menopausal

• childbearing potential, including any female who has had a negative serum pregnancy test within 1 week prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception.

1. Patients entering the study must be willing to provide a serum sample at baseline and at off-study for disease progression for correlative serum proteomic testing.

2. Willingness to provide a plasma sample at baseline, and at off-study for disease progression for correlative testing of circulating plasma biomarkers.

3. Patients entering this study must be willing to provide tissue from a previous tumor biopsy (if available) for correlative tissue testing.

4. Patients must be able to understand the nature of this study, give written informed consent, and comply with study requirements.

Exclusion Criteria:

1. 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 ≥3 years.

2. Prior treatment with EGFR tyrosine kinase inhibitors or vascular endothelial factor receptor tyrosine kinase inhibitors for NSCLC. [Note: prior bevacizumab (Avastin®) use is permitted].

3. Prior use of an investigational agent within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study drug.

4. History of any one or more of the following cardiovascular conditions within the past 6 months:

• Cardiac angioplasty or stenting

• Myocardial infarction

• Unstable angina

• Coronary artery bypass graft surgery

• Symptomatic peripheral vascular disease

• Class III or IV congestive heart failure, as defined by New York Heart Association classification

1. History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for 1 week prior to first dose of study drug. Screening with CNS imaging (CT or magnetic resonance imaging) is required only if clinically indicated or if the subject has a history of CNS metastases.

2. Women who are pregnant or lactating. All females of childbearing potential must have negative serum or urine pregnancy tests within 7 days prior to study treatment.

3. Poorly controlled hypertension [defined as systolic blood pressure of ≥150 mmHg or diastolic blood pressure of ≥90mmHg].

4. Presence of uncontrolled infection.

5. Prolongation of heart rate-corrected QT interval (QTc) ≥480 msec (using Bazett's formula).

6. Use of any of the medications on the prohibited medication list within 14 days of study treatment (with the exception of Amiodarone, which is prohibited from 6 months prior to screening through discontinuation from the study).

7. A serious underlying medical condition that would impair the ability of the patient to receive protocol treatment.

8. Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major).

9. Minor surgical procedures (with the exception of the placement of portacath or other central venous access) performed less than 7 days prior to beginning protocol treatment.

10. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism (PE), or untreated DVT within the past 6 months.

11. Previous treatment with cetuximab.

12. Patients with hemoptysis or tumor cavitation at baseline.

13. Any prior history of hypertensive crisis or hypertensive encephalopathy.

14. Pulmonary hemorrhage/bleeding event within 6 weeks prior to beginning study treatment.

15. Any other non-pulmonary hemorrhage/bleeding event ≥ grade 3 within 28 days of study treatment.

16. Evidence or history of bleeding diathesis.

17. Serious non-healing wound, ulcer, or bone fracture.

18. Known or suspected allergy/hypersensitivity to any agent given in the course of this trial.

19. Clinically significant gastrointestinal (GI) abnormalities.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Florida Cancer Specialists	Fort Myers	Florida	United States	33901
2	Suburban Hem Onc	Lawrenceville	Georgia	United States	30045
3	Oncology Hematology Care	Cincinnati	Ohio	United States	45242
4	South Carolina Oncology Associates, PA	Columbia	South Carolina	United States	29210
5	Chattanooga Oncology Hematology Associates	Chattanooga	Tennessee	United States	37404
6	Family Cancer Center	Collerville	Tennessee	United States	38119
7	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37023
8	Virginia Cancer Institute	Richmond	Virginia	United States	23235

Sponsors and Collaborators

• SCRI Development Innovations, LLC
• GlaxoSmithKline
• OSI Pharmaceuticals

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: SCRI Development Innovations, LLC
• ClinicalTrials.gov Identifier: NCT01027598
• Other Study ID Numbers: SCRI LUN 200
• First Posted: Dec 8, 2009
• Last Update Posted: Jan 29, 2016
• Last Verified: Dec 1, 2015

• Keywords provided by SCRI Development Innovations, LLC: Lung Cancer; Previously Treated Advanced Non Small Cell Lung Cancer; Erlotinib; Pazopanib
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Erlotinib Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Erlotinib + Pazopanib	Erlotinib + Placebo
Arm/Group Description	Erlotinib: 150 mg orally daily Pazopanib: 600 mg orally daily	Erlotinib: 150 mg orally daily Placebo: orally daily
Period Title: Overall Study
STARTED	134	67
COMPLETED	0	0
NOT COMPLETED	134	67

Baseline Characteristics

Arm/Group Title	Arm A	Arm B	Total
Arm/Group Description	Erlotinib + Pazopanib Erlotinib: 150 mg orally daily Pazopanib: 600 mg orally daily	Erlotinib + Placebo Erlotinib: 150 mg orally daily Placebo: orally daily	Total of all reporting groups
Overall Participants	134	67	201
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	66	67	67
Sex: Female, Male (Count of Participants)
Female	63 47%	28 41.8%	91 45.3%
Male	71 53%	39 58.2%	110 54.7%
Region of Enrollment (participants) [Number]
United States	134 100%	67 100%	201 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	The length of time, in months, that patients were alive from first date of protocol treatment until worsening of 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.
Time Frame	14 months

Outcome Measure Data

Analysis Population Description

All treated patients

Arm/Group Title	Arm A	Arm B
Arm/Group Description	Erlotinib + Pazopanib Erlotinib: 150 mg orally daily Pazopanib: 600 mg orally daily	Erlotinib + Placebo Erlotinib: 150 mg orally daily Placebo: orally daily
Measure Participants	134	67
Median (95% Confidence Interval) [months]	2.6	1.8

2. Secondary Outcome

Title	Overall Survival
Description	The length of time, in months, that patients were alive from first date of protocol treatment until death.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

All treated patients

Arm/Group Title	Arm A	Arm B
Arm/Group Description	Erlotinib + Pazopanib Erlotinib: 150 mg orally daily Pazopanib: 600 mg orally daily	Erlotinib + Placebo Erlotinib: 150 mg orally daily Placebo: orally daily
Measure Participants	134	67
Median (95% Confidence Interval) [months]	6.76	6.7

3. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	The percentage of patients having an objective benefit from treatment 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; Objective Response (OR) = CR + PR.
Time Frame	18 Months

Outcome Measure Data

Analysis Population Description

Includes all patients who were evaluated for response

Arm/Group Title	Arm A	Arm B
Arm/Group Description	Erlotinib + Pazopanib Erlotinib: 150 mg orally daily Pazopanib: 600 mg orally daily	Erlotinib + Placebo Erlotinib: 150 mg orally daily Placebo: orally daily
Measure Participants	99	56
Number [percentage of evaluated participants]	12.12 9%	5.36 8%

Adverse Events

Time Frame	18 Months
Arm/Group Title	Arm A		Arm B
Arm/Group Description	Erlotinib + Pazopanib Erlotinib: 150 mg orally daily Pazopanib: 600 mg orally daily		Erlotinib + Placebo Erlotinib: 150 mg orally daily Placebo: orally daily
All Cause Mortality
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	47/134 (35.1%)		19/67 (28.4%)
Blood and lymphatic system disorders
Anemia	3/134 (2.2%)		0/67 (0%)
Cardiac disorders
Cardiac Arrest	2/134 (1.5%)		0/67 (0%)
Myocardial Infarction	2/134 (1.5%)		0/67 (0%)
Atrial Fibrillation	1/134 (0.7%)		0/67 (0%)
Cardiac disorders - Other, tachycardia	1/134 (0.7%)		0/67 (0%)
Pericardial effusion	1/134 (0.7%)		0/67 (0%)
Gastrointestinal disorders
Diarrhea	1/134 (0.7%)		2/67 (3%)
Dysphagia	1/134 (0.7%)		1/67 (1.5%)
abdominal pain	1/134 (0.7%)		0/67 (0%)
Gastrointestinal disorders - Other, hematemesis	1/134 (0.7%)		0/67 (0%)
Gastrointestinal disorders - Other, small bowel obstruction	1/134 (0.7%)		0/67 (0%)
Vomiting	1/134 (0.7%)		0/67 (0%)
General disorders
General disorders and administration site conditions - Other, disease progression	8/134 (6%)		4/67 (6%)
Death NOS	1/134 (0.7%)		0/67 (0%)
fever	0/134 (0%)		1/67 (1.5%)
General disorders and administration site conditions - Other, failure to thrive	1/134 (0.7%)		0/67 (0%)
Non-cardiac chest pain	1/134 (0.7%)		0/67 (0%)
Hepatobiliary disorders
Cholecystitis	1/134 (0.7%)		0/67 (0%)
Infections and infestations
Infections and infestations - Other, pneumonia	8/134 (6%)		2/67 (3%)
Infections and infestations - Other, bacteremia	1/134 (0.7%)		0/67 (0%)
Infections and infestations - Other, Staphylococcus	1/134 (0.7%)		0/67 (0%)
Sepsis	0/134 (0%)		1/67 (1.5%)
Urinary tract infection	1/134 (0.7%)		0/67 (0%)
Investigations
alanine aminotransferase increased	2/134 (1.5%)		0/67 (0%)
aspartate aminotransferase increased	2/134 (1.5%)		0/67 (0%)
blood bilirubin increased	1/134 (0.7%)		0/67 (0%)
Weight Loss	1/134 (0.7%)		0/67 (0%)
Metabolism and nutrition disorders
Dehydration	6/134 (4.5%)		1/67 (1.5%)
hypercalcemia	0/134 (0%)		1/67 (1.5%)
hyperglycemia	1/134 (0.7%)		0/67 (0%)
Hyponatremia	1/134 (0.7%)		0/67 (0%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	3/134 (2.2%)		0/67 (0%)
Arthralgia	1/134 (0.7%)		0/67 (0%)
Pain in extremity	1/134 (0.7%)		0/67 (0%)
Nervous system disorders
Ataxia	1/134 (0.7%)		0/67 (0%)
dizziness	0/134 (0%)		1/67 (1.5%)
Syncope	1/134 (0.7%)		0/67 (0%)
Psychiatric disorders
Psychiatric disorders - Other, change in mental status	2/134 (1.5%)		1/67 (1.5%)
Confusion	1/134 (0.7%)		0/67 (0%)
Renal and urinary disorders
Acute kidney injury	1/134 (0.7%)		0/67 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/134 (0%)		3/67 (4.5%)
Pleural Effusion	0/134 (0%)		2/67 (3%)
Aspiration	1/134 (0.7%)		0/67 (0%)
Hypoxia	1/134 (0.7%)		0/67 (0%)
Pneumonitis	1/134 (0.7%)		0/67 (0%)
Pneumothorax	1/134 (0.7%)		0/67 (0%)
Respiratory Failure	0/134 (0%)		1/67 (1.5%)
Respiratory, thoracic and mediastinal disorders - Other, COPD exacerbation	1/134 (0.7%)		0/67 (0%)
Respiratory, thoracic and mediastinal disorders - Other, hemoptysis	0/134 (0%)		1/67 (1.5%)
Respiratory, thoracic and mediastinal disorders - Other, respiratory distress	1/134 (0.7%)		0/67 (0%)
Skin and subcutaneous tissue disorders
Pruritus	1/134 (0.7%)		0/67 (0%)
Vascular disorders
Thromboembolic event	4/134 (3%)		1/67 (1.5%)
Other (Not Including Serious) Adverse Events
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	132/134 (98.5%)		66/67 (98.5%)
Blood and lymphatic system disorders
Anemia	20/134 (14.9%)		4/67 (6%)
Gastrointestinal disorders
Diarrhea	92/134 (68.7%)		36/67 (53.7%)
Nausea	55/134 (41%)		25/67 (37.3%)
Vomiting	32/134 (23.9%)		13/67 (19.4%)
Gastroesophageal Reflux Disease	14/134 (10.4%)		1/67 (1.5%)
Constipation	6/134 (4.5%)		6/67 (9%)
Mucositis	9/134 (6.7%)		3/67 (4.5%)
General disorders
Fatigue	68/134 (50.7%)		30/67 (44.8%)
Fever	7/134 (5.2%)		3/67 (4.5%)
General Disorders And Administration Site Conditions - Other, Disease Progression	6/134 (4.5%)		4/67 (6%)
Infections and infestations
Infections And Infestations - Other, Pneumonia	9/134 (6.7%)		2/67 (3%)
Investigations
Weight Loss	36/134 (26.9%)		11/67 (16.4%)
Platelet Count Decreased	20/134 (14.9%)		4/67 (6%)
White Blood Cell Decreased	11/134 (8.2%)		1/67 (1.5%)
Metabolism and nutrition disorders
Anorexia	48/134 (35.8%)		17/67 (25.4%)
Dehydration	27/134 (20.1%)		9/67 (13.4%)
Musculoskeletal and connective tissue disorders
Generalized Muscle Weakness	27/134 (20.1%)		6/67 (9%)
Nervous system disorders
Dysgeusia	14/134 (10.4%)		3/67 (4.5%)
Headache	11/134 (8.2%)		3/67 (4.5%)
Dizziness	10/134 (7.5%)		3/67 (4.5%)
Psychiatric disorders
Insomnia	8/134 (6%)		2/67 (3%)
Renal and urinary disorders
Proteinuria	38/134 (28.4%)		14/67 (20.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	30/134 (22.4%)		12/67 (17.9%)
Cough	24/134 (17.9%)		10/67 (14.9%)
Skin and subcutaneous tissue disorders
Rash	34/134 (25.4%)		16/67 (23.9%)
Dry Skin	12/134 (9%)		9/67 (13.4%)
Rash Acneiform	11/134 (8.2%)		8/67 (11.9%)
Pruritus	14/134 (10.4%)		4/67 (6%)
Vascular disorders
Hypertension	9/134 (6.7%)		2/67 (3%)

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 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