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A Phase II, Open Label, Non-randomized Study of Second or Third Line Treatment With the Combination of Sorafenib and Everolimus in Patients Affected by Relapsed and Non-resectable High-grade Osteosarcoma

Phase 2
18 Years
Open (Enrolling)
Metastatic Osteosarcoma, Relapsed Osteosarcoma

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Trial Information

A Phase II, Open Label, Non-randomized Study of Second or Third Line Treatment With the Combination of Sorafenib and Everolimus in Patients Affected by Relapsed and Non-resectable High-grade Osteosarcoma

Patients affected by metastatic or relapsed osteosarcoma which progressed after first or
further line treatments still have a poor outcome. Standard chemotherapy has limited
activity in these patients.

In a previous study in patient affected by relapsed unresectable osteosarcoma, sorafenib
alone demonstrated promising activity. In the preclinical setting, everolimus was able to
improve the activity of sorafenib. Sorafenib and everolimus, by hitting crucial pathways
which are essential for osteosarcoma cell proliferation and survival, with an entirely
different approach aimed to overcome the resistance to standard chemotherapy showed by
relapsed osteosarcoma. In this trial, all patients will be treated with sorafenib and
everolimus at the dosage of 800 mg and 5 mg per day, respectively. Both drugs have to be
taken orally. The treatment will be continued until progression or unacceptable toxicities.
The objective of the present trial is to obtain a 50% rate of patients alive and free from
progression of their disease 6 months after trial enrolment. The disease will be evaluated
every 2 months with a CT scan.

Inclusion Criteria:

- Patients with histologically documented and not surgically resectable or metastatic
high-grade osteosarcoma which progressed after first or second line treatments for
relapsing disease

- Measurable disease as defined by RECIST criteria vs. 1.1 (bone lesions are allowed).
Baseline evaluations must be completed within 28 days prior to enrollment

- Eastern Cooperative Oncology Group(ECOG) Performance Status of 0 or 1. ECOG PS 2
patients are eligible if the PS 2 depends solely on orthopedic problems

- Estimated life expectancy of at least 3months

- Age≥18 years

- Adequate bone marrow, liver and renal function: Hemoglobin>9.0g/dl, Absolute
neutrophil count>1,500/mm3, Platelet>100,000/μl Total bilirubin<1.5 times the upper
limit of normal (ULN), ALT and AST<2.5xULN (<5xULN for patients with liver
involvement of their cancer), PT-INR/PTT<1.5xULN, Serum creatinine<2xULN

- Written informed consent

Exclusion Criteria:

- Dementia or significantly altered mental status that would prohibit the understanding
or rendering of informed consent and compliance with the requirements of this

- Patients with any severe and/or uncontrolled medical conditions such as unstable
angina pectoris, symptomatic congestive heart failure, myocardial infarction
≤6months, serious uncontrolled cardiac arrhythmia, uncontrolled hyperlipidemia,
active or uncontrolled severe infection, cirrhosis, chronic or persistent active
hepatitis or severely impaired lung function.

- History of HIV infection and active clinically serious infections (>grade 2 according
to NCI-CTCAE vs. 4.0)

- Symptomatic metastatic brain or meningeal tumors (unless the patient is >6months from
definitive therapy, has a negative imaging study within 4weeks of study entry and is
clinically stable with respect to the tumor at the time of study entry)

- Patients with seizure disorders requiring medication

- Pregnant or breast-feeding patients. Women of childbearing potential must have a
negative pregnancy test performed within 7days of the start of treatment. Both men
and women must use adequate barrier birth control measures during the course of the
trial and 8weeks after last dose of study drug

- Patients with evidence or history of bleeding diathesis

- Patients undergoing renal dialysis

- Patients unable to swallow oral medications

- Uncontrolled diabetes (fasting glucose>2xULN)

- Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent (except corticosteroids with a daily dosage equivalent to
prednisone ≤20mg for adrenal insufficiency). Patients receiving corticosteroids must
be on a stable dose for ≥4weeks prior to the first dose of Everolimus. Topical or
inhaled corticosteroids are permitted

- Patients with a history of another malignancy within 5years prior to study entry,
except curatively treated non-melanotic skin cancer or in-situ cervical cancer skin
or other solid tumors curatively treated with no evidence of disease for ≥3years.
Patients with severe and/or uncontrolled concurrent medical disease that in the
opinion of the investigator could cause unacceptable safety risks or compromise
compliance with the protocol

- Anticancer chemotherapy or immunotherapy during the study or within 4weeks of study

- Radiotherapy during study or within 3weeks of start of study drug. (Palliative
radiotherapy will be allowed)

- Major surgery within 4weeks of start of study

- Investigational drug therapy outside of this trial during or within 4weeks of study

- Prior exposure to the study drugs or their analogues

- Patients with known hypersensitivity to sorafenib, everolimus or other rapamycin
analogs, or to its excipients

- Substance abuse, medical, psychological or social conditions that may interfere with
the patient's participation in the study or evaluation of the study results

- A history of noncompliance to medical regimens or inability or unwillingness to
return for scheduled visits

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression Free Survival rate at 6 months

Outcome Description:

Progression Free Survival rate at 6 months refers to the rate of patients alive and free from progression of the disease at 6 months from registration into the study. Disease will be assessed every 8 weeks up to 2 years until progression or death whichever came first.

Outcome Time Frame:

6 months from registration into the study

Safety Issue:


Principal Investigator

Massimo Aglietta, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

IRCC Candiolo


Italy: Ministry of Health

Study ID:




Start Date:

June 2011

Completion Date:

September 2013

Related Keywords:

  • Metastatic Osteosarcoma
  • Relapsed Osteosarcoma
  • osteosarcoma
  • sorafenib
  • everolimus
  • sarcoma
  • Osteosarcoma