Phase II Study of Regorafenib as Maintenance Therapy

• ClinicalTrials.gov Identifier: NCT03793361
• Recruitment Status: Recruiting
• First Posted: January 4, 2019
• Last Update Posted: February 14, 2023
• Sponsor: Centre Oscar Lambret
• Information provided by (Responsible Party): Centre Oscar Lambret

Study Description

Brief Summary:

Multicenter double-blind placebo-controlled randomized Phase II study comparing regorafenib® to placebo, as maintenance therapy in metastatic soft-tissue non-adipocytic sarcomas experiencing stable disease or response after 6 cycles of doxorubicin-based chemotherapy as 1st line chemotherapy.

Condition or disease	Intervention/treatment	Phase
Metastatic Soft Tissue Sarcoma	Drug: Regorafenib; Drug: Placebo	Phase 2

Detailed Description:

Patients will be randomized 1:1 using a centralized randomization software, assuring concealment, with a minimization program controlling for the following factors:

• Histological subgroups: leiomyosarcoma versus synovial sarcoma versus other histological subtype
• Response to doxorubicin-based chemotherapy: partial response versus stable disease
• Centers

The treatment will be administrated as long as it appears beneficial. Evaluations will be made every 8 weeks until 6 months and then every 3 months

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 126 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy of Regorafenib as Maintenance Therapy in Non-adipocytic Soft Tissue Sarcoma Having Received First-line Doxorubicin-based Chemotherapy
• Actual Study Start Date: May 15, 2019
• Estimated Primary Completion Date: March 2024
• Estimated Study Completion Date: March 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A; Regorafenib	Drug: Regorafenib; Oral Drug in the form of 40 mg tablets - Regorafenib (120 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. Provided by BAYER; Other Name: stivarga
Placebo Comparator: Arm B; Placebo	Drug: Placebo; Oral tablets - 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 Provided by BAYER

Outcome Measures

Primary Outcome Measures :

1. To assess the efficacy of regorafenib compared to placebo [ Time Frame: from the date of randomization to the date of first observed disease progression (according to RECIST 1.1 criteria) or death from any cause, up to 12 months after the beginning of the treatment ]
   Progression-Free Survival will be measured from the date of randomization until the date of radiological progression (according to RECIST 1.1 criteria) or death (if death occurs before progression).

Secondary Outcome Measures :

1. To assess the efficacy of regorafenib compared to placebo [ Time Frame: from the date of randomization to the date of death from any cause ]
   in terms of overall survival
2. To assess the efficacy of regorafenib compared to placebo [ Time Frame: from the date of randomization to the date of first observed disease progression (according to RECIST 1.1) or death from any cause, up to 12 months after the beginning of the treatment ]
   Best response according to RECIST 1.1 evaluated by central radiological review: Complete Response, CR, or Partial Response, PR, achieved during the maintenance therapy. CR and PR will be counted as objective response to estimate the objective response rate (ORR)
3. To assess the efficacy of regorafenib compared to placebo [ Time Frame: from the date of randomization to the date of death from any cause, up to 12 months after the beginning of the treatment ]
   Time to start subsequent line of anticancer therapy defined as the time interval from the date of randomization to the date of start subsequent line of anticancer therapy. Patient data will be censored at the date of last follow-up visit for patients alive at last follow-up visit without having started subsequent line of anticancer therapy. Death without having started subsequent line of anticancer therapy will be counted as a competing event.
4. To assess the safety of regorafenib [ Time Frame: Baseline, every 4 weeks, up to 12 months after the beginning of the treatment ]
   Compared to placebo - Toxicity according to NCI-CTC AE V5.0 over the whole treatment duration plus 30 days, excluding AE unequivocally related to the disease under study or its progression. Adverse events of grade 3 or more (grade 3+) will be counted as severe adverse events
5. To assess the relative benefit/risk ratio [ Time Frame: up to 12 months ]
   using the Q-TWiST approach - Quality-adjusted time without symptoms of disease or toxicity computed from survival times (overall survival and progression-free survival) and adverse events data (date of occurrence of grade 3+ adverse event classified as drug-related)

Other Outcome Measures:

1. assessment of the predictive value of SUMSCAN signature [ Time Frame: up to 12 months ]
   genomic signature established on initial diagnostic biopsies or resection specimen and identifying sarcoma patients benefitting from anti-angiogenetic agents

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age ≥18 years
• Histologically proven soft tissue sarcoma including leiomyosarcoma, synovial sarcoma and other sarcomas
• Patients in partial response or stable disease after 6 cycles of doxorubicin-based first-line chemotherapy for metastatic/locally advanced soft tissue sarcoma
• Metastatic/locally advanced disease not amenable to surgical resection with curative intent
• Eastern Cooperative Oncology Group (ECOG) Performance Status =0 or 1
• Measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST 1.1.
• Available tumor tissue for translational research program
• Adequate bone marrow, renal, and hepatic function, as evidenced by the following within 7 days of study treatment initiation:
• Absolute neutrophil count (ANC) ≥1,500/mm3
• Platelets ≥100,000/mm3
• Hemoglobin ≥9.0 g/dL
• Serum creatinine ≤1.5 x upper limit of normal (ULN)
• Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2
• AST and 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 with liver involvement of their cancer)
• 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 urinanalysis shows 1+ protein or more, a 24-hour urine collection will be required and must show total protein excretion <1000 mg/24 hours
• 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 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.)
• Women of childbearing potential and male subjects must agree to use adequate contraception for the duration of study participation and up to 3 months following completion of therapy. Adequate contraception is defined as any medically recommended method (or combination of methods) as per standard of care.
• 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).
• In the assessment of the investigator, patients are able to comply with study requirements
• Signed, IRB-approved written informed consent
• Patient covered by the French "Social Security" regime

Exclusion Criteria:

• Prior adjuvant or neoadjuvant chemotherapy not allowing at least 6 cycles of doxorubicin-based chemotherapy at metastatic stage
• Complete response to 1st line chemotherapy for metastatic/locally advanced soft tissue sarcoma
• Disease progression during the 1st line of chemotherapy
• Time interval between the last cycle of doxorubicin-based chemotherapy superior to 8 weeks
• Primary bone sarcoma
• All forms of liposarcoma
• Some particular histologic types, i.e., PNET/Ewing, alveolar or embryonal rhabdomyosarcoma, Perivascular epithelioid cell sarcoma (PECoMA), low grade endometrial stromal tumor, desmoid tumor
• Prior treatment with tyrosine kinase inhibitor
• 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 a maximum of 7 days before start of treatment
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of Day 1 of treatment
• Active cardiac disease including any of the following: Congestive heart failure (New York Heart Association [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 (Systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg despite optimal medical management)
• Arterial or venous thrombotic or embolic events such as myocardial infarction, cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within 6 months of starting on study drug
• Any hemorrhage or bleeding event > Grade 4 within 4 weeks of start of treatment
• Ongoing infection >Grade 2 according to NCI Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v. 5.0)
• 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 4 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
• Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
• Inability to swallow oral medications, Any mal-absorption condition
• Pleural effusion or ascites that causes respiratory compromise (Grade 2 dyspnea)

Contacts and Locations

Contacts

Contact: Emilie HEYMAN-DECOUPIGNY; +33320295918; promotion@o-lambret.fr

Locations

France

CHRU Besançon; Recruiting

Besançon, France, 25000

Contact: Loïc CHAIGNEAU, MD lchaigneau@chu-besancon.fr

Principal Investigator: Loïc CHAIGNEAU, MD

Sub-Investigator: Elsa KALBACHER, MD

Sub-Investigator: Guillaume MEYNARD, MD

Institut Bergonié; Recruiting

Bordeaux, France, 33076

Contact: Antoine ITALIANO, PhD a.italiano@bordeaux.unicancer.fr

Principal Investigator: Antoine ITALIANO, PhD

Sub-Investigator: Sophie COUSIN, MD

Sub-Investigator: Maud TOULMONDE, MD

Sub-Investigator: Kévin BOURCIER, MD

Centre François Baclesse; Recruiting

Caen, France, 14076

Contact: Corinne DELCAMBRE, MD c.delambre@baclesse.unicancer.fr

Principal Investigator: Corrine DELCAMBRE, MD

Sub-Investigator: Laure MOISE, MD

Sub-Investigator: Pierre-Emmanuel BRACHET, MD

Sub-Investigator: Mélanie DOS SANTOS, MD

Sub-Investigator: Emeline MERIAUX, MD

Sub-Investigator: George EMILE, MD

Sub-Investigator: Alison JOHNSON, MD

Centre Georges-François LECLERC; Recruiting

Dijon, France, 21079

Contact: Isabelle DESMOULINS, MD idesmoulins@cgfl.fr

Principal Investigator: Isabelle DESMOULINS, MD

Sub-Investigator: Alice HERVIEU, MD

Centre Oscar Lambret; Recruiting

Lille, France, 59020

Contact: Nicolas PENEL, PhD +33320295920 n-penel@o-lambret.fr

Principal Investigator: Nicolas PENEL, PhD

Sub-Investigator: Diane PANNIER, MD

Sub-Investigator: Thomas RYCKEWAERT, MD

Sub-Investigator: Samira MAKHLOUFI, MD

Sub-Investigator: Antonin BROYELLE, MD

Sub-Investigator: Valérie CHEVALIER-EVAIN, MD

Sub-Investigator: Charlotte BELLIER, MD

Centre Léon Bérard; Recruiting

Lyon, France, 69373

Contact: Jean-Yves BLAY, PhD jean-yves.blay@lyon.unicancer.fr

Principal Investigator: Jean-Yves BLAY, PhD

Sub-Investigator: Isabelle-Laure RAY COQUARD, MD

Sub-Investigator: Mehdi BRAHMI, MD

Sub-Investigator: Armelle DUFRESNE, MD

Sub-Investigator: Mélodie CARBONNAUX, MD

Sub-Investigator: Hélène VANACKER, MD

Hôpital La Timone; Recruiting

Marseille, France, 13005

Contact: Florence DUFFAUD, PhD florence.duffaud@ap-hm.fr

Principal Investigator: Florence DUFFAUD, PhD

Sub-Investigator: Sébastien SALAS, MD

Sub-Investigator: Marie MEURER, MD

Sub-Investigator: Elise LAVIT, MD

Institut Paoli-Calmettes; Recruiting

Marseille, France, 13273

Contact: François BERTUCCI, PhD bertuccif@ipc.unicancer.fr

Principal Investigator: François BERTUCCI, PhD

Sub-Investigator: Delphine PERROT, MD

Sub-Investigator: Audrey MONNEUR, MD

Sub-Investigator: Simon LAUNAY, MD

Sub-Investigator: Myriam PALOMARES, MD

Sub-Investigator: Anthony GONCALVES, PhD

Sub-Investigator: Elika LOIR, MD

Institut régional du Cancer de Montpellier; Recruiting

Montpellier, France, 34298

Contact: Nelly FIRMIN Nelly.Firmin@icm.unicancer.fr

Principal Investigator: Nelly FIRMIN, MD

Sub-Investigator: Didier CUPISSOL, MD

Centre René Gauducheau; Recruiting

Nantes, France, 44805

Contact: Emmanuelle BOMPAS, MD emmanuelle.bompas@ico.unicancer.fr

Principal Investigator: Emmanuelle BOMPAS, MD

Sub-Investigator: Frédéric ROLLAND, MD

Sub-Investigator: Damien VANSTEENE, MD

Sub-Investigator: Judith RAIMBOURG, MD

Sub-Investigator: Carole GOURMELON, MD

Sub-Investigator: Audrey ROLLOT, MD

Sub-Investigator: Cyriac BLONZ, MD

Sub-Investigator: Mélanie SAINT-JEAN, MD

Sub-Investigator: Sandrine HIRET, MD

Sub-Investigator: Marie ROBERT, MD

Centre Antoine Lacassagne; Recruiting

Nice, France, 06189

Contact: Esma SAADA-BOUZID, MD esma.saada-bouzid@nice-unicancer.fr

Principal Investigator: Esma SAADA-BOUZID, MD

Sub-Investigator: Anthoine THYSS, PhD

Sub-Investigator: Lauris GASTAUD, MD

Sub-Investigator: Frédéric PEYRADE, MD

Sub-Investigator: Agnès DUCOULOMBIER, MD

Sub-Investigator: Annick BOSCAGLI-MELAINE, MD

Sub-Investigator: Nicolas MARTIN, MD

Sub-Investigator: Thibault LE BOURGEOIS, MD

Institut Curie; Recruiting

Paris, France, 75005

Contact: Sophie PIEPERNO-NEUMANN, MD sophie.piperno-neumann@curie.fr

Principal Investigator: Sophie PIEPERNO-NEUMANN, MD

Sub-Investigator: Valérie LAURENCE, MD

Sub-Investigator: Jean-Yves PIERGA, PhD

Sub-Investigator: Sarah WATSON, MD

Chu Poitiers; Recruiting

Poitiers, France, 86000

Contact: Nicolas ISAMBERT, MD 0549444538 nicolas.isambert@chu-poitiers.fr

Principal Investigator: Nicolas ISAMBERT, MD

Sub-Investigator: Camille EVRARD, MD

Sub-Investigator: Marjorie HIRSCH, MD

Institut Godinot; Recruiting

Reims, France, 51100

Contact: Pauline SOIBINET, MD 0326504382 pauline.soibinet@reims.unicancer.fr

Principal Investigator: Pauline SOIBINET, MD

Sub-Investigator: Jean-Christophe EYMARD, MD

Centre Eugène Marquis; Recruiting

Rennes, France, 35042

Contact: Angélique BRUNOT, MD a.brunot@rennes.unicancer.fr

Principal Investigator: Angélique BRUNOT, MD

Sub-Investigator: Christophe PERRIN, MD

Sub-Investigator: Marc PRACHT, MD

Sub-Investigator: Eloïse BOURIEN, MD

Sub-Investigator: Florian ESTRADE, MD

Sub-Investigator: Céline LESCURE, MD

Sub-Investigator: Alexandra FRELAU, MD

Sub-Investigator: Léa MUZELLEC, MD

Centre Henri Becquerel; Recruiting

Rouen, France, 76038

Contact: Cécile GUILLEMET, MD cecile.guillemet@chb.unicancer.fr

Principal Investigator: Cécile GUILLEMET, MD

Sub-Investigator: Jean-Christophe THERY, MD

Institut de Cancérologie Lucien Neuwirth; Recruiting

Saint-Priest-en-Jarez, France, 42270

Contact: Olivier COLLARD, MD olivier.collard@icloire.fr

Principal Investigator: Olivier COLLARD, MD

Sub-Investigator: Cécile VASSAL, MD

Sub-Investigator: Benoîte MERY, MD

Hôpitaux universitaires de Strasbourg; Recruiting

Strasbourg, France, 67000

Contact: Jean-Emmanuel KURTZ, PhD j-emmanuel.kurtz@chru-strasbourg.fr

Principal Investigator: Jean-Emmanuel KURTZ, PhD

Sub-Investigator: Gabriel MALOUF, MD

Sub-Investigator: Justine GANTZER, MD

Institut Claudius Regaud; Recruiting

Toulouse, France, 31059

Contact: Christine CHEVREAU, MD chevreau.christine@iuct.oncopole.fr

Principal Investigator: Christine CHEVREAU, MD

Sub-Investigator: Carlos GOMEZ-ROCA, MD

Sub-Investigator: Thibaud VALENTIN, MD

Sub-Investigator: Sarah BETRIAN, MD

Sub-Investigator: Audrey RABEAU, MD

Sub-Investigator: Iphigénie KORAKIS, MD

Institut Gustave Roussy; Recruiting

Villejuif, France, 94805

Contact: Benjamin VERRET, MD sarah.dumont@gustaveroussy.fr

Principal Investigator: Benjamin VERRET, MD

Sub-Investigator: Axel LE CESNE, PhD

Sub-Investigator: Julien DOMONT, MD

Sub-Investigator: Olivier MIR, MD

Sponsors and Collaborators

Centre Oscar Lambret

Investigators

• Study Director: Nicolas PENEL, PhD; Centre Oscar Lambret

More Information

• Responsible Party: Centre Oscar Lambret
• ClinicalTrials.gov Identifier: NCT03793361
• Other Study ID Numbers: EREMISS
• First Posted: January 4, 2019
• Last Update Posted: February 14, 2023
• Last Verified: February 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Sarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms