Phase II Study of Regorafenib in Metastatic Soft Tissue Sarcoma

Sarcoma Clinical Trial

— REGO-SARC  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01900743
• Other study ID #: REGO-SARC-1214
• Secondary ID: 2012-005743-24
• Status: Completed
• Phase: Phase 2
• Start date: June 5, 2013
• Est. completion date: September 16, 2020

Study information

• Verified date: April 2021
• Source: Centre Oscar Lambret
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 219
• Est. completion date: September 16, 2020
• Est. primary completion date: September 16, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Sarcoma

Intervention

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.
• 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

Locations

Country	Name	City	State
Austria	Medizinische Universität Graz	Graz
Austria	Universitätsklinik für Innere Medizin I	Innsbruck
Austria	LKH	Klagenfurt
Austria	Krankenhaus der Barmherzigen Schwestern Linz	Linz
Austria	AKH-Wien	Wien
France	Hôpital St Jacques	Besancon
France	Institut Bergonié	Bordeaux
France	Centre François Baclesse	Caen
France	Centre GF Leclercq	Dijon
France	Centre Oscar Lambret	Lille
France	Centre Léon Bérard	Lyon
France	Hôpital de La Timone	Marseille
France	Institut Paoli Calmettes	Marseille
France	Centre René Gauducheau	Nantes
France	Centre Antoine Lacassagne	Nice
France	Hôpital Cochin	Paris
France	Hôpital Saint Louis	Paris
France	Institut Curie	Paris
France	Centre Eugène Marquis	Rennes
France	Centre Henri Becquerel	Rouen
France	Institut Curie - Hôpital René Huguenin	Saint Cloud
France	Institut de Cancérologie Lucien Neuwirth (ICL)	St Priest En Jarez
France	Institut Claudius Regaud	Toulouse
France	Centre Alexis Vautrin	Vandoeuvre Les Nancy
France	Institut Gustave Roussy	Villejuif

Sponsors (2)

Lead Sponsor	Collaborator
Centre Oscar Lambret	Bayer

Countries where clinical trial is conducted

Austria,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Potential predictive factors for regorafenib response.	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)	Up to 2 years
Primary	Progression-free survival (PFS)	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	Up to 2 years
Secondary	Growth modulation index	Growth modulation index in patients receiving regorafenib after randomization	Up to 2 years
Secondary	Toxicity according to NCI-CTC AE V4.0.	The monitoring of the toxicity of the regorafenib which can have a liver toxicity for exemple.	Baseline, every 4 weeks, up to the end of study
Secondary	Progression-free rate at 3 and 6 months (PFR-3 and PFR-6)	According to the RECIST 1.1	At month 3 and at month 6
Secondary	Time to progression	According to the RECIST 1.1 Every 4 weeks, Up to 2 years	Up to 2 years
Secondary	Overall survival	Time from the date of randomization to the date of death from any cause	Up to 2 years
Secondary	Response rate	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.	Up to 2 years
Secondary	Duration of response	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.	Up to 2 years