Study of LAM561 Acid in Pediatric Patients With Malignant Glioma and Other Advanced Solid Tumors

Inclusion Criteria:

1. Age <18 years

2. Diagnosis: Patients must have a histologically- or cytologically-confirmed advancedsolid malignancy that is progressive, recurrent or refractory to standard-of-caretreatment, or for which there is no standard therapy. Examples of tumors that lack astandard therapy include, but are not limited to, high-grade glioma, diffuse midlineglioma, and diffuse intrinsic pontine glioma. For patients with a radiographicdiagnosis of diffuse midline glioma or diffuse intrinsic pontine glioma, histologicor cytologic confirmation of their diagnosis is not required.

3. Timing of therapy:

• Patients must be enrolled before treatment begins. Treatment must start within 14 days of study enrollment.

• All clinical and laboratory studies to determine eligibility must be performedwithin 7 days prior to enrollment unless otherwise indicated in the eligibilitysection.

4. Patients must have a Lansky or Karnofsky performance status score of ≥ 50%,corresponding to ECOG categories of 0, 1 or 2. Use Karnofsky for patients > 16 yearsof age and Lansky for patients ≤ 16 years of age. Patients who are unable to walkbecause of paralysis, but who are up in a wheelchair will be considered ambulatoryfor the purpose of assessing the performance score.

5. Able to swallow and ingest oral medication or have a NG or G-tube for drugadministration

6. Able to undergo adequate tumor imaging, via computerized tomography (CT) or magneticresonance imaging (MRI) scans or any other standardized tumor assessment methodbased on tumor type (PET, MIBG, etc) to evaluate disease evolution

7. Adequate hematologic, renal, liver function as demonstrated by laboratory values:

• ANC ≥ 1,000/ul

• Hemoglobin ≥8.0 gm/dl

• Platelet count ≥ 100,000/ul

• Adequate Liver Function Defined As

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and

• SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age.

8. Adequate Renal Function Defined As Either

• Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73m2

• or a serum creatinine less than or equal to the institutional normal for age

9. No history of QTc prolongation, and a normal QTc interval at screening/baseline (QTc ≤450 msec)

10. No evidence of a bleeding diathesis

11. Negative pregnancy test in women of childbearing potential within 7 days ofinitiating investigational therapy

12. Patient or legal guardian must give written, informed consent or assent (whenapplicable) -

13. Recent mothers must agree not to breast feed while receiving medications on study.

Exclusion Criteria:

1. Age ≥ 18 years

2. Known hypersensitivity to any component of the study drug

3. Use of any other investigational drug within five half-lives of that drug prior tothe first dose of LAM561

4. Any National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE version 4.0) >Grade 1 toxicities from prior chemotherapy or radiotherapy thatcould impact on safety outcome assessment

5. Any surgery within 14 days prior to the first dose of LAM561 (excluding shunt orline insertion)

6. Known >Grade 1 intracranial or intratumoral hemorrhage either by CT or MRI scanwithin the last 1 month. Patients with resolving hemorrhage changes, punctuatehemorrhage or hemosiderin may enter the study

7. A history of significant or uncontrolled cardiovascular disease, including New YorkHeart Association Class III-IV heart failure, a left ventricular ejection fractionwhich is clinically significantly abnormal as measured by 2-dimensional (2-D)echocardiogram or Multi Gated Acquisition(MUGA) scan, unstable angina or myocardialinfarction within the preceding 6 months

8. Known impairment of gastrointestinal (GI) function that could alter the absorptionof study drug (e.g. active Crohn's disease, malabsorption syndrome or states,unresolved diarrhea, small bowel resection or gastric by-pass surgery)

9. Patients who are unable to take oral medications because of significant uncontrolledvomiting will be excluded.

10. A history of uncontrolled hyperlipidemia and/or the need for concurrent lipidlowering therapy

11. Concurrent severe and/or uncontrolled other medical disease (e.g. uncontrolleddiabetes mellitus, active uncontrolled infection) that could compromiseparticipation in the study

12. Need for warfarin, phenytoin or sulphonylureas (glibenclamide, glimepiride,glipizide,glyburide or nateglanide)

13. Any serious and/or unstable pre-existing medical, psychiatric or other conditionwhich in the Investigator's opinion could interfere with subject safety, obtainingwritten informed consent, or compliance with the study protocol

14. Pregnant female patients are not eligible for this study. Pregnancy tests with anegative result must be obtained in all post-menarchal females.

15. Lactating females must agree they will not breastfeed a child while on this study.

16. Males and females of reproductive potential may not participate unless they agree touse an effective contraceptive method and continue to do so for at least 6 monthsafter the completion of therapy.