A Study of Varlilumab and IMA950 Vaccine Plus Poly-ICLC in Patients With WHO Grade II Low-Grade Glioma (LGG)

Low-grade gliomas (LGG), the most common of which are pilocytic astrocytomas, diffuse
astrocytomas, and oligodendrogliomas are a diverse family of central nervous system (CNS)
neoplasms that occur in children and adults. Based on data from the American Cancer Society
and Central Brain Tumor Registry of the United States (CBRTUS), approximately 1,800 LGG were
diagnosed in 2006, thus representing approximately 10% of newly diagnosed primary brain
tumors in the United States. Pilocytic astrocytomas (WHO grade I) are the most common brain
tumor in children 5 to 19 years of age. Diffuse astrocytomas and oligodendrogliomas are all
considered WHO grade II low grade gliomas (LGG) and are more common in adults. Pilocytic
astrocytomas are generally well circumscribed histologically and radiographically and
amenable to cure with gross total resection. In contrast, the diffuse astrocytomas and
oligodendrogliomas are more infiltrative and less amenable to complete resection. From a
molecular genetics standpoint, the most common alterations in LGG are IDH1 mutations and
mutations in the tumor suppressor gene TP53, located on chromosome 17, the gene product of
which is a multifunctional protein involved in the regulation of cell growth, cell death
(apoptosis), and transcription. Additionally, several molecular factors are of favorable
prognostic significance, particularly the presence of 1p/19q co-deletion and isocitrate
dehydrogenase (IDH) mutations.

WHO grade II LGGs are at risk to undergo malignant transformation into more aggressive and
lethal WHO grade III or IV high-grade glioma (HGG). Even with a combination of available
therapeutic modalities (i.e., surgery, radiation therapy [RT], chemotherapy), the invasive
growth and resistance to therapy exhibited by these tumors results in recurrence and death in
most patients. Although postoperative RT in LGG significantly improves 5-year
progression-free survival (PFS), it does not prolong overall survival (OS) compared with
delayed RT given at the time of progression. Early results from a randomized trial of
radiation therapy plus procarbazine, lomustine, and vincristine (PCV) chemotherapy for
supratentorial adult LGG (RTOG 9802) demonstrated improved PFS in patients receiving PCV plus
RT compared RT alone. Nonetheless, PCV is considerably toxic and currently not widely used
for management of glioma patients. Although chemotherapy with temozolomide (TMZ) is currently
being investigated in LGG patients, it is unknown whether it confers improved OS in these
patients. Further, our recent study has indicated that 6 of 10 LGG cases treated with TMZ
progressed to HGG with markedly increased exome mutations and, more worrisome, driver
mutations in the RB and AKT-mTOR pathways, with predominant C>T/G>A transitions at CpC and
CpT dinucleotides, strongly suggesting a signature of TMZ-induced mutagenesis; this study
also showed that in 43% of cases, at least half of the mutations in the initial tumor were
undetected at recurrence, while IDH mutations were the only type of mutations that persisted
in the initial and recurrent tumors. These data suggests the possibility that treatment of
LGG patients with TMZ may enhance oncogenic mutations and genetic elusiveness of LGG,
therefore calling for development of safer and effective therapeutic modalities such as
vaccines.

Taken together, LGG are considered a premalignant condition for HGG, such that novel
interventions to prevent malignant transformation need to be evaluated in patients with LGG.
Immunotherapeutic modalities, such as vaccines, may offer a safe and effective option for
these patients due to the slower growth rate of LGG (in contrast with HGG), which should
allow sufficient time for multiple immunizations and hence high levels of anti-glioma
immunity. Because patients with LGGs are generally not as immuno-compromised as patients with
HGG, they may also exhibit greater immunological response to and benefit from the vaccines.
Further, the generally mild toxicity of vaccines may improve quality of life compared with
chemotherapy or RT.

Inclusion Criteria:

- Patients must be ≥ 18 years old.

- Pathological criteria - Participants must have WHO grade II astrocytoma,
oligoastrocytoma or oligodendroglioma that has been histologically confirmed by prior
biopsy or surgical resection. If patients have already undergone biopsy and have
pathological diagnosis in a non-UCSF institute, pathology must be reviewed and
confirmed at UCSF.

- Patients must be positive for HLA-A2 based on flow-cytometry or genotyping

- Before enrollment, patients must show non-enhancing T2-FLAIR lesions that need to be
surgically resected and are likely WHO grade II glioma.

- Surgical resection of at least 0.5 grams of tumor

- Both newly diagnosed (with available pathological diagnosis) and recurrent patients
can be eligible. Prior radiation therapy (RT) after the initial diagnosis will be
allowed but there must be at least 6 months from the completion of RT (or
radiosurgery) to signed informed consent.

- Prior chemotherapy and any systemic molecularly targeted anti-tumor therapy will be
allowed.

- Patients must have a Karnofsky performance status (KPS) of ≥ 70%.

- Off or low dose (≤ 4 mg/day by Decadron) corticosteroid at least two weeks before the
first pre-surgical vaccine

- Adequate organ function within 14 days of study registration including: 1) Adequate
bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) ≥1.0 x
10^9/L, absolute lymphocytes ≥400/μL, platelets ≥100 x 10^9/L; hemoglobin ≥ 8 g/dL; 2)
Hepatic: - Total bilirubin ≤ 1.5 x upper limit of normal (ULN) and SGPT (ALT) ≤ 2.5 x
upper limit of normal (ULN), and 3) Renal: Normal serum creatinine or creatinine
clearance ≥60 ml/min/1.73 m^2

- Must be free of systemic infection. Subjects with active infections (whether or not
they require antibiotic therapy) may be eligible after complete resolution of the
infection. Subjects on antibiotic therapy must be off antibiotics for at least 7 days
before beginning treatment.

- Sexually active females of child bearing potential must agree to use adequate
contraception (diaphragm, birth control pills, injections, intrauterine device [IUD],
surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration
of the vaccination period. Sexually active males must agree to use barrier
contraceptive for the duration of the vaccination period.

- Patient must sign an informed consent document indicating that they are aware of the
investigational nature of this study, which includes an authorization for the release
of their protected health information

Exclusion Criteria:

- Presence of gliomatosis cerebri, cranial or spinal leptomeningeal metastatic disease

- Presence of T1 Gadolinium (Gd)-enhancing lesions (on MRI) suggestive of high-grade
glioma

- Pathological diagnosis for the resected tumor demonstrates transformation to higher
grade (i.e. WHO grade III or IV) or gliomas. If a patient who received pre-surgical
vaccines is diagnosed as high-grade glioma (HGG), the patient will be withdrawn from
the study and considered for therapeutic options for HGG (trials for HGG or standard
of care). The tumor tissue of such a case would be brought to the lab before the
pathological diagnosis is made; and thus would be processed before the lab is informed
of the final HGG diagnosis. Because HGG tissue may still reflect the vaccine effects,
we will evaluate the tumor tissue to help us develop future approaches for HGG.

- Pregnant women are excluded from this study. Pregnancy testing will be performed on
all menstruating females within 14 days prior to study enrollment

- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection (e.g. active or chronic hepatitis B and C), symptomatic congestive heart
failure, unstable angina pectoris, or psychiatric illness/social situations that would
limit compliance with study requirements

- History or current status of immune system abnormalities such as hyperimmunity (e.g.,
autoimmune diseases) that needed to be treated by systemic therapy, such as
immuno-suppressants and hypoimmunity (e.g., myelodysplastic disorders, marrow
failures, AIDS, transplant immunosuppression).

- Receiving ongoing treatment with immunosuppressive drugs, or dexamethasone > 4mg