Neoadjuvant Nivolumab Plus Ipilimumab for Newly Diagnosed Malignant Peripheral Nerve Sheath Tumor

The purpose of the study is to evaluate safety and feasibility of neoadjuvant nivolumab plus ipilimumab prior to standard therapy (surgery, chemotherapy or radiation therapy) in patients with Neurofibromatosis Type 1 (NF1) and newly diagnosed pre-malignant and malignant peripheral nerve sheath tumors (MPNST) for whom surgery for resection of tumor is indicated.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

18

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Recruiting
        • Johns Hopkins Medical Institution
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

12 years to 100 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Histologically confirmed diagnosis of atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP), low grade malignant peripheral nerve sheath tumor (MPNST) or high grade MPNST in accordance with the Miettinen et al diagnostic criteria via biopsy
  • Plexiform neurofibroma or other tumors such as optic pathway glioma, other low-grade glioma or other neoplasm in addition to the ANNUBP, low grade MPNST or high grade MPNST that is stable (has not required treatment in the last 12 months and is not anticipated to need treatment in the next 12 months)
  • Measureable disease by RECIST criteria in at least one site.
  • Karnofsky Performance Scale ≥ 60%
  • No contraindications for Nivolumab or Ipilimumab
  • Normal organ and marrow function on routine laboratory tests
  • Evidence of post-menopausal status or negative urinary/serum pregnancy test for female pre-menopausal subjects. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause
  • Ability to understand and willingness of sign consent form
  • Willingness to comply with the protocol for the duration of the study

Exclusion Criteria:

  • Chemotherapy or other investigational agent for the current episode of newly diagnosed atypical neurofibroma or MPNST
  • Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL-2 antibody
  • Known allergy to compounds of similar chemical or biologic composition to Nivolumab or Ipilimumab
  • Pregnant or breastfeeding women
  • Known history of Human Immunodeficiency Virus
  • Active infection requiring therapy, including known positive tests for Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA)
  • Active autoimmune disease, history of autoimmune disease or history of syndrome that required systemic steroids or immunosuppressive medications, e.g. organ, tissue, or allogenic hematopoietic stem cell transplant (HSCT) recipients. Exceptions include those with resolved childhood asthma/atopy. Subjects with asthma who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study. Subjects are also permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
  • A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  • Use of any vaccines against infectious diseases (e.g. varicella, influenza, etc.) up to 4 weeks (28 days) before receiving nivolumab and ipilimumab.
  • Prisoners or subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness
  • Prior radiation doses equivalent to, or greater than, 8000 centigray (cGy) to the target lesions at 200 cGy fractions at any time point
  • Any radiation to the the target lesions within 6 months of enrollment
  • Other concurrent severe and/or uncontrolled medical disease, which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration, congestive heart failure, etc.)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Immunotherapy with Nivolumab and Ipilimumab
Nivolumab 4.5 mg/kg every 3 weeks (Q3W) x 2 Ipilimumab 1 mg/kg Q3W x 2 Nivolumab monotherapy 4.5mg/kg Q3W concurrent with standard therapy Nivolumab monotherapy should be held for at least 2 weeks before and 2 weeks after surgery
Nivolumab 4.5 mg/kg Q3W x 2
Ipilimumab 1 mg/kg Q3W x 2

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum Tolerated Dose (MTD) as determined by number of participants with dose limiting toxicities (DLT)
Time Frame: Up to 2 years
Maximum tolerated dose will be determined by the maximum dose at which the least number of participants experience dose-limiting toxicity. The dose limiting toxicity is defined using the Common Terminology Criteria for Adverse Events (CTCAE).
Up to 2 years
Safety of combination nivolumab and ipilimumab as assessed by number of participants who experience adverse events
Time Frame: Up to 2 years
Number of participants who experience grade 1 or higher adverse events, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).
Up to 2 years
Feasibility of combination nivolumab and ipilimumab as assessed by number of participants who experience adverse events
Time Frame: Up to 2 years
Number of participants who experience grade 1 or higher adverse events, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).
Up to 2 years
Feasibility of combination nivolumab and ipilimumab as assessed by number of participants who achieve a response
Time Frame: Up to 2 years
Number of participants who achieve a response (improved progression free survival).
Up to 2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety as assessed by number of treatment-emergent adverse events in patients on combination nivolumab and ipilimumab with NF1, standard low, or high grade MPNST therapy
Time Frame: Up to 2 years
Number of participants who experience grade 1 or higher adverse events, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0)
Up to 2 years
Objective response rate (ORR)
Time Frame: Up to 2 years.
Proportion of participants with measurable disease at baseline and have been re-evaluated after at least 1 cycle of therapy with observed reduction in tumor burden as defined by RECIST and iRECIST criteria after 2 doses of nivolumab and ipilimumab.
Up to 2 years.
Change in pain levels in relation to target tumor as assessed by the Numeric Rating Scale
Time Frame: Baseline, Week 6, 4 months, and 8 months
Evaluate pain levels in participants related to target tumor via the Numeric Rating Scale. Assessment to be performed at baseline, Week 6, 4 months, and 8 months via numeric grading scale (0 through 10) recorded by participant via survey in order to determine an improvement or worsening of pain throughout treatment. Lower scores indicate no pain or decreased levels of pain while higher score indicate increased levels of pain.
Baseline, Week 6, 4 months, and 8 months
Change in pain levels in relation to target tumor as assessed by the Pain Interference Index
Time Frame: Baseline, Week 6, 4 months, and 8 months
Evaluate pain in participants related to target tumor via the Pain Interference Index (6-24 years). Assessment to be performed at baseline, Week 6, 4 months, and 8 months via numeric grading scale (0 through 6) recorded by participant via survey In order to determine an improvement or worsening of pain throughout treatment. Lower scores indicate no interference or decreased levels of interference in every day life while higher scores indicate increased interference in ever day life.
Baseline, Week 6, 4 months, and 8 months
Change in pain levels in relation to target tumor as assessed by the Patient-Reported Outcome Measurement Information System
Time Frame: Baseline, Week 6, 4 months, and 8 months
Evaluate pain in participants related to target tumor via the Patient-Reported Outcome Measurement Information System (PROMIS). Assessment to be performed at at baseline, Week 6, 4 months, and 8 months via numeric grading scale (1 through 5) recorded by participant via survey in order to determine an improvement or worsening of pain throughout treatment. Higher scores indicate no to low difficulty in mobility while lower scores indicate increased difficulty or inability in mobility.
Baseline, Week 6, 4 months, and 8 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective response rate (ORR)
Time Frame: At 4 months post intervention
Proportion of participants who had measurable disease at baseline and have been re-evaluated after at least 1 cycle of therapy with observed reduction in tumor burden as defined by RECIST and iRECIST criteria at 4 months.
At 4 months post intervention
Progression Free Survival
Time Frame: Up to 2 years
Proportion of participants who achieve progression free survival post treatment
Up to 2 years
Tumor Response as assessed by immune markers in tumor samples
Time Frame: Up to 2 years
Analyses may include phosphorylated protines of signaling pathways and phenotypes of infiltrating immune cell populations including but not limited to CD3, CD4, FoxP3, CD25, CD8, CD45, CD11b, CD163, CD206, CD68, CD56, CD20, CD45RO and granzyme B. Pathologists will assign an intratumoral and peritumoral immune cell infiltrate grade of 0 through 3. Immunohistochemical analysis of exploratory markers will focus on areas including but not limited to: B7 family ligands PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, B7-H4, as well as inhibitory receptors on lymphocytes, including PD-1, 2B4, LAG-3, BTLA, Tim-3, CTLA-4, and TIGIT.
Up to 2 years
Pharmacodynamic activity as assessed by markers in blood samples
Time Frame: Up to 2 years
T cell subsets (including CD4, CD8, and Treg with CD25 and Foxp3) will be analyzed as well as co-stimulatory and co-inhibitory molecule expression and markers for T cell activation state (e.g., CD25, HLADR, CD45RO, LAP, PD-1, PD-L1, LAG-3, ICOS, OX40, 41BB). B cells (CD19, CD20, PD-1, PD-L1, PD-L2, ICOSL), dendritic cells and macrophages (CD68, CD83, CD1a, PD-L1, PD-L2, 4-1BB, 4-1BBL, ICOSL, HLA-DR) and natural killer cells (CD56) will be enumerated and characterized. Myeloid derived suppressor cells (MDSCs) will be enumerated by staining for CD14, CD11b, and HLADR expression.
Up to 2 years
CD3 Cell Count
Time Frame: Up to 1 year
CD3 cell count in cells/mm^3
Up to 1 year
CD4 Cell Count
Time Frame: Up to 1 year
CD4 cell count in cells/mm^3
Up to 1 year
FoxP3 Cell Count
Time Frame: Up to 1 year
FoxP3 cell count in cells/mm^3
Up to 1 year
CD25 Cell Count
Time Frame: Up to 1 year
CD25 cell count in cells/mm^3
Up to 1 year
CD8 Cell Count
Time Frame: Up to 1 year
CD8 cell count in cells/mm^3
Up to 1 year
CD45 Cell Count
Time Frame: Up to 1 year
CD45 cell count in cells/mm^3
Up to 1 year
CD11b Cell Count
Time Frame: Up to 1 year
CD11b cell count in cells/mm^3
Up to 1 year
CD163 Cell Count
Time Frame: Up to 1 year
CD163 cell count in cells/mm^3
Up to 1 year
CD206 Cell Count
Time Frame: Up to 1 year
CD206 cell count in cells/mm^3
Up to 1 year
CD68 Cell Count
Time Frame: Up to 1 year
CD68 cell count in cells/mm^3
Up to 1 year
CD56 Cell Count
Time Frame: Up to 1 year
CD56 cell count in cells/mm^3
Up to 1 year
CD20 Cell Count
Time Frame: Up to 1 year
CD20 cell count in cells/mm^3
Up to 1 year
CD45RO Cell Count
Time Frame: Up to 1 year
CD45RO cell count in cells/mm^3
Up to 1 year
Granzyme B Cell Count
Time Frame: Up to 1 year
Granzyme B cell count in cells/mm^3
Up to 1 year
PD-L1 Cell Count
Time Frame: Up to 1 year
PD-L1 cell count in cells/mm^3
Up to 1 year
PD-L2 Cell Count
Time Frame: Up to 1 year
PD-L2 cell count in cells/mm^3
Up to 1 year
B7-H3 Cell Count
Time Frame: Up to 1 year
B7-H3 cell count in cells/mm^3
Up to 1 year
B7-H4 Cell Count
Time Frame: Up to 1 year
B7-H4 cell count in cells/mm^3
Up to 1 year
PD-1 Cell Count
Time Frame: Up to 1 year
PD-1 cell count in cells/mm^3
Up to 1 year
2B4 Cell Count
Time Frame: Up to 1 year
2B4 cell count in cells/mm^3
Up to 1 year
LAG-3 Cell Count
Time Frame: Up to 1 year
LAG-3 cell count in cells/mm^3
Up to 1 year
BTLA Cell Count
Time Frame: Up to 1 year
BTLA cell count in cells/mm^3
Up to 1 year
Tim-3 Cell Count
Time Frame: Up to 1 year
Tim-3 cell count in cells/mm^3
Up to 1 year
CTLA-4 Cell Count
Time Frame: Up to 1 year
CTLA-4 cell count in cells/mm^3
Up to 1 year
TIGIT Cell Count
Time Frame: Up to 1 year
TIGIT cell count in cells/mm^3
Up to 1 year
HLA-DR Cell Count
Time Frame: Up to 1 year
HLA-DR cell count in cells/mm^3
Up to 1 year
LAP Cell Count
Time Frame: Up to 1 year
LAP cell count in cells/mm^3
Up to 1 year
CD14 Cell Count
Time Frame: Up to 1 year
CD14 cell count in cells/mm^3
Up to 1 year
ICOS Cell Count
Time Frame: Up to 1 year
ICOS cell count in cells/mm^3
Up to 1 year
OX40 Cell Count
Time Frame: Up to 1 year
OX40 cell count in cells/mm^3
Up to 1 year
4-1BB Cell Count
Time Frame: Up to 1 year
4-1BB cell count in cells/mm^3
Up to 1 year
4-1BBL Cell Count
Time Frame: Up to 1 year
4-1BBL cell count in cells/mm^3
Up to 1 year
ICOSL Cell Count
Time Frame: Up to 1 year
ICOSL cell count in cells/mm^3
Up to 1 year
CD19 Cell Count
Time Frame: Up to 1 year
CD19 cell count in cells/mm^3
Up to 1 year
CD1a Cell Count
Time Frame: Up to 1 year
CD1a cell count in cells/mm^3
Up to 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Collaborators

Investigators

  • Principal Investigator: Jaishri Blakeley, MD, Johns Hopkins University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 8, 2021

Primary Completion (Estimated)

June 1, 2025

Study Completion (Estimated)

August 1, 2026

Study Registration Dates

First Submitted

July 7, 2020

First Submitted That Met QC Criteria

July 7, 2020

First Posted (Actual)

July 10, 2020

Study Record Updates

Last Update Posted (Actual)

July 3, 2023

Last Update Submitted That Met QC Criteria

June 29, 2023

Last Verified

June 1, 2023

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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