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

Primary Purpose

Sarcoma, Solid Tumor, Adult, Solid Tumor, Childhood

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Nivolumab
Sponsored by
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sarcoma

Eligibility Criteria

12 Months - 40 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Johns Hopkins All Children's Hospital
  • Johns Hopkins HospitalRecruiting
  • Albert Einstein College of Medicine, Children's Hospital at MontefioreRecruiting
  • New York Medical Center/ Maria Fareri Children's HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Nivolumab

Arm Description

Adults: 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks. Children and Adolescents weighing 40 kg or more: 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks. Children and Adolescents weighing less than 40 kg: 3 mg/kg IV over 30 minutes every 2 weeks.A maximum of 24 cycles will be given on study.

Outcomes

Primary Outcome Measures

Adverse events attributed to Nivolumab for patients enrolled in this study
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

Overall survival
Overall survival for patients enrolled in this study

Full Information

First Posted
March 2, 2018
Last Updated
February 8, 2023
Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT03465592
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 1, 2018 (Actual)
Primary Completion Date
January 2027 (Anticipated)
Study Completion Date
March 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
Bristol-Myers Squibb

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sarcoma, Solid Tumor, Adult, Solid Tumor, Childhood

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Adults: 240 mg IV (in a vein) over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks. Children and Adolescents weighing 40 kg or more: 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks. Children and Adolescents weighing less than 40 kg: 3 mg/kg IV over 30 minutes every 2 weeks. A maximum of 24 cycles will be given on study. Participants may continue to receive Nivolumab unless they develop serious side effects or the tumor worsens. There were two parts to this study. The first part, Part A, was for patients who have relapsed or have progressive disease after their BMT. Part A is now closed. The second part, Part B, is for patients who have not yet relapsed or progressed after BMT.
Masking
None (Open Label)
Allocation
N/A
Enrollment
39 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Nivolumab
Arm Type
Experimental
Arm Description
Adults: 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks. Children and Adolescents weighing 40 kg or more: 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks. Children and Adolescents weighing less than 40 kg: 3 mg/kg IV over 30 minutes every 2 weeks.A maximum of 24 cycles will be given on study.
Intervention Type
Drug
Intervention Name(s)
Nivolumab
Other Intervention Name(s)
BMS-936558, MDX1106, ONO-4538
Intervention Description
Administered IV
Primary Outcome Measure Information:
Title
Adverse events attributed to Nivolumab for patients enrolled in this study
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).
Time Frame
4 years
Secondary Outcome Measure Information:
Title
Overall survival
Description
Overall survival for patients enrolled in this study
Time Frame
4 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Months
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must be ≥ 12 months and ≤ 50 years of age at the time of study enrollment. Patients with histologically confirmed solid tumors with an estimated poor long term survival. Performance Level: Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 60 for patients ≤16 years of age. Patients must be post RIC haploidentical BMT. Patients must have fully recovered from the acute toxic effects of prior BMT. Concomitant radiation therapy can be administered in the setting of this trial. 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. Organ Function Requirements: I. Adequate Hematologic Parameters: For patients with solid tumors without known bone marrow involvement: Peripheral absolute neutrophil count (ANC) ≥ 500/mm3 Platelet count ≥ 50,000/mm3 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: Creatinine clearance or radioisotope Glomerular filtration rate (GFR) ≥ 70ml/min/1.73 m2 or 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: Bilirubin (sum of conjugated + unconjugated) ≤1.5 x upper limit of normal (ULN) for age Serum glutamic pyruvic transaminase (SGPT) (ALT) ≤110 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L. 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: 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. Inhaled or topical steroids and adrenal replacement steroid doses are permitted in the absence of active auto- or allo-immune disease 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. Infection: Patients who have an uncontrolled infection. 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. 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. Allergies and Adverse Drug Reaction History of allergy to study drug components. History of severe hypersensitivity reaction to any monoclonal antibody. 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Megan Petrycki, RN
Phone
410-955-0432
Email
mpetryc1@jhmi.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Tammy Scott, RN
Phone
410-614-5990
Email
scottta@jhmi.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nicolas Llosa, MD
Organizational Affiliation
Johns Hopkins University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Johns Hopkins All Children's Hospital
City
Saint Petersburg
State/Province
Florida
ZIP/Postal Code
33701
Country
United States
Individual Site Status
Active, not recruiting
Facility Name
Johns Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicolas Llosa, MD
Phone
410-502-4997
Email
nllosa1@jhmi.edu
First Name & Middle Initial & Last Name & Degree
Megan Petrycki, RN
Phone
410-955-0432
Email
mpetryc1@jhmi.edu
First Name & Middle Initial & Last Name & Degree
Nicolas Llosa, MD
Facility Name
Albert Einstein College of Medicine, Children's Hospital at Montefiore
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
David Loeb, MD
Phone
718-839-7497
Email
david.loeb@einstein.yu.edu
First Name & Middle Initial & Last Name & Degree
David Loeb, MD
Facility Name
New York Medical Center/ Maria Fareri Children's Hospital
City
Valhalla
State/Province
New York
ZIP/Postal Code
10595
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Allyson Flower, MD
Phone
914-594-2131
Email
Allyson_Flower@nymc.edu
First Name & Middle Initial & Last Name & Degree
Allyson Flower, MD
First Name & Middle Initial & Last Name & Degree
Mitchell Cario, MD

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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