Using Nivolumab after Half-Matched Bone Marrow Transplant for Sarcoma

Single-arm, Open-label, Phase 1b/2 Trial of Nivolumab Therapy Following Partially HLA Mismatched (Haploidentical) Bone Marrow Transplant in Children and Young Adults With High Risk, Recurrent or Refractory Sarcomas

This study is testing if a new drug called Nivolumab can help prevent or delay the return of high-risk sarcomas in children and adults after they receive a special type of bone marrow transplant.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 39 (estimated)
• Ages: 12 Months to 40 Years
• Sex: All
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Academic / other)
• Drugs / interventions: Nivolumab, radiation, cyclophosphamide
• Locations: 4 sites (St. Petersburg, Florida and 3 other locations)
• Trial ID: NCT03465592 on ClinicalTrials.gov

What this trial studies

This trial investigates the safety and efficacy of Nivolumab, an investigational drug, administered after a haploidentical bone marrow transplant in patients with high-risk sarcomas. The study aims to determine if Nivolumab can prevent or delay relapse in patients who have recently undergone this type of transplant. Participants will include children and adults who have either relapsed or are at high risk of relapse. The trial will also explore how Nivolumab affects blood and tumor responses post-transplant.

Who should consider this trial

Good fit: Ideal candidates are individuals aged 12 months to 50 years who have undergone a haploidentical bone marrow transplant and have high-risk solid tumors.

Not a fit: Patients with solid tumors that are not high-risk or those who have not undergone a haploidentical bone marrow transplant may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could significantly improve survival rates and quality of life for patients with high-risk sarcomas.

How similar studies have performed: Previous studies have shown promise with similar approaches using Nivolumab in other cancer types, but this specific application in haploidentical transplant settings is novel.

Eligibility criteria

Inclusion Criteria:

1. Patients must be ≥ 12 months and ≤ 50 years of age at the time of study enrollment.
2. Patients with histologically confirmed solid tumors with an estimated poor long term survival.
3. Performance Level: Karnofsky ≥ 50% for patients \> 16 years of age and Lansky ≥ 60 for patients ≤16 years of age.
4. Patients must be post RIC haploidentical BMT.
5. Patients must have fully recovered from the acute toxic effects of prior BMT.
6. Concomitant radiation therapy can be administered in the setting of this trial.
7. Subjects must consent to allow for a baseline tumor biopsy. If a biopsy is not feasible, then archival tumor material must be made available. Tumor biopsies to be taken (if a subject's tumor is thought to be reasonably safe and easy to biopsy) at baseline (any time prior to the first dose after eligibility is met) and at Cycle 2 (4-6 cores per time point) or when lesions are visualized on physical examination or imaging studies in the case of no identifiable masses at cycle 2. Additional optional biopsies may be obtained later in the course of study treatment. The proposed investigation is considered a non-significant risk (NSR). A significant risk procedure is generally considered to be one for which the procedure-associated absolute risk of mortality or major morbidity, in the patient's clinical setting and at the institution completing the procedure, is 2% or higher. Diagnostic Tissue Samples Tissue, fluid, or blood may be collected from standard of care procedures used to treat or diagnose immune related toxicities/GVHD.
8. Organ Function Requirements:

   I. Adequate Hematologic Parameters:
   1. For patients with solid tumors without known bone marrow involvement:

      * Peripheral absolute neutrophil count (ANC) ≥ 500/mm3
      * Platelet count ≥ 50,000/mm3
   2. Patients with known bone marrow metastatic disease will be eligible for study without the above criteria. They may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions. These patients will not be evaluable for hematologic toxicity.

   II. Adequate Renal Function Defined as:
   1. Creatinine clearance or radioisotope Glomerular filtration rate (GFR) ≥ 70ml/min/1.73 m2 or
   2. A serum creatinine based on age/gender as follows:

      * Age 1 to \<2 years, Male: 0.6 and Female: 0.6
      * Age 2 to \<6 years, Male: 0.8 and Female: 0.8
      * Age 6 to \<10 years, Male: 1 and Female:1
      * Age 10 to \<13 years, Male: 1.2 and Female 1.2
      * Age 13 to \<16 years, Male: 1.5 and Female 1.4
      * Age ≥ 16 years, Male: 1.7 and Female 1.4

   III. Adequate Liver Function Defined as:
   1. Bilirubin (sum of conjugated + unconjugated) ≤1.5 x upper limit of normal (ULN) for age
   2. Serum glutamic pyruvic transaminase (SGPT) (ALT) ≤110 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.
9. Patients must have been registered on protocol J12106 "A Phase II Trial of Reduced Intensity Conditioning and HLA-matched or Partially HLA-mismatched (HLA-haploidentical) Related Donor Bone Marrow Transplant for High-risk Solid Tumors" before enrolling on this study.Patient may be screened prior to Day +120 but first dose of study drug must be given on or after Day +120.

Exclusion Criteria:

1. GVHD: any history of Stage 4 skin GVHD or Stage 3 gut/liver GVHD (a.k.a. overall Grade III/IV GVHD) or any severe chronic GVHD. Any person with ≤ Grade II GVHD must be off systemic immunosuppressive therapy for at least 2 weeks prior to receiving Nivolumab therapy.
2. Inhaled or topical steroids and adrenal replacement steroid doses are permitted in the absence of active auto- or allo-immune disease
3. BMT-related toxicities: patients who developed idiopathic pneumonia syndrome (IPS) or veno-occlusive hepatic disease (VOD) must be off systemic immunosuppression and/or defibrotide for at least 14 days to be eligible.
4. Infection: Patients who have an uncontrolled infection.
5. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
6. Has active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
7. Allergies and Adverse Drug Reaction

   1. History of allergy to study drug components.
   2. History of severe hypersensitivity reaction to any monoclonal antibody.
8. Pregnancy or Breast Feeding: Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of study treatment with nivolumab and 5 months after the last dose of study treatment {i.e., 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo approximately five half-lives. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of study treatment with nivolumab and 7 months after the last dose of study treatment {i.e., 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo approximately five half-lives.

Where this trial is running

St. Petersburg, Florida and 3 other locations

• Johns Hopkins All Children's Hospital — St. Petersburg, Florida, United States (Active_not_recruiting)
• Johns Hopkins Hospital — Baltimore, Maryland, United States (Recruiting)
• Albert Einstein College of Medicine, Children's Hospital at Montefiore — The Bronx, New York, United States (Recruiting)
• New York Medical Center/ Maria Fareri Children's Hospital — Valhalla, New York, United States (Recruiting)

Study contacts

• Principal investigator: Nicolas Llosa, MD — Johns Hopkins University
• Study coordinator: Megan Petrycki, RN

Conditions Sarcoma; Solid Tumor, Adult; Solid Tumor, Childhood