Clinical Trial 19487

• Overview

  Study Title:

  A Phase Ib/II Study to Evaluate the Safety, Feasibility and Efficacy of Nivolumab or Nivolumab in Combination with Azacitidine in Patients with Recurrent, Resectable Osteosarcoma

  Summary:

  The purpose of the study is to see if Nivolumab or Nivolumab in combination with Azacitidine given to patients before and after surgery is safe and to see if patients are able to successfully complete the treatment before their surgery without any extended delays in treatment.

  Objective:

  Phase I Objective: investigate the safety and feasibility of Nivolumab in combination with Azacitidine given neo-adjuvantly and adjuvantly in subjects with recurrent, resectable osteosarcoma. Feasibility will be evaluated as the successful completion of preoperative treatment and proceeding to surgery without any extended treatment related delays defined as >50 days from preplanned Day 0 in this context. Phase II Primary Objective: Efficacy (EFS): determine if the combination of Azacitidine and Nivolumab, administered both neo-adjuvantly and adjuvantly, improve event free survival to 40% compared to the 20% 12-month historical control used for recurrent osteosarcoma studies in the Childrens Oncology Group. Phase II Secondary Objective: Efficacy (OS): assess overall survival in patients with recurrent, resectable osteosarcoma patients receiving neoadjuvant therapy. Exploratory Objectives: To determine changes in expression of selected immune markers compared to baseline, in the blood and metastatic tumor tissue from patients receiving neoadjuvant therapy; to determine changes in the quality and quantity of tumor infiltrating lymphocytes; and to compare findings in tumor specimens from treated patients to findings in an existing cohort of untreated patients on a companion tissue collection protocol. To explore the association between Nivolumab +/] Azacitidine exposure and selected pharmaco]dynamic markers in the peripheral blood and in the tumor microenvironment.

• Treatments

  Therapies:

  Chemotherapy (NOS); Immunotherapy

  Medications:

  BMS-936558 (Nivolumab); Nivolumab (Opdivo); azacitidine (5-azacitidine)

• Inclusion Criteria

  • Participants must be ≤ 39 years of age > Participants must have had a histologic diagnosis of osteosarcoma at original diagnosis > Participants 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 participant ineligible for this study. The participants treating team must consider the participants disease to be resectable and the participant 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. Participants 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).
  • Participants must have a performance status corresponding to ECOG scores of 0, 1 or 2, using the Karnofsky scale for participants ≥ 16 years of age and the Lansky scale for participants > Prior Therapy: Participants must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to the start of protocol therapy Participants cannot have received myelosuppressive therapy within two weeks of starting treatment (4 weeks if prior therapy was with a nitrosurea) Participant 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 RT (small port) or ≥ 6 weeks for treatment that incudes substantial bone marrow radiation from the start of protocol therapy
  • Participants must have normal organ and marrow function within 7 days of starting protocol therapy as defined below per protocol.
  • All participants 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 b. 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 Nivoluamb. One method should be highly effective and the other method being either highly effective or less effective as listed per protocol. > Concomitant Medications: Participants receiving the following are not eligible: Corticosteroids or other immunosuppressive medications, Participants who are currently receiving other investigational agents or other anti-cancer therapy, Participants 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
  • Intercurrent Illnesses: Participants with uncontrolled intercurrent illness including, but not limited to: (a) Ongoing or active infection (b) Symptomatic congestive heart failure (c) Unstable angina pectoris (d) Cardiac arrhythmia (e) Psychiatric illness/social situations that would limit compliance with study requirements
  • Autoimmune disorders: Participants with a history of any Grade autoimmune disorder are not eligible.
  • Participants 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. > Participants who are considered unable to comply with the safety monitoring requirements of the study are not eligible. > Participants with known HIV or hepatitis B or C are excluded. > Participants who have received prior solid organ transplantation are not eligible. > Participants who have received prior anti-PD-1 directed therapy (mAb or small molecule) are not eligible

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