PLX3397 in Children and Young Adults With Refractory Leukemias and Refractory Solid Tumors Including Neurofibromatosis Type 1 (NF1) Associated Plexiform Neurofibromas (PN)

Background

- Traditional therapeutic approaches to pediatric cancer have focused on cytotoxic agents
and, more recently, targeted inhibition of cellular signaling pathways through the use
of small molecule kinase inhibitors. Despite these interventions, significant numbers of
pediatric cancer patients develop recurrent and resistant disease. Targeting the tumor
microenvironment is a promising but incompletely explored strategy for the treatment of
pediatric cancer and non-cancer tumors.

- This trial will begin to explore the disruption of the interaction between neoplastic
cells and the myeloid component of the tumor microenvironment as a treatment strategy
for pediatric cancers and neurofibromatosis type 1 (NF1) related plexiform neurofibromas
(PN) and malignant peripheral nerve sheath tumor (MPNST).

- PLX3397 is an orally available small molecule inhibitor of class III protein tyrosine
kinases including Kit, CSF1R (colony stimulating factor 1 receptor)/Fms (Feline
McDonough Sarcoma), and oncogenic Flt3 (Fms like tyrosine kinase).

Primary Objectives

- Phase I: Evaluate the safety and tolerability of PLX3397, and determine a recommended
phase II dose of PLX3397 in pediatric patients with refractory solid tumors including
NF1 MPNST and brain tumors or refractory leukemias, limited to acute myelogenous
leukemia (AML) and acute lymphoblastic leukemia (ALL).

- Phase II: Determine the anti-tumor activity of PLX3397 in patients with NF1 PN.
Objective response rate (ORR) will be defined as the proportion of patients with a
partial response (PN volume decrease greater than or equal to 20% determined by
volumetric MRI analysis). PN Cohort temporarily suspended as requested by the FDA due to
IND Safety Report of 07 October 2016.

Secondary Objectives

- Phase I: To study the plasma pharmacokinetics (PK) of PLX3397 in the pediatric age
group.

- Phase I:To preliminarily determine the antitumor activity within the confines of a phase
1 study for recurrent or refractory pediatric solid tumors and leukemia (AML and ALL).

- Phase I/II: To determine the effect of PLX3397 on circulating biomarkers of c-kit and
CSF-1R

inhibition.

-Phase II cohort of NF1 PN temporarily suspended as requested by the FDA due to IND

Safety Report of 07 October 2016.

-Phase I/II: To determine the effect of PLX3397 on the MPNST microenvironment. Phase II
cohort of NF1 PN temporarily suspended as requested by the FDA due to IND Safety Report of 07
October 2016.

Phase II cohort of NF1 PN temporarily suspended as requested by the FDA due to IND Safety
Report of 07 October 2016.

- Phase II: Evaluate the biologic activity and extended tolerability of PLX3397

- Phase II: Determine the duration of response in patients with PN.

- Phase II: Evaluate the effect of PLX3397 on patient reported (quality of life and pain)
and

functional outcomes; and validate patient reported outcomes in patients with NF1 PN in Phase
II study

-Phase II: In patients with progressive MPNST PN at enrollment: Evaluate the time to
progression (TTP) compared to a historical placebo control group, and to the TTP prior to

enrollment on study in patients serving as their own control.

Eligibility

- Tumor type:

- Phase I: Children (greater than or equal to 3 and lessthan or equal to 21 years of
age) with recurrent or refractory solid tumors including primary neoplasms of the
central nervous system and patients with NF1 and MPNST. NF1 PN only Cohort
temporarily suspended as requested by the FDA due to IND Safety Report of 07
October 2016, or Children (greater than or equal to 3 and less than or equal to 21
years of age) with refractory leukemias (AML or ALL) (Phase 1).

- Phase II: Patients with NF1 and inoperable PN, that cause morbidity (greater than
or equal to 3 and lessthan or equal to 35 years of age). PN Cohort temporarily
suspended as requested by the FDA due to IND Safety Report of 07 October 2016.

- Subjects must have adequate performance status, be able to swallow tablets, may not be
pregnant or breastfeeding, and have adequate major organ function. Subjects with history
of severe or uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection, symptomatic cardiovascular or pulmonary disease, or history of
prolonged QT syndrome will be excluded.

Design

- Phase I

- Using a rolling-six phase I design with 2-6 subjects per dose level and standard
definitions of MTD (during cycle 1) and DLT.

- PLX3397 will be administered orally (200 mg capsules) once daily on a continuous
basis for cycles of 28 days without a rest period between cycles. Patients must be
able to swallow intact capsules. Dosing will be based on body surface area (BSA),
and the total weekly dose will be rounded to within 10% of calculated dose using a
dosing nomogram.

- At the MTD, the recommended phase II dose level will be expanded to up to 12
patients with attempts made to enroll at least 3 patients with refractory solid
tumors and 3 patients with refractory acute leukemia (ALL and AML) to gain more
experience with the toxicities and pharmacokinetics of PLX3397 in these disease
cohorts. Attempts will be made to enroll equal numbers of patients between the ages
of 3 and 12 years and over 12 years of age to gain pharmacokinetic and safety data
over a broad age range.

- Phase II (PN Cohort temporarily suspended as requested by the FDA due to IND Safety
Report of 07 October 2016.)

- A Simon 2-stage design will be used: 9 evaluable patients with NF1 and inoperable
PN that cause morbidity will be enrolled on the initial stage, and if greater than
or equal to 1/9 patients have a response (PN volume decrease greater than or equal
to 20% compared to baseline), enrollment will be expanded to a total of 17
evaluable patients.

- Impact of therapy on patient-reported outcomes will be evaluated in patients with
PN. This study will assess both general health-related qualify of life (QOL) and
pain (pain intensity and pain interference) as patient-reported outcomes (PROs).

- To complete both Phase I and Phase II portions, a maximum of (24 + 17= 41 plus up
to 6 to replace inevaluable patients) 47 patients will be accrued in 2 to 2.5
years.

- INCLUSION CRITERIA:

Enrollment in the cohort of patients with NF1 inoperable plexiform neurofibromas (PN) is
temporarily suspended as of Amendment G as requested by the FDA due to IND Safety Report of
07 October 2016. Patient accrual of patients with NF1 and MPNST may continue in the Phase I
Portion.

- Diagnosis:

- Phase I: Patients must have recurrent or refractory solid tumors or acute
leukemia (limited to AML or ALL) or have been intolerant of prior therapies,
confirmed by the Laboratory of Pathology, NCI, e.g., solid tumors including
rhabdomyosarcoma, Ewing sarcoma, soft tissue sarcomas. These may include primary
neoplasms of the central nervous system, such as high-grade (WHO grade III-IV)
glioma. Patients with diffuse intrinsic pontine glioma (DIPG) or optic pathway
glioma are exempt from histologic verification. For DIPG typical MRI findings
must be present which include hypo- or isointense on T1-weighted imaging,
hyperintense on FLAIR or T2-weighted imaging, epicenter in the pons in the face
of a typical clinical presentation. Optic pathway glioma are located in the optic
pathway and are typically hypo- or iso-intense on T1 and hyperintense on
T2-weighted images.

- In addition, patients with NF1 and with malignant peripheral nerve sheath tumor
(MPNST).

- Phase II temporarily suspended as requested by the FDA due to IND Safety Report of 07
October 2016

- Phase II: inoperable PN causing morbidity, such as (but not limited to) head and
neck lesions that could compromise the airway or great vessels, brachial or
lumbar plexus lesions that could cause nerve compression and loss of function,
lesions that could result in major deformity (e.g., orbital lesions) or
significant cosmetic problems, lesions of the extremity that cause limb
hypertrophy or loss of function, and painful lesions in patients with NF1.

- Histologic confirmation of PN tumor is not necessary in the presence of
consistent clinical and radiographic findings, but should be considered if
malignant degeneration of a PN is clinically suspected.

- A PN is defined as a neurofibroma that has grown along the length of a nerve and
may involve multiple fascicles and branches. A spinal PN involves two or more
levels with connection between the levels or extending laterally along the nerve.
In addition to PN, all study subjects must have either positive genetic testing
for NF1 confirmed in a CLIA certified laboratory or have at least one other
diagnostic criterion for NF1 listed below (NIH Consensus conference):

- Six or more cafe-au-lait macules (greater than or equal to 0.5cm in
prepubertal subjects or greater than or equal to 1.5 cm in post pubertal
subjects)

- Freckling in axilla or groin

- Optic glioma

- Two or more Lisch nodules

- A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or
thinning of long bone cortex)

- A first-degree relative with NF1

- Patients must have relapsed after or be refractory to effective standard
therapies. For NF1 PN there is no standard medical therapy, and therefore no
requirement for prior therapy. There are no limits on number of prior
therapeutic regimens.

- Disease status: Phase I: Patients with refractory solid tumors including patients with
NF1 and MPNST must have evaluable disease, patients with refractory leukemia must have
M2 or M3 bone marrow.

--Phase II: Patients must have measurable disease.Phase II temporarily suspended as
requested by the FDA due to IND Safety Report of 07 October 2016

- Age (must have BSA greater than or equal to 0.55 m2):

- Phase I: greater than or equal to 3 and less than or equal to 21 years of age

- Phase II: greater than or equal to 3 and less than or equal to 35 years of age

- Informed Consent: All patients or their legal guardians (if the patient is<18 years
old) must sign an IRB-approved document of informed consent to demonstrate their
understanding of the investigational nature and the risks of this study before any
protocol-related studies are performed. When appropriate, pediatric subjects will be
included in all discussions.

- Patients must be able to swallow capsules.

- Performance Status: Karnofsky greater than or equal to 50% for patients > 16 years of
age and

Lansky greater than or equal to 50% for patients less than or eqal to 16 years of age.
Subjects who are wheelchair bound because of paralysis will be considered ambulatory when
they are up in their wheelchair. Subjects have to be able to travel to the NIH for
evaluations.

-Prior therapy:

Patients must have fully recovered (to Grade 1) from the acute toxic effects of all prior
anti-cancer therapy.

- Myelosuppressive chemotherapy: At least 21 days after the last dose of
myelosuppressive chemotherapy (42 days if prior nitrosourea).

- Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic
agent. For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur. The duration of this interval must be discussed with the
study chair.

- Immunotherapy: At least 42 days after the completion of any type of immunotherapy,
e.g. tumor vaccines.

- Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a
monoclonal antibody.

- XRT: At least 7 days after local palliative XRT (small port); At least 150 days must
have elapsed if prior TBI or if greater than or equal to 50% radiation of pelvis;
greater than or equal to 14 days from whole brain radiation, craniospinal radiation,
or targeted radiation to CNS tumors. At least 42 days must have elapsed if other
substantial BM radiation.

- HSCT: greater than or equal to 56 days from stem cell transplant with no evidence of
active graft vs. host disease; must be off immunosuppressive therapy for at least 4
weeks and have no active graft-versus-host disease (GVHD) at the time of entry onto
this trial.

- Surgery: greater than or equal to 14 days from surgery

- Others: greater than or equal to 7 days from last dose of short active hematopoietic
growth factors, i.e. filgrastim, greater than or equal to 14 days for long-acting,
i.e. pegfilgrastim.

- Steroids: Patients with CNS tumors who are managed with steroids are eligible if they
have no worsening neurologic deficits and are on a stable or decreasing dose of
corticosteroids for greater than or equal to 7 days prior to registration. Patients
with leukemia receiving corticosteroids or hydroxyurea are eligible provided that the
corticosteroids are not being used to manage GVHD and there has been no increase in
corticosteroid of hydroxyurea dose for 7 days prior to starting PLX3397

- Patient must have adequate hematologic, hepatic, and renal function, defined by:

- Absolute neutrophil count >= 1.5 (SqrRoot) 10^9/L

- Hemoglobin > 10 g/dL

- Platelet count >= 100 (SqrRoot) 10^9/L

- AST and ALT less than or equal to upper limit of normal (ULN)

- TBil and DBil less than or equal to ULN with an exception of patients with confirmed
Gilbert's syndrome. For

patients with confirmed Gilberts syndrome, the TBil should be less than or equal to 1.5
(SqrRoot) ULN

- Serum creatinine less than or equal to 1.5 (SqrRoot) ULN

- Exceptions:

- Known active or chronic human immunodeficiency virus (HIV) or hepatitis C virus
(HCV) infection, or positive hepatitis B (Hep B) surface antigen. Prior hepatitis
infection that has been treated with highly effective therapy with no evidence of
residual infection and with normal liver function (ALT, AST, total and direct
bilirubin less than or equal to ULN) is allowed.

- Hepatobiliary diseases including biliary tract diseases, autoimmune hepatitis,
inflammation, fibrosis, cirrhosis of liver caused by viral, alcohol, or genetic
reasons. Gilbert's disease is allowed if TBil is less than or equal to 1.5 x ULN.

- Contraception: Women of child-bearing potential must agree to use an
effective method of birth control during treatment and for 3 months after
receiving their last dose of study drug. Fertile men must also agree to use
an acceptable method of birth control while on study drug and for at least 3
months after last dose.

EXCLUSION CRITERIA:

- Individuals who are pregnant or breast feeding or who become pregnant while enrolled
on this trial will be excluded from participation, due to the unknown effects of
PLX3397 on a growing fetus or newborn child.

- Individuals with malignant peripheral nerve sheath tumors will not be eligible to
participate in the phase II portion of the trial.

- Ongoing treatment with any other cancer therapy or investigational agent, with the
exception of IT chemotherapy for leukemia, when indicated.

- Individuals who require therapy with warfarin.

- 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.

- Active untreated infection.

- Known chronic Hepatitis B or C, or HIV infection.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to PLX3397 or other agents used in study.

- Patients with PT and/or INR higher than or equal to 1.5 time upper limit of normal,
unless patients have lupus anticoagulant in which case they are eligible if cleared by
hematology.

- Drugs that strongly inhibit or potentiate CYP3A4:

- During Phase I: patients who have received these drugs within 14 days or within 5
half-lives of the drug (whichever is longer) prior to study initiation will be
excluded.

- During Phase II: These drugs should be avoided if possible, as these drugs could
increase or decrease blood levels of PLX3397.