Sorafenib and Erlotinib in Treating Patients With Metastatic or Unresectable Solid Tumors

Study Overview
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Brief Summary
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RATIONALE: Sorafenib and erlotinib may stop the growth of tumor cells by blocking blood flow to the tumor and by blocking some of the enzymes needed for cell growth. PURPOSE: This phase I trial is studying the side effects and best dose of sorafenib and erlotinib in treating patients with metastatic or unresectable solid tumors.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose and recommended phase II dose of sorafenib and erlotinib in patients with metastatic or unresectable solid tumors. Secondary Determine the optimal biologically effective dose of this regimen that will lead to hypophosphorylation of epidermal growth factor receptor (EGFR), ERK, Akt, and vascular endothelial growth factor receptor (VEGFR), and inhibition of angiogenesis and apoptosis with tolerable toxicity in these patients. Correlate the pharmacokinetic profiles of this regimen with toxicity and biological activity in these patients. Determine, preliminarily, the antitumor activity of this regimen in these patients. Correlate phosphorylation status of EGFR, ERK, Akt, and VEGFR with antitumor activity of this regimen in these patients. OUTLINE: This is a multicenter, open label, non-randomized, dose-escalation study. Patients receive oral sorafenib alone once or twice daily on days -6 to 0*. Patients then receive oral sorafenib once or twice daily and oral erlotinib once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. NOTE: *Not considered part of course 1; considered a run-in period only. Cohorts of 3-6 patients receive escalating doses of sorafenib and erlotinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. An additional 10 patients are treated at the MTD. After completion of study treatment, patients are followed at 4 weeks and then at least annually thereafter. PROJECTED ACCRUAL: A total of 16-28 patients will be accrued for this study within 5-14 months.

Official Title
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A Phase I Study of BAY 43-9006 (Sorafenib) in Combination With OSI-774 (Erlotinib; Tarceva) in Advanced Solid Tumors

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: erlotinib hydrochloride
* Drug: sorafenib tosylate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed solid tumor Metastatic or unresectable disease Standard curative or palliative measures do not exist OR are no longer effective Measurable disease by radiography (for patients treated at the maximum tolerated dose [MTD] only) Tumor accessible for serial biopsies (for patients treated at the MTD only) No known brain metastases PATIENT CHARACTERISTICS: Age 18 and over Performance status ECOG 0-2 OR Karnofsky 60-100% Life expectancy More than 12 weeks Hematopoietic WBC ≥ 3,000/mm^3 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 No bleeding diathesis or coagulopathy Hepatic Bilirubin normal AST and ALT ≤ 2.5 times ULN PT INR ≤ 1.5 unless on full-dose warfarin Renal Creatinine normal OR Creatinine clearance ≥ 60 mL/min Cardiovascular No uncontrolled hypertension (i.e., systolic blood pressure [BP] > 140 mm Hg or diastolic BP > 90 mm Hg despite medication) No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Ophthalmic No abnormalities of the cornea, including any of the following: Dry eye syndrome Sjögren's syndrome Congenital abnormalities (e.g., Fuch's dystrophy) Abnormal slit-lamp examination using a vital dye (e.g., fluorescein or Bengal-Rose) Abnormal corneal sensitivity test (e.g., Schirmer test or similar tear production test) Gastrointestinal No active peptic ulcer disease that would impair the ability to swallow pills No gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Willing to undergo serial biopsies, positron emission tomography, and CT scanning (for patients treated at the MTD only) No ongoing or active infection No significant traumatic injury within the past 3 weeks No history of allergic reaction to drugs of similar chemical or biological composition to study drugs No psychiatric illness or social situation that would preclude study compliance No other condition that would impair the ability to swallow pills No other uncontrolled illness PRIOR CONCURRENT THERAPY: Biologic therapy No concurrent prophylactic hematopoietic colony-stimulating factors Chemotherapy More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered Endocrine therapy Not specified Radiotherapy More than 4 weeks since prior radiotherapy (except for low dose, non-myelosuppressive radiotherapy) and recovered Surgery More than 3 weeks since prior major surgery No prior surgical procedure affecting absorption Other No prior sorafenib or erlotinib No other prior agents targeting Raf, vascular endothelial growth factor (VEGF), VEGF receptor, or epidermal growth factor receptor No other concurrent investigational agents No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital) No concurrent CYP3A4 inducers (e.g., rifampin or Hypericum perforatum [St. John's wort]) No other concurrent anticancer therapy Concurrent prophylactic anticoagulation therapy (e.g., low-dose warfarin) allowed provided PT INR < 1.1 times upper limit of normal (ULN) Concurrent full-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 allowed provided both of the following criteria are met: Patient has an in range INR (between 2-3) while on a stable-dose of oral anti-coagulant OR a stable-dose of low molecular weight heparin No active bleeding OR pathological condition that would confer a high risk of bleeding (e.g., tumor involving a major vessel or known varices)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OSI-774 erlotinib) and Bay 43-9006 (Sorafenib)<br>Sorafenib administered alone for a 1-week run-in period, and then both drugs e given together continuously, with every 28 days considered as a cycle. Three dose levels assessed. | Drug: erlotinib hydrochloride<br> <br> Drug: sorafenib tosylate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose and recommended phase II dose |  | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamic outcomes |  | Pre study and cycle 1 | 
| Pharmacokinetic outcomes |  | Pre-study, cycle 1 and cycle 2 | 
| Antitumor activity |  | Every 8 wks | 
| Correlation of EGFR, AKT, ERK and VEGFR with antitumor activity |  | If responses or prolonged stable disease are observed | 
| EGFR activating mutations, gene amplification status, EGFR intron 1 polymorphism if responses or prolonged disease stabilization are seen |  | If responses or prolonged stable disease are observed | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified adult solid tumor, protocol specific