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Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

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.

Torisel

Pfizer CT.gov Call Center

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)

Study Evaluating Biomarkers In Relapsed/Refractory Pediatric Solid Tumors

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

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.

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.

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).

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).

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.

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.

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.

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.

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.

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%.

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.

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

AUC (0-t)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t).

AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.

CL is a quantitative measure of the rate at which a drug substance is removed from the body.

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.

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.

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.

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.

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).

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.

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.

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.

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.

AUC (0-t)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t)

AUCss is a measure of the serum concentration of the drug at steady state. It is used to characterize drug absorption.

Pharmacokinetic parameters determined in whole blood; derived from the concentration-versus-time profiles using noncompartmental analysis method. Measured as nanograms per milliliter (ng/mL).

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.

Pfizer

The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Temsirolimus 10 mg/m\^2 administered intravenously once weekly over 60 minutes infusion.

Temsirolimus 10 mg/m^2: Part 1

Temsirolimus 25 mg/m\^2 intravenously administered once weekly over 60 minutes infusion.

Temsirolimus 25 mg/m^2: Part 1

Temsirolimus 75 mg/m\^2 intravenously administered once weekly over 60 minutes infusion.

Temsirolimus 75 mg/m^2: Part 1

Temsirolimus 150 mg/m\^2 intravenously administered once weekly over 60 minutes infusion.

Temsirolimus 150 mg/m^2: Part 1

Participants with high-grade glioma were administered temsirolimus 75 mg/m\^2 intravenously once weekly over 60 minutes infusion.

High-grade Glioma: Part 2

Participants with neuroblastoma were administered temsirolimus 75 mg/m\^2 intravenously once weekly over 60 minutes infusion.

Neuroblastoma: Part 2

Participants with rhabdomyosarcoma were administered temsirolimus 75 mg/m\^2 intravenously once weekly over 60 minutes infusion.

Rhabdomyosarcoma: Part 2

Participants received temsirolimus intravenously once weekly over 60 minutes infusion in dose escalation schemes of 10 mg/m\^2, 25 mg/m\^2, 75 mg/m\^2 and 150 mg/m\^2.

Part 1

Participants with high-grade glioma, neuroblastoma and rhabdomyosarcoma were administered temsirolimus 75 mg/m\^2 intravenously once weekly over 60 minutes infusion.

Part 2 Total

Greater than or equal to(>=)1 to less than16 years

>=16 to less than 18 years

>=18 to less than or equal to 21 years

Age, Customized

Sex: Female, Male

Pfizer ClinicalTrials.gov Call Center

SAEs

Temsirolimus 10 milligrams per square meter (mg/m\^2) administered intravenously once weekly over 60 minutes infusion.

Temsirolimus 25 mg/m\^2 administered intravenously once weekly over 60 minutes infusion.

Temsirolimus 75 mg/m\^2 administered intravenously once weekly over 60 minutes infusion.

Temsirolimus 150 mg/m\^2 administered intravenously once weekly over 60 minutes infusion.

Safety population included all participants who received at least 1 dose of study medication.

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs): Part 1

Number of Participants Who Reached Maximum Tolerated Dose Due to Dose Limiting Toxicity: Part 1

Cycle 1 (n = 4, 5, 3, 7)

Cycle 2 (n = 4, 4, 3, 5)

Safety population included all participants who received at least 1 dose of study medication. Here, 'n' signifies those participants who were evaluable for particular cycle for each group respectively.

Maximum Observed Plasma Concentration (Cmax): Part 1

Time to Reach Maximum Observed Plasma Concentration (Tmax): Part 1

Cycle 1 (n = 4, 4, 1, 4)

Cycle 2 (n = 4, 3, 3, 5)

Safety population included all participants who received at least 1 dose of study medication. Here, the 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure for each group respectively. Here, 'n' signifies those participants who were evaluable for particular cycle for each group respectively.

Plasma Decay Half-Life (t1/2): Part 1

Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)]: Part 1

Area Under the Concentration-Time Curve (AUC): Part 1

Clearance (CL): Part 1

Volume of Distribution at Steady State (Vss): Part 1

Complete response

Partial response

Stable disease

Progressive disease

Unknown response

Efficacy evaluable population included all participants who received at least 3 doses of study medication. Here, the 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure for each group respectively.

Percentage of Participants With Best Overall Response: Part 1

Efficacy evaluable population included all participants who received at least 3 doses of study treatment. Here, the 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure for each group respectively.

Percentage of Participants Exhibiting Freedom From Progression at Week 12: Part 2

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs): Part 2

Number of Participants With Drug Related Treatment Emergent Adverse Events (TEAEs): Part 2

Number of Participants With Drug Related Grade 3 and Higher Treatment Emergent Adverse Events (TEAEs): Part 2

Died=Yes

Died within 30 days of last dose

Number of Participants Who Died: Part 2

Number of Participants With Drug Related Serious Adverse Events (SAEs): Part 2

Number of Participants With Adverse Events Causing Temporary Stop of Study Treatment: Part 2

Number of Participants With Adverse Events Causing Dose Reduction of Study Treatment: Part 2

Number of Participants With Drug Related Treatment Emergent Adverse Events (TEAEs): Part 1

Number of Participants With Drug Related Grade 3 and Higher Treatment Emergent Adverse Events (TEAEs): Part 1

Number of Participants Who Died: Part 1

Number of Participants With Drug Related Serious Adverse Events (SAEs): Part 1

Number of Participants With Adverse Events Causing Temporary Stop of Study Treatment: Part 1

Number of Participants With Adverse Events Causing Dose Reduction of Study Treatment: Part 1

Temperature >39 degrees C

Respiratory rate >20 bpm

Systolic/Diastolic BP >200/110 mmHg

Number of Participants With Potentially Clinically Important (PCI) Changes in Vital Signs: Part 1

Number of Participants With Potentially Clinically Important (PCI) Changes in Vital Signs: Part 2

Number of Participants With Potentially Clinically Important (PCI) Values by National Cancer Institute Common Terminology Criteria (NCI-CTC) Grade for Laboratory Values: Part 2

Participants with high-grade glioma, neuroblastoma and rhabdomyosarcoma were administered temsirolimus 75 mg/m\^2 intravenously once weekly over 60 minutes infusion..

Safety population included all participants who received at least 1 dose of study medication. Here, the 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.

Maximum Observed Plasma Concentration (Cmax): Part 2

Average Plasma Concentration (Cavg): Part 2

Time to Reach Maximum Observed Plasma Concentration (Tmax): Part 2

Safety population included all participants who received at least 1 dose of study medication. Here, the 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure for.

Plasma Decay Half-Life (t1/2): Part 2

Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)]: Part 2

Number of Participants With Potentially Clinically Important (PCI) Values by National Cancer Institute Common Terminology Criteria (NCI-CTC) Grade for Laboratory Values: Part 1

Percentage of Participants With Objective Response (OR) at Week 12: Part 2

Area Under the Concentration-time Curve at Steady State (AUCss): Part 2

Clearance (CL): Part 2

Concentration in Plasma (Cp) and Concentration in Plasma at Time Zero (Cp Time 0): Part 1 and Part 2

Number of Participants for Change From Baseline in the Phosphorylation of Mammalian Target of Rapamycin (mTOR) Pathway Proteins: Part 1 and Part 2

Temsirolimus 10 milligram per square meter (mg/m\^2) administered intravenously once weekly over 60 minutes infusion.

All Pediatric Oncology and Bone Marrow Transplantation Service patients with a histologically proven tumor for whom there is an intent to treat with chemotherapy

will be the collection of normal cells and assessments of toxicity following chemotherapy at routine clinic visits.

buccal swabs and obtaining peripheral blood

Paul Meyers, MD

The purpose of this study is to develop tests that will allow us to determine who will react differently to the drugs used to treat cancer. We also want to see who will react differently with preparing for a bone marrow transplant.

The title of this study is interindividual genetic variability as a determinant of chemotherapy toxicity and response in pediatric oncology/bone marrow transplantation patients. We will collect blood from pediatric oncology/bone marrow transplantation patients who are going to receive chemotherapy in order to assess several defined genetic polymorphisms that may be involved in chemotherapy toxicity and response. The polymorphisms will be assessed on normal mononuclear cells by a combination of techniques. We will determine whether these polymorphisms occur in pediatric oncology/bone marrow transplantation patients and their correlation with different clinical features during and following therapy including toxicity and response. The presence or absence of polymorphisms will be correlated with patient outcome and tumor recurrence.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study Evaluating Biomarkers In Relapsed/Refractory Pediatric Solid Tumors	NCT00106353	Adenocarcinoma Neoplasms	Torisel	1 Year - 21 Years	Pfizer
Interindividual Genetic Variability as a Determinant of Chemotherapy Toxicity and Response in Pediatric Bone Marrow Transplantation Patients	NCT00578630	Neoplasms	buccal swabs an...	-	Memorial Sloan Kettering Cancer Center

Spots Global Cancer Trial Database for pediatric tumors