A Phase Ib Clinical Trial to Evaluate Early Immunologic Pharmacodynamic Parameters Following Neoadjuvant Anti-PD-1 (Nivolumab), or the Combination of Anti-PD-1 Plus Anti-CTLA-4 (Nivolumab Plus Ipilimumab) in Patients With Surgically Accessible Glioblastoma

Protocol # :
Glioblastoma Multiforme
Grade IV Astrocytoma
Disease Sites
Brain and Nervous System
Principal Investigator
Wen, Patrick, Yung

Trial Description

This research trial is studying the safety and effectiveness of nivolumab in combination with
ipilimumab and surgery when used in the treatment of recurrent glioblastoma.

The names of the study drugs involved in this study are:

- Nivolumab

- Ipilimumab

- Placebo (IV solution with no medicine)

- Zr-89 Crefmirlimab berdoxam (optional sub-study)

Eligibility Requirements

Inclusion Criteria:

- Have histologically confirmed World Health Organization Grade IV IDH wildtype
glioblastoma or variants including gliosarcoma or IDH wildtype glioma with molecularly
features of glioblastoma.

- Previous first line therapy with at least radiotherapy.

- Patients must be undergoing surgery that is clinically indicated as determined by
their care providers.

- Be at first or second relapse. Note: Relapse is defined as progression following
initial therapy (i.e., radiation ± chemotherapy).

- Participants must have shown unequivocal evidence for tumor progression by MRI per
RANO criteria.

- Participants must have confirmation of availability of sufficient tissue from prior
surgery revealing glioblastoma or variants for submission following registration. The
following amount of tissue is required:

- 1 formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred) OR

- 10 FFPE unstained slides (5 μm thick)

- An interval of at least 12 weeks from the completion of radiation therapy to
registration unless there is unequivocal histologic confirmation of tumor progression.

- Participants must have recovered to grade 0 or 1 or pre-treatment baseline from
clinically significant toxic effects of prior therapy (including but not limited to
exceptions of alopecia, laboratory values listed per inclusion criteria, and
lymphopenia (which is common after therapy with temozolomide).

- An interval of at least 4 weeks (to registration) between prior surgical resection or
one week for stereotactic biopsy.

- From registration, the following time periods must have elapsed: 5 half-lives from any
investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide
and 6 weeks from nitrosoureas), 4 weeks from antibodies, or 4 weeks (or 5 half-lives,
whichever is shorter) from other anti-tumor therapies (including vaccines). No washout
period required from tumor treating fields (TTF).

- Be willing and able to provide written informed consent/assent for the trial.

- Be ≥ 18 years of age on day of signing informed consent.

- Have a Karnofsky performance status (KPS) ≥ 70.

- MRI within 14 days prior of registration.

- All screening labs should be performed within 14 days of registration and demonstrate
adequate organ function as defined below:

- Absolute neutrophil count (ANC) ≥1,500 /mcL

- Platelets ≥100,000 / mcL

- Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7
days of assessment)

- Serum creatinine OR measured or calculated a creatinine clearance (GFR can be
used in place of creatinine or CrCl) ≤1.5 X institutional upper limit of normal
(ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
(Creatinine clearance should be calculated per institutional standard.)

- Serum total bilirubin ≤ 1.5 X institutional ULN OR direct bilirubin ≤
institutional ULN for subjects with total bilirubin levels > 1.5 institutional

- AST (SGOT) and ALT (SGPT) ≤ 2.5 X institutional ULN OR ≤ 5 X institutional ULN
for subjects with Gilberts syndrome

- Albumin ≥ 2.5 mg/dL

- International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X
institutional ULN unless subject is receiving anticoagulant therapy as long as PT
or PTT is within therapeutic range of intended use of anticoagulants

- Activated Partial Thromboplastin Time (aPTT) ≤1.5 X institutional ULN unless
subject is receiving anticoagulant therapy as long as PT or PTT is within
therapeutic range of intended use of anticoagulants

- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to registration. If the urine test is positive or
cannot be confirmed as negative, a serum pregnancy test will be required. Women are
considered post-menopausal and not of child bearing potential if they have had 12
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g.,
age appropriate, history of vasomotor symptoms) or six months of spontaneous
amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have had
surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago.
In the case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment if she considered not of child
bearing potential.

- Women of child-bearing potential (WOCBP), defined as all women physiologically capable
of becoming pregnant, must use highly effective contraception during study treatment
and for 5 months after study discontinuation. Highly effective contraception is
defined as either:

- True Abstinence: When this is in line with the preferred and usual lifestyle of
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
postovulation methods) and withdrawal are not acceptable methods of

- Sterilization: Surgical bilateral oophorectomy (with or without hysterectomy) or
tubal ligation at least six weeks ago. In case of oophorectomy alone, only when
the reproductive status of the woman has been confirmed by follow up hormone
level assessment (as described above).

- Male Partner Sterilization (with the appropriate post-vasectomy documentation of
the absence of sperm in the ejaculate). For female subjects on the study, the
vasectomised male partner should be the sole partner for that participant.

- Use of a combination of any two of the following:

- Placement of an intrauterine device (IUD) or intrauterine system (IUS)

- Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal

- Appropriate hormonal contraceptives (including any registered and marketed
contraceptive agent that contains an estrogen and/or a progestational agent
- including oral, subcutaneous, intrauterine, or intramuscular agents).

- Male subjects should agree to use adequate method of contraception starting with the
first dose of study therapy through 7 months after the last dose of therapy.

Exclusion Criteria:

- IDH mutation by immunohistochemistry.

- Current or planned participation in a study of an investigational agent or using an
investigational device.

- Has a diagnosis of immunodeficiency.

- Has tumor primarily localized to the brainstem or spinal cord.

- Has presence of diffuse leptomeningeal disease or extracranial disease.

- Has received systemic immunosuppressive treatments, aside from systemic
corticosteroids (such as methotrexate, chloroquine, azathioprine, etc.) within six
months of registration.

- Has received bevacizumab or aflibercept. VEGFR inhibitors are allowed.

- Requires treatment with high dose systemic corticosteroids defined as dexamethasone >
2 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of

- Has received prior interstitial brachytherapy, implanted chemotherapy, stereotactic
radiosurgery or therapeutics delivered by local injection or convection enhanced

- Has history of known coagulopathy that increases risk of bleeding or a history of
clinically significant hemorrhage within 12 months of registration.

- Has a known history of active TB (Bacillus Tuberculosis).

- Has gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3
within 6 months of registration.

- Has a known additional malignancy that is progressing or requires active treatment.
Those patients whose natural history or treatment does not have the potential to
interfere with the safety or efficacy assessment of the investigational regimen will
be eligible including, but not limited to, basal cell carcinoma of the skin, squamous
cell carcinoma of the skin, localized prostate cancer not requiring treatment, or in
situ cervical cancer that has undergone potentially curative therapy.

- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

- Has known history of, or any evidence of active non-infectious pneumonitis.

- Has an active infection requiring systemic therapy.

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator. Examples
include but are not limited to symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit
compliance with study requirements.

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

- Is pregnant, breastfeeding, or expecting to conceive within the projected duration of
the trial, starting with the screening visit through 5 months after the last dose of
trial treatment. It is unknown whether nivolumab and/or ipilimumab is excreted in
human milk or may have adverse effects on a fetus in utero. Since many drugs are
excreted in human milk, and because of the potential for serious adverse reactions in
the nursing infant or fetus, these subjects are not eligible for enrollment.

- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-Cytotoxic T-lymphocyte-Associated Antigen-4 (CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways).

- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).

- Has received a live vaccine within 30 days prior to registration.

- Has a known hypersensitivity to any of the study therapy products.