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NCT04465643 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE1
Status at capture
COMPLETED
Registry last update
2026-07-10

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part
eligibility Criteria
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.)
healthy Volunteers
false
maximum Age
100 Years
minimum Age
12 Years
sex
ALL
std Ages
  1. CHILD
  2. ADULT
  3. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    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
    intervention Names
    1. Drug: Nivolumab
    2. Drug: Ipilimumab
    label
    Immunotherapy with Nivolumab and Ipilimumab
    type
    OTHER
interventions
  1. arm Group Labels
    1. Immunotherapy with Nivolumab and Ipilimumab
    description
    Nivolumab 4.5 mg/kg Q3W x 2
    name
    Nivolumab
    type
    DRUG
  2. arm Group Labels
    1. Immunotherapy with Nivolumab and Ipilimumab
    description
    Ipilimumab 1 mg/kg Q3W x 2
    name
    Ipilimumab
    type
    DRUG
Study design
allocation
NA
intervention Model
SINGLE_GROUP
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
13
type
ACTUAL
Registered outcome plans (not posted results)
other Outcomes
  1. description
    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.
    measure
    Objective response rate (ORR)
    time Frame
    At 4 months post intervention
  2. description
    Proportion of participants who achieve progression free survival post treatment
    measure
    Progression Free Survival
    time Frame
    Up to 2 years
  3. description
    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.
    measure
    Tumor Response as assessed by immune markers in tumor samples
    time Frame
    Up to 2 years
  4. description
    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.
    measure
    Pharmacodynamic activity as assessed by markers in blood samples
    time Frame
    Up to 2 years
  5. description
    CD3 cell count in cells/mm\^3
    measure
    CD3 Cell Count
    time Frame
    Up to 1 year
  6. description
    CD4 cell count in cells/mm\^3
    measure
    CD4 Cell Count
    time Frame
    Up to 1 year
  7. description
    FoxP3 cell count in cells/mm\^3
    measure
    FoxP3 Cell Count
    time Frame
    Up to 1 year
  8. description
    CD25 cell count in cells/mm\^3
    measure
    CD25 Cell Count
    time Frame
    Up to 1 year
  9. description
    CD8 cell count in cells/mm\^3
    measure
    CD8 Cell Count
    time Frame
    Up to 1 year
  10. description
    CD45 cell count in cells/mm\^3
    measure
    CD45 Cell Count
    time Frame
    Up to 1 year
  11. description
    CD11b cell count in cells/mm\^3
    measure
    CD11b Cell Count
    time Frame
    Up to 1 year
  12. description
    CD163 cell count in cells/mm\^3
    measure
    CD163 Cell Count
    time Frame
    Up to 1 year
primary Outcomes
  1. description
    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).
    measure
    Safety of combination nivolumab and ipilimumab as assessed by number of participants who experience adverse events
    time Frame
    Up to 2 years
  2. description
    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).
    measure
    Feasibility of combination nivolumab and ipilimumab as assessed by number of participants who experience adverse events
    time Frame
    Up to 2 years
  3. description
    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).
    measure
    Maximum Tolerated Dose (MTD) as determined by number of participants with dose limiting toxicities (DLT)
    time Frame
    Up to 2 years
  4. description
    Number of participants who start standard of care treatment within 8 week
    measure
    Feasibility of combination nivolumab and ipilimumab as assessed by number of participants who start standard of care within standard treatment window
    time Frame
    Up to 8 weeks
secondary Outcomes
  1. description
    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)
    measure
    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
  2. description
    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.
    measure
    Objective response rate (ORR)
    time Frame
    Up to 2 years.
  3. description
    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.
    measure
    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
  4. description
    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.
    measure
    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
  5. description
    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.
    measure
    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
Full study description
brief Summary
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.
Source references
Source notices and limitations
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      1. context
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    Preserved source evidence · Not medical advice