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A Phase II Study Evaluating Efficacy and Safety of Regorafenib in Patients With Metastatic Bone Sarcomas (REGOBONE)

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ClinicalTrials.gov Identifier: NCT02389244
Recruitment Status : Recruiting
First Posted : March 17, 2015
Last Update Posted : August 16, 2018
Sponsor:
Information provided by (Responsible Party):
UNICANCER

Brief Summary:

INDICATION:

Metastatic bone sarcomas: conventional high grade osteosarcoma, Ewing sarcoma of bone, intermediate or high-grade chondrosarcomas and chordomas


Condition or disease Intervention/treatment Phase
Ewing Sarcomas Chondrosarcomas Osteosarcomas Chondroma Drug: Regorafenib Drug: Placebo Phase 2

Detailed Description:

METHODOLOGY:

Randomized, placebo-controlled, multicentric, phase II study -This is a double-blind placebo-controlled trial, with 4 cohort: cohort A: Osteosarcoma cohort B: Ewing sarcoma cohort C: Chondrosarcoma cohort D : chondroma. Cohort A, B and C will involve a total of 36 patients (24 Regorafenib + 12 placebo). And cohort D a total of 24 evaluable patients (16 Regorafenib + 8 placebo) 132 patients who meet the eligibility criteria will be randomly assigned in a 2:1 ratio to the following treatment groups :

The Arm A:

Regorafenib (160 mg/d) once daily for the 3 weeks on / 1 week off plus Best Supportive Care (BSC) until progression (according to RECIST 1.1), intolerance or withdrawal of consent .

Patients receiving regorafenib who experience disease progression and for whom in the investigator opinion, treatment with regorafenib is providing clinical benefit, may continue the treatment following consultation with the study coordinator and the sponsor.

The Arm B:

Placebo plus BSC until progression (according to RECIST V1.1) intolerance or withdrawal of consent. Patients who have received placebo will receive open-label regorafenib after objective tumor progression.

Patients will be stratified at randomization according to histology .


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 132 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized Phase II, Placebo-controlled, Multicenter Study Evaluating Efficacy and Safety of Regorafenib in Patients With Metastatic Bone Sarcomas
Study Start Date : September 2014
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : March 2021


Arm Intervention/treatment
Experimental: Regorafenib

For adult patients (≥ 18 years old) : 160 mg/d once daily for the 3 weeks on / 1 week off plus Best Supportive Care (BSC) until progression (according to RECIST 1.1), intolerance or withdrawal of consent .

For children Age ≥ 10 years to < 18 years old and BSA ≥ 1.30 m2, regorafenib (82 mg/m²) once daily for the 3 weeks on/1 week off (without exceeding 160mg/day) plus Best Supportive care (BSC) until progression (according to RECIST 1.1), intolerance or withdrawal of consent.

Drug: Regorafenib
For adults patients and children with BSA ≥ 1.70 m² : 4 tablets once daily until progression or unacceptable toxicity For children with BSA ≥ 1.30 and ≤ 1.69 m² : 3 tablets once daily until progression or unacceptable toxicity
Other Name: Stivarga

Placebo Comparator: placebo
Placebo plus BCS until progression (according to RECIST V1.1) intolerance or withdrawal of consent. Patients who have received placebo will receive open-label regorafenib after objective tumor progression.
Drug: Placebo
For adults patients and children with BSA ≥ 1.70 m² : 4 tablets once daily and switch to regorafenib after confirmed progression For children with BSA ≥ 1.30 and ≤ 1.69 m² : 3 tablets once daily and switch to regorafenib after confirmed progression
Other Name: Placebo tablet




Primary Outcome Measures :
  1. The primary efficacy endpoint is progression free survival (PFS) [defined using RECIST 1.1] after central radiological review [ Time Frame: expected average duration of 3 months ]
    from the date of randomization until the date of radiological progression or death whatever the cause


Secondary Outcome Measures :
  1. Objective response rate [ Time Frame: 6 months ]
    complete response (CR) or partial response (PR) according to RECIST 2009, version 1.1, for all cohorts, and CHOI criteria for chordoma

  2. Disease control rate at 6 months [ Time Frame: 6 months ]
    from the date of randomization until the date of death due to any cause

  3. Overall survival [ Time Frame: the time from the date of randomization until the date of death due to any cause (up to 6 months) ]
  4. Duration of response [ Time Frame: expected average duration of 6 months ]
    objective response of CR or PR, whichever is noted earlier, to first disease progression or death before progression

  5. Progression-free rate at 3 and 6 months [ Time Frame: at 3 and 6 months ]
  6. Time to progression [ Time Frame: from date of randomization until the date of first observation of progression (up to 6 months) ]
  7. Growth Modulation Index defined as ratio of time to progressive disease (PD) under regorafenib to time to progression (TTP) under previous treatment [ Time Frame: time to PD under regorafenib to TTP under previous treatment (up to 6 months) ]
  8. Toxicity according to NCI-CTCAE V4-0 [ Time Frame: expected average duration of 6 months ]
    according to NCI-CTCAE V4-0 (National Cancer Institut Common Terminology Criteria for Adverse Events)

  9. Pain assessment using Visual analog scale (VAS), DN4 scale (Neuropathic Pain Diagnostic Questionnaire) and NPSI scale (Neuropathic Pain Symptom Inventory) [ Time Frame: expected average duration of 6 months ]
    for chordomas cohort only

  10. PFS [ Time Frame: from date of randomization until the date of first observation of progression (up to 6 months) ]
    Progression Free Survival according to Choi criteria for Chordoma



Information from the National Library of Medicine

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Ages Eligible for Study:   10 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients must have histologically confirmed diagnosis of bone sarcoma (osteosarcoma, Ewing sarcoma of bone, chondrosarcoma or chordoma) ;
  2. Patients with confirmed disease progression at study entry.
  3. Metastatic disease not amenable to surgical resection or radiation with curative intent;
  4. Patients must have measurable disease ;
  5. Prior treatment :

    at least one, but no more than two prior chemotherapy regimen for metastatic disease for osteosarcoma, chondrosarcoma and Ewing sarcoma; neo-adjuvant /maintenance therapy are not counted towards this requirement. Chordoma not pretreated or with 1 or 2 prior (combination) chemotherapy regimen or with one or two prior molecularly targeted therapy, but no more than 2 prior lines of treatment (whatever the indication) can be included. At least 4 weeks since last chemotherapy (6 weeks in case of nitrosoureas and mitomycin C), immunotherapy or any other pharmacological treatment and/or radiotherapy;

  6. Age ≥ 10 years for osteosarcomas, Ewing sarcomas and chondrosarcomas (for chordomas, patients must be ≥ 18 years);
  7. Body Surface Area ≥ 1.30 m²
  8. Life expectancy of greater than 3 months;
  9. ECOG performance status < 2 (Karnofsky ≥ 60%) for adults patients;
  10. Karnofsky scale ≥ 60 % for children aged > 12 years old / Lansky scale ≥ 60 % for children aged ≤ 12 years old
  11. Patients must have adequate bone marrow, renal, and hepatic function, as evidenced by the following within 7 days of study treatment initiation : normal organ function as defined below :

    • Absolute neutrophil count ≥ 1.5 Giga/L
    • Platelets ≥ 100 Giga/L
    • Hemoglobin≥ 9 g/dL
    • Serum creatinin ≤ 1.5 x ULN (Upper Limit of Normal)
    • Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2 according to the modified Diet in Renal Disease (MDRD) abbreviated formula
    • AST (aspartate transaminase) and ALT (alanine transaminase) ≤2.5 x ULN
    • Bilirubin ≤1.5 X ULN
    • Alkaline phosphatase ≤2.5 x ULN (≤5 x ULN in patient with liver involvement of their cancer). If Alkaline phosphatase > 2.5 ULN, hepatic isoenzymes 5-nucleotidase or GGT tests must be performed; hepatic isoenzymes 5-nucleotidase must be within the normal range and/or GGT < 1.5 x ULN
    • lipase ≤1.5 x ULN.
    • Spot urine must not show 1+ or more protein in urine or the patient will require a repeat urine analysis. If repeat urinalysis shows 1+ protein or more, a 24-hour urine collection will be required and must show total protein excretion <1000 mg/24 hours
  12. International Normalized Ratio(INR)/ Partial Thromboplastin Time (PTT) ≤1.5 x ULN;
  13. Recovery to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug/procedure related toxicity (except alopecia, anemia, and hypothyroidism);
  14. Women of childbearing potential and male patients must agree to use adequate contraception for the duration of study participation and up to 3 months following completion of therapy;
  15. Women of childbearing potential must have a negative serum β-HCG pregnancy test within 7 days prior randomization and/or urine pregnancy test within 48 hours before the first administration of the study treatment;
  16. Signed informed consent form by adult patients and/orpatients parents/legal representatives (if age < 18 years) and age appropriate assent form by the patients' parents/legal representatives obtained before any study specific procedure is conducted
  17. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures;
  18. Patients or parents/legal representativesaffiliated to the Social Security System.

Exclusion Criteria:

  1. Prior treatment with any VEGFR inhibitor;
  2. Soft tissue sarcoma;
  3. Other cancer (different histology) within 5 years prior to randomization;
  4. Major surgical procedure, open biopsy, significant trauma, within the last 28 days before randomization;
  5. Cardiovascular dysfunction:

    • Left ventricular ejection fraction (LVEF) < 50%
    • Congestive heart failure (New York Heart Association [NYHA]) ≥ 2
    • Myocardial infarction <6 months before study
    • Cardiac arrhythmias requiring therapy
    • Uncontrolled hypertension
    • Unstable angina or new-onset angina
  6. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within the last 6 months before randomization;
  7. Severe hepatic impairment (Child-Pugh C);
  8. Ongoing infection > Grade 2 according to NCI-CTCAE v4.0;
  9. Known history of human immunodeficiency virus (HIV) infection;
  10. Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy ;
  11. Difficulties with swallowing study tablets;
  12. Prior anticancer therapy, including radiotherapy, endocrine therapy, immunotherapy, chemotherapy (CT) within the last 4 weeks (6 weeks for nitrosoureas and mitomycin C), or other investigational agents ; Concomitant antalgic palliative radiotherapy allowed;
  13. Concurrent enrolment in another clinical trial in which investigational therapies are administered;
  14. Known hypersensitivity to the active substance or to any of the excipients;
  15. Pregnant women, women who are likely to become pregnant or are breast-feeding;
  16. For adult patients, individual deprived of liberty or placed under the authority of a tutor;
  17. Patients with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial;
  18. Patients with history of non compliance to medical regimens or unwilling or unable to comply with the protocol.
  19. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent;
  20. Non-healing wound, non-healing ulcer, or non-healing bone fracture;
  21. Patients with evidence or history of any bleeding diathesis, irrespective of severity;
  22. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication.
  23. Use of biological response modifiers, such as granulocyte colony stimulating factor (G-CSF), within 3 weeks of study entry.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02389244


Contacts
Contact: Laure MONARD 33 (0)173797309 l-monard@unicancer.fr

Locations
France
Hopital Jean Monjoz Not yet recruiting
Besancon, France, 25030
Principal Investigator: Elsa KALBACHER, MD         
Institut Bergonie Recruiting
Bordeaux, France, 33076
Principal Investigator: Antoine ITALIANO, MD         
Centre Francois Baclesse Recruiting
Caen, France, 14176
Principal Investigator: Corinne DELCAMBRE, MD         
Centre Georges Francois Leclerc Recruiting
Dijon, France, 21079
Principal Investigator: Nicolas ISAMBERT, MD         
Centre Oscar Lambret Recruiting
Lille, France, 59020
Principal Investigator: Nicolas PENEL, MD         
Centre Léon Berard Recruiting
Lyon, France, 69373
Principal Investigator: Jean Yves BLAY, MD PhD         
Institut Paoli Calmettes Recruiting
Marseille, France, 13273
Principal Investigator: François BERTUCCI, MD PhD         
La Timone University Hospital Recruiting
Marseille, France, 13385
Principal Investigator: Florence DUFFAUD, MD PhD         
ICM Val d'Aurelle Recruiting
Montpellier, France, 34298
Principal Investigator: Didier CUPISSOL, MD         
Centre Antoine Lacassagne Recruiting
Nice, France, 06189
Principal Investigator: Antoine THYSS, MD PhD         
Hôpital Cochin Recruiting
Paris, France, 75014
Principal Investigator: Pascaline BOUDOU-ROUQUETTE, MD         
Institut Curie Recruiting
Paris, France
Principal Investigator: Sophie PIPERNO-NEUMANN, MD         
Centre Eugene Marquis Recruiting
Rennes, France, 35042
Principal Investigator: Christophe PERRIN, MD         
Institut de cancerologie de l'ouest site Rene Gauducheau Recruiting
Saint Herblain, France, 44805
Principal Investigator: Emmanuelle BOMPAS, MD         
Institut de Cancérologie Lucien Neuwirth (ICLN) Recruiting
Saint Priest en Jarez, France, 42270
Principal Investigator: Olivier COLLARS, MD         
Institut Claudius Regaud Recruiting
Toulouse, France, 31052
Principal Investigator: Christine CHEVREAU, MD         
CHU Bretonneau Recruiting
Tours, France, 37000
Principal Investigator: Helene VEGAS, MD         
Institut de cancerologie de lorraine alexis Vautrin Recruiting
Vandoeuvre les Nancy, France, 54519
Principal Investigator: Maria RIOS, MD         
Gustave Roussy Recruiting
Villejuif, France, 94800
Principal Investigator: Olivier MIR, MD         
Sponsors and Collaborators
UNICANCER
Investigators
Principal Investigator: Florence DUFFAUD, MD PhD La Timone University Hospital

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: UNICANCER
ClinicalTrials.gov Identifier: NCT02389244     History of Changes
Other Study ID Numbers: UC-0150/1309
First Posted: March 17, 2015    Key Record Dates
Last Update Posted: August 16, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: no individual participant data is shared

Additional relevant MeSH terms:
Sarcoma
Osteosarcoma
Sarcoma, Ewing
Chondrosarcoma
Chondroma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue