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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03465592
Recruitment Status : Recruiting
First Posted : March 14, 2018
Last Update Posted : January 14, 2020
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Sarcoma Solid Tumor, Adult Solid Tumor, Childhood Drug: Nivolumab Phase 1 Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 39 participants
Intervention Model: Single Group Assignment
Intervention Model Description:

Nivolumab will be infused intravenously (IV, in a vein) over 60 minutes every 14 days for a maximum of 24 doses (12 cycles). A cycle is considered 28 days. Participants may continue to receive Nivolumab unless they develop serious side effects or the tumor worsens.

There are two parts to this study. The first part, Part A, is for patients who have relapsed or have progressive disease after their BMT. Part A will enroll approximately 3-9 patients. The second part, Part B, is for patients who have not yet relapsed or progressed after BMT. Part A will be completed to prove that administering the experimental drug after BMT is safe and part B will begin once part A is completed

Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 1, 2018
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : March 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Nivolumab
Nivolumab 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.
Drug: Nivolumab
Administered IV
Other Names:
  • BMS-936558
  • MDX1106
  • ONO-4538




Primary Outcome Measures :
  1. Adverse events attributed to Nivolumab for patients enrolled in this study [ Time Frame: 4 years ]
    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 :
  1. Overall survival [ Time Frame: 4 years ]
    Overall survival for patients enrolled in this study



Information from the National Library of Medicine

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Ages Eligible for Study:   12 Months to 40 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03465592


Contacts
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Contact: Megan Petrycki, RN 410-955-0432 mpetryc1@jhmi.edu
Contact: Tammy Scott, RN 410-614-5990 scottta@jhmi.edu

Locations
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United States, Maryland
Johns Hopkins Hospital Recruiting
Baltimore, Maryland, United States, 21287
Contact: Nicolas Llosa, MD    410-502-4997    nllosa1@jhmi.edu   
Contact: Megan Petrycki, RN    410-955-0432    mpetryc1@jhmi.edu   
Principal Investigator: Nicolas Llosa, MD         
United States, New York
Albert Einstein College of Medicine, Children's Hospital at Montefiore Not yet recruiting
Bronx, New York, United States, 10467
Contact: David Loeb, MD    718-839-7497    david.loeb@einstein.yu.edu   
Principal Investigator: David Loeb, MD         
New York Medical Center/ Maria Fareri Children's Hospital Not yet recruiting
Valhalla, New York, United States, 10595
Contact: Allyson Flower, MD    914-594-2131    Allyson_Flower@nymc.edu   
Principal Investigator: Allyson Flower, MD         
Sub-Investigator: Mitchell Cario, MD         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Bristol-Myers Squibb
Investigators
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Principal Investigator: Nicolas Llosa, MD Johns Hopkins University

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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT03465592    
Other Study ID Numbers: J17124
IRB00143746 ( Other Identifier: JHMIRB )
First Posted: March 14, 2018    Key Record Dates
Last Update Posted: January 14, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Sarcoma
Neoplasms
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents