Clinical Trials /

Trial of Nivolumab Following Partially Human Leukocyte Antigen (HLA) Mismatched BMT in Children & Adults With Sarcoma

NCT03465592

Description:

This research is being done to find out if an investigational drug, Nivolumab, can be safely administered after a "half-matched" (haplo) bone marrow transplant (BMT), and if the investigational drug will help to prevent or delay relapse or progression of sarcomas. In this study investigators will also be trying to learn more about how the investigational drug changes blood and/or tumors. Participants are eligible for this trial if they have recently undergone a "half-matched" (haplo) bone marrow transplant and have either relapsed or are at high risk to relapse.

Related Conditions:
  • Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trial of Nivolumab Following Partially Human Leukocyte Antigen (HLA) Mismatched BMT in Children & Adults With Sarcoma
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: J17124
  • SECONDARY ID: IRB00143746
  • NCT ID: NCT03465592

Conditions

  • Sarcoma
  • Solid Tumor, Adult
  • Solid Tumor, Childhood

Interventions

DrugSynonymsArms
NivolumabBMS-936558, MDX1106, ONO-4538Nivolumab

Purpose

This research is being done to find out if an investigational drug, Nivolumab, can be safely administered after a "half-matched" (haplo) bone marrow transplant (BMT), and if the investigational drug will help to prevent or delay relapse or progression of sarcomas. In this study investigators will also be trying to learn more about how the investigational drug changes blood and/or tumors. Participants are eligible for this trial if they have recently undergone a "half-matched" (haplo) bone marrow transplant and have either relapsed or are at high risk to relapse.

Detailed Description

      High risk, recurrent, or refractory solid tumors in pediatric, adolescent and young adult
      (AYA) patients have an extremely poor prognosis despite current intensive treatment regimens.
      Johns Hopkins piloted an allogeneic bone marrow transplant (alloBMT) platform using a reduced
      intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for
      this population of pediatric and AYA solid tumor patients.With this strategy, investigators
      demonstrated that RIC haploBMT with post-transplant cyclophosphamide (PTCy) is feasible and
      has acceptable toxicities in patients with incurable pediatric and AYA solid tumors; thus,
      this approach serves as a platform for post-transplant strategies to prevent relapse and
      optimize progression free survival. In this trial, the central hypothesis is that the
      efficacy of alloBMT for high risk solid tumors can be improved by developing methods to
      augment donor T cell responses against antigens selectively or uniquely expressed by tumor
      tissue.

      Investigators aim to demonstrated that Programmed death-ligand 1 (PD-1) blockade with
      nivolumab will be safe and well tolerated after RIC haplo BMT, initially in a relapsed
      population (Part A) and ultimately when given pre-emptively (Part B).
    

Trial Arms

NameTypeDescriptionInterventions
NivolumabExperimentalNivolumab of 3 mg/kg IV will be infused over 60 minutes every 14 days, for a maximum of 24 cycles. A cycle will be considered 28 days. Participants may continue to receive Nivolumab unless they develop serious side effects or the tumor worsens.
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must be ≥ 12 months and ≤ 40 years of age at the time of study enrollment.

          2. Patients with histologically confirmed sarcomas with an estimated <10% chance of 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. Palliative (limited-field) radiation therapy is permitted, but only for pain control
             to sites of bone disease present at baseline and only if all of the following criteria
             are met:

               1. Repeat imaging (mandatory) demonstrates no new sites of bone metastases.

               2. The lesion being considered for palliative radiation is not a target lesion.

               3. The case is discussed with the BMS medical monitor, and the medical monitor
                  agrees that the conditions required to receive palliative radiation are met.

          7. For Part A, patients must have evidence of disease progression or relapse based on
             standard restaging scans (RECIST criteria) and/or biopsy.

          8. Subjects must consent to allow for a baseline tumor biopsy from a tumor site that is
             NOT the only site of measurable disease. If a biopsy is not feasible, then archival
             tumor material must be made available.

          9. Organ Function Requirements:

        I. Adequate Hematologic Parameters:

          1. For patients with solid tumors without known bone marrow involvement:

               -  Peripheral absolute neutrophil count (ANC) ≥ 750/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.

        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, including history of
             hepatitis.

          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. Subjects with brain metastasis are excluded from this study. Subjects with brain
             metastases are eligible if these have been treated and there is no magnetic resonance
             imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete
             and within 28 days prior to first dose of study drug administration.

          8. Treatment with any chemotherapy, radiation therapy, biologics for cancer, or
             investigational therapy within 28 days of first administration of study treatment
             (subjects with prior cytotoxic or investigational products < 4 weeks prior to
             treatment might be eligible after discussion between investigator and sponsor, if
             toxicities from the prior treatment have been resolved to Common Terminology Criteria
             for Adverse Events (CTCAE) grade 1 level).

          9. Physical and Laboratory Test Findings:

               1. Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBV sAg)
                  test or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid
                  (RNA) or HCV antibody test indicating acute or chronic infection.

               2. Subjects must not be dependent on continuous supplemental oxygen use.

         10. Allergies and Adverse Drug Reaction

               1. History of allergy to study drug components.

               2. History of severe hypersensitivity reaction to any monoclonal antibody.

         11. 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.
      
Maximum Eligible Age:40 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Adverse events attributed to Nivolumab for patients enrolled in this study
Time Frame:4 years
Safety Issue:
Description:Cumulative adverse events from Nivolumab therapy administered after reduced intensity conditioning (RIC) haploidentical bone marrow transplant (haploBMT) in children and young adults with high risk sarcomas at the time of relapse (part A) or pre-emptively (part B).

Secondary Outcome Measures

Measure:Overall survival
Time Frame:4 years
Safety Issue:
Description:Overall survival for patients enrolled in this study

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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