Clinical trial NCT02048371: SARC024: A Blanket Protocol to Study Oral Regorafenib in Patients With Selected Sarcoma Subtypes
Official title: SARC024: A Blanket Protocol to Study Oral Regorafenib in Patients With Selected Sarcoma Subtypes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Liposarcoma
Osteogenic Sarcoma
Ewing/Ewing-like Sarcoma
Rhabdomyosarcoma
Mesenchymal Chondrosarcoma
Lead sponsor: Sarcoma Alliance for Research through Collaboration
Sponsor class: OTHER
First posted: 2014-01-29
Enrollment: 131
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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 \[Hypericum perforatum\])

Primary outcomes:
measure: Progression-free Survival (PFS). Cohort A and Cohort B
timeFrame: up to 3 years
measure: Progression-free Survival (PFS). Cohort C, Cohort D, and Cohort E
timeFrame: up to 16 weeks
Secondary outcomes:
measure: The Number of Participants With Reported CTCAE (Common Terminology Criteria for Adverse Events) Version 4.03 Adverse Events. All Cohorts.
timeFrame: up to 3 years
measure: Overall Response Rate (ORR). All Cohorts.
timeFrame: up to 3 years
measure: Progression-free Survival (PFS), Cohorts A and B, After Crossover.
timeFrame: up to 3 years
measure: Response Rate (RR), Cohorts A and B, After Crossover.
timeFrame: up to 3 years
measure: Time to Tumor Progression (TTP), Cohorts A and B, After Crossover.
timeFrame: up to 3 years
measure: Overall Survival (OS). Cohorts A and B, After Crossover.
timeFrame: up to 3 years
measure: Disease Specific Survival (DSS). Cohorts A and B, After Crossover.
timeFrame: up to 3 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Santa Monica
country: United States
facility: Sarcoma Oncology Research Center
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic - Florida
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Boston
country: United States
facility: Dana Farber/Partners Cancer Care
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic - Minnesota
state: Minnesota
city: Charlotte
country: United States
facility: Carolinas Healthcare System
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
Study officials:
affiliation: University of Pennsylvania
name: Robert Maki, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Riedel RF, Ballman KV, Lu Y, Attia S, Loggers ET, Ganjoo KN, Livingston MB, Chow W, Wright J, Ward JH, Rushing D, Okuno SH, Reed DR, Liebner DA, Keedy VL, Mascarenhas L, Davis LE, Ryan C, Reinke DK, Maki RG. A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Regorafenib Versus Placebo in Advanced/Metastatic, Treatment-Refractory Liposarcoma: Results from the SARC024 Study. Oncologist. 2020 Nov;25(11):e1655-e1662. doi: 10.1634/theoncologist.2020-0679. Epub 2020 Aug 20.
citation: Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies? Expert Opin Emerg Drugs. 2019 Sep;24(3):153-171. doi: 10.1080/14728214.2019.1654455. Epub 2019 Aug 14.
citation: Davis LE, Bolejack V, Ryan CW, Ganjoo KN, Loggers ET, Chawla S, Agulnik M, Livingston MB, Reed D, Keedy V, Rushing D, Okuno S, Reinke DK, Riedel RF, Attia S, Mascarenhas L, Maki RG. Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma. J Clin Oncol. 2019 Jun 1;37(16):1424-1431. doi: 10.1200/JCO.18.02374. Epub 2019 Apr 23.