Skip to main content

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

Trial Status: Active

Background: - Some people with cancer have solid tumors. Others have refractory leukemia. This doesn t go away after treatment. Researchers want to see if a drug called PLX3397 can shrink tumors or stop them from growing. Objectives: - To find the highest safe dose and side effects of PLX3397. To see if it helps treat certain types of cancer. Eligibility: - People ages 3 22 with a solid tumor or leukemia that has returned or not responded to cancer therapies. - For Phase II, people ages 3 31 with a Neurofibromatosis Type 1 (NF1) Associated Plexiform Neurofibroma (PN) that cannot be removed with surgery. Design: - Participants will be screened with: - Medical history - Physical exam - Blood and urine tests - Heart tests - Scans or other tests of the tumor - Participants will take PLX3397 as a capsule once daily for a 28-day cycle. They can do this for up to 2 years. - During the study, participants will have many tests and procedures. They include repeats of the screening tests. Participants will keep a diary of symptoms. - Participants with solid tumors will have scans or x-rays. - Participants with NF1 PN will have MRI scans. - Participants with leukemia will have blood tests. They may have a bone marrow sample taken. - Some participants may have a biopsy. - When finished taking PLX3397, participants will have follow-up visits. They will repeat the screening tests and note side effects. - Phase II will follow the same procedures as Phase I above, but participants will also fill out questionnaires about their pain and quality of life.

Inclusion Criteria

  • - INCLUSION CRITERIA: - 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: 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. - Age (must have BSA greater than or equal to 0.55 m^2): - 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 - Ability of subject or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document. --For subjects <18 years old their legal guardian must give informed consent. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those > 7 years of age, when appropriate - 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. - 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 = (QT)/RR0.33) - Contraception: Women of child-bearing potential must agree to use an effective method of birth control during treatment and for 1 month 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 one week 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.


National Institutes of Health Clinical Center
Status: ACTIVE
Contact: National Cancer Institute Referral Office
Phone: 888-624-1937


- 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).


- 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, 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 less than or equal to 35 years of age).

- 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.


- 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

- 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


Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
National Cancer Institute

Principal Investigator
Rosandra Natasha Reich Kaplan

  • Primary ID 150093
  • Secondary IDs NCI-2018-02301, 15-C-0093, NCI-2015-00457
  • ID NCT02390752