Clinical Trial Details
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NCT02390752 : Phase I/II Trial of PLX3397 in Children and Young Adults With Refractory Leukemias and Refractory Solid Tumors Including Neurofibromatosis Type 1 (NF1) Associated Plexiform Neurofibromas (PN)
PhasePhase 1/Phase 2
AgesMin: 3 Years Max: 30 Years

- 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. This may include primary neoplasms of the central nervous system, such as
high-grade (WHO grade III-IV) glioma. In addition, patients with NF1 inoperable plexiform
neurofibromas (PN) causing morbidity will be eligible. 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.

- Phase II: inoperable PN causing morbidity in patients with NF1, with evidence of
progression within the previous 12 months. 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 caf(SqrRoot)(Copyright)-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 must have evaluable
disease, patients with NF1 PN must have measurable disease, patients with refractory
leukemia must have M2 or M3 bone marrow.

--Phase II: Patients must have measurable disease.

- 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 30 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

-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 organ function:

- Adequate bone marrow reserve: ANC greater than or equal to 1000/mm3, Hemoglobin
greater than or equal to 9 gm/dL (transfusion permitted), platelets greater than
or equal to 100,000/mm3 (transfusion independent (except for patients with
marrow involvement by disease where there is no blood count requirement, except
for platelet count which must be greater than or equal to 25,000 prior to
enrollment (can be achieved with transfusion).

- Adequate renal function: serum creatinine normal for age or calculated CrCl
greater than or equal to 70 ml/min/1.73 m2

- Adequate hepatic function: AST and ALT less than or equal to 3.0 X ULN,
Bilirubin less than or equal to 1.5 X ULN, and albumin greater than or equal to
2.5 gm/dl. However, in the presence of liver metastases or in patients with
refractory leukemias, AST and ALT must be < 5 X ULN. Albumin greater than or
equal to 2.8 gm/dl.

- Cardiac ejection fraction greater than or equal to 50%, and QTcF < 450 ms
(male) or < 470 ms (female) on ECG at Baseline. (Fridericia's Formula: QTcF =

- 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.


- 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.

- 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.

- 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.

- Drugs that strongly inhibit or potentiate CYP3A4 should be avoided if possible, as
these drugs could increase or decrease blood levels of PLX3397.
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