A Blanket Protocol to Study Oral Regorafenib in Patients With Refractory Liposarcoma, Osteogenic Sarcoma, and Ewing/Ewing-like Sarcomas

This study is not yet open for participant recruitment.
Verified February 2014 by Sarcoma Alliance for Research through Collaboration
Sponsor:
Information provided by (Responsible Party):
Sarcoma Alliance for Research through Collaboration
ClinicalTrials.gov Identifier:
NCT02048371
First received: January 10, 2014
Last updated: February 25, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Liposarcoma
Osteogenic Sarcoma
Ewing/Ewing-like Sarcoma
Drug: Regorafenib
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Blanket Protocol to Study Oral Regorafenib in Patients With Refractory Liposarcoma, Osteogenic Sarcoma, and Ewing/Ewing-like Sarcomas

Resource links provided by NLM:


Further study details as provided by Sarcoma Alliance for Research through Collaboration:

Primary Outcome Measures:
  • The progression-free survival (PFS) [ Time Frame: up to 3 years ]
    The progression-free survival is the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse. Cohort A (liposarcoma) and Cohort B (osteogenic sarcoma). PFS will be evaluated according to RECIST (Response Evaluation Criteria In Solid Tumors) 1.1

  • The progression-free survival (PFS) [ Time Frame: up to 16 weeks ]
    The progression-free survival is the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse. Cohort C (Ewing/Ewing-like sarcoma). PFS will be evaluated according to RECIST (Response Evaluation Criteria In Solid Tumors) 1.1


Secondary Outcome Measures:
  • The incidence of reported CTCAE (Common Terminology Criteria for Adverse Events) version 4.0 [ Time Frame: up to 3 years ]
    Common Toxicity Criteria, also referred to as the Common Terminology Criteria for Adverse Events (CTCAE), is a standardised classification of side effects used in assessing drugs for cancer therapy. Cohorts A, B and C. PFS will be evaluated according to RECIST (Response Evaluation Criteria In Solid Tumors) 1.1

  • Overall response rate (ORR) [ Time Frame: up to 3 years ]
    The overall response rate (ORR) is the percentage of patients whose cancer shrinks or disappears after treatment. ORR will be evaluated according to RECIST (Response Evaluation Criteria In Solid Tumors) 1.1

  • Time to tumor progression (TTP) [ Time Frame: up to 3 years ]
    Time to tumor progression (TTP) is the length of time from the date of diagnosis or the start of treatment for a disease until the disease starts to get worse or spread to other parts of the body. TTP will be evaluated according to RECIST (Response Evaluation Criteria In Solid Tumors) 1.1


Estimated Enrollment: 126
Study Start Date: March 2014
Estimated Study Completion Date: February 2017
Estimated Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Regorafenib
160 mg daily; 21 days on and 7 days off
Drug: Regorafenib
Placebo Comparator: Placebo
21 days on and 7 days off
Drug: Placebo

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed advanced/metastatic liposarcoma, osteogenic sarcoma, or Ewing/Ewing-like sarcoma of soft tissue or bone. This study will accept the diagnosis made at the investigator's center.
  • 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. Baseline imaging must be performed within 28 days of Day 1 of study.
  • Adequate organ function within 14 days of registration INR (International Normalized Ratio) : patients with no prior evidence of underlying abnormality in coagulation parameters exists, according to the written documentation of the treating physician
  • Evidence of progression of disease as defined by RECIST 1.1 (i.e. new disease sites or 30% 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.
  • 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. 4.0 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.
  • 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 randomization3.2.11
  • Evidence or history of bleeding diathesis or coagulopathy
  • 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 4.0
  • 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
  • Persistent proteinuria: Grade 3 NCI-CTCAE v 4.0 (> 3.5 g/24 h, measured by urine protein:creatinine ratio on a random urine sample)
  • 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 4.0 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]).
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT02048371

Contacts
Contact: Brenda Steltzriede 734-930-7600 bsteltzriede@sarctrials.org
Contact: Vesna Milacic 734-930-7600 vmilacic@sarctrials.org

Locations
United States, New York
Mount Sinai Medical Center Not yet recruiting
New York, New York, United States, 10129-6174
Contact: Robert Maki, MD    212-659-6815    robert.maki@mssm.edu   
Principal Investigator: Robert Maki, MD         
Sponsors and Collaborators
Sarcoma Alliance for Research through Collaboration
Investigators
Principal Investigator: Robert Maki, MD, PhD Tisch Cancer Institute Mount Sinai Medical Center
  More Information

No publications provided

Responsible Party: Sarcoma Alliance for Research through Collaboration
ClinicalTrials.gov Identifier: NCT02048371     History of Changes
Other Study ID Numbers: SARC024
Study First Received: January 10, 2014
Last Updated: February 25, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Liposarcoma
Osteosarcoma
Sarcoma
Neoplasms, Adipose Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue

ClinicalTrials.gov processed this record on April 23, 2014