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

This study has suspended participant recruitment.
(toxicity (protocol amendment under approval))
Sponsor:
Collaborators:
Novartis
Bayer
Information provided by:
Southern Europe New Drug Organization
ClinicalTrials.gov Identifier:
NCT01226056
First received: October 18, 2010
Last updated: October 20, 2010
Last verified: October 2010
  Purpose

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.


Condition Intervention Phase
Advanced Solid Tumors
Drug: RAD001 in combination with sorafenib
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
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

Resource links provided by NLM:


Further study details as provided by Southern Europe New Drug Organization:

Primary Outcome Measures:
  • Phase I: Maximum Tolerated Dose (MTD) [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Phase I: Pharmacokinetics profile of both drugs [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
  • Phase II: overall survival [ Time Frame: 15 months ] [ Designated as safety issue: No ]
  • Tumor response [ Time Frame: every 8 weeks ] [ Designated as safety issue: No ]
    Evaluated according to RECIST criteria

  • Objective Response Rate (ORR) [ Time Frame: 15 months ] [ Designated as safety issue: No ]
  • Incidence and severity of AEs [ Time Frame: 36 months ] [ Designated as safety issue: Yes ]
    graded according to CTCAE criteria v3.0


Estimated Enrollment: 45
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)
Arms Assigned Interventions
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.

Other Names:
  • RAD001 (Everolimus)
  • Sorafenib (Nexavar®)

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with progressive disease of advanced solid tumours judged non suitable for standard treatment
  2. 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
  3. At least 1 uni-dimensional measurable lesion according to modified RECIST
  4. Life expectancy of at least 12 weeks
  5. Age ≥ 18 years old
  6. ECOG Performance Status of 0 or 1
  7. 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)
    • ALT and AST ≤2.5 x ULN (≤5 x ULN for patients with liver involvement of their cancer)
    • Alkaline phosphatase ≤4 x ULN
    • PT-INR/PTT <1.5 x ULN
    • Serum albumin levels ≥2.5 mg/dl
    • Serum creatinine ≤1.5 x ULN
  8. HBV/HCV testing in the 2 weeks before treatment start in specific categories of patient with hepatitis B and C risk factors and in additional patients at the discretion of the investigators according to guidelines in Appendix 6.
  9. All fertile patients must use adequate contraception while on study and for three subsequent months
  10. Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to performing any study specific procedures

Exclusion Criteria:

  1. 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
  2. History of HIV infection or chronic hepatitis B or C
  3. Patients with NSCLC squamous histotype
  4. 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
  5. Deep venous thrombosis or pulmonary embolus within 1 year or ongoing need for full-dose oral or parenteral anticoagulation
  6. Clinically active infections (> Grade 2 NCI-CTC AE version 3.0)
  7. Evidence of CNS tumor metastases
  8. History of organ allograft
  9. Pre-existing thyroid abnormality where thyroid function cannot be maintained in the normal range by medication
  10. Serious, non-healing wound, ulcer, or bone fracture
  11. Second malignancies within the past 5 years (except for non - melanoma skin cancer and cervical carcinoma in situ)
  12. Pregnant or breast-feeding patients
  13. Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
  14. Any condition that is unstable or could jeopardize the safety of the patient and his/her compliance in the study
  15. Patients unable to swallow oral medications
  16. Any malabsorption condition
  17. Prior treatment with sorafenib or m-TOR inhibitors
  18. Ongoing requirement for systemic corticosteroid medication or other immunosuppressants
  19. Radiotherapy within 3 weeks of start of study drug. Palliative radiotherapy is allowed. Major surgery within 4 weeks of study entry
  20. Radiotherapy involving > 30% of the active bone marrow
  21. Autologous bone marrow transplant or stem cell rescue within 4 months of study entry
  22. Use of biologic response modifiers, such as G-CSF, within 3 week of study entry. Patients taking chronic erythropoietin are permitted provided no dose adjustment is undertaken within 2 months prior to the study or planned during the study period
  23. Investigational drug therapy outside of this trial during or within 4 weeks of study entry
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01226056

Locations
Italy
Istituto Europeo di Oncologia,
Milano, Italy, 20141
Sponsors and Collaborators
Southern Europe New Drug Organization
Novartis
Bayer
Investigators
Study Chair: filippo De Braud, MD IEO, Milano (Italy)
  More Information

No publications provided

Responsible Party: Scientific Director, SENDO
ClinicalTrials.gov Identifier: NCT01226056     History of Changes
Other Study ID Numbers: S075SORD01
Study First Received: October 18, 2010
Last Updated: October 20, 2010
Health Authority: Italy: Istituto Superiore di Sanità

Keywords provided by Southern Europe New Drug Organization:
advanced solid tumors
Sorafenib (Nexavar®)
RAD001 (everolimus)
tumor molecular targets

Additional relevant MeSH terms:
Neoplasms
Everolimus
Sirolimus
Sorafenib
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 15, 2014