SARC038: Phase 2 Study of Regorafenib and Nivolumab in Osteosarcoma

  • STATUS
    Recruiting
  • End date
    Jun 12, 2026
  • participants needed
    48
  • sponsor
    Sarcoma Alliance for Research through Collaboration
Updated on 12 March 2022
monoclonal antibodies
biologic agent
systemic therapy
measurable disease
lipase
growth factor
MRI
hematopoietic growth factors
progressive disease
neutrophil count
cancer chemotherapy
pegfilgrastim
myelosuppressive chemotherapy
cellular therapy
dyspnea at rest
immunomodulators
left ventricular fractional shortening
recurrent osteosarcoma

Summary

A phase 2 study of regorafenib in combination with nivolumab in patients with refractory or recurrent osteosarcoma.

Description

This is a single arm, Simon two-stage historically controlled study to compare the 4 month progression-free survival rate of patients with relapsed/refractory osteosarcoma treated with regorafenib in combination with nivolumab to those who received regorafenib alone (historical control).

Details
Condition Osteosarcoma, Osteosarcoma in Children, Osteosarcoma Recurrent, Osteosarcoma Metastatic
Treatment Nivolumab, Regorafenib 40 MG, Regorafenib 20MG
Clinical Study IdentifierNCT04803877
SponsorSarcoma Alliance for Research through Collaboration
Last Modified on12 March 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Age ≥ 5 years at the time of enrollment. Every effort will be made to ensure that 50% of patients will be ≤ 21 years of age
Confirmation by a pathologist of a diagnosis of localized or metastatic high grade osteosarcoma (excluding osteosarcoma associated with Paget disease of bone or extraskeletal osteosarcoma) that is recurrent or refractory after at least 1 prior line of systemic therapy in the neoadjuvant, adjuvant setting, or metastatic. For the purposes of this study, refractory is defined as progressive disease by RECIST 1.1 while on active therapy
Performance Status: Lansky (≤ 16 years of age) or Karnofsky (>16 years of age) performance score of ≥ 70, or Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1. See Appendix A. Patients who are unable to walk because of paralysis, but who are up and about in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
At least one site of measurable disease on CT/MRI scan as defined by RECIST 1.1. Baseline imaging must be performed within 21 days of Day 1 of study therapy
Must be able to swallow intact pills
Adequate organ and bone marrow function within 7 days of Day 1 of study therapy defined as
Absolute Neutrophil Count (ANC) ≥ 1000/mm3
Platelets ≥ 75 000/mm3
Hemoglobin ≥ 8 g/ dL (transfusions allowed)
ALT and AST ≤ 3 x institutional upper limit of normal (ULN) or ≤ 5.0 x institutional ULN if considered due to tumor
Serum albumin ≥ 3 g/dL
Serum total bilirubin ≤ 1.5 x institutional ULN. NOTE: Patients with elevated bilirubin secondary to Gilbert's disease are eligible to participate in the study
Serum creatinine ≤ 3 x institutional ULN or 24-hour creatinine clearance ≥ 30 ml/min (calculated creatinine clearance using Cockcroft formula is acceptable)
Normal free T4. Replacement therapy allowed
Serum lipase ≤ 1.5 x ULN
INR ≤ 1.5 x ULN
Urine protein: Meets one of the following criteria: (i) urinary protein by urine dipstick is ≤ 100mg/dL or ≤ 2+ (ii) Urine Protein Creatinine(UPC) ratio <3.5 (iii) 24-hour urine protein was measured, urinary protein ≤ 3500 mg
Adequate pulmonary function defined as
No evidence of dyspnea at rest
No exercise intolerance due to pulmonary insufficiency
Pulse Oximetry >92% on room air
Adequate cardiac function defined as
QTc ≤ 480 msec
Shortening fraction ≥ 27% by echocardiogram or ejection fraction ≥ 50% by gated radionuclide study or echocardiogram
New York Heart Association Functional Classification Class I or II congestive heart failure (CHF)
No clinically significant cardiac arrhythmias, stroke or myocardial infarction within 6 months prior to enrollment
Prior Therapy: All prior treatment-related toxicities must have resolved to ≤ Grade 1 or be determined clinically stable by the Investigator
Myelosuppressive chemotherapy: Patients must not have received myelosuppressive chemotherapy within 3 weeks of enrollment
Hematopoietic growth factors: At least 7 days must have elapsed since the completion of therapy with a white blood cell or platelet growth factor. At least 14 days must have elapsed after receiving pegfilgrastim
Biologic (anti-neoplastic agent): At least 7 days must have elapsed since completion of therapy with a biologic agent
Monoclonal antibodies: At least 21 days must have elapsed since prior therapy that included a monoclonal antibody (e.g., dinutuximab, denosumab, bevacizumab)
Radiotherapy: ≥ 2 weeks must have elapsed since local palliative XRT (small port); ≥ 3 months must have elapsed if prior craniospinal XRT was received, if ≥ 50% of the pelvis was irradiated, or if TBI was received; ≥ 6 weeks must have elapsed if other substantial bone marrow irradiation was given
Autologous Stem Cell Transplant or Rescue or Cellular Therapy: ≥ 2 months must have elapsed since transplant/cellular therapy
Voluntary, written informed consent
Negative urine or serum pregnancy test in women of childbearing potential. Women of childbearing potential includes pre-menopausal girls with evidence of puberty onset, and adult women through the end of the first 2 years of the onset of menopause. Testing should be completed ≤ 7 days prior to Day 1 of study
Fertile men and women of childbearing potential must agree to use an effective method of birth control from Day 1 of study and for 5 months after last dose of nivolumab or for 8 weeks after last dose of regorafenib, whichever is longer
Effective methods of birth control include: surgical sterility (subject or subject's partner), barrier device (condom, diaphragm), contraceptive coil (IUD), abstinence, or oral contraception
Patients with central nervous system (CNS) disease are eligible if they have received prior radiotherapy or surgery to sites of CNS metastatic disease and are without evidence of progression for at least 4 weeks after CNS therapy

Exclusion Criteria

Patients with prior or concurrent malignancy whose natural history or treatment does have the potential to interfere with the safety or efficacy assessment of the investigational regimen in this trial
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 (thoracotomy or laparotomy, etc.), laparoscopic biopsy, trauma within 28 days, or significant traumatic injury within 28 days prior to Day 1 of study or who have not recovered adequately from prior surgery
Women who are pregnant or nursing/breastfeeding
Known hypersensitivity to excipients of the formulations of regorafenib or nivolumab or similar agents
Inability to comply with protocol required procedures
Patients with known active brain or leptomeningeal metastases
Prior therapy with an immune checkpoint inhibitor or a tyrosine kinase inhibitor targeting VEGF
Patients with autoimmune disease
Chronic use of immunosuppressive therapies
Received any investigational drug within 28 days of study enrollment
Uncontrolled infection
Known active HIV. Testing is not required. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. However, strong CYP3A4 inhibitors are prohibited
Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected)
Prior allogeneic hematopoietic stem cell/bone marrow transplant or solid organ transplant
Uncontrolled hypertension defined as on average, > 140 systolic pressure or > 90 diastolic pressure in patient ≥ 18 y/o or > 95th percentile for age/gender in patients < 18 y/o despite medical management. If blood pressure is borderline, ensure patient is properly prepared (relaxed, sitting in chair for > 3 minutes), proper technique is used (correct cuff size and positioning), and document 2 separate recordings, each at least >5 minutes apart
History of clinically significant venous or arterial thrombotic or embolic event requiring systemic anticoagulation within 6 months of enrollment
Requirement of oral anticoagulant therapy with oral vitamin K antagonists (warfarin). Low-dose anticoagulants for maintenance of patency of central venous device or prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin or direct oral anticoagulants is allowed, providing the event prompting treatment occurred > 6 months prior. Subjects who are prophylactically being treated with an agent such as heparin will be allowed to participate, provided no prior evidence of underlying abnormality in coagulation parameters exists
Presence of non-healing wound, non-healing ulcer or fracture (excluding pathologic fracture)
Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE Grade 2 dyspnea)
Significant currently active gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease, malabsorption, or CTCAE Grade ≥ 2 diarrhea of any etiology
Patients who require systemic corticosteroids (excluding temporary usage for tests, prophylactic administration for allergic reactions, or to maintain physiologic steroid levels for adrenal insufficiency) or immunosuppressants, or who have received such a therapy <14 days before enrollment
Live/attenuated vaccine administered within 30 days of enrollment
Patients receiving or requiring strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort)
Any hemorrhage or bleeding event CTCAE ≥ Grade 3 within 28 days of study enrollment
Body surface area (BSA) < 0.4 m2
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