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Phase II Open Label, Non-randomized Study of Sorafenib and Everolimus in Relapsed and Non-resectable Osteosarcoma (SERIO)

Primary Purpose

Metastatic Osteosarcoma, Relapsed Osteosarcoma

Status
Completed
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Sorafenib
Everolimus
Sponsored by
Italian Sarcoma Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metastatic Osteosarcoma focused on measuring osteosarcoma, sorafenib, everolimus, sarcoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Fondazione del Piemonte per l'Oncologia IRCC Candiolo

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

sorafenib and everolimus

Arm Description

This is an open label study: all patients will be treated with sorafenib 400 mg twice a day in combination with everolimus 5mg per day

Outcomes

Primary Outcome Measures

Progression Free Survival rate at 6 months
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.

Secondary Outcome Measures

progression free survival
Progression Free Survival (PFS) refers to the time from registration into the study to the date of progressive disease or death whichever came first assessed every 8 weeks up to 2 years. In the absence of progression, time will be censored at the date of last tumor assessment or follow-up
overall survival
Overall survival (OS) is the time interval between date of registration into study and the date of death. For alive patients, time will be censored at the date of last follow-up.
Overall response rate
Overall response rate refers to the rate of patients with complete, partial or minimal responses (defined as shrinkage of target lesions between 10 and 30%) according to RECIST 1.1. Disease will be assessed every 8 weeks up to 2 years.
Duration of response
Duration of response refers to the time from the date of the first assessement of non-progression to the date of progressive disease or death. Disease will be assessed every 8 weeks up to 2 years until progression or death whichever came first. In the absence of progression time will be censored at the date of last tumor assessment or follow-up.
Non-dimensional pattern of response
Non-dimensional pattern of response refers to the evaluation of any consistent variation in radio metabolic diagnostic test (i.e. PET or Bone scan) and/or changes in signal intensity, contrast uptake/enhancement and tumor density at CT/MRI according to Modified Response Criteria (MRC). From this point of view, patients will be considered in response if there has been an objective response or at least ONE of the following criteria are met: An unequivocal reduction in tumor density at CT scan; An unequivocal reduction in signal intensity and/or contrast enhancement at MRI; An unequivocal reduction in SUV at PET scan; An unequivocal reduction in bone scan uptake. Disease will be assessed every 8 weeks up to 2 years until progression or death whichever came first.
clinical benefit
Clinical Benefit will be prospectively evaluated by means of Pain and Analgesic Scale recording of analgesic consume and as lack of progression of disease at six months.
Safety
Safety will be captured by recording: physical examinations, vital signs, performance status/body weight; blood tests and chemistry tests; intensity and severity of adverse events, use of analgesic medication at each visit until 28 days after last dose of study treatment assumption up to 2 years. Adverse events will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0

Full Information

First Posted
March 1, 2013
Last Updated
June 16, 2015
Sponsor
Italian Sarcoma Group
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1. Study Identification

Unique Protocol Identification Number
NCT01804374
Brief Title
Phase II Open Label, Non-randomized Study of Sorafenib and Everolimus in Relapsed and Non-resectable Osteosarcoma
Acronym
SERIO
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

2. Study Status

Record Verification Date
June 2015
Overall Recruitment Status
Completed
Study Start Date
June 2011 (undefined)
Primary Completion Date
December 2014 (Actual)
Study Completion Date
December 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Italian Sarcoma Group

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Osteosarcoma, Relapsed Osteosarcoma
Keywords
osteosarcoma, sorafenib, everolimus, sarcoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
38 (Actual)

8. Arms, Groups, and Interventions

Arm Title
sorafenib and everolimus
Arm Type
Experimental
Arm Description
This is an open label study: all patients will be treated with sorafenib 400 mg twice a day in combination with everolimus 5mg per day
Intervention Type
Drug
Intervention Name(s)
Sorafenib
Other Intervention Name(s)
BAY 43-9006, Nexavar
Intervention Description
Sorafenib tablet 200 milligrams packed in bottle containing 140 tablets. Sorafenib will be administered orally twice daily at the same time every day. Two 200 mg tablets will be taken either one hour before or two hours after a meal followed by a glass of water in the morning and in the evening. In general, patient should have a low to moderate fat meal. Patients will receive Sorafenib until progression, toxicity, withdrawal of informed consent or clinical investigator decision
Intervention Type
Drug
Intervention Name(s)
Everolimus
Other Intervention Name(s)
RAD001, Afinitor, Certican
Intervention Description
Everolimus is formulated in tablets of 2.5 or 5 mg strength, blister-packed under aluminum foil in units of 10 tablets. Everolimus will be administered orally once daily at the same time every day immediately after a meal, as a single dose of 5 mg. Patients should have a low-fat breakfast. After this light meal, study medication of Everolimus is to be taken. The tablets of Everolimus should not be chewed or crushed. Patients will receive Everolimus until progression, toxicity, withdrawal of informed consent or clinical investigator decision
Primary Outcome Measure Information:
Title
Progression Free Survival rate at 6 months
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.
Time Frame
6 months from registration into the study
Secondary Outcome Measure Information:
Title
progression free survival
Description
Progression Free Survival (PFS) refers to the time from registration into the study to the date of progressive disease or death whichever came first assessed every 8 weeks up to 2 years. In the absence of progression, time will be censored at the date of last tumor assessment or follow-up
Time Frame
From randomization until progression or death whichever came first up to 2 years
Title
overall survival
Description
Overall survival (OS) is the time interval between date of registration into study and the date of death. For alive patients, time will be censored at the date of last follow-up.
Time Frame
From randomization until death followed up to 5 years
Title
Overall response rate
Description
Overall response rate refers to the rate of patients with complete, partial or minimal responses (defined as shrinkage of target lesions between 10 and 30%) according to RECIST 1.1. Disease will be assessed every 8 weeks up to 2 years.
Time Frame
From randomization until progression or death whichever came first up to 2 years
Title
Duration of response
Description
Duration of response refers to the time from the date of the first assessement of non-progression to the date of progressive disease or death. Disease will be assessed every 8 weeks up to 2 years until progression or death whichever came first. In the absence of progression time will be censored at the date of last tumor assessment or follow-up.
Time Frame
calculated from date of first assessement of non-progression until progression or death whichever came first up to 2 years
Title
Non-dimensional pattern of response
Description
Non-dimensional pattern of response refers to the evaluation of any consistent variation in radio metabolic diagnostic test (i.e. PET or Bone scan) and/or changes in signal intensity, contrast uptake/enhancement and tumor density at CT/MRI according to Modified Response Criteria (MRC). From this point of view, patients will be considered in response if there has been an objective response or at least ONE of the following criteria are met: An unequivocal reduction in tumor density at CT scan; An unequivocal reduction in signal intensity and/or contrast enhancement at MRI; An unequivocal reduction in SUV at PET scan; An unequivocal reduction in bone scan uptake. Disease will be assessed every 8 weeks up to 2 years until progression or death whichever came first.
Time Frame
calculated from randomization until progression or death whichever came first up to 2 years
Title
clinical benefit
Description
Clinical Benefit will be prospectively evaluated by means of Pain and Analgesic Scale recording of analgesic consume and as lack of progression of disease at six months.
Time Frame
evaluated at each visit from randomizzation until progression or death whichever came first up to 2 years
Title
Safety
Description
Safety will be captured by recording: physical examinations, vital signs, performance status/body weight; blood tests and chemistry tests; intensity and severity of adverse events, use of analgesic medication at each visit until 28 days after last dose of study treatment assumption up to 2 years. Adverse events will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Time Frame
assessed at each visit from randomizzation until 28 days after the last dose of study treatment assumption up to 2 years
Other Pre-specified Outcome Measures:
Title
Expression of MAPKs pathway, VEGFR, PDGFR, Ezrin/Moesin and mTOR pathway (pS6 expression)
Description
Immunohistochemical evaluation of the expression of MAPKs pathway, VEGFR, PDGFR, Ezrin/Moesin and mTOR pathway (pS6 expression)on tissue samples from primary or metastatic tumors.
Time Frame
as soon as tissue samples are available or within 2 months from subject study entry
Title
Correlation between oncogenes/metabolic pathways and clinical outcome parameters
Description
Correlation of both primary and secondary objectives with the expression of the following oncogenes/metabolic pathways: MAPKs, VEGFR, PDGFR, Ezrin/Moesin and mTOR pathway (pS6 expression)
Time Frame
at the time of first survival analysis performed at least 6 months after last subject registration
Title
Predictive and prognostic role of serum lactate dehydrogenase and serum alkaline phosphatase
Description
Serum samples for evaluation of levels of lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) will be collected at each visit until progression or death whichever came first up to 2 years.
Time Frame
at the time of first survival analysis performed at least 6 months after last subject registration

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Massimo Aglietta, MD
Organizational Affiliation
IRCC Candiolo
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Giovanni Grignani, MD
Organizational Affiliation
IRCC Candiolo
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Piero Picci, MD
Organizational Affiliation
Italian Sarcoma Group
Official's Role
Study Chair
Facility Information:
Facility Name
Fondazione del Piemonte per l'Oncologia IRCC Candiolo
City
Candiolo
State/Province
Torino
ZIP/Postal Code
10060
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
25498219
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.
Results Reference
derived

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Phase II Open Label, Non-randomized Study of Sorafenib and Everolimus in Relapsed and Non-resectable Osteosarcoma

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