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

Study Overview
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Brief Summary
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An open label, non-randomized study in pediatric patients with advanced high-grade gliomas and other solid tumors. The study will be performed in two phases: a dose escalation phase in up to 18 patients following a standard 3+3 design to establish dose-limiting toxicity (DLT) and a safe dose of LAM561 followed by an expanded safety cohort of up to 10 patients treated at the Maximum Tolerated Dose (MTD). If the MTD is well tolerated in the expanded safety cohort, that dose becomes the Recommended Phase 2 Dose (RP2D). Glioma patients and other solid tumor patients (including non-glial brain tumors) will be treated as a single cohort. Patients with either tumor type will be allowed to enroll on the study as positions are made available. No tumor type will be given priority over another and there is no minimum number of glioma patients or solid tumor patients that must be enrolled on the trial.

Detailed Description
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The dose of LAM561 each patient will receive will depend on the dose cohort into which they are enrolled. Once a patient is allocated a dose of LAM561 (either in the dose escalation phase or the expanded safety cohort), it is planned that they will continue to receive the same dose on a daily basis in treatment cycles of 21 days (3 weeks), which may be repeated continuously without therapy interruption, until any criterion for discontinuation is met (clinical or radiological progression of disease, clinically unacceptable toxicity, or another general discontinuation criterion is met as defined in Section 5.5). In the event of significant gastrointestinal toxicity, the treatment schedule may be modified from continuous dosing to an intermittent regime (e.g. 1 week of dosing followed by 1 week not dosing), except during Cycle 1 of the dose escalation phase. In the case of toxicity, the dose of LAM561 may be reduced or delayed by no more than 14 days at the discretion of the Investigator. Treatment holidays of no more than 14 days are also permitted for reasons other than toxicity, except during Cycle 1 of the dose escalation phase. Intra-patient dose escalation may be permitted in certain specific circumstances (and only if ≤ Grade 2 toxicity was observed during previous treatment cycles), but toxicity will not be considered for definition of DLT. It is expected that most patients will receive between one and 6 cycles of LAM561 for a treatment period of 3 to 18 weeks. The treatment period may be extended provided that no DLT has been observed and if in the opinion of the Investigator the patient is showing benefit from treatment with LAM561. Patients demonstrating clinical benefit from LAM561 will have the option of continuing treatment under compassionate use once the study has concluded.

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

Conditions
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High-grade Glioma, Solid Tumor, Unspecified, Child

Intervention / Treatment
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* Drug: LAM561


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age <18 years Diagnosis: Patients must have a histologically- or cytologically-confirmed advanced solid malignancy that is progressive, recurrent or refractory to standard-of-care treatment, or for which there is no standard therapy. 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 performed within 7 days prior to enrollment unless otherwise indicated in the eligibility section. 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 years of age and Lansky for patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair will be considered ambulatory for the purpose of assessing the performance score. Able to swallow and ingest oral medication or have a NG or G-tube for drug administration Able to undergo adequate tumor imaging, via computerized tomography (CT) or magnetic resonance imaging (MRI) scans or any other standardized tumor assessment method based on tumor type (PET, MIBG, etc) to evaluate disease evolution 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. 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 No history of QTc prolongation, and a normal QTc interval at screening/baseline (QTc ≤450 msec) No evidence of a bleeding diathesis Negative pregnancy test in women of childbearing potential within 7 days of initiating investigational therapy Patient or legal guardian must give written, informed consent or assent (when applicable) - Recent mothers must agree not to breast feed while receiving medications on study. Exclusion Criteria: Age ≥ 18 years Known hypersensitivity to any component of the study drug (see Section 6.1) Use of any other investigational drug within five half-lives of that drug prior to the first dose of LAM561 Anti-cancer therapy within 4 weeks prior to the first dose of LAM561 (6 weeks for mitomycin and nitrosureas, 4 weeks for curative-intent radiotherapy, and 2 weeks for palliative radiotherapy) Any National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE version 4.0) >Grade 1 toxicities from prior chemotherapy or radiotherapy that could impact on safety outcome assessment Any surgery within 14 days prior to the first dose of LAM561 (excluding shunt or line insertion) Known >Grade 1 intracranial or intratumoral hemorrhage either by CT or MRI scan within the last 1 month. Patients with resolving hemorrhage changes, punctuate hemorrhage or hemosiderin may enter the study A history of significant or uncontrolled cardiovascular disease, including New York Heart Association Class III-IV heart failure, a left ventricular ejection fraction which is clinically significantly abnormal as measured by 2-dimensional (2-D) echocardiogram or Multi Gated Acquisition(MUGA) scan, unstable angina or myocardial infarction within the preceding 6 months Known impairment of gastrointestinal (GI) function that could alter the absorption of study drug (e.g. active Crohn's disease, malabsorption syndrome or states, unresolved diarrhea, small bowel resection or gastric by-pass surgery) Patients who are unable to take oral medications because of significant uncontrolled vomiting will be excluded. A history of uncontrolled hyperlipidemia and/or the need for concurrent lipid lowering therapy Concurrent severe and/or uncontrolled other medical disease (e.g. uncontrolled diabetes mellitus, active uncontrolled infection) that could compromise participation in the study Need for warfarin, phenytoin or sulphonylureas (glibenclamide, glimepiride, glipizide,glyburide or nateglanide) Any serious and/or unstable pre-existing medical, psychiatric or other condition which in the Investigator's opinion could interfere with subject safety, obtaining written informed consent, or compliance with the study protocol Pregnant female patients are not eligible for this study. Pregnancy tests with a negative result must be obtained in all post-menarchal females. Lactating females must agree they will not breastfeed a child while on this study. Males and females of reproductive potential may not participate unless they agree to use an effective contraceptive method and continue to do so for at least 6 months after the completion of therapy.

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: An open label, non-randomized study in pediatric patients with advanced high-grade gliomas and other solid tumors. The study will be performed in two phases: a dose escalation phase in up to 18 patients following a standard 3+3 design to establish dose-limiting toxicity (DLT) and a safe dose of LAM561 followed by an expanded safety cohort of up to 10 patients treated at the Maximum Tolerated Dose (MTD). If the MTD is well tolerated in the expanded safety cohort, that dose becomes the Recommended Phase 2 Dose (RP2D). Glioma patients and other solid tumor patients (including non-glial brain tumors) will be treated as a single cohort. Patients with either tumor type will be allowed to enroll on the study as positions are made available. No tumor type will be given priority over another and there is no minimum number of glioma patients or solid tumor patients that must be enrolled on the trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>The dose level corresponds to 80% of the maximum tolerated dose of LAM561 in adult patients when adjusted for body surface area. The escalation will be to the 100%, and 120% of the maximum tolerated dose of LAM561 in adult patients when adjusted for body surface area. Dose escalation decisions will be made by all active Investigators in collaboration with the Medical Monitor when at least three patients have completed the DLT observation period (Cycle 1) at each dose level. When the third patient at any given dose level has received 14 days of therapy, an escalation teleconference will be scheduled after that patient has completed the DLT observation period (Cycle 1). The decision to progress to the next dose level will be made on the basis of review of all significant LAM561-related toxicities. | Drug: LAM561<br>* Once a patient is allocated a dose of LAM561, they will receive the same dose on a daily basis in treatment cycles of 21 days (3 weeks), which may be repeated without therapy interruption until a criterion for discontinuation (clinical or radiological progression of disease, clinically unacceptable toxicity, or another general criterion) is met. The starting dose will be 2.8 g/m2 twice daily. If tolerated, doses will be escalated to 3.5 g/m2 twice daily and then to a third dose level of 4.2 g/m2 twice daily. These dose levels correspond to 80%, 100%, and 120% of the maximum tolerated dose of LAM561 in adult patients when adjusted for body surface area. A total of 3 dose cohorts are anticipated for the dose escalation phase of the study, with up to 6 patients enrolled at each dose level according to a standard 3+3 design. During each dose cohort, at least 1 week must elapse between the first and subsequent patients receiving treatment with LAM561.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of LAM561 | To determine the safety and tolerability of LAM561 in pediatric patients (under 18 years) when administered orally using a continuous dosing schedule. It will be evaluated through the adverse events [AEs], physical examinations and vital signs, laboratory safety tests and 12-lead electrocardiograms [ECGs]. | Between 1 to 6 cycles (each cycle is 3 weeks) | 
| To identify the Recommended Phase 2 Dose (RP2D) of LAM561 in pediatric patients | The RP2D of LAM561 in pediatric patients will be the Maximum Tolerated Dose during the safety cohort and it's well tolerared. | Between 1 to 6 cycles (each cycle is 3 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize LAM561 PK profile | The maximum plasma drug concentration observed | During cycles 1 (Days 1, 8 and 15) and 2 (Day 1) (each cycle is 3 weeks) and at the end of study visit (30 days of the last LAM561 dose) | 
| Characterize LAM561 PK profile | The time at which the maximum plasma concentration is observed | During cycles 1 (Days 1, 8 and 15) and 2 (Day 1) (each cycle is 3 weeks) and at the end of study visit (30 days of the last LAM561 dose) | 
| Characterize LAM561 PK profile | The area under the plasma concentration versus time curve from time zero to the last quantifiable sampling point, AUC0-t, calculated by using the linear trapezoidal method | During cycles 1 (Days 1, 8 and 15) and 2 (Day 1) (each cycle is 3 weeks) and at the end of study visit (30 days of the last LAM561 dose) | 
| Characterize LAM561 PK profile | Accumulation ratio (R Cmax). Accumulation ratio calculated from Cmax after repeat dosing and Cmax after single dosing | During cycles 1 (Days 1, 8 and 15) and 2 (Day 1) (each cycle is 3 weeks) and at the end of study visit (30 days of the last LAM561 dose) | 
| Characterize LAM561 PK profile | Accumulation ratio (R AUC0-t) Accumulation ratio calculated from AUC(0-t) after repeat dosing and AUC(0-t) after single dosing | During cycles 1 (Days 1, 8 and 15) and 2 (Day 1) (each cycle is 3 weeks) and at the end of study visit (30 days of the last LAM561 dose) | 
| To assess the preliminary anti-tumor efficacy of LAM561 | Efficacy will be assessed by radiological response of the tumor to treatment | Screening and every four cycles (12 weeks) |