Clinical trial NCT04465643: Neoadjuvant Nivolumab Plus Ipilimumab for Newly Diagnosed Malignant Peripheral Nerve Sheath Tumor
Official title: Neoadjuvant Nivolumab Plus Ipilimumab for Newly Diagnosed Malignant Peripheral Nerve Sheath Tumor
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Nerve Sheath Tumors
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2020-07-10
Enrollment: 18
Sex: ALL
Minimum age (years): 12
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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.)

Primary outcomes:
measure: Safety of combination nivolumab and ipilimumab as assessed by number of participants who experience adverse events
timeFrame: Up to 2 years
measure: Feasibility of combination nivolumab and ipilimumab as assessed by number of participants who experience adverse events
timeFrame: Up to 2 years
measure: Maximum Tolerated Dose (MTD) as determined by number of participants with dose limiting toxicities (DLT)
timeFrame: Up to 2 years
measure: Feasibility of combination nivolumab and ipilimumab as assessed by number of participants who achieve a response
timeFrame: Up to 2 years
Secondary outcomes:
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
timeFrame: Up to 2 years
measure: Objective response rate (ORR)
timeFrame: Up to 2 years.
measure: Change in pain levels in relation to target tumor as assessed by the Numeric Rating Scale
timeFrame: Baseline, Week 6, 4 months, and 8 months
measure: Change in pain levels in relation to target tumor as assessed by the Pain Interference Index
timeFrame: Baseline, Week 6, 4 months, and 8 months
measure: Change in pain levels in relation to target tumor as assessed by the Patient-Reported Outcome Measurement Information System
timeFrame: Baseline, Week 6, 4 months, and 8 months
Other outcomes:
measure: Objective response rate (ORR)
timeFrame: At 4 months post intervention
measure: Progression Free Survival
timeFrame: Up to 2 years
measure: Tumor Response as assessed by immune markers in tumor samples
timeFrame: Up to 2 years
measure: Pharmacodynamic activity as assessed by markers in blood samples
timeFrame: Up to 2 years
measure: CD3 Cell Count
timeFrame: Up to 1 year
measure: CD4 Cell Count
timeFrame: Up to 1 year
measure: FoxP3 Cell Count
timeFrame: Up to 1 year
measure: CD25 Cell Count
timeFrame: Up to 1 year
measure: CD8 Cell Count
timeFrame: Up to 1 year
measure: CD45 Cell Count
timeFrame: Up to 1 year
measure: CD11b Cell Count
timeFrame: Up to 1 year
measure: CD163 Cell Count
timeFrame: Up to 1 year
measure: CD206 Cell Count
timeFrame: Up to 1 year
measure: CD68 Cell Count
timeFrame: Up to 1 year
measure: CD56 Cell Count
timeFrame: Up to 1 year
measure: CD20 Cell Count
timeFrame: Up to 1 year
measure: CD45RO Cell Count
timeFrame: Up to 1 year
measure: Granzyme B Cell Count
timeFrame: Up to 1 year
measure: PD-L1 Cell Count
timeFrame: Up to 1 year
measure: PD-L2 Cell Count
timeFrame: Up to 1 year
measure: B7-H3 Cell Count
timeFrame: Up to 1 year
measure: B7-H4 Cell Count
timeFrame: Up to 1 year
measure: PD-1 Cell Count
timeFrame: Up to 1 year
measure: 2B4 Cell Count
timeFrame: Up to 1 year
measure: LAG-3 Cell Count
timeFrame: Up to 1 year
measure: BTLA Cell Count
timeFrame: Up to 1 year
measure: Tim-3 Cell Count
timeFrame: Up to 1 year
measure: CTLA-4 Cell Count
timeFrame: Up to 1 year
measure: TIGIT Cell Count
timeFrame: Up to 1 year
measure: HLA-DR Cell Count
timeFrame: Up to 1 year
measure: LAP Cell Count
timeFrame: Up to 1 year
measure: CD14 Cell Count
timeFrame: Up to 1 year
measure: ICOS Cell Count
timeFrame: Up to 1 year
measure: OX40 Cell Count
timeFrame: Up to 1 year
measure: 4-1BB Cell Count
timeFrame: Up to 1 year
measure: 4-1BBL Cell Count
timeFrame: Up to 1 year
measure: ICOSL Cell Count
timeFrame: Up to 1 year
measure: CD19 Cell Count
timeFrame: Up to 1 year
measure: CD1a Cell Count
timeFrame: Up to 1 year
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins Medical Institution
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Jaishri Blakeley, MD
role: PRINCIPAL_INVESTIGATOR
References: