Sorafenib in Combination With RAD001 in Advanced Solid Tumors Selected on Molecular Targets

NCT01226056 | Suspended Phase 1

• 1 other identifier: S075SORD01
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Advanced Solid Tumors

Keywords

advanced solid tumors; Sorafenib (Nexavar®); RAD001 (everolimus); tumor molecular targets

Outcome Measures

Primary Outcomes (2)

• Phase I: Maximum Tolerated Dose (MTD)

  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.

  6 weeks

• Phase II: PFS (Progression Free survival) rate

  3 months

Secondary Outcomes (5)

• Phase I: Pharmacokinetics profile of both drugs

  6 weeks

• Phase II: overall survival

  15 months

• Tumor response

  every 8 weeks

• Objective Response Rate (ORR)

  15 months

• Incidence and severity of AEs

  36 months

Study Arms (1)

RAD001 in combination with sorafenib

EXPERIMENTAL

Drug: RAD001 in combination with sorafenib

Interventions

RAD001 in combination with sorafenib DRUG

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.

Also known as: RAD001 (Everolimus), Sorafenib (Nexavar®)

RAD001 in combination with sorafenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with progressive disease of advanced solid tumours judged non suitable for standard treatment
• Biopsiable lesion or archive tissue not older than 1 year to assess the expression of:
• phosphorylated AKT
• phosphorylated p70S6
• RKIP (Raf Kinase Inhibitor Protein)
• phosphorylated ERK1/2 The presence of at least one of the previous targets will be mandatory for patient enrolment
• At least 1 uni-dimensional measurable lesion according to modified RECIST
• Life expectancy of at least 12 weeks
• Age ≥ 18 years old
• ECOG Performance Status of 0 or 1
• Adequate bone marrow, liver, and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to start of first dose:
• Haemoglobin ≥9.0 g/dL (5.6 mmol/L)
• Absolute neutrophil count (ANC)≥1.5 x 109/L
• Platelet count ≥100 x 109/L
• Total bilirubin ≤1.5 x upper limit of normal (ULN)

You may not qualify if:

• History of cardiac disease: congestive heart failure (NYHA II-IV), active coronary artery disease - CAD (MI more than 6 months prior to study entry is allowed), cardiac arrhythmias requiring antiarrhythmic therapy (betablockers or digoxin are permitted) or uncontrolled hypertension
• History of HIV infection or chronic hepatitis B or C
• Patients with NSCLC squamous histotype
• Recurrent hemoptysis or cerebrovascular accident within 12 months, or peripheral vascular disease with claudication on less than 1 block (about 150 metres), or history of clinically significant bleeding non-traumatic
• Deep venous thrombosis or pulmonary embolus within 1 year or ongoing need for full-dose oral or parenteral anticoagulation
• Clinically active infections (\> Grade 2 NCI-CTC AE version 3.0)
• Evidence of CNS tumor metastases
• History of organ allograft
• Pre-existing thyroid abnormality where thyroid function cannot be maintained in the normal range by medication
• Serious, non-healing wound, ulcer, or bone fracture
• Second malignancies within the past 5 years (except for non - melanoma skin cancer and cervical carcinoma in situ)
• Pregnant or breast-feeding patients
• Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
• Any condition that is unstable or could jeopardize the safety of the patient and his/her compliance in the study
• Patients unable to swallow oral medications

Sponsors & Collaborators

• Southern Europe New Drug Organization: lead
• Novartis: collaborator
• Bayer: collaborator

Study Sites (1)

Istituto Europeo di Oncologia,

Milan, 20141, Italy

Location

MeSH Terms

Interventions

Everolimus; Sorafenib

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Phenylurea Compounds; Urea; Amides; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• filippo De Braud, MD

  IEO, Milano (Italy)

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: October 18, 2010
• First Posted: October 21, 2010
• Study Start: March 1, 2009
• Primary Completion: September 1, 2012
• Study Completion: December 1, 2012
• Last Updated: October 21, 2010

Record last verified: 2010-10

Locations

IT (1)