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Phase II Study of Regorafenib in Metastatic Soft Tissue Sarcoma (REGO-SARC)

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ClinicalTrials.gov Identifier: NCT01900743
Recruitment Status : Completed
First Posted : July 16, 2013
Last Update Posted : April 9, 2021
Sponsor:
Collaborator:
Bayer
Information provided by (Responsible Party):
Centre Oscar Lambret

Tracking Information
First Submitted Date  ICMJE July 9, 2013
First Posted Date  ICMJE July 16, 2013
Last Update Posted Date April 9, 2021
Actual Study Start Date  ICMJE June 5, 2013
Actual Primary Completion Date September 16, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 30, 2018)
Progression-free survival (PFS) [ Time Frame: Up to 2 years ]
Progression-Free Survival will be measured from the date of randomization until the date of radiological progression or death (if death occurs before progression). Progression-free rate at 3 and 6 months (PFR-3 and PFR-6), time to progression, response rate and duration of response, overall survival according to RECIST 1.1 criteria
Original Primary Outcome Measures  ICMJE
 (submitted: July 12, 2013)
To evaluate the progression-free survival (PFS) [ Time Frame: Up to 2 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 30, 2018)
  • Growth modulation index [ Time Frame: Up to 2 years ]
    Growth modulation index in patients receiving regorafenib after randomization
  • Toxicity according to NCI-CTC AE V4.0. [ Time Frame: Baseline, every 4 weeks, up to the end of study ]
    The monitoring of the toxicity of the regorafenib which can have a liver toxicity for exemple.
  • Progression-free rate at 3 and 6 months (PFR-3 and PFR-6) [ Time Frame: At month 3 and at month 6 ]
    According to the RECIST 1.1
  • Time to progression [ Time Frame: Up to 2 years ]
    According to the RECIST 1.1 Every 4 weeks, Up to 2 years
  • Overall survival [ Time Frame: Up to 2 years ]
    Time from the date of randomization to the date of death from any cause
  • Response rate [ Time Frame: Up to 2 years ]
    the proportion of patients with the best overall tumor response of partial response (PR) or complete response (CR) according to RECIST 1.1 guidelines that is achieved during treatment or within 30 days after termination of study medication.
  • Duration of response [ Time Frame: Up to 2 years ]
    the number of days from the date of first documented objective response of PR or CR, whichever is noted earlier, to first disease progression or death before progression. Patients without progression or death before progression at the time of analysis will be censored at the date of their last tumor assessment.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 12, 2013)
  • To explore the growth modulation index in patients receiving regorafenib after randomization [ Time Frame: Up to 2 years ]
  • To evaluate toxicity according to NCI-CTC AE V4.0. [ Time Frame: Baseline, every 4 weeks, up to the end of study ]
  • To evaluate progression-free rate at 3 and 6 months (PFR-3 and PFR-6) [ Time Frame: At month 3 and at month 6 ]
    According to the RECIST 1.1
  • To evaluate time to progression [ Time Frame: Up to 2 years ]
    According to the RECIST 1.1 Every 4 weeks, Up to 2 years
  • To evaluate overall survival [ Time Frame: Up to 2 years ]
    Time from the date of randomization to the date of death from any cause
  • To evaluate response rate [ Time Frame: Up to 2 years ]
  • To evaluate duration of response [ Time Frame: Up to 2 years ]
Current Other Pre-specified Outcome Measures
 (submitted: March 30, 2018)
Potential predictive factors for regorafenib response. [ Time Frame: Up to 2 years ]
The monitoring of the factors which can induce a regorafenib response (Formalin fixed, paraffin embedded (FFPE) or fresh frozen tissue samples collected either from the primary tumor or from metastatic sites, or both will be analyzed)
Original Other Pre-specified Outcome Measures
 (submitted: July 12, 2013)
To identify potential predictive factors for regorafenib response. [ Time Frame: Up to 2 years ]
 
Descriptive Information
Brief Title  ICMJE Phase II Study of Regorafenib in Metastatic Soft Tissue Sarcoma
Official Title  ICMJE Activity and Safety of Regorafenib in Patients With Metastatic Soft Tissue Sarcoma Previously Treated With Anthracycline-based Chemotherapy : a Multinational, Randomized, Phase II, Placebo-controlled Trial
Brief Summary

This is an international (France, Austria and Germany), randomized, double-blind, placebo-controlled, phase II study to evaluate the efficacy and safety of regorafenib in patients with histologically proven metastatic and/or unresectable Soft Tissue Sarcoma (STS) after failure or intolerance to doxorubicin (or other anthracycline).

Five cohorts will be defined:

Cohort A: Liposarcoma Cohort B: Leiomyosarcoma Cohort C: Synovial sarcoma Cohort D: other sarcomas (see Appendix C) Cohort E: Leiomyosarcoma, Synovial sarcoma and other sarcomas listed in Appendix C previously treated with pazopanib Approximately 226 patients who meet the eligibility criteria will be randomly assigned in a 1:1 ratio to one of the treatment groups.

Detailed Description

The standard of care for metastatic soft tissue sarcoma is doxorubicin +/- ifosfamide. After failure or intolerance to doxorubicin, there is no standard of care. In Europe, two are currently approved for the treatment of soft tissue sarcoma after failure/intolerance to doxorubicin: trabectedin (Yondelis®) for all histological subtype and pazopanib (Votrient ®) for all subtypes excluding liposarcomas. Nevertheless, none of these drugs improve the overall survival over placebo.

The study is composed of 3 periods:

  1. A Screening Period,
  2. A Treatment Period,
  3. And a Survival Follow-up Period. Patients randomized to be treated with regorafenib will receive the treatment orally for 3 weeks of every 4 week (28 days) cycle (ie, 3 weeks on/1 week off).

Patients randomized to the placebo arm will be treated for 3 weeks of every 4 weeks cycle (ie, 3 weeks on/1 week off).

In addition to the regorafenib and placebo treatments, patients will receive best supportive care. Best supportive care includes any method to preserve the comfort and dignity of the patients and excludes any disease-specific anti-neoplastic therapy such as any kinase inhibitor,chemotherapy, radiation therapy, or surgical intervention.

Patients receiving placebo, who experience disease progression may be offered open-label regorafenib(cross-over option).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Sarcoma
Intervention  ICMJE
  • Drug: Regorafenib
    Regorafenib (160 mg/d) once daily for three weeks on / one week off plus Best Supportive Care (BSC)until progression (according to RECIST 1.1), intolerance or consent withdrawal.
    Other Name: stivarga
  • Drug: Placebo
    Placebo plus BSC until progression (according to RECIST 1.1) or unacceptable toxicity. Patients who have received placebo may be offered open-label regorafenib (cross-over option) after objective tumor progression
Study Arms  ICMJE
  • Experimental: Arm A
    Regorafenib (160 mg/d) once daily for 3 weeks on / 1 week off plus Best Supportive Care (BSC) until progression (according to RECIST 1.1), intolerance or consent withdrawal.
    Intervention: Drug: Regorafenib
  • Placebo Comparator: Arm B
    Placebo plus BSC until progression (according to RECIST 1.1) or unacceptable toxicity. Patients who have received placebo may be offered open-label regorafenib (cross-over option) after objective tumor progression
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 30, 2018)
219
Original Estimated Enrollment  ICMJE
 (submitted: July 12, 2013)
192
Actual Study Completion Date  ICMJE September 16, 2020
Actual Primary Completion Date September 16, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age ≥18 years
  • Histological documentation of soft tissue sarcoma (including uterus)with available Formalin Fixed Paraffin Embedded (FFPE) blocks. Eligible soft tissue sarcomas are non-adipocytic soft tissue sarcomas
  • Prior treatment with doxorubicin or other anthracycline. Moreover, patients eligible in the Cohort E must have received pazopanib
  • Metastatic disease not amenable to surgical resection with curative intent
  • Documentation of progression within the last 6 months
  • Measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST 1.1.
  • Performance status ≤1(ECOG)
  • Life expectancy ≤ 3 months
  • Adequate bone marrow, renal, and hepatic function:
  • INR/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 will be performed until INR/PTT is stable.
  • 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.
  • Recovery to 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).
  • In the assessment of the investigator, patient is able to comply with study requirements
  • Signed, IRB-approved written informed consent

Exclusion Criteria:

  • More than 3 lines of systemic treatment for metastatic sarcoma
  • Histological subtypes listed in Appendix C (especially GIST, osseous sarcoma, embryonal or alveolar rhabdomyosarcoma). Patients with liposarcoma are not eligible in the cohort E
  • Primary bone sarcoma
  • Prior treatment with regorafenib
  • Known history of or concomitant malignancy likely to affect life expectancy in the judgment of the investigator
  • Pregnant or breastfeeding patients. Women of childbearing potential must have a pregnancy test performed before start of treatment
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of treatment
  • Active cardiac disease including any of the following: Congestive heart failure (NYHA) ≥Class 2, Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
  • Uncontrolled hypertension (SBP >150 mmHg or diastolic pressure >90 mmHg despite optimal medical management)
  • 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)
  • Ongoing infection >Grade 2 according to NCI-CTCAE v4.0
  • Known history of human immunodeficiency virus (HIV) infection
  • Known history of chronic hepatitis B or C
  • Patients with seizure disorder requiring medication
  • History of organ allograft
  • Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event > Grade 3 within 4 weeks of start of treatment
  • Non-healing wound, ulcer, or bone fracture
  • Renal failure requiring hemo- or peritoneal dialysis
  • Dehydration according to NCI-CTC v 4.0 Grade >1
  • Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
  • Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation, including lactose
  • Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
  • Inability to swallow, malabsorption condition
  • Pleural effusion or ascites that causes respiratory compromise (Grade 2 dyspnea)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01900743
Other Study ID Numbers  ICMJE REGO-SARC-1214
2012-005743-24 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Centre Oscar Lambret
Study Sponsor  ICMJE Centre Oscar Lambret
Collaborators  ICMJE Bayer
Investigators  ICMJE
Study Director: Nicolas PENEL, PhD Centre Oscar Lambret - France
Principal Investigator: Thomas BRODOWICZ, PhD AKH-Wien - Austria
PRS Account Centre Oscar Lambret
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP