SARC038: Phase 2 Study of Regorafenib and Nivolumab in Osteosarcoma

  • End date
    Jun 18, 2026
  • participants needed
  • sponsor
    Sarcoma Alliance for Research through Collaboration
Updated on 7 October 2022
monoclonal antibodies
biologic agent
systemic therapy
measurable disease
growth factor
hematopoietic growth factors
progressive disease
neutrophil count
cancer chemotherapy
myelosuppressive chemotherapy
cellular therapy
dyspnea at rest
left ventricular fractional shortening
recurrent osteosarcoma
refractory osteosarcoma


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


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).

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 on7 October 2022


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
Histologically confirmed high grade osteosarcoma (excluding osteosarcoma associated with Paget disease of bone or extraskeletal osteosarcoma) at diagnosis or relapse
Must have relapsed or refractory osteosarcoma following at least one line of systemic
therapy for the initial treatment of osteosarcoma
Must be able to swallow intact pills
Performance Status: Lansky (≤ 16 years of age) or Karnofsky (>16 years of age)
performance score of ≥ 70, or Eastern Cooperative Oncology Group (ECOG) performance
Absolute Neutrophil Count (ANC) ≥ 1000/mm3
score 0 or 1. See Appendix A. Patients who are unable to walk because of paralysis
Platelets ≥ 75 000/mm3
but who are up and about in a wheelchair, will be considered ambulatory for the
Hemoglobin ≥ 8 g/ dL (transfusions allowed)
purpose of assessing the performance score
At least one site of measurable disease on CT/MRI scan as defined by RECIST 1.1
Serum albumin ≥ 3 g/dL
Baseline imaging must be performed within 21 days of Day 1 of study therapy
Adequate organ and bone marrow function within 7 days of Day 1 of study therapy
Normal free T4. Replacement therapy allowed
defined as
Serum lipase ≤ 1.5 x ULN
INR ≤ 1.5 x ULN
Adequate pulmonary function defined as
ALT and AST ≤ 3 x institutional upper limit of normal (ULN) or ≤ 5.0 x institutional
No evidence of dyspnea at rest
ULN if considered due to tumor
Pulse Oximetry >92% on room air
Serum total bilirubin ≤ 1.5 x institutional ULN. NOTE: Patients with elevated
Adequate cardiac function defined as
bilirubin secondary to Gilbert's disease are eligible to participate in the study
QTc ≤ 480 msec
Serum creatinine ≤ 3 x institutional ULN or 24-hour creatinine clearance ≥ 30 ml/min
(calculated creatinine clearance using Cockcroft formula is acceptable)
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)
-hour urine protein was measured, urinary protein ≤ 3500 mg
No activity limitation due to pulmonary insufficiency
Voluntary, written informed consent
Shortening fraction ≥ 27% by echocardiogram or ejection fraction ≥ 50% by gated
radionuclide study or echocardiogram
No congestive heart failure (CHF) worse than New York Heart Association Functional
Classification Class I
No clinically significant cardiac arrhythmias, stroke or myocardial infarction within
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
Negative urine or serum pregnancy test in women of childbearing potential. Women of
childbearing potential includes pre-menarchal 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
Patients >18 years must be willing to undergo tumor biopsy at study entry and
post-treatment biopsy for biologic correlates. If biopsy is contra-indicated, enrollment
must be approved by study PI and archival tissue must be available

Exclusion Criteria

Women who are pregnant or nursing/breastfeeding
Inability to comply with protocol required procedures
Patients with autoimmune disease
Chronic use of immunosuppressive therapies
Received any investigational drug within 28 days of study enrollment
Uncontrolled infection
Live/attenuated vaccine administered within 30 days of enrollment
Any hemorrhage or bleeding event CTCAE ≥ Grade 3 within 28 days of study enrollment
Body surface area (BSA) < 0.4 m2
Patients with prior or concurrent malignancy whose natural history or treatment has
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, or significant
traumatic injury within 28 days prior to Day 1 of study or who have not recovered
adequately from prior surgery
Known hypersensitivity to excipients of the formulations of regorafenib or nivolumab
or similar agents
Prior therapy with an immune checkpoint inhibitor or a tyrosine kinase inhibitor
targeting VEGF
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
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
Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE Grade 2
Significant currently active gastrointestinal disorders with diarrhea as a major
symptom e.g., Crohn's disease, malabsorption, or CTCAE Grade ≥ 2 diarrhea of any
Patients with history of bowel perforation or fistula formation
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)
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