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

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: NCT04465643
Recruitment Status : Recruiting
First Posted : July 10, 2020
Last Update Posted : June 21, 2022
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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.

Condition or disease Intervention/treatment Phase
Nerve Sheath Tumors Drug: Nivolumab Drug: Ipilimumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Neoadjuvant Nivolumab Plus Ipilimumab for Newly Diagnosed Malignant Peripheral Nerve Sheath Tumor
Actual Study Start Date : June 8, 2021
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : August 2026


Arm Intervention/treatment
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
Drug: Nivolumab
Nivolumab 4.5 mg/kg Q3W x 2

Drug: Ipilimumab
Ipilimumab 1 mg/kg Q3W x 2




Primary Outcome Measures :
  1. 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).

  2. 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).

  3. 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).

  4. 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).


Secondary Outcome Measures :
  1. 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)

  2. 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.

  3. 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.

  4. 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.

  5. 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.


Other Outcome Measures:
  1. 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.

  2. Progression Free Survival [ Time Frame: Up to 2 years ]
    Proportion of participants who achieve progression free survival post treatment

  3. 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.

  4. 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.

  5. CD3 Cell Count [ Time Frame: Up to 1 year ]
    CD3 cell count in cells/mm^3

  6. CD4 Cell Count [ Time Frame: Up to 1 year ]
    CD4 cell count in cells/mm^3

  7. FoxP3 Cell Count [ Time Frame: Up to 1 year ]
    FoxP3 cell count in cells/mm^3

  8. CD25 Cell Count [ Time Frame: Up to 1 year ]
    CD25 cell count in cells/mm^3

  9. CD8 Cell Count [ Time Frame: Up to 1 year ]
    CD8 cell count in cells/mm^3

  10. CD45 Cell Count [ Time Frame: Up to 1 year ]
    CD45 cell count in cells/mm^3

  11. CD11b Cell Count [ Time Frame: Up to 1 year ]
    CD11b cell count in cells/mm^3

  12. CD163 Cell Count [ Time Frame: Up to 1 year ]
    CD163 cell count in cells/mm^3

  13. CD206 Cell Count [ Time Frame: Up to 1 year ]
    CD206 cell count in cells/mm^3

  14. CD68 Cell Count [ Time Frame: Up to 1 year ]
    CD68 cell count in cells/mm^3

  15. CD56 Cell Count [ Time Frame: Up to 1 year ]
    CD56 cell count in cells/mm^3

  16. CD20 Cell Count [ Time Frame: Up to 1 year ]
    CD20 cell count in cells/mm^3

  17. CD45RO Cell Count [ Time Frame: Up to 1 year ]
    CD45RO cell count in cells/mm^3

  18. Granzyme B Cell Count [ Time Frame: Up to 1 year ]
    Granzyme B cell count in cells/mm^3

  19. PD-L1 Cell Count [ Time Frame: Up to 1 year ]
    PD-L1 cell count in cells/mm^3

  20. PD-L2 Cell Count [ Time Frame: Up to 1 year ]
    PD-L2 cell count in cells/mm^3

  21. B7-H3 Cell Count [ Time Frame: Up to 1 year ]
    B7-H3 cell count in cells/mm^3

  22. B7-H4 Cell Count [ Time Frame: Up to 1 year ]
    B7-H4 cell count in cells/mm^3

  23. PD-1 Cell Count [ Time Frame: Up to 1 year ]
    PD-1 cell count in cells/mm^3

  24. 2B4 Cell Count [ Time Frame: Up to 1 year ]
    2B4 cell count in cells/mm^3

  25. LAG-3 Cell Count [ Time Frame: Up to 1 year ]
    LAG-3 cell count in cells/mm^3

  26. BTLA Cell Count [ Time Frame: Up to 1 year ]
    BTLA cell count in cells/mm^3

  27. Tim-3 Cell Count [ Time Frame: Up to 1 year ]
    Tim-3 cell count in cells/mm^3

  28. CTLA-4 Cell Count [ Time Frame: Up to 1 year ]
    CTLA-4 cell count in cells/mm^3

  29. TIGIT Cell Count [ Time Frame: Up to 1 year ]
    TIGIT cell count in cells/mm^3

  30. HLA-DR Cell Count [ Time Frame: Up to 1 year ]
    HLA-DR cell count in cells/mm^3

  31. LAP Cell Count [ Time Frame: Up to 1 year ]
    LAP cell count in cells/mm^3

  32. CD14 Cell Count [ Time Frame: Up to 1 year ]
    CD14 cell count in cells/mm^3

  33. ICOS Cell Count [ Time Frame: Up to 1 year ]
    ICOS cell count in cells/mm^3

  34. OX40 Cell Count [ Time Frame: Up to 1 year ]
    OX40 cell count in cells/mm^3

  35. 4-1BB Cell Count [ Time Frame: Up to 1 year ]
    4-1BB cell count in cells/mm^3

  36. 4-1BBL Cell Count [ Time Frame: Up to 1 year ]
    4-1BBL cell count in cells/mm^3

  37. ICOSL Cell Count [ Time Frame: Up to 1 year ]
    ICOSL cell count in cells/mm^3

  38. CD19 Cell Count [ Time Frame: Up to 1 year ]
    CD19 cell count in cells/mm^3

  39. CD1a Cell Count [ Time Frame: Up to 1 year ]
    CD1a cell count in cells/mm^3



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years to 100 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.)

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): NCT04465643


Contacts
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Contact: Jaishri Blakeley, MD 410-955-8837 jblakel3@jhmi.edu
Contact: Stella Krawiec 410-502-1962 skrawie1@jhmi.edu

Locations
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United States, Maryland
Johns Hopkins Medical Institution Recruiting
Baltimore, Maryland, United States, 21287
Contact: Jaishri Blakeley, MD    410-955-8837    jblakel3@jhmi.edu   
Contact: Stella Krawiec    410-502-1962    skrawie1@jhmi.edu   
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Bristol-Myers Squibb
Investigators
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Principal Investigator: Jaishri Blakeley, MD Johns Hopkins University
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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT04465643    
Other Study ID Numbers: J20112
IRB00215437 ( Other Identifier: Johns Hopkins University )
First Posted: July 10, 2020    Key Record Dates
Last Update Posted: June 21, 2022
Last Verified: June 2022

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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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Nerve Sheath Neoplasms
Neurofibrosarcoma
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplasms
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Fibrosarcoma
Neoplasms, Fibrous Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Sarcoma
Neurofibroma
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action