Clinical Trials /

Efficacy and Safety of Regorafenib as Maintenance Therapy After First-line Treatment in Patients With Bone Sarcomas

NCT04055220

Description:

This is a randomized, double-blinded, 2 arms study concerning patients with bone sarcoma after the first line therapy. In the first arm, patients will be treated with regorafenib for a maximum of 12 months as maintenance therapy after first line therapy (chemotherapy and surgery), whereas in the second arm, patients will be treated with placebo (standard of care). The comparison between this two arms will allow to determine whether or not regorafenib is efficient for disease control, in terms of Relapse-Free Survival improvement.

Related Conditions:
  • Bone Sarcoma
  • Osteosarcoma
Recruiting Status:

Recruiting

Phase:

N/A

Trial Eligibility

Document

Title

  • Brief Title: Efficacy and Safety of Regorafenib as Maintenance Therapy After First-line Treatment in Patients With Bone Sarcomas
  • Official Title: A Randomized, Placebo-controlled, Double-blinded, Multicentre Study Evaluating the Efficacy and Safety of Regorafenib as Maintenance Therapy After First-line Treatment in Patients With Bone Sarcomas

Clinical Trial IDs

  • ORG STUDY ID: REGOSTA (ET18-272)
  • NCT ID: NCT04055220

Conditions

  • Bone Sarcoma
  • Osteosarcoma

Interventions

DrugSynonymsArms
Treatment by RegorafenibStivargaRegorafenib
Treatment by PlaceboStandard of carePlacebo

Purpose

This is a randomized, double-blinded, 2 arms study concerning patients with bone sarcoma after the first line therapy. In the first arm, patients will be treated with regorafenib for a maximum of 12 months as maintenance therapy after first line therapy (chemotherapy and surgery), whereas in the second arm, patients will be treated with placebo (standard of care). The comparison between this two arms will allow to determine whether or not regorafenib is efficient for disease control, in terms of Relapse-Free Survival improvement.

Detailed Description

      Bone sarcomas are rare primary bone cancers, although, their frequency has been increasing by
      0.3% per year over the last decade. They include a very large number of tumour types
      belonging to the family of primary malignant bone tumours and originate from bone as
      Osteosarcomas (OS), Chondrosarcomas (CS), Fibrosarcomas, Chordomas, …

      Current conventional treatments for OS combine chemotherapy and surgery. Compared with
      surgery alone, multimodal treatment of high-grade sarcomas increases disease-free survival
      probabilities from only 10%-20% to 50-65% depending on the bone sarcoma type. In general,
      despite second-line treatment, the prognosis of recurrent disease has remained poor, with
      long-term post-relapse survival of <20%.

      The outcome of bone sarcoma has been dramatically improved by the addition of chemotherapy in
      the 70' and 80' but has remained remarkably stable in the last 3 decades, with a survival
      rate largely plateaued, despite introduction of novel regimens, both in localized and
      metastatic disease, in children and in adults. Primary bone cancer presented challenges in
      new drug development partly because of their rarity and heterogeneity. Thus, improving
      treatments for these diseases is a high priority, but advances have been few in recent years.
      In this context, maintenance therapy may be an interesting option as a way to prolong the
      benefit of first-line chemotherapy.

      Regorafenib may play a role in the maintenance setting for bone sarcomas (as improved
      Progression-Free Survival and sustained responses were observed in the REGOBONE study) in
      maintaining the initial response to chemotherapy and delaying the need for further treatment
      at relapse, while exerting a manageable associated toxicity and minimal negative impact on
      health-related quality of life.

      Currently there is no available agent used as maintenance therapy after first-line
      chemotherapy. In the context of a clinical trial with close monitoring, it is, thus,
      acceptable to consider a placebo-control group.

      On this basis, this study propose to conduct a double-blinded randomized controlled trial to
      evaluate the efficacy of regorafenib versus placebo in the treatment of patients with bone
      sarcomas, who have no evidence of disease after neoadjuvant and/or adjuvant chemotherapies.

      The main goal of the present study is then to explore whether sequential addition of
      regorafenib after completion of a standard induction chemotherapy in patients with bone
      sarcomas would improve outcomes in term of event-free-survival (EFS) defined by local or
      distant recurrence of the disease.

      Results will be stratified on the "high-risk" versus "low-risk" of relapse. As response to
      neoadjuvant chemotherapy and metastatic status at time of diagnosis are known to be important
      on patient's outcome, stratification will rely on a combined criteria taking into account
      these two factors. Thus, "high-risk" of relapse will be defined by the group of patients who
      are poor responders to neoadjuvant chemotherapy and/or in metastatic setting at diagnosis,
      whereas "low-risk" of relapse will be defined by the group of patients who have no metastatic
      disease at time of diagnosis and are good responders to neoadjuvant chemotherapy.
    

Trial Arms

NameTypeDescriptionInterventions
RegorafenibExperimentalTreatment will be divided in 28 days cycles, including a 21-day period of treatment by regorafenib followed by a 7-day period of rest. In case of toxicity, dose can be reduced or treatment interrupted according to Specific Product Characteristics (SPC). Patients can receive up to a maximum of 13 cycles (maximum treatment period : 12 Months).
  • Treatment by Regorafenib
PlaceboPlacebo ComparatorTreatment will be divided in 28 days cycles, including a 21-day period of treatment by placebo followed by a 7-day period of rest. In case of toxicity, dose can be reduced or treatment interrupted according to Specific Product Characteristics (SPC). Patients can receive up to a maximum of 13 cycles (maximum treatment period : 12 Months).
  • Treatment by Placebo

Eligibility Criteria

        INCLUSION CRITERIA :

        I1. Age ≥ 16 years at the day of consenting to the study;

        I2. Patients must have histologically confirmed diagnosis of primary bone sarcoma of one of
        the following histotypes:

          -  OS (conventional-intramedullary/central high grade, small cell, telangiectatic or
             high-grade surface OS);

          -  Bone sarcomas other than Ewing sarcoma, chondrosarcoma and chordoma;

        I3. Availability of archival Formalin-Fixed Paraffin Embedded (FFPE) block.

        I4. Prior treatment for localized or metastatic disease for bone sarcoma must have been
        completed. It should include:

          -  Neoadjuvant chemotherapy with documented assessment of histological response

          -  Local procedure: Surgery (or radiotherapy if tumour is unresectable)

          -  Adjuvant chemotherapy (Nota Bene: patients with histotype different from OS may not
             have received adjuvant treatment) For OS, excepted from head and neck, neoadjuvant
             and/or adjuvant chemotherapy should include methotrexate-based regimen for patients <
             18 years old or anthracycline and cisplatin-based regimen for patients ≥ 18 years old.

        For head and neck OS, neoadjuvant and/or adjuvant chemotherapy should include adriamycin,
        cisplatin or ifosfamide-based regimen.

        For non-OS, neoadjuvant and/or adjuvant chemotherapy should include adriamycin and/or
        cisplatin-based regimen.

        I5. Recovery to NCI-CTCAE v5 Grade 0 or 1 level or recovery to baseline preceding the prior
        treatment from any previous drug/procedure related toxicity (except alopecia, anaemia, and
        hypothyroidism);

        I6. Interval between the last chemotherapy administration and the date of randomisation :
        at least 4 weeks but no longer than 2 months;

        I7. Confirmed complete remission or no evidence of disease (for metastatic disease);

        Patients with pulmonary micro nodules can be included provided they do not meet the
        following criteria:

          -  At least one lung nodule of 10 mm or more

          -  And/or at least two nodules well limited between 6-9 mm

          -  And/or at least 5 nodules well limited of 5 mm or less All the other situations will
             be considered as doubtful lesions except in case of metastatic disease confirmed
             during the lung surgery of the residual lung lesions after pre-operative chemotherapy.
             If no other metastatic localisation is detected at the initial staging, the patient
             will be considered as localised disease and eligible for randomisation.

        I8. Life expectancy of greater than 12 months;

        I9. Karnofsky Performance status ≥ 70 (patients younger than 18-year old) or Eastern
        Cooperative Oncology Group (ECOG) performance status < 2 (adult patients) (Cf. appendix 2);

        I10. Patients must have adequate bone marrow, renal, and hepatic function, as evidenced by
        the following within 7 days of study treatment initiation :

          -  Absolute neutrophil count ≥ 1.5 Giga/l

          -  Platelets ≥ 100 Giga/l

          -  Haemoglobin ≥ 9 g/dl

          -  Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN)

          -  Glomerular filtration rate (GFR) ≥ 30 ml/min/1.73m2 according to the Modified Diet in
             Renal Disease (MDRD) abbreviated formula

          -  Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5.0
             × ULN for patients with liver involvement of their cancer)

          -  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 Gamma-Glutamyltransferase (GGT) < 1.5 x ULN.

          -  Lipase ≤ 1.5 x ULN

          -  Spot urine must not show ≥ 1 "+"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;

        I11. International Normalized Ratio (INR)/Partial Thromboplastin Time (PTT) ≤ 1.5 x ULN;
        Patients who are therapeutically treated with an agent such as warfarin or heparin will be
        allowed to participate provided that no prior evidence of underlying abnormality in
        coagulation parameters exists. Close monitoring of at least weekly evaluations will be
        performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the
        local standard of care;

        I12. Women of childbearing potential and male patients must agree to use adequate
        contraception (Appendix 4) for the duration of study participation and up to 8 weeks
        following completion of therapy;

        I13. Women of childbearing potential must have a negative serum β-Human Chorionic
        Gonadotropin (HCG) pregnancy test within 7 days prior randomization and/or urine pregnancy
        test within 48 hours before the first administration of the study treatment;

        I14. Patients, and their parents when applicable, must sign and date an informed consent
        document indicating that they have been informed of all the pertinent aspects of the trial
        prior to enrolment;

        I15. Patients must be willing and able to comply with scheduled visits, treatment plan,
        laboratory tests and other study procedures;

        I16. Patients covered by a medical insurance.

        EXCLUSION CRITERIA :

        E1. Prior treatment with any VEGFR inhibitor (thus, any prior exposure to sunitinib,
        sorafenib, pazopanib, bevacizumab, or other VEGFR inhibitor);

        E2. All soft tissue sarcomas (including but not limited to soft tissue osteosarcoma and
        Ewing soft tissue sarcoma), and Ewing sarcoma, chondrosarcoma and chordoma;

        E3. Prior history of other malignancies other than study disease (except for basal cell or
        squamous cell carcinoma of the skin or carcinoma in situ of the cervix) within 3 years
        prior to randomization;

        E4. Cardiovascular dysfunction:

          -  Left ventricular ejection fraction (LVEF) < 50%,

          -  Congestive heart failure ≥ New York Heart Association (NYHA) class 2,

          -  Myocardial infarction < 6 months prior to first study drug administration,

          -  Cardiac arrhythmias requiring therapy (beta blockers or digoxin are permitted),

          -  Unstable (angina symptoms at rest) or new-onset angina (begun within the last 3 months
             prior to first study drug administration);

        E5. Uncontrolled hypertension (systolic blood pressure > 150 mm Hg or diastolic pressure >
        90 mm Hg despite optimal treatment);

        E6. 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 the first study drug administration;

        E7. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
        before the first study drug administration;

        E8. Ongoing infection > Grade 2 according to NCI-CTCAE v5;

        E9. Known history of human immunodeficiency virus (HIV) infection;

        E10. Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral
        therapy;

        E11. Dehydration according to NCI-CTCAE v5 Grade > 1;

        E12. Difficulties to swallow oral medication and/or any mal-absorption condition and/or any
        Gastrointestinal (GI) disease that may significantly alter the absorption of regorafenib
        (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption
        syndrome, or small bowel resection);

        E13. Patients with seizure disorder requiring medication;

        E14. Concurrent enrolment in another clinical trial in which investigational therapies are
        administered;

        E15. Known hypersensitivity to the active substance or to any of the excipients;

        E16. Pregnant women, women who are likely to become pregnant or are breast-feeding;

        E17. 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;

        E18. Patients with history of non-compliance to medical regimens or unwilling or unable to
        comply with the protocol;

        E19. Interstitial lung disease with ongoing signs and symptoms at the time of informed
        consent;

        E20. Non-healing wound, non-healing ulcer, or non-healing bone fracture;

        E21. Patients with evidence or history of any bleeding diathesis, irrespective of severity;

        E22. Any haemorrhage or bleeding event ≥ NCI-CTCAE v5 Grade 3 within 4 weeks prior to the
        first study drug administration;

        E23. Clinically significant unrelated systemic illness (e.g., serious infection or
        significant cardiac, pulmonary, hepatic, or other organ dysfunction) that would compromise
        the patient's ability to tolerate study treatment or would likely interfere with study
        procedures or results;

        E24. Patients using prohibited concomitant and/or concurrent medications (see section
        "Prohibited concomitant/concurrent treatments");

        E25. Patients under tutorship or curatorship.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:16 Years
Eligible Gender:All
Healthy Volunteers:Accepts Healthy Volunteers

Primary Outcome Measures

Measure:Relapse-Free Survival (RFS)
Time Frame:Up to 5 years
Safety Issue:
Description:RFS will be defined as the time from randomization to relapse, or death from any cause, whichever occurs first. Patients alive without relapse at the time of the analysis will be censored at the date of last tumour assessment. The Kaplan-Meier approach will be used to estimate median RFS for each study arm. The two-sided log-rank test, stratified on randomization stratification factors, will be used to compare RFS between the investigational arm and the control arm. The stratified Cox-regression (with proportional hazards) will be used to estimate the hazard ratio and to calculate the 95% confidence intervals of the hazard ratio.

Secondary Outcome Measures

Measure:Time to Treatment Failure (TTF)
Time Frame:Up to 1 year
Safety Issue:
Description:TTF will be defined as the time from the date of randomization to the date of permanent discontinuation of the study treatment, whichever is the cause. Patient not known to have withdrawn treatment before 12 months (study treatment duration) will be censored at the time of treatment stop. TTF survival will be estimated using the Kaplan-Meier method, and will be described in terms of medians along with the associated 2-sided 95% confidence interval for the estimates.
Measure:Overall Survival (OS)
Time Frame:Up to 5 years
Safety Issue:
Description:OS will be defined as the time from date of randomization to the date of death, from any cause. Patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive. OS survival will be estimated using the Kaplan-Meier method, and will be described in terms of medians along with the associated 2-sided 95% confidence interval for the estimates.
Measure:Patient's Quality of Life (QoL)
Time Frame:Up to 5 years
Safety Issue:
Description:The patient's Quality of Life will be assessed using the EORTC QLQ-C30. Scores will be calculated at each time point according to the scoring manuals. Descriptive statistics will be used to evaluate baseline scores and evolution of scores from baseline to each time point (Every 3 months since baseline, then every 4 months after second year surveillance). Data will be compared between arms using the Student's t-test. The QoL data will also be presented graphically if deemed relevant.
Measure:Patient's tolerance to treatment
Time Frame:Up to 5 years
Safety Issue:
Description:The safety will be described mainly on the frequency of adverse events coded using the common toxicity criteria (NCI-CTCAE v5.0) grade. Descriptive statistics will be provided for characterizing and assessing patient tolerance to treatment. Adverse events will be coded according to the MedDRA®.
Measure:Compliance To Treatment
Time Frame:Up to 1 year
Safety Issue:
Description:The compliance to treatment will be described using the proportion of patients requiring dose reduction and temporary or permanent treatment discontinuation.

Details

Phase:N/A
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Centre Leon Berard

Trial Keywords

  • Maintenance therapy
  • First line therapy
  • Regorafenib
  • Randomization
  • Double-blinded
  • Placebo controlled
  • Relapse-free survival
  • Time to treatment failure
  • Overall survival
  • Quality of life
  • Tolerance
  • Compliance
  • Bone sarcoma
  • Osteosarcoma
  • Efficacy
  • Complete response
  • Tyrosine kinase inhibitor
  • Multi-target inhibitor

Last Updated

April 16, 2020