Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04055220
Recruitment Status : Recruiting
First Posted : August 13, 2019
Last Update Posted : April 17, 2020
Sponsor:
Information provided by (Responsible Party):
Centre Leon Berard

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Bone Sarcoma Osteosarcoma Drug: Treatment by Regorafenib Drug: Treatment by Placebo Not Applicable

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 168 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : March 3, 2020
Estimated Primary Completion Date : October 1, 2024
Estimated Study Completion Date : October 1, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Regorafenib

Arm Intervention/treatment
Experimental: Regorafenib

Treatment 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).

Drug: Treatment by Regorafenib
Treatment for 13 cycles (12 months) maximum. During each cycle, patient will take 3 tablets, once a day, corresponding to a total of 120 mg Regorafenib, during 21 days, followed by 7 days without treatment.
Other Name: Stivarga

Placebo Comparator: Placebo

Treatment 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).

Drug: Treatment by Placebo
Treatment for 13 cycles (12 months) maximum. During each cycle, patient will take 3 placebo tablets, once a day, during 21 days, followed by 7 days without placebo treatment.
Other Name: Standard of care




Primary Outcome Measures :
  1. Relapse-Free Survival (RFS) [ Time Frame: Up to 5 years ]
    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 :
  1. Time to Treatment Failure (TTF) [ Time Frame: Up to 1 year ]
    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.

  2. Overall Survival (OS) [ Time Frame: Up to 5 years ]
    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.

  3. Patient's Quality of Life (QoL) [ Time Frame: Up to 5 years ]
    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.

  4. Patient's tolerance to treatment [ Time Frame: Up to 5 years ]
    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®.

  5. Compliance To Treatment [ Time Frame: Up to 1 year ]
    The compliance to treatment will be described using the proportion of patients requiring dose reduction and temporary or permanent treatment discontinuation.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.


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): NCT04055220


Contacts
Layout table for location contacts
Contact: Julien GAUTIER +33 426 55 68 29 julien.gautier@lyon.unicancer.fr

Locations
Layout table for location information
France
Hôpital Jean Minjoz Recruiting
Besançon, France, 25000
Contact: Elsa KALBACHER       seraphine.vizoso@lyon.unicancer.fr   
Institut Bergonié Not yet recruiting
Bordeaux, France, 33076
Contact: Antoine ITALIANO       a.italiano@bordeaux.unicancer.fr   
Centre Oscar Lambret Not yet recruiting
Lille, France, 59020
Contact: Nicolas PENEL       n-penel@o-lambret.fr   
Centre Léon Bérard Recruiting
Lyon, France, 69373
Contact: Jean-Yves BLAY       jean-yves.blay@lyon.unicancer.fr   
APHM - Hôpital Timone Recruiting
Marseille, France, 13385
Contact: Florence DUFFAUD       florence.duffaud@ap-hm.fr   
ICM Val d'Aurelle Not yet recruiting
Montpellier, France, 34298
Contact: Nelly FIRMIN       nelly.firmin@icm.unicancer.fr   
Centre Antoine Lacassagne Not yet recruiting
Nice, France, 061789
Contact: Esma SAADA-BOUZID       esma.saada-bouzid@nice.unicancer.fr   
Institut Curie Recruiting
Paris, France, 75005
Contact: Sophie PIPERNO-NEUMANN       sophie.piperno-neumann@curie.fr   
APHP Hôpital Cochin Not yet recruiting
Paris, France, 75014
Contact: Pascaline BOUDOU-ROUQUETTE       pascaline.boudou@aphp.fr   
Centre Eugène Marquis Not yet recruiting
Rennes, France, 35042
Contact: Christophe PERRIN       c.perrin@rennes.unicancer.fr   
ICO René Gauducheau Not yet recruiting
Saint-Herblain, France, 44805
Contact: Emmanuelle BOMPAS       emmanuelle.bompas@ico.unicancer.fr   
Institut de Cancérologie Lucien Neuwirth Recruiting
Saint-Priest-en-Jarez, France, 42270
Contact: Olivier COLLARD       olivier.collard@icloire.fr   
IUCT-Oncopole Not yet recruiting
Toulouse, France, 31059
Contact: Christine CHEVREAU       chevreau.christine@iuct-oncopole.fr   
ICL Alexis Vautrin Not yet recruiting
Vandœuvre-lès-Nancy, France, 54519
Contact: Maria RIOS       m.rios@nancy.unicancer.fr   
Institut Gustave Roussy Not yet recruiting
Villejuif, France, 94805
Contact: Olivier MIR       olivier.mir@gustaveroussy.fr   
Sponsors and Collaborators
Centre Leon Berard
Investigators
Layout table for investigator information
Principal Investigator: Jean-Yves BLAY Centre Léon Bérard (Lyon)
Principal Investigator: Florence DUFFAUD Hôpital de la Timone (MARSEILLE)
Principal Investigator: Sophie PIPERNO-NEUMANN Institut Curie Paris
Layout table for additonal information
Responsible Party: Centre Leon Berard
ClinicalTrials.gov Identifier: NCT04055220    
Other Study ID Numbers: REGOSTA (ET18-272)
First Posted: August 13, 2019    Key Record Dates
Last Update Posted: April 17, 2020
Last Verified: March 2020

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Centre Leon Berard:
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
Additional relevant MeSH terms:
Layout table for MeSH terms
Sarcoma
Osteosarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue