JAK2 Inhibitor WP1066 in Treating Patients With Recurrent Malignant Glioma or Progressive Metastatic Melanoma in the Brain

PRIMARY OBJECTIVES; I. Identify the maximum tolerated dose (MTD) of WP1066 (JAK2 inhibitor
WP1066) in patients with recurrent malignant glioma (glioblastoma, anaplastic glioma), and
melanoma patients with progressive brain metastasis.

II. Assess the safety and tolerability of WP1066 in patients with recurrent malignant glioma
and melanoma patients with progressive brain metastasis using the National Cancer Institute
(NCI) Common Toxicity Criteria (CTC) with special attention directed at determining whether
any induced autoimmune reactions occur.

SECONDARY OBJECTIVES:

I. Pharmacokinetic analysis of the in vivo bioavailability of WP1066. II. Assess overall
response rate (ORR) in patients with recurrent malignant gliomas and progressive metastatic
melanoma to the brain.

III. Assess immunological response in patients with recurrent malignant glioma and melanoma
patients with progressive brain metastasis treated with WP1066.

IV. Assess time to radiographically assessed progression and/or response in patients treated
with WP1066.

V. Assess progression-free survival (PFS) and overall survival (OS) in patients treated with
WP1066.

VI. Estimate the proportion of patients treated with WP1066 who develop additional melanoma
metastatic lesions, including those in the central nervous system (CNS).

OUTLINE: This is a dose-escalation study.

Patients receive JAK2 inhibitor WP1066 orally (PO) twice daily (BID) on Monday, Wednesday,
and Friday of weeks 1 and 2. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 and 2 months.

Inclusion Criteria:

- Patients must have histologically confirmed progressive brain metastases from melanoma
or recurrent malignant glioma (glioblastoma, anaplastic glioma), for which standard
curative or palliative measures, with the exception of surgery, do not exist or are no
longer effective

- Patients must have measurable disease in the brain, defined as at least one lesion
that can be accurately measured in at least one dimension as >= 10 mm by brain
magnetic resonance imaging (MRI); MRI of the brain (with and without gadolinium
enhancement) is to be performed using standard 5-mm slices with 2.5-mm spacing for
comparison to subsequent MRI scans

- In the case of malignant glioma patients, they must have previously undergone
standard-of-care treatment including surgery, radiation, and first line adjuvant
chemotherapy prior to the experimental treatment (WP1066); in the case of melanoma
patients with brain metastasis, they may have previously undergone a resection (with
radiographic evidence of progression), have undergone gamma knife radiosurgery (with
radiographic evidence of progression), or have been treated with other systemic
therapies that failed

- Karnofsky performance scale score >= 60%

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,000/mcL

- Platelets >= 75,000/mcL

- Total bilirubin =< 1.6

- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Prothrombin time (PT)/partial thromboplastin time (PTT) < 1.5 x normal institutional
standard

- Ability to understand and the willingness to sign a written informed consent document

- Melanoma patients must be intolerant of, or have disease that has proven refractory to
approved therapies such as B-Raf proto-oncogene, serine/threonine kinase (BRAF) or
mitogen-activated protein kinase kinase 1 (MEK1) inhibitors for BRAF-positive
metastatic melanoma and/or checkpoint blockade with either anti-programmed cell death
1 (PD1) or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) for metastatic
melanoma

- Willing and able to tolerate brain MRI's with contrast

- Patients with stable seizures (e.g., no seizures for >= 14 days and not requiring
escalation or addition of anti-epileptic drugs) will be eligible

- Patients who are eligible for the surgical expansion cohort are identified by the
clinical team who have made the independent decision that the patient would benefit
from non-emergent palliative surgical resection (i.e. they are not a candidate for
gamma knife or other type of standard therapy).

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas) prior to entering the study or those who have not recovered from adverse
events due to agents administered more than 4 weeks earlier; biological agents, immune
modulators, and targeted therapeutic approaches require a 2-week washout window

- Patients who are receiving any other investigational agents require a 4 week washout
period; patients who have received cellular or gene therapy at any time are not
eligible

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to WP1066

- Patients who are receiving drugs that significantly interact with the cytochrome P450
(CYP450) enzyme(s) are ineligible; however, if they are switched to other medications
with a 2-week washout window, they will be eligible; patients are also excluded if
they have been exposed within 7 days of planned first study treatment day to
medications that are predominantly cytochrome P450, family 2, subfamily D, polypeptide
6 (CYP2D6), cytochrome P450, family 2, subfamily C, polypeptide 9 (2C9) or cytochrome
P450, family 2, subfamily C, polypeptide 19 (2C19) substrates, strong inhibitors or
inducers, and sensitive substrates of cytochrome P450, family 3, subfamily A,
polypeptide 4 (CYP3A4) with narrow therapeutic range

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- No single lesion can be larger than 3 cm in maximal diameter; there may not be midline
shift exceeding 5 mm or hydrocephalus

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with WP0166; female subjects of childbearing potential should be
willing to use 2 methods of birth control prior to study entry, during the study, and
for 2 months after the last dose of the study drug or be surgically sterile; subjects
of childbearing potential are those who have not been surgically sterilized or have
not been free from menses for > 1 year; should a woman become pregnant or suspect she
is pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately; men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
participation, and 4 months after completion of WP1066 administration

- Human immunodeficiency virus (HIV)-positive patients receiving combination
antiretroviral therapy are ineligible

- Patients who have received bevacizumab, Gliadel, or are on active therapy with Optune
are not eligible.

- It will be at the principal investigator's (PIs) discretion to enroll a patient who
has a small, asymptomatic brain hemorrhage, but patients who have had symptomatic
hemorrhages will be excluded

- Patients requiring escalation of the corticosteroid dose will be excluded, but
patients receiving a stable or decreasing dose for at least one week will be eligible

- The presence of diffuse leptomeningeal disease will be an exclusion criterion for this
study; this is secondary to the inadequacy of measuring the extent of the tumor burden
within this setting and the very poor prognosis of these patients

- Patients who have a corrected QT (QTc) interval > 450 ms at base line will be
excluded; concomitant use of agents that prolong the QT interval will be avoided

- Malignant glioma patients within 12 weeks of completion of radiation concurrent
temozolomide will be excluded

- Melanoma patients with large or symptomatic brain metastasis, and in whom
neurosurgical removal is indicated will not be eligible for this trial

- Patients with uncontrolled seizures or seizure requiring escalation or addition of
anti-epileptic drugs will be excluded