SORAVE - Sorafenib and Everolimus in Solid Tumors

Non-Small Cell Lung Cancer Clinical Trial

— SORAVE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00933777
• Other study ID #: SORAVE
• Status: Completed
• Phase: Phase 1
• First received: July 2, 2009
• Last updated: May 24, 2016
• Start date: July 2009
• Est. completion date: February 2015

Study information

• Verified date: May 2016
• Source: University of Cologne
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial Summary

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)

Description:

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: February 2015
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

Drug:
• Combination of sorafenib and everolimus
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

Locations

Country	Name	City	State
Germany	Center for Integrated Oncology, Dep.I of Internal Medicine, University Hospital Cologne	Cologne

Sponsors (1)

Lead Sponsor	Collaborator
University of Cologne

Country where clinical trial is conducted

Germany, 

References & Publications (10)

Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, Park Y, Liou SH, Marshall B, Boni JP, Dukart G, Sherman ML. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004 Mar 1;22(5):909-18. — View Citation

Cascone T, Gridelli C, Ciardiello F. Combined targeted therapies in non-small cell lung cancer: a winner strategy? Curr Opin Oncol. 2007 Mar;19(2):98-102. Review. — View Citation

Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34. Erratum in: N Engl J Med. 2007 Jul 12;357(2):203. — View Citation

Herbst RS, Johnson DH, Mininberg E, Carbone DP, Henderson T, Kim ES, Blumenschein G Jr, Lee JJ, Liu DD, Truong MT, Hong WK, Tran H, Tsao A, Xie D, Ramies DA, Mass R, Seshagiri S, Eberhard DA, Kelley SK, Sandler A. Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J Clin Oncol. 2005 Apr 10;23(11):2544-55. Epub 2005 Mar 7. — View Citation

Moore M, Hirte HW, Siu L, Oza A, Hotte SJ, Petrenciuc O, Cihon F, Lathia C, Schwartz B. Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol. 2005 Oct;16(10):1688-94. Epub 2005 Jul 8. — View Citation

O'Donnell A, Faivre S, Burris HA 3rd, Rea D, Papadimitrakopoulou V, Shand N, Lane HA, Hazell K, Zoellner U, Kovarik JM, Brock C, Jones S, Raymond E, Judson I. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol. 2008 Apr 1;26(10):1588-95. doi: 10.1200/JCO.2007.14.0988. Epub 2008 Mar 10. — View Citation

Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med. 2004 Jan 22;350(4):379-92. Review. Erratum in: N Engl J Med. 2009 Apr 30;360(18):1917. — View Citation

Stroobants S, Verschakelen J, Vansteenkiste J. Value of FDG-PET in the management of non-small cell lung cancer. Eur J Radiol. 2003 Jan;45(1):49-59. Review. — View Citation

Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M, Faghih M, Brendel E, Voliotis D, Haase CG, Schwartz B, Awada A, Voigtmann R, Scheulen ME, Seeber S. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol. 2005 Feb 10;23(5):965-72. Epub 2004 Dec 21. — View Citation

Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, Martinelli E, Ramon y Cajal S, Jones S, Vidal L, Shand N, Macarulla T, Ramos FJ, Dimitrijevic S, Zoellner U, Tang P, Stumm M, Lane HA, Lebwohl D, Baselga J. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol. 2008 Apr 1;26(10):1603-10. doi: 10.1200/JCO.2007.14.5482. Epub 2008 Mar 10. Erratum in: J Clin Oncol. 2010 Dec 20;28(36):5350. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To define a feasible treatment schedule for the combination therapy with sorafenib and everolimus		July 2009 - December 2011	Yes
Secondary	To determine the maximum tolerated dose (MTDs) of everolimus in combination with 2 x 400 mg sorafenib daily		July 2009 - December 2011	Yes
Secondary	To analyze pharmacokinetic (PK) profiles (AUC, Cmax) of sorafenib and everolimus during combination therapy		July 2009 - December 2012	Yes
Secondary	To determine the safety profile of the combination therapy with sorafenib + everolimus		July 2009 - December 2012	Yes
Secondary	To correlate KRAS-mutation status with treatment response (extension phase)		December 2011 - December 2012	No

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