Phase II Study of Regorafenib as Maintenance Therapy

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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Efficacy of Regorafenib as Maintenance Therapy in Non-adipocytic Soft Tissue Sarcoma Having Received First-line Doxorubicin-based Chemotherapy

Conditions
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Metastatic Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: Regorafenib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Regorafenib | Drug: Regorafenib<br>* 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<br>* Other names: stivarga;|
| Placebo Comparator: Arm B<br>Placebo | Drug: Placebo<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the efficacy of regorafenib compared to placebo | 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). | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the efficacy of regorafenib compared to placebo | in terms of overall survival | from the date of randomization to the date of death from any cause | 
| To assess the efficacy of regorafenib compared to placebo | 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) | 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 | 
| To assess the efficacy of regorafenib compared to placebo | 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. | from the date of randomization to the date of death from any cause, up to 12 months after the beginning of the treatment | 
| To assess the safety of regorafenib | 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 | Baseline, every 4 weeks, up to 12 months after the beginning of the treatment | 
| To assess the relative benefit/risk ratio | 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) | up to 12 months |