SORAVE - Sorafenib and Everolimus in Solid Tumors

Study Overview
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Brief Summary
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Dose finding part: A phase I clinical trial to evaluate the safety of combined sorafenib and everolimus treatment in patients with relapsed solid tumors (finished). Extension part:Treatment of non-small cell lung cancer (NSCLC) with KRAS mutation after ≥ 1st relapse (recruiting)

Detailed Description
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Dose finding part: Patients will be recruited to receive combination of defined sorafenib dose (2x400mg) with increasing dose of everolimus (2.5mg, 5mg, 7.5mg, 10mg). There will be a run-in phase of 14 days of everolimus followed by combination sorafenib+everolimus starting from day 15. The combination will be continued as long as it is tolerated by the patient and the patient benefits from the treatment according to RECIST criteria. The maximal tolerated dose will be establish in 3+3 design. Patients will be recruited sequentially at least 14 days apart. The next dose level according to 3+3 design will be initiated if all patients on the previous dose level reach day 29. Extension part: Patients will be treated with a dose of 7,5 mg Everolimus for 14 days (run-in phase) and sorafenib 2x 400 mg until progression

Official Title
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SORAVE-Sorafenib and Everolimus in Solid Tumors. A Phase I Clinical Trial to Evaluate the Safety of Combined Sorafenib and Everolimus Treatment in Patients With Relapsed Solid Tumors

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific, Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Combination of sorafenib and everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with solid tumors relapsed after and/or refractory to standard therapy (dose finding part), KRAS mutated NSCLC patients after ≥ 1st relapse for the extension phase ≥ 18 years of age Performance status ECOG 0-2 Life expectancy of at least 12 weeks Subjects with at least one measurable (CT or MRI) lesion Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening: Hemoglobin ≥ 9.0 g/dL Absolute neutrophil count (ANC) ≥ 1,500 /mm3 Platelet count ≥ 100 000/µL Total bilirubin ≤ 1,5x upper limit of normal (ULN) ALT and AST ≤ 2,5x ULN (≤ 5x ULN for patients with liver involvement) Alkaline phosphatase < 4x ULN Potassium within normal limits (WNL) or correctable with supplements Total calcium (corrected for serum albumin) WNL or correctable with supplements Magnesium WNL or correctable with supplements PT-INR/PTT < 1.5 x ULN [Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists] Serum creatinine ≤ 1.5 x upper limit of normal or creatinine clearance (CrCl) ≥ 50 ml/min calculated by either Cockcroft-Gault or by 24 hours urine collection More than 14 days since previous systemic therapy, radiotherapy and surgery Negative urine or serum HCG in women of childbearing potential Signed and dated informed consent before the start of specific protocol procedures Exclusion Criteria: Squamous cell carcinoma histology in non-small cell lung cancer History of cardiac disease: congestive heart failure > NYHA class 2; active Coronary Arterial Disease (CAD), (MI more than 6 months prior to study entry is allowed); cardiac arrythmias requiring anti-arrythmic therapy (except, when controlled by beta blockers or digoxin) or uncontrolled hypertension; for Extension phase: Long QT-Syndrome Active skin, mucosa, ocular or GI disorders of grade > 1 Uncontrolled diabetes ≥ grade 3 hypercholesterolemia/hypertriglyceridemia or ≥ grade 2 hypercholesterolemia / hypertriglyceridemia with history of CAD (despite lipid lowering treatment if given) Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus and sorafenib (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) History of HIV infection or previously sero-positive for the virus History of Hepatitis B or/and C or previously sero-positive for the Hepatitis B or/and C virus Leptomeningeal or uncontrolled brain metastases, including patients who continue to require glucocorticoids or intrathecal chemotherapy for brain or leptomeningeal metastases (documented by lumbar puncture) Treatment with any other investigational drugs within the previous 14 days Patients with seizure disorder requiring anti-epileptics History of organ allograft Patients with evidence or history of bleeding diathesis Patients undergoing renal dialysis Previous treatment with mTOR inhibitors and/or known hypersensitivity to mTOR inhibitors Past or current history of cancer other than the entry diagnosis EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively treated > 3 years prior to study entry Any person being in an institution on assignment of the respective authority Any medical, mental or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or understand the patient information Women who are pregnant or breast feeding, or women who are able to conceive and unwilling to practice an effective method of birth control (safe hormonal methods or/and barrier contraception) during study and 2 months after the last study drug intake For Extension part: Patients with medication that prolongs QTc and cannot be withdrawn (if the QTc prolonging medication is withdrawn - there must be a time interval of at least 7 days before starting treatment with sorafenib, in case of amiodarone the time interval is at least 90 days) Testing for Hepatitis B is mandatory

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapy with everolimus and sorafenib<br>Dose finding: Treatment with defined dose of sorafenib of 2x400 mg with increasing dose of everolimus (2.5 mg, 5 mg, 7.5 mg, 10 mg) Extension: Treatment with defined dose of sorafenib of 2x400 mg with everolimus 7.5 mg | Drug: Combination of sorafenib and everolimus<br>* Dose finding: Treatment with defined dose of sorafenib of 2x400 mg with increasing dose of everolimus (2.5 mg, 5 mg, 7.5 mg, 10 mg) Extension: Treatment with defined dose of sorafenib of 2x400 mg with everolimus 7.5 mg<br>* Other names: Nexavar, RAD001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To define a feasible treatment schedule for the combination therapy with sorafenib and everolimus |  | July 2009 - December 2011 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the maximum tolerated dose (MTDs) of everolimus in combination with 2 x 400 mg sorafenib daily |  | July 2009 - December 2011 | 
| To analyze pharmacokinetic (PK) profiles (AUC, Cmax) of sorafenib and everolimus during combination therapy |  | July 2009 - December 2012 | 
| To determine the safety profile of the combination therapy with sorafenib + everolimus |  | July 2009 - December 2012 | 
| To correlate KRAS-mutation status with treatment response (extension phase) |  | December 2011 - December 2012 |