SARC024: A Blanket Protocol to Study Oral Regorafenib in Patients With Selected Sarcoma Subtypes
Condition: Liposarcoma; Osteogenic Sarcoma; Ewing/Ewing-like Sarcoma; Rhabdomyosarcoma; Mesenchymal Chondrosarcoma
MeSH terms: Sarcoma; Rhabdomyosarcoma; Liposarcoma; Chondrosarcoma; Osteosarcoma; Chondrosarcoma, Mesenchymal
Intervention: Regorafenib; Placebo
Intervention description: Adults: 160 mg daily; 21 days on and 7 days off Pediatrics: 82mg/m2 (rounding to the nearest 20mg) daily; 21 days on and 7 days off; 21 days on and 7 days off
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 131.0
Sex: All
Minimum age: 5 Years
Healthy volunteers: No

Summary:

      Although regorafenib was approved for use in patients who had progressive GIST despite
      imatinib and/or sunitinib on the basis of phase II and phase III data, it has not been
      examined in a systematic fashion in patients with other forms of sarcoma.

      Given the activity of sorafenib, sunitinib and pazopanib in soft tissue sarcomas, and
      evidence of activity of sorafenib in osteogenic sarcoma and possibly Ewing/Ewing-like
      sarcoma, there is precedent to examine SMOKIs (small molecule oral kinase inhibitors) such as
      regorafenib in sarcomas other than GIST. It is also recognized that SMOKIs (small molecule
      oral kinase inhibitors)such as regorafenib, sorafenib, pazopanib, and sunitinib have
      overlapping panels of kinases that are inhibited simultaneously. While not equivalent, most
      of these SMOKIs (small molecule oral kinase inhibitors) block vascular endothelial growth
      factor and platelet derived growth factors receptors (VEGFRs and PDGFRs), speaking to a
      common mechanism of action of several of these agents.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age ≥ 10 year for Liposarcoma, Osteosarcoma, Ewing sarcoma and Mesenchymal
             Chondrosarcoma; Age ≥ 5 years for Rhabdomyosarcoma cohorts

          -  Weight ≥ 15 kg (33 lb)

          -  Patients must have histologically or cytologically confirmed advanced/metastatic
             liposarcoma, osteogenic sarcoma, Ewing/Ewing-like sarcoma of soft tissue or bone,
             fusion-positive alveolar rhabdomyosarcoma or embryonal
             rhabdomyosarcoma/fusion-negative alveolar rhabdomyosarcoma , or mesenchymal
             chondrosarcoma

          -  WHO Performance Status 0, 1 or 2. A maximum of 1/3 of patients in cohorts A & B may be
             WHO performance status 2

          -  At least one prior line of systemic therapy for the sarcoma diagnosis (neoadjuvant,
             adjuvant or metastatic disease)

          -  All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v 4.0 Grade
             1 or less (except alopecia) at the time of signing the Informed Consent Form (ICF)

          -  Subject must be able to swallow and retain oral medication

          -  At least one site of measurable disease on x-ray/CT/MRI scan as defined by RECIST 1.1

          -  Adequate organ function within 14 days of registration

          -  Written, voluntary informed consent

          -  Fertile men and women of childbearing potential must agree to use an effective method
             of birth control from Day 1 of study and for 3 months after last study drug
             administration in both sexes, as assessed by the investigator. Women of childbearing
             potential include pre-menopausal women and women within the first 2 years of the onset
             of menopause. Women of childbearing potential must have a negative pregnancy test less
             than or equal to seven days prior to Day 1 of study. The definition of adequate
             contraception will be based on the judgement of the investigator.

          -  Evidence of progression of disease as defined by RECIST 1.1 (i.e. new disease sites or
             20% growth of index lesions) within 6 months of registration

          -  Patients with central nervous system disease are eligible for enrollment if they have
             received prior radiotherapy or surgery to sites of CNS (central nervous system)
             metastatic disease and are without evidence of clinical progression for at least 12
             weeks after therapy

        Exclusion Criteria:

          -  Patients with documentation of well differentiated liposarcoma only (of the well
             differentiated/dedifferentiated liposarcoma family) are specifically excluded, owing
             to its characteristically slow growth. If high grade areas are suspected
             (dedifferentiation), but not proved by pathology analysis (e.g. after primary
             resection of a well-differentiated liposarcoma), a biopsy must be performed to
             demonstrate the high-grade dedifferentiated disease

          -  Prior systemic therapy with a small molecule oral kinase inhibitor, including but not
             limited to: pazopanib, sunitinib, sorafenib, everolimus, sirolimus, vemurafenib,
             dasatinib and trametinib

          -  Previous assignment to treatment during this study. Subjects permanently withdrawn
             from study participation will not be allowed to re-enter study. Patients who progress
             on placebo are specifically allowed to enroll on the treatment arm of the study if
             they meet all other entry criteria

          -  Concurrent, clinically significant, active malignancies within 12 months of study
             enrollment

          -  Patients with severe and/or uncontrolled concurrent medical disease that in the
             opinion of the investigator could cause unacceptable safety risks or compromise
             compliance with the protocol

          -  Major surgery within 28 days prior to study registration or those patients who have
             not recovered adequately from prior surgery

          -  Patients who have received wide field radiotherapy ≤ 28 days (defined as > 50% of
             volume of pelvis bones or equivalent) or limited field radiation for palliation < 14
             days prior to study registration or those patients who have not recovered adequately
             from side effects of such therapy

          -  Patients who have received prior systemic therapy < 14 days prior to study
             registration or have not recovered adequately from toxicities to CTCAE v. 4.03 grade 1
             or less; prior investigational therapy may not have been given < 5 half-lives of last
             dose of treatment, or < 14 days, whichever is greater

          -  Patients who have had prior autologous, or allogeneic bone marrow transplant

          -  Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm
             Hg [NCI-CTCAE v 4.0] on repeated measurement) despite optimal medical management

          -  Active or clinically significant cardiac disease including: Congestive heart
             failure-New York Heart Association (NYHA) > class II, Active coronary artery disease,
             Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or
             digoxin, Unstable angina (anginal symptoms at rest), new onset angina within 3 months
             before randomization, or myocardial infarction within 6 months before randomization

          -  Evidence or history of bleeding diathesis

          -  Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to study
             registration

          -  Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular
             accident (including transient ischemic attacks) deep vein thrombosis or pulmonary
             embolism within 6 months of start of study treatment

          -  Known history of human immunodeficiency virus (HIV) infection or current chronic or
             active hepatitis B or C infection requiring treatment with antiviral therapy.

          -  Ongoing infection > Grade 2 NCI-CTCAE v 4.03

          -  Presence of a non-healing wound, non-healing ulcer, or benign bone fracture (patients
             with stress insufficiency fractures e.g. from osteoporosis or pathological fracture
             from tumor are eligible for study)

          -  Patients with seizure disorder requiring medication

          -  Proteinuria > 100 mg/dl on urine analysis

          -  Interstitial lung disease with ongoing signs and symptoms at the time of informed
             consent

          -  Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE version
             4.03 Grade 2 dyspnea)

          -  History of organ allograft (including corneal transplant).

          -  Known or suspected allergy or hypersensitivity to regorafenib, or excipients of the
             formulations given during the course of this trial

          -  Any malabsorption condition.

          -  Women who are pregnant or breast-feeding.

          -  Any condition which, in the investigator's opinion, makes the subject unsuitable for
             trial participation

          -  Substance abuse, medical, psychological or social conditions that may interfere with
             the subject's participation in the study or evaluation of the study results

          -  Inability to comply with protocol required procedures

          -  Use of any herbal remedy (e.g. St. John wort [Hypericum perforatum])