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Nivolumab with or without Azacitidine in Treating Patients with Recurrent Resectable Osteosarcoma

Trial Status: Active

This phase I / II trial studies the best dose and side effects of azacitidine and how well it works with or without nivolumab in treating patients with osteosarcoma that has come back (recurrent) and can be removed by surgery (resectable). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab and azacitidine together may work better compared to nivolumab alone in treating patients with osteosarcoma.

Inclusion Criteria

  • Patients must have had a histologic diagnosis of osteosarcoma at original diagnosis
  • Patients with an isolated pulmonary recurrence of osteosarcoma can be enrolled on this study * Any history of metastatic disease at a site other than lung would make the patient ineligible for this study * The patient’s treating team must consider the patient’s disease to be resectable and the patient must be willing to undergo resection of all disease, including any lung lesion meeting criteria for likely metastatic disease, defined as: 3 or more lesions >= 3 mm in diameter OR a single lesion >= 5 mm * Patients with bilateral disease are eligible provided their disease is considered resectable. Resectable pulmonary nodules are defined as nodules that can be removed without performing a pneumonectomy (e.g. nodules immediately adjacent to the main stem bronchus or main pulmonary vessels)
  • Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2, using the Karnofsky scale for patients >= 16 years of age and the Lansky scale for patients < 16 years of age
  • Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to the start of protocol therapy * Patients cannot have received myelosuppressive therapy within two weeks of starting treatment (4 weeks if prior therapy was with a nitrosourea) * Patient cannot have received a biologic (anti-neoplastic agent) within 7 days of the start of protocol therapy * Recovery from radiation therapy is defined as >= 2 weeks for local palliative radiation therapy (RT) (small port) or >= 6 weeks for treatment that includes substantial bone marrow radiation from the start of protocol therapy
  • Absolute neutrophil count >= 750/mcL (within 7 days of starting protocol therapy)
  • Platelets >= 75,000/mcL (within 7 days of starting protocol therapy)
  • Total bilirubin =< 1.5 x institutional upper limit of normal (within 7 days of starting protocol therapy)
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (within 7 days of starting protocol therapy)
  • Creatinine clearance >= 70 mL/min/1.73 m^2 measure by radioisotope glomerular filtration rate (GFR) (within 7 days of starting protocol therapy) OR
  • Serum creatinine < the upper limit of normal based on age and gender (within 7 days of starting protocol therapy): * Age: Maximum serum creatinine (mg/dL) ** 1 to < 2 years: 0.6 (male and female) ** 2 to < 6 years: 0.8 (male and female) ** 6 to < 10 years: 1 (male and female) ** 10 to < 13 years: 1.2 (male and female) ** 13 to < 16 years: 1.5 (male), 1.4 (female) ** >= 16 years: 1.7 (male), 1.4 (female)
  • All patients and/or their parents or legal guardians must have the ability to understand and the willingness to sign a written informed consent/assent document

Exclusion Criteria

  • Pregnant or breast-feeding women will not be entered on this study, because there is no available information regarding human fetal or teratogenic toxicities. Females that are postmenarchal must have a negative serum or urine pregnancy test within 24 hours of starting protocol therapy
  • Males and females of reproductive potential may not participate unless they have agreed to the use of, at minimum, two methods of contraception during and after treatment * Women of childbearing potential should adhere to contraception for a period of 5 months after the last dose of nivolumab * Men who are sexually active with women of child bearing potential should adhere to contraception for a period of 7 months after the last dose of nivolumab * One method should be highly effective and the other method being either highly effective or less effective as listed below: ** HIGHLY EFFECTIVE METHODS OF CONTRACEPTION *** Male condoms with spermicide *** Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena by women of child-bearing potential (WOCBP) subjects or male subject's WOCBP partner. Female partners of male subjects participating in the study may use hormone based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug *** Progestogen only hormonal contraception associated with inhibition of ovulation *** Intrauterine hormone-releasing system (IUS) *** Nonhormonal IUDs, such as ParaGard *** Tubal ligation *** Vasectomy *** Complete abstinence - complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs. Subjects who choose complete abstinence are not required to use a second method of contraception, but female subjects must continue to have pregnancy tests. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence ** LESS EFFECTIVE METHODS OF CONTRACEPTION *** Diaphragm with spermicide *** Cervical cap with spermicide *** Vaginal sponge *** Male condom without spermicide *** Progestin only pills by WOCBP subjects or male subject's WOCBP partner *** Female condom - A male and female condom must not be used together ** UNACCEPTABLE METHODS OF CONTRACEPTION *** Periodic abstinence (calendar, symptothermal, post-ovulation methods) *** Withdrawal (coitus interruptus) *** Spermicide only *** Lactation amenorrhea method (LAM)
  • Patients receiving the following are not eligible: * Corticosteroids or other immunosuppressive medications * Patients who are currently receiving other investigational agents or other anti-cancer therapy * Patients must agree not to receive any live/attenuated vaccine (e.g. varicella, zoster, yellow fever, rotavirus, oral polio and measles, mumps, rubella [MMR]) during treatment and until 100 days post last dose of nivolumab
  • Patients with uncontrolled intercurrent illness including, but not limited to: * Ongoing or active infection * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Psychiatric illness/social situations that would limit compliance with study requirements
  • Patients with a history of any grade autoimmune disorder are not eligible * Asymptomatic laboratory abnormalities (e.g. antinuclear antibodies [ANA], rheumatoid factor, altered thyroid function studies) will not render a patient ineligible in the absence of a diagnosis of an autoimmune disorder * Patients with >= grade 2 hypothyroidism due to history of autoimmunity are not eligible (hypothyroidism due to previous irradiation or thyroidectomy will not impact eligibility)
  • Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab (e.g. another humanized antibody) or azacitidine are not eligible
  • Patients who are considered unable to comply with the safety monitoring requirements of the study are not eligible
  • Patients with known human immunodeficiency virus (HIV) or hepatitis B or C are excluded
  • Patients who have received prior solid organ transplantation are not eligible
  • Patients who have received prior anti-PD-1 directed therapy (monoclonal antibody [mAb] or small molecule) are not eligible


Los Angeles
Children's Hospital Los Angeles
Status: ACTIVE
Contact: Leo Mascarenhas


Children's Hospital Colorado
Status: ACTIVE
Contact: Carrye Rudolph Cost
Phone: 720-777-6672


Connecticut Children's Medical Center
Status: ACTIVE
Contact: Michael Scott Isakoff


Alfred I duPont Hospital for Children
Status: ACTIVE
Contact: Emi H. Caywood
Phone: 302-651-5500


University of Florida Health Science Center - Gainesville
Status: ACTIVE
Contact: Joanne Pigues Lagmay
Phone: 352-273-9120
University of Miami Miller School of Medicine-Sylvester Cancer Center
Status: ACTIVE
Contact: Julio Cesar Barredo
Saint Petersburg
Johns Hopkins All Children's Hospital
Status: ACTIVE
Contact: Jonathan Layne Metts
Moffitt Cancer Center
Status: ACTIVE
Contact: Mihaela Druta
Phone: 813-745-3242


University of Kentucky / Markey Cancer Center
Status: ACTIVE
Contact: James Thomas Curry Badgett
Phone: 859-218-0332

North Carolina

Chapel Hill
UNC Lineberger Comprehensive Cancer Center
Status: ACTIVE
Contact: Patrick Andrew Thompson
Carolinas Medical Center / Levine Cancer Institute
Status: ACTIVE
Contact: Javier E. Oesterheld
Phone: 704-381-9900
Duke University Medical Center
Status: ACTIVE
Contact: Lars Martin Wagner


Cleveland Clinic Foundation
Status: ACTIVE
Contact: Matteo Maria Trucco
Nationwide Children's Hospital
Status: ACTIVE
Contact: Bhuvana Anantha Setty
Phone: 614-722-3561


Vanderbilt University / Ingram Cancer Center
Status: ACTIVE
Contact: Scott C. Borinstein


UT Southwestern / Simmons Cancer Center-Dallas
Status: ACTIVE
Contact: Patrick J. Leavey
Phone: 214-456-2382
M D Anderson Cancer Center
Status: ACTIVE
Contact: Jonathan Benjamin Gill


I. To investigate the safety and feasibility of nivolumab in combination with azacitidine given neoadjuvantly and adjuvantly in subjects with recurrent, resectable osteosarcoma.


I. To determine if the combination of azacitidine and nivolumab, administered both neo-adjuvantly and adjuvantly, improve event free survival over the 20% 12-month historical control used for recurrent osteosarcoma studies in the Children’s Oncology Group.

II. To assess overall survival in patients with recurrent, resectable osteosarcoma patients receiving neoadjuvant therapy.


I. To determine changes in expression of selected immune markers, including T-cell specific, antigen presentation-related, and IFN gamma signaling-related genes compared to baseline in the blood and metastatic tumor tissue from patients receiving neoadjuvant therapy.

II. To determine changes in the quality and quantity of tumor infiltrating lymphocytes.

III. To compare findings in tumor specimens from treated patients to findings in an existing cohort of untreated patients on a companion tissue collection protocol.

IV. To evaluate the gut microbiome in subjects enrolled on this trial and the relationship between the microbiome profile, event free survival, and autoimmune adverse events in subjects with osteosarcoma treated with nivolumab and azacitidine.

V. To explore the association between nivolumab with or without (+/‐) azacitidine exposure and selected pharmaco‐dynamic markers in the peripheral blood and in the tumor microenvironment.

OUTLINE: This is a phase I, dose-escalation study of azacitidine followed by a phase II study. Patients are assigned to 1 of 2 arms based on the number of previously enrolled patients.

ARM I: The first 6 patients enrolled on the study receive nivolumab intravenously (IV) over 30 minutes on days 1 and 15. Between days 28-35, patients undergo surgical resection. Between days 49-84, treatment with nivolumab continues, repeating every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Subsequently enrolled patients receive nivolumab IV over 30 minutes on days 1 and 15 and azacitidine IV over 15 minutes on days 1-5, 8 and 9. Between days 28-35, patients undergo surgical resection. Beginning between days 49-84, treatment with nivolumab and azacitidine continues, repeating every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 100 days, then every 10 weeks and every 3 months.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Moffitt Cancer Center

Principal Investigator
Mihaela Druta

  • Primary ID MCC-19487
  • Secondary IDs NCI-2019-05230
  • ID NCT03628209