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

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)

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.

Study Overview

• Status: Completed
• Conditions: Non Small Cell Lung Cancer
• Intervention / Treatment: Drug: Pazopanib; Drug: Erlotinib

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 Type: Interventional
• Enrollment (Actual): 202
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists
  • Georgia
    • Lawrenceville, Georgia, United States, 30045
      • Suburban Hem Onc
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care
  • South Carolina
    • Columbia, South Carolina, United States, 29210
      • South Carolina Oncology Associates, PA
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Oncology Hematology Associates
    • Collerville, Tennessee, United States, 38119
      • Family Cancer Center
    • Nashville, Tennessee, United States, 37023
      • Tennessee Oncology, PLLC
  • 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:

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.
9. 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.
10. Willingness to provide a plasma sample at baseline, and at off-study for disease progression for correlative testing of circulating plasma biomarkers.
11. Patients entering this study must be willing to provide tissue from a previous tumor biopsy (if available) for correlative tissue testing.
12. 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
5. 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.
6. 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.
7. Poorly controlled hypertension [defined as systolic blood pressure of ≥150 mmHg or diastolic blood pressure of ≥90mmHg].
8. Presence of uncontrolled infection.
9. Prolongation of heart rate-corrected QT interval (QTc) ≥480 msec (using Bazett's formula).
10. 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).
11. A serious underlying medical condition that would impair the ability of the patient to receive protocol treatment.
12. 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).
13. 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.
14. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism (PE), or untreated DVT within the past 6 months.
15. Previous treatment with cetuximab.
16. Patients with hemoptysis or tumor cavitation at baseline.
17. Any prior history of hypertensive crisis or hypertensive encephalopathy.
18. Pulmonary hemorrhage/bleeding event within 6 weeks prior to beginning study treatment.
19. Any other non-pulmonary hemorrhage/bleeding event ≥ grade 3 within 28 days of study treatment.
20. Evidence or history of bleeding diathesis.
21. Serious non-healing wound, ulcer, or bone fracture.
22. Known or suspected allergy/hypersensitivity to any agent given in the course of this trial.
23. Clinically significant gastrointestinal (GI) abnormalities.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	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.	14 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	The length of time, in months, that patients were alive from first date of protocol treatment until death.	18 months
Objective Response Rate (ORR)	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.	18 Months

Collaborators and Investigators

• Sponsor: SCRI Development Innovations, LLC
• Collaborators: GlaxoSmithKline; OSI Pharmaceuticals
• Investigators: Study Chair: David R Spigel, M.D., SCRI Development Innovations, LLC

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: December 4, 2009
• First Submitted That Met QC Criteria: December 7, 2009
• First Posted (Estimate): December 8, 2009

Study Record Updates

• Last Update Posted (Estimate): January 29, 2016
• Last Update Submitted That Met QC Criteria: December 22, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: Lung Cancer; Erlotinib; Pazopanib; Previously Treated Advanced Non Small Cell Lung Cancer
• 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
• Other Study ID Numbers: SCRI LUN 200