Study Evaluating Biomarkers In Relapsed/Refractory Pediatric Solid Tumors

Study Overview
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Brief Summary
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This is an open label, two-part study of temsirolimus given as a 60-minute intravenous (IV) infusion once weekly to pediatric subjects with advanced solid tumors. Part 1 is an ascending-dose study to evaluate the safety of IV temsirolimus given once weekly to subjects ages 1 to 21 years with advanced solid tumors disease that is recurrent or refractory to standard therapy or for whom standard therapy is not available. (enrollment completed) Part 2 will be conducted in three groups of children with refractory or relapsed pediatric solid tumors. Subjects with the following tumor types will be enrolled: neuroblastoma, rhabdomyosarcoma, and high-grade gliomas. Subjects will receive IV temsirolimus once weekly until disease progression or unacceptable toxicity. (recruiting)

Official Title
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A Phase I/II Safety and Exploratory Pharmacogenomic/Pharmacodynamic Study of Intravenous Temsirolimus (CCI-779) in Pediatric Subjects With Relapsed/Refractory Solid Tumors

Conditions
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Adenocarcinoma, Neoplasms

Intervention / Treatment
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* Drug: Torisel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria: Part 1 only: - Subjects with a histological diagnosis of advanced cancer (solid tumors or central nervous system [CNS] tumors) with disease that is recurrent or refractory to standard therapy or for whom standard therapy is not available (histological confirmation waived for brain stem gliomas and optic pathway tumors) Part 2 only: Subjects with histologically confirmed diagnosis of refractory or relapsed: Neuroblastoma, High-grade gliomas: glioblastoma multiforme, anaplastic astrocytomas, and other high-grade gliomas (histological confirmation waived for brain stem gliomas), Rhabdomyosarcoma. Measurable disease (for subjects with neuroblastoma, evaluable disease as determined by a positive metaiodobenzylguanidine (MIBG) scan will also be permitted). Exclusion Criteria: Exclusion Criteria: Subjects receiving enzyme-inducing anticonvulsants. Pulmonary hypertension or pneumonitis Active infection or serious intercurrent illness Other exclusions apply

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1.0<br> | Drug: Torisel<br>* 60-minute intravenous (IV) infusion once weekly to pediatric subjects with advanced solid tumors. Part 1 is an ascending-dose study to evaluate the safety of IV temsirolimus given once weekly to subjects ages 1 to 21 years with advanced solid tumors disease that is recurrent or refractory to standard therapy or for whom standard therapy is not available. (enrollment completed) Part 2 will be conducted in three groups of children with refractory or relapsed pediatric solid tumors. Subjects with the following tumor types will be enrolled: neuroblastoma, rhabdomyosarcoma, and high-grade gliomas. Subjects will receive IV temsirolimus once weekly until disease progression or unacceptable toxicity.<br>* Other names: temsirolimus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs): Part 1 | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | Baseline up to End of Treatment (EOT) (within 30 days of last dose) | 
| Number of Participants With Drug Related Treatment Emergent Adverse Events (TEAEs): Part 1 | TEAEs are events that occurred on or after initial treatment that were absent before treatment or worsened during the treatment period relative to the pretreatment state. AEs that occurred within 30 days of the last administration of study treatment can be attributed to the treatment period. | Baseline up to EOT (within 30 days of last dose) | 
| Number of Participants With Drug Related Grade 3 and Higher Treatment Emergent Adverse Events (TEAEs): Part 1 | TEAEs are events that occurred on or after initial treatment that were absent before treatment or worsened during the treatment period relative to the pretreatment state. AEs that occurred within 30 days of the last administration of study treatment can be attributed to the treatment period. National Cancer Institute (NCI)-graded Common Toxicity Criteria (CTC) provides descriptive terminology for adverse event reporting. A grading (severity) scale is provided for each adverse event term. Grades range from 0 (none) to 5 (death). | Baseline up to EOT (within 30 days of last dose) | 
| Number of Participants Who Died: Part 1 | Deaths were reported from baseline throughout the 30 day period after last study treatment. After the 30 day reporting period, only deaths believed related to study treatment were to be reported (as SAEs). | Baseline up to EOT (within 30 days of last dose) | 
| Number of Participants With Drug Related Serious Adverse Events (SAEs): Part 1 | SAEs include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability / incapacity or are a congenital anomaly or birth defect in the offspring of a study subject. Participants with documented study treatment toxicity were followed weekly until recovering. After the 30 day reporting period, only SAEs believed to be related to study treatment were to be reported. | Baseline up to EOT (within 30 days of last dose) | 
| Number of Participants With Adverse Events Causing Temporary Stop of Study Treatment: Part 1 | Temporary interruption of study treatment; may be followed by resumption of study treatment at current dose or dose modification as determined by the investigator and medical monitor. | Baseline up to EOT (within 30 days of last dose) | 
| Number of Participants With Adverse Events Causing Dose Reduction of Study Treatment: Part 1 | Dose reduction for individual participant allowed if a dose limiting toxicity (DLT) occurred; may continue treatment following reduction by 1 to 2 dose levels (determined by investigator and medical monitor). DLT= failure to recover to National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) version 3.0 grade 0 to 2 (or within 1 grade of starting values for pre-existing laboratory abnormalities) from a treatment-related toxicity within 3 weeks (leading to a treatment delay of >3 weeks) unless investigator and medical monitor agree participant should remain in the study. | Baseline up to EOT (within 30 days of last dose) | 
| Number of Participants With Potentially Clinically Important (PCI) Changes in Vital Signs: Part 1 | Number of participants who met the criteria for PCI changes (based on baseline values before treatment); criteria defined as body temperature >39 degrees Celsius (C), respiratory rate >20 beats per minute (bpm), and systolic and diastolic blood pressure (BP) >200/110 millimeters of mercury (mmHg). Participants may be reported in more than 1 category. | Baseline up to EOT (within 30 days of last dose) | 
| Number of Participants With Potentially Clinically Important (PCI) Values by National Cancer Institute Common Terminology Criteria (NCI-CTC) Grade for Laboratory Values: Part 1 | Number of participants who met the PCI criteria (grades 1 through 5) for laboratory values (hematology and serum chemistry). NCI-CTC provides descriptive terminology for adverse event reporting. A grading (severity) scale is provided with grades ranging from 0 (none), 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening or disabling), to 5 (death). Participants may be reported in more than 1 category. | Baseline up to EOT (within 30 days of last dose) | 
| Percentage of Participants With Objective Response (OR) at Week 12: Part 2 | Measured as Complete response (CR), Very good partial response (VGPR), or Partial response (PR) on at least 2 occasions greater than or equal to (>=) 4 weeks apart within first 12 weeks. CR=disappearance of all primary and metastatic lesions; Homovanillic acid, Vanillymandelic acid (HVA/VMA) normal; bone marrow immunocytology negative. VGPR=disappearance of all metastatic lesions (residual areas of uptake on bone permitted); 90 to 99 percent (%) decrease in primary disease measurement; HVA/VMA normal or both decreased >90%. PR=at least 50% decrease in primary and metastatic disease. Number of bone sites decreased by at least 50%. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Reached Maximum Tolerated Dose Due to Dose Limiting Toxicity: Part 1 | Maximum tolerated dose (MTD) defined as the dose level at which >=2 of 3 participants or >=2 of 6 participants if the dose level had been expanded, experienced a dose limiting toxicity (DLT) by day 21 after the first dose of study treatment. DLT defined as failure to recover to NCI-CTCAE version 3.0 grade 0 to 2 (or within 1 grade of starting values for pre-existing laboratory abnormalities) from a treatment-related toxicity within 3 weeks (leading to a treatment delay of > 3 weeks) unless the investigator and the medical monitor agree that the subject should remain in the study. | Baseline up to Month 6 | 
| Maximum Observed Plasma Concentration (Cmax): Part 1 |  | 0 (pre-dose), 1, 2, 6, 24, and 168 hours (hrs) post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days) | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax): Part 1 |  | 0 (pre-dose), 1, 2, 6, 24, and 168 hrs post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days) | 
| Plasma Decay Half-Life (t1/2): Part 1 | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | 0 (pre-dose), 1, 2, 6, 24, and 168 hrs post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days) | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)]: Part 1 | AUC (0-t)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t). | 0 (pre-dose), 1, 2, 6, 24, and 168 hrs post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days) | 
| Area Under the Concentration-Time Curve (AUC): Part 1 | AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. | 0 (pre-dose), 1, 2, 6, 24, and 168 hrs post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days) | 
| Clearance (CL): Part 1 | CL is a quantitative measure of the rate at which a drug substance is removed from the body. | 0 (pre-dose), 1, 2, 6, 24, and 168 hrs post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days) | 
| Volume of Distribution at Steady State (Vss): Part 1 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. | 0 (pre-dose), 1, 2, 6, 24, and 168 hrs post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days) | 
| Percentage of Participants With Best Overall Response: Part 1 | Best overall response is the best response recorded from baseline until disease progression or recurrence. Measured as CR, PR, SD, PD, or Unknown. CR=disappearance of all primary and metastatic lesions. PR=at least a 50% decrease in primary disease measurement. SD=no new lesions; decrease of <50% in all lesions with no lesion increasing >25%. PD=any new lesion; at least a 25% increase in any disease measurement (reference smallest disease measurement recorded since start of treatment); or appearance of 1 or more new lesions. Tumor response considered Unknown if assessment prior to Day 37. | Baseline until disease progression or recurrence (actual greatest response day is up to Day 49) | 
| Percentage of Participants Exhibiting Freedom From Progression at Week 12: Part 2 | Freedom from progression measured as Stable Disease (SD) or better and no Progressive Disease (PD); (CR+VGPR+Mixed Response [MR]+PR+SD). CR=disappearance of all primary and metastatic lesions. VGPR=disappearance of all metastatic lesions. MR=no new lesions; at least 50% decrease in any 1 disease measurement with <50% decrease in any other disease measurement or an increase of <25% in any lesion). SD=no new lesions; decrease of <50% in all lesions with no lesion increasing >25%. PD=at least a 25% increase in any disease measurement; or the appearance of 1 or more new lesions. | Week 12 | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs): Part 2 | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | Baseline up to EOT (within 30 days of last dose) | 
| Number of Participants With Drug Related Treatment Emergent Adverse Events (TEAEs): Part 2 | Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. | Baseline up to EOT (within 30 days of last dose) | 
| Number of Participants With Drug Related Grade 3 and Higher Treatment Emergent Adverse Events (TEAEs): Part 2 | Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. NCI-CTC provides descriptive terminology for adverse event reporting. A grading (severity) scale is provided for each adverse event term. Grades range from 0 (none) to 5 (death). | Baseline up to EOT (within 30 days of last dose) | 
| Number of Participants Who Died: Part 2 | Deaths were reported from baseline throughout the 30 day period after last study treatment. After the 30 day reporting period, only deaths believed related to study treatment were to be reported (as SAEs). | Baseline up to EOT (within 30 days of last dose) | 
| Number of Participants With Drug Related Serious Adverse Events (SAEs): Part 2 | An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Participants with documented study treatment toxicity were followed weekly until recovering. After the 30 day reporting period, only SAEs believed to be related to study treatment were to be reported. | Baseline up to EOT (within 30 days of last dose) | 
| Number of Participants With Adverse Events Causing Temporary Stop of Study Treatment: Part 2 | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Temporary interruption of study treatment may be followed by resumption of study treatment at current dose or dose modification as determined by the investigator and medical monitor. | Baseline up to EOT (within 30 days of last dose) | 
| Number of Participants With Adverse Events Causing Dose Reduction of Study Treatment: Part 2 | Dose reduction for individual participant allowed if a DLT occurred; may continue treatment following reduction by 1 to 2 dose levels (determined by investigator and medical monitor). DLT= failure to recover to National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) version 3.0 grade 0 to 2 (or within 1 grade of starting values for pre-existing laboratory abnormalities) from a treatment-related toxicity within 3 weeks (leading to a treatment delay of >3 weeks) unless investigator and medical monitor agree participant should remain in the study. | Baseline up to EOT (within 30 days of last dose) | 
| Number of Participants With Potentially Clinically Important (PCI) Changes in Vital Signs: Part 2 | Number of participants who met the criteria for PCI changes (based on baseline values before treatment); criteria defined as body temperature >39 degrees C, respiratory rate >20 bpm, and systolic and diastolic BP >200/110 mmHg. Participants may be reported in more than 1 category. | Baseline up to EOT (within 30 days of last dose) | 
| Number of Participants With Potentially Clinically Important (PCI) Values by National Cancer Institute Common Terminology Criteria (NCI-CTC) Grade for Laboratory Values: Part 2 | Number of participants who met the PCI criteria (grades 1 through 5) for laboratory values (hematology and serum chemistry). NCI-CTC provides descriptive terminology for adverse event reporting. A grading (severity) scale is provided with grades ranging from 0 (none), 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening or disabling), to 5 (death). Participants may be reported in more than 1 category. | Baseline up to EOT (within 30 days of last dose) | 
| Maximum Observed Plasma Concentration (Cmax): Part 2 |  | 0 (pre-dose), 1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days) | 
| Average Plasma Concentration (Cavg): Part 2 |  | 0 (pre-dose), 1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days) | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax): Part 2 |  | 0 (pre-dose),1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days) | 
| Plasma Decay Half-Life (t1/2): Part 2 | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | 0 (pre-dose), 1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days) | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)]: Part 2 | AUC (0-t)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t) | 0 (pre-dose), 1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days) | 
| Area Under the Concentration-time Curve at Steady State (AUCss): Part 2 | AUCss is a measure of the serum concentration of the drug at steady state. It is used to characterize drug absorption. | 0 (pre-dose), 1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days) | 
| Clearance (CL): Part 2 | CL is a quantitative measure of the rate at which a drug substance is removed from the body. | 0 (pre-dose),1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days) | 
| Concentration in Plasma (Cp) and Concentration in Plasma at Time Zero (Cp Time 0): Part 1 and Part 2 | Pharmacokinetic parameters determined in whole blood; derived from the concentration-versus-time profiles using noncompartmental analysis method. Measured as nanograms per milliliter (ng/mL). | Part 1: 0 (pre-dose), 1, 2, 6, 24, and 168 hrs post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2; Part2: 0 (pre-dose), 1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days) | 
| Number of Participants for Change From Baseline in the Phosphorylation of Mammalian Target of Rapamycin (mTOR) Pathway Proteins: Part 1 and Part 2 | Optional bone marrow sampling for pharmacodynamic analysis of effects of study treatment. Data may not be collected for a majority of patients and was not to be summarized if collection was sparse. | Part 1:Baseline,1,2,6,24,168 hrs post-dose of Cycle 1;additional 0 (Pre-dose),24,72,96 hrs, Day 16 to 21 of cycle 2, EOT(within 30 days of last dose); Part 2:Baseline,Day16 to 21 in Cycle 2, at time of disease progression, EOT(within 30 days of last dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric Tumors