Sorafenib in Combination With RAD001 in Advanced Solid Tumors Selected on Molecular Targets
Sorafenib is an oral multikinase inhibitor and among its targets are several RTKs involved in tumor genesis (Raf, Flt-3, c-Kit and RET) and angiogenesis (VEGFR1, 2 and 3 and PDGFRß). Therefore sorafenib inhibits tumor growth by a dual mechanism, acting either directly on the tumor (through inhibition of Raf and Kit signaling) and/or on tumor angiogenesis (through inhibition of VEGFR and PDGFR signaling.
RAD001 is a novel derivative of rapamycin. It selectively inhibits mTOR directly blocking tumor cells by preventing tumor cell growth and proliferation and indirectly by inhibiting angiogenesis (via potent inhibition of the HIF-1 and consequently VEGF production).
Targeting mTOR in combination with sorafenib might lead to more profound effects on tumor cell biology than could be achieved through individual targeting of some proteins.
New drugs have often met only limited success since not always target pathways responsible for tumor development and growth are targeted. To overcome this problem, the specific pathways targeted by the investigators two drugs will be analyzed in each single patient before the inclusion.
|Advanced Solid Tumors||Drug: RAD001 in combination with sorafenib||Phase 1 Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I/II Trial With Sorafenib in Combination With RAD001 Administered Orally in Patients With Advanced Solid Tumors, Selected on the Base of Molecular Targets|
- Phase I: Maximum Tolerated Dose (MTD) [ Time Frame: 6 weeks ]The maximum tolerated dose (MTD) is defined as the dose in which 2 of 3 or 2 of 6 patients experience a DLT. The Recommended Dose is identified as one dose level below the MTD.
- Phase II: PFS (Progression Free survival) rate [ Time Frame: 3 months ]
- Phase I: Pharmacokinetics profile of both drugs [ Time Frame: 6 weeks ]
- Phase II: overall survival [ Time Frame: 15 months ]
- Tumor response [ Time Frame: every 8 weeks ]Evaluated according to RECIST criteria
- Objective Response Rate (ORR) [ Time Frame: 15 months ]
- Incidence and severity of AEs [ Time Frame: 36 months ]graded according to CTCAE criteria v3.0
|Study Start Date:||March 2009|
|Estimated Study Completion Date:||December 2012|
|Estimated Primary Completion Date:||September 2012 (Final data collection date for primary outcome measure)|
|Experimental: RAD001 in combination with sorafenib||
Drug: RAD001 in combination with sorafenib
Phase I / Dose escalation: during the first cycle RAD001 (2.5-10 mg/day) will be administered alone, once a day, on days 1-14 to allow PK-profiling of the drug. From day 15 sorafenib administration (400-800 mg/day) twice a day will be added.
The cycle 1 will last 6 weeks, subsequent cycles will last 4 weeks (the 2 drugs administered in combination from day 1 to day 28).
Phase II: The drugs will be administered at the Recommended Dose and each treatment cycle will last 4 weeks.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01226056
|Istituto Europeo di Oncologia,|
|Milano, Italy, 20141|
|Study Chair:||filippo De Braud, MD||IEO, Milano (Italy)|