Clinical trial NCT01804374: Phase II Open Label, Non-randomized Study of Sorafenib and Everolimus in Relapsed and Non-resectable Osteosarcoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Osteosarcoma
Relapsed Osteosarcoma
Keywords: osteosarcoma
sorafenib
everolimus
sarcoma
Lead sponsor: Italian Sarcoma Group
Sponsor class: NETWORK
First posted: 2013-03-05
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a trial for patients affected by metastatic or relapsed osteosarcoma which progressed after first or further line treatments. In this trial, all patients will be treated until progression or unacceptable toxicity with sorafenib and everolimus. The treatment with sorafenib and everolimus aimed to obtain a 50% rate of patients free from further progression of the disease after 6 months from study entry.

Detailed description: 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.

Eligibility criteria: 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 protocol
* 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 entry
* 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 entry
* 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

Primary outcomes:
measure: Progression Free Survival rate at 6 months
timeFrame: 6 months from registration into the study
Secondary outcomes:
measure: progression free survival
timeFrame: From randomization until progression or death whichever came first up to 2 years
measure: overall survival
timeFrame: From randomization until death followed up to 5 years
measure: Overall response rate
timeFrame: From randomization until progression or death whichever came first up to 2 years
measure: Duration of response
timeFrame: calculated from date of first assessement of non-progression until progression or death whichever came first up to 2 years
measure: Non-dimensional pattern of response
timeFrame: calculated from randomization until progression or death whichever came first up to 2 years
measure: clinical benefit
timeFrame: evaluated at each visit from randomizzation until progression or death whichever came first up to 2 years
measure: Safety
timeFrame: assessed at each visit from randomizzation until 28 days after the last dose of study treatment assumption up to 2 years
Other outcomes:
measure: Expression of MAPKs pathway, VEGFR, PDGFR, Ezrin/Moesin and mTOR pathway (pS6 expression)
timeFrame: as soon as tissue samples are available or within 2 months from subject study entry
measure: Correlation between oncogenes/metabolic pathways and clinical outcome parameters
timeFrame: at the time of first survival analysis performed at least 6 months after last subject registration
measure: Predictive and prognostic role of serum lactate dehydrogenase and serum alkaline phosphatase
timeFrame: at the time of first survival analysis performed at least 6 months after last subject registration
Locations:
city: Candiolo
country: Italy
facility: Fondazione del Piemonte per l'Oncologia IRCC Candiolo
state: Torino
Study officials:
affiliation: IRCC Candiolo
name: Massimo Aglietta, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: IRCC Candiolo
name: Giovanni Grignani, MD
role: STUDY_DIRECTOR
affiliation: Italian Sarcoma Group
name: Piero Picci, MD
role: STUDY_CHAIR
References:
citation: Grignani G, Palmerini E, Ferraresi V, D'Ambrosio L, Bertulli R, Asaftei SD, Tamburini A, Pignochino Y, Sangiolo D, Marchesi E, Capozzi F, Biagini R, Gambarotti M, Fagioli F, Casali PG, Picci P, Ferrari S, Aglietta M; Italian Sarcoma Group. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial. Lancet Oncol. 2015 Jan;16(1):98-107. doi: 10.1016/S1470-2045(14)71136-2. Epub 2014 Dec 11.