Sorafenib and Erlotinib or Sorafenib Alone in Advanced Non-Small Cell Lung Cancer Progressing on Erlotinib

Randomized Phase II Trial of Sorafenib and Erlotinib or Sorafenib Alone in Patients With Advanced Non-Small Cell Lung Cancer Progressing on Erlotinib

This is a randomized, open-label, multi-center, Phase II study of treatment of patients with advanced NSCLC who have progressed on erlotinib with the combination of sorafenib and erlotinib or sorafenib alone.

Inclusion Criteria:

1. Histologically confirmed stage IIIB/IV or relapsed non-small cell lung carcinoma (squamous carcinoma, adenocarcinoma, or large cell carcinoma). Patients with mixed tumors with small-cell elements are ineligible.
2. Patients with no more than 2 prior lines of therapy, with the latest of those therapies being single-agent erlotinib.
3. Evidence of progressive disease on erlotinib as assessed by the treating physician. Erlotinib must be the last treatment for NSCLC prior to enrollment into this study. Patients may be on erlotinib until enrollment. If erlotinib has already been stopped, the period of time off Erlotinib cannot exceed 14 days prior to study enrollment.
4. Patients must have experienced a clinical benefit (complete response [CR], partial response [PR], or stable disease [SD]) from prior therapy with erlotinib for a period of 8 weeks.
5. Patient must have one measurable lesion measuring at least 10 mm in the longest diameter (LD) by spiral computed tomography (CT), or 20 mm with conventional techniques according to the Response Evaluation Criteria in Solid Tumors (RECIST).
6. Recovery from any toxic effects of erlotinib to ≤ grade 1 per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).
7. Completion of palliative radiation therapy prior to the start of study treatment. Previously irradiated lesions in the advanced setting cannot be included as target lesions unless clear tumor progression has been observed following the completion of radiation therapy.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
9. Absolute neutrophil count (ANC) >=1,500 and platelets >=75,000 (within 7 days prior to initial study treatment).
10. Hemoglobin >=9 g/dL (within 7 days prior to initial treatment).
11. International normalized ratio (INR) <=1.5 or prothrombin time (PT)/partial thromboplastin time (PTT) within normal limits (WNL) of the institution if not on anticoagulation therapy. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate with the therapeutic range established prior to study treatment initiation.
12. Serum creatinine <=1.5 x institutional upper limit of normal (ULN) within 7 days prior to initial study treatment. If the absolute value is greater than 2mg/dL, the creatinine clearance, calculated according to the Cockroft-Gault formula, must be >=45 mL/min to be eligible.
13. Bilirubin <=1.5 x the ULN; transaminases <=3 x institutional ULN, except in known hepatic metastasis, wherein these may be >=5 x institutional ULN.
14. Patients must be able to understand the nature of this study, give written informed consent, and comply with study requirements.
15. Agreement of male patients (with partners of childbearing potential) and female patients of childbearing potential to use effective contraception to prevent pregnancy during treatment and for a minimum of 90 days thereafter. Additionally, women should not breastfeed during this time.

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 (DFS) >=3 years.

2. Pregnancy or lactation. All females of child-bearing potential must have negative serum or urine pregnancy tests within 7 days prior to study treatment.

3. Prior epithelial growth factor receptor (EGFR) inhibitors, with the exception of erlotinib, are not allowed. This includes both tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. Prior vascular endothelial growth factor (VEGF) inhibitors, with the exception of bevacizumab, are not allowed.

4. Significant cardiac disease within 90 days of starting study treatment including:

   • superior vena cava syndrome
   • new onset angina
   • congestive heart failure (CHF) > Class 2 per New York Heart Association (NYHA) classification
   • arrhythmia
   • valvular heart disease.

5. Myocardial infarction within 6 months prior to initiation of study treatment

6. Cardiomegaly on chest imaging or ventricular hypertrophy on electrocardiogram (ECG) unless the left ventricular ejection fraction (LVEF) is within normal range for the institution.

7. Poorly controlled hypertension (defined as systolic blood pressure [BP] >150 mm Hg and/or diastolic BP >100 mm Hg on antihypertensive medications).

8. Unstable angina (anginal symptoms at rest).

9. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

10. Presence of cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmia.

11. A serious active infection (> grade 2) at the time of treatment

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

13. Untreated brain metastases. Patients who have treated metastases >=4 weeks out (with surgery and/or radiation therapy) and no evidence of central nervous system (CNS) progression are eligible.

14. Treatment with a non-approved or investigational drug within 28 days of initial study treatment.

15. A major surgical procedure, open biopsy, or significant traumatic injury within 28 days of beginning treatment or anticipation of need for major surgery during the course of the study.

16. Thrombolic or embolic events such as a stroke and transient ischemic attack (TIA) within the past 6 months.

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

18. Pulmonary hemorrhage/bleeding event >= grade 2 within 28 days of initial study treatment.

19. Any other non-pulmonary hemorrhage/bleeding event >= grade 3 within 28 days of initial study treatment.

20. Evidence or history of bleeding diathesis or coagulopathy.

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

22. Use of St. John's Wort or rifampin (rifampicin).

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

24. Any malabsorption problem.

25. Any condition that impairs the patient's ability to swallow whole pills.