Conditions: Lymphoblastic Leukemia, Acute, Childhood Lymphoblastic Lymphoma Peripheral T-cell Lymphoma
Keywords: Relapse Lymphoblastic Leukemia Refractory Temsirolimus Acute Childhood Pediatric ALL NHL LL PTL
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 16
Healthy volunteers: no

Brief summary:
This is a phase I study of temsirolimus (Torisel) combined with dexamethasone, cyclophosphamide and etoposide in patients with relapsed acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LL) or peripheral T-cell lymphoma (PTL).

Detailed description:
Studies have shown that mTOR inhibitors (MTI) inhibit growth of pre-B and T-cell ALL cell lines in vitro and in ALL xenograft models. The MTI temsirolimus was chosen for use in this study due to its weekly intravenous dosing, its more predictable blood levels, and availability of a single-agent pediatric MTD and its sustained biologic effect due to conversion to sirolimus. This study will determine the maximum tolerated dose of temsirolimus that can given in combination with dexamethasone, cyclophosphamide and etoposide in relapsed ALL, LL or PTL. A standard 3-patient cohort dose-escalation design will be used. Response to treatment will be evaluated. Biology tests will be done to evaluate minimal residual disease (MRD), temsirolimus' effect on glucocorticoid resistance, and mTOR inhibition.

Arms:
arm 1: This is the starting dose of temsirolimus at 7.5 mg/m\^2 given IV. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. arm 2: If Dose Level 1 is tolerated, the study will escalate to Dose Level 2 following the dose escalation schedule. Dose Level 2 will be administered via IV at 10 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. arm 3: If Dose Level 2 is tolerated, the study will escalate to Dose Level 3 following the dose escalation schedule. Dose Level 3 will be administered via IV at 15 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. arm 4: If Dose Level 3 is tolerated, the study will escalate to Dose Level 4 following the dose escalation schedule. Dose Level 4 will be administered via IV at 25 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Temsirolimus will not be escalated beyond Dose Level 4.

Interventions: intervention 1: Temsirolimus intervention 2: Etoposide intervention 3: Cyclophosphamide intervention 4: Methotrexate intervention 5: Hydrocortisone intervention 6: Cytarabine
Intervention descriptions: intervention 1: Dose will be assigned at study entry. Give IV over 30 minutes on days 1 and 8. intervention 2: 100 mg/m2 IV over 1-2 hours daily x 5 on Days 1-5. intervention 3: 440 mg/m2 IV daily x 5 on Days 1-5 given over 30-60 minutes. intervention 4: PATIENTS WITH CNS 1 COURSES 2, 4, 6, 8: Give intrathecally to patients who were CNS1 at study entry day 1 of each course at the doses listed below.

* Age 1 - 1.99 give 8 mg of methotrexate
* Age 2 - 2.99 give10 mg of methotrexate
* Age 3 - 8.99 give 12 mg of methotrexate
* Age ≥ 9 give 15 mg of methotrexate

PATIENTS WITH CNS 2 or 3 DISEASE

-COURSE 1: Give intrathecally to patients with CNS 2 or 3 disease at the doses defined by age below on day 6 and then weekly until the patient is CNS 1.

COURSES 2-8: Give intrathecally to patients who were CNS 3 at study entry on day 1 of each course.

* 8 mg for patients age 1-1.99
* 10 mg for patients age 2-2.99
* 12 mg for patients 3-8.99 years of age
* 15 mg for patients \>9 years of age intervention 5: Given with Methotrexate and Cytarabine for patients with CNS 2 or 3 disease.

COURSE 1: Give intrathecally to patients with CNS 2 or 3 disease at the doses defined by age below on day 6 and then weekly until the patient is CNS 1.

COURSES 2-8: Give intrathecally to patients who were CNS 3 at study entry on day 1 of each course.

* 8 mg for patients age 1-1.99
* 10 mg for patients age 2-2.99
* 12 mg for patients 3-8.99 years of age
* 15 mg for patients \>9 years of age intervention 6: For Patients who are CNS1 COURSE 1: Give intrathecally to patients with CNS1 disease at the dose defined by age below on day 1 of course 1 if no other IT was given within 1 week of day 1 of course 1

* Age 1 - 1.99 give 30 mg of Cytarabine
* Age 2 - 2.99 give 50mg of Cytarabine
* Age ≥ 3 give 70 mg of Cytabine

For Patients with CNS 2 or 3 Disease COURSE 1: Give intrathecally to patients with CNS 2 or 3 disease at the doses defined by age below on day 1 if no other IT chemotherapy given within 1 week of day 1 of course 1. Then give weekly until the patient is CNS 1 or 2 (investigator discretion). No more than 5 weekly doses to be given in cycle 1.

COURSES 2-8: Give intrathecally to patients who were CNS 2or 3 at study entry on day 1 of each course.

* 16 mg for patients age 1-1.99
* 20 mg for patients age 2-2.99
* 24 mg for patients 3-8.99 years of age
* 30 mg for patients \>9 years of age

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
T2014-001 A Phase I Trial of Temsirolimus (CCI-779, Pfizer, 
Inc.) in Combination with Etoposide and Cyclophosphamide in 
Children with Relapsed Acute Lymphoblastic Leukemia and 
Non-Hodgkins Lymphoma 
NCT number: 
NCT01614197 
Document date: 
18-JAN-2018 
 


 
 
 
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T2014-001 A Phase I Trial of Temsirolimus (CCI-779, Pfizer, Inc.) in 
Combination with Etoposide and Cyclophosphamide in Children with 
Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkins 
Lymphoma  
 
PROTOCOL CO-CHAIRPERSON:  
Susan R. Rheingold, MD 
 
PROTOCOL CO-CHAIRPERSON:  
Lewis B. Silverman, MD 
 
VICE-CHAIR 
James A.  Whitlock, MD 
 
TACL MEMBER INSTITUTIONS 
 
All Children’s Hospital – Johns Hopkins 
Medical College of Wisconsin 
Baylor College of Medicine – Texas Children’s 
Hospital 
Nationwide Children’s Hospital 
Ann & Robert H. Lurie Children’s Hospital of Chicago 
Oregon Health & Science University 
British Columbia Children’s Hospital 
Primary Children’s Hospital 
Children's Healthcare of Atlanta  
Rainbow Babies & Children’s Hospital 
Children’s Hospital and Clinics of Minnesota 
Royal Children’s Hospital, Melbourne 
Children’s Hospital Los Angeles 
Sainte-Justine University Hospital Center  
Children’s Hospital New York-Presbyterian 
Seattle Children’s Hospital 
Children’s Hospital Orange County 
Sidney Kimmel Cancer Center at Johns Hopkins 
Children’s Hospital of Philadelphia 
St. Jude Children’s Research Hospital Memphis 
Children’s National Medical Center 
Sydney Children’s Hospital 
Cincinnati Children’s Hospital 
The Children’s Hospital at Westmead 
Cook Children’s Medical Center 
The Children’s Hospital, University of Colorado  
CS Mott Children’s Hospital, Ann Arbor 
UCSF School of Medicine 
Dana-Farber Cancer Institute 
University of Miami 
Hospital for Sick Children, Toronto 
University of Texas Southwestern Medical Center 
 Levine Children's Hospital at Carolinas Medical 
Center  
 
 
TACL OPERATIONS CENTER 
CHLA, 4650 Sunset Blvd., MS-54, Los Angeles, CA 90027 
Phone: (323) 361-5429 Fax: (877) 904-2166 
 
 https://tacl.chla.usc.edu/tacl TACL protocols and their content are for research purposes only and should 
not be copied, redistributed or used for any other purpose. The procedures in this protocol are intended 
only for use at TACL member institutions under the direction of TACL physicians. The most current 
version of the protocol should be accessed at https://tacl.chla.usc.edu . 
TACL Protocol: T2014-001 
Original Version Date: 
  
12-18-2014 
 
 
Amendment #1: 01-
26-2016 
 
Activated: 3-17-2015 
Amendment #2:  1-18-2018 
 
 
 
TACL 
Therapeutic Advances in  
Childhood Leukemia & Lymphoma 
 


 
 
 
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Table of Contents: 
STUDY COMMITTEE ................................................................................................................................... 5 
ABSTRACT................................................................................................................................................... 6 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) ........................................................................... 7 
2.0 
BACKGROUND ................................................................................................................................ 8 
2.1 
Introduction/Rationale for Development ............................................................................................ 8 
2.2 
Preclinical Studies ............................................................................................................................. 8 
2.3 
Adult Studies ................................................................................................................................... 10 
2.4 
Pediatric Studies ............................................................................................................................. 12 
3.0 
PATIENT ELIGIBILITY CRITERIA AND ENROLLMENT .............................................................. 14 
3.1 
Patient Reservation ......................................................................................................................... 14 
3.2 
Enrollment ....................................................................................................................................... 14 
3.3 
Inclusion Eligibility Criteria .............................................................................................................. 15 
3.4       Exclusion Eligibility Criteria ............................................................................................................. 17 
3.5 
Regulatory ....................................................................................................................................... 19 
4.0 
TREATMENT PROGRAM .............................................................................................................. 20 
4.2 
Disease Evaluations ........................................................................................................................ 21 
4.3 
Dose Escalation Schedule .............................................................................................................. 22 
4.4 
Criteria to begin Course 2 and subsequent courses ....................................................................... 22 
4.5 
Dose-Limiting Toxicity (DLT) ........................................................................................................... 24 
4.6 
Dose Modifications .......................................................................................................................... 25 
4.7  
Drug Interactions ............................................................................................................................. 30 
5.0 
SUPPORTIVE CARE ...................................................................................................................... 32 
5.1  
Concurrent Therapy ........................................................................................................................ 32 
5.2  
Infection Control .............................................................................................................................. 32 
5.3  
Supportive Care .............................................................................................................................. 34 
6.0 
DRUG INFORMATION ................................................................................................................... 35 


 
 
 
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6.1 
Temsirolimus (CCI-779, Torisel®, Rapamycin analog, WAY-130779) ........................................... 35 
6.2 
Etoposide  (Vepesid®, Etopophos®,VP-16) NSC #141540 ........................................................... 39 
6.3 
Cyclophosphamide (Cytoxan) NSC #26271 ................................................................................... 41 
6.4 
IT Methotrexate (MTX, amethopterin, Trexall®) NSC #000740 ...................................................... 42 
6.5 
Leucovorin Calcium (LCV, Wellcovorin®, citrovorum factor, folinic acid) NSC #003590 ............... 44 
6.6 
IT Cytarabine ................................................................................................................................... 45 
6.7 
Intrathecal Triples (Methotrexate/Hydrocortisone/Cytarabine, ITT) ................................................ 46 
7.0   REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ACCESSIONED ............................ 49 
7.1 
Required Clinical, Laboratory and Disease Evaluation ................................................................... 49 
7.2 
Required Observations Following Completion of Protocol Therapy ............................................... 50 
8.0 
CORRELATIVE AND PHARMACOKINETIC STUDIES ................................................................ 52 
8.1 
Bone Marrow MRD (Required for Leukemia patients) .................................................................... 52 
8.2 
Bone Marrow Correlative Biology Studies (Optional)...................................................................... 53 
8.3 
PBMC Correlative Biology Studies (Optional) ................................................................................. 55 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY, OFF STUDY CRITERIA AND 
STUDY TERMINATION .............................................................................................................................. 57 
9.1 
Criteria for Removal from Protocol Therapy ................................................................................... 57 
9.2 
Off Study Criteria ............................................................................................................................. 57 
9.3 
Termination of the Study by TACL ................................................................................................ 577 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................................... 59 
10.1 
Statistical Considerations for Dose Escalation Criteria ................................................................... 59 
10.2 
Patient Accrual and Study Duration ................................................................................................ 60 
10.3 
Interim Monitoring of Toxic Death ................................................................................................... 60 
10.4 
Inclusion of Women and Minorities ................................................................................................. 60 
11.0 
RESPONSE CRITERIA .................................................................................................................. 61 
11.1 
Bone Marrow Status Definitions ...................................................................................................... 61 
11.2 
Response Criteria for Patients With Leukemia ............................................................................... 61 
11.3 
CNS Response Criteria ................................................................................................................... 61 


 
 
 
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11.4  Response Criteria for Patients with Lymphoma ................................................................................. 62 
11.5 
Best Response ................................................................................................................................ 66 
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS ..................................................................... 69 
12.1 
Definitions ........................................................................................................................................ 69 
12.2 
Data Collection ................................................................................................................................ 69 
12.3 
Reporting Serious Adverse Events or Serious Suspected Adverse Reactions .............................. 70 
12.4 
Institutional Reporting to the IRB .................................................................................................... 71 
13.0 
DATA AND SAFETY MONITORING .............................................................................................. 72 
13.1 
Data Submission ............................................................................................................................. 72 
13.2 
Weekly Safety Review .................................................................................................................... 72 
13.3 
Data Safety and Monitory Committee (DSMC) ............................................................................... 72 
14.0 
REFERENCES ................................................................................................................................ 73 
15.0 
SAMPLE INFORMED CONSENT .................................................................................................. 76 
APPENDIX I:  
PERFORMANCE STATUS SCALES/SCORES ............................................................. 91 
APPENDIX II:  
CYP3A4 INDUCERS AND INHIBITORS ........................................................................ 94 


 
 
 
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 STUDY COMMITTEE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 


 
 
 
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 ABSTRACT  
 
One in five children with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) will 
develop recurrent disease despite strategies of risk stratification and modern intensified chemotherapy. 
The combination of etoposide and cyclophosphamide is used widely in an attempt to salvage the 
refractory and relapsed lymphoblastic leukemia and lymphoma population. Therefore we propose a 
Phase 1 study to determine the feasibility and safety of adding two weekly doses of intravenous 
temsirolimus to standard ALL salvage therapy with 5 days of cyclophosphamide and etoposide.  
 
 
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in signal transduction 
pathways which regulate cell growth and proliferation.1-3 While mutations in mTOR do not frequently occur 
in human cancer46, constitutive activation of signal transduction proteins related to the mTOR pathway 
(AKT kinase, S6K1, PI3K) or loss of proteins linked to mTOR (PTEN) are found in numerous 
malignancies.1, 3, 4 Studies have shown that mTOR inhibitors (MTI) inhibit growth of pre-B and T-cell ALL 
cell lines in vitro and in ALL xenograft models.5 In preclinical studies, ALL cell lines treated with 
temsirolimus showed synergism with many chemotherapeutic agents, including etoposide and 
dexamethasone.6 The PPTP found in vivo combinations of sirolimus and cyclophosphamide were more 
effective than either agent used alone.7  
 
The MTI temsirolimus was chosen for use in this study due to its weekly intravenous dosing, its more 
predictable blood levels, and availability of a single-agent pediatric MTD and its sustained biologic effect 
due to conversion to sirolimus.8 
 


 
 
 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Objectives 
 
1.1.1 
To determine the maximum tolerated dose (MTD) of temsirolimus when combined with 
etoposide and cyclophosphamide in pediatric and young adult patients with relapsed ALL 
or NHL.  
 
1.1.2 
To define the dose-limiting toxicity (DLT) and describe other serious toxicities of 
temsirolimus in combination with etoposide and cyclophosphamide in pediatric and young 
adult patients with relapsed ALL or NHL.  
 
1.2 
Secondary Objectives 
 
1.2.1 
To determine the response rate in refractory ALL and NHL patients within the confines of      
a Phase 1 study. 
 
 
1.2.2 
To evaluate responsiveness of patient lymphoblasts to mTOR inhibition using in vitro and 
in vivo pharmacodynamic (PD) assessments. 
 
1.2.3 
To describe minimal residual disease (MRD) levels present at end of cycle 1 therapy in 
patients with bone marrow involvement of disease. 


 
 
 
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2.0 
BACKGROUND 
 
 
2.1 
Introduction/Rationale for Development 
 
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in 
signal transduction pathways which regulate cell growth and proliferation 1-3. Its activation 
triggers resting cells to increase the translation of a subset of messenger RNAs whose 
proteins are required for cell-cycle progression from the G1 to S phase of the cell cycle 
(reviewed in 1-3). While mTOR itself is not frequently mutated in human cancer, 
constitutive activation of signal transduction proteins related to the mTOR pathway (AKT 
kinase, S6K1, PI3K) or loss of proteins linked to mTOR (PTEN) are found in numerous 
malignancies.1-4   
 
One in five children with ALL will develop recurrent disease despite strategies of risk 
stratification and modern intensified chemotherapy. The prognosis for these patients is 
poor even with aggressive retrieval strategies with high dose chemotherapy and stem cell 
rescue.,9,10 Newer agents are needed to treat these patients. Biologically targeted cancer 
agents, including signal transduction inhibitors like mammalian target of rapamycin 
inhibitors (MTIs), have shown great promise in treating hematologic malignancies.2, 5, 11 
While signal transduction inhibitors may be efficacious as single agents, it is more likely 
that these targeted agents will demonstrate greater efficacy in combination with cytotoxic 
agents.  
 
 
 
2.1.1 
Rationale for Chemotherapy Backbone 
The combination of etoposide and cyclophosphamide is used widely in an 
attempt to salvage the refractory and relapsed lymphoblastic leukemia and 
lymphoma 
population. 
Using 
the 
3-[4,5-dimethyl-thiazole-2,5-diphenyl] 
tetrazolium bromide (MTT) cytotoxicity assay, both case/control and matched set 
comparisons of initial and relapse samples showed that relapse samples retain 
sensitivity to etoposide and cyclophosphamide, which are used minimally in front-
line protocols.12 Combining newer, targeted agents with known successful 
salvage therapies may potentiate response.  
 
 
2.2 
Preclinical Studies 
 
 
2.2.1 
Antitumor Activity 
Studies have shown that MTIs inhibit growth of B-precursor ALL lines in vitro, inducing 
apoptosis in both primary cell cultures 3 and NOD/SCID xenograft models.5 Testing of 
the mTOR inhibitor sirolimus by the Pediatric Preclinical Testing Program (PPTP) in vitro 
showed maximal inhibition of 5 ALL cell lines ranging from 23-77%, with all 3 T-cell ALL 
lines having maximal inhibition greater than 70%.7 In vivo rapamycin induced significant 
EFS differences in 5 of 8 ALL xenografts, including 2 of 2 T-cell ALL xenografts.7 
 
Synergism with Chemotherapy 
In preclinical studies, ALL cell lines treated with temsirolimus showed synergism with 
methotrexate, dexamethasone, L-asparaginase, etoposide and doxorubicin (Fig. 1). 6 
Figure 1 depicts MTT data for each drug combination in 1 representative cell line. Grey 
bars represent untreated, slashed bars represent MTI alone, black bars represent 
cytotoxic alone, and dotted bars represent combined effect. All data is normalized to 
untreated baseline (Y axis). Each group of 4 bars represents a combination with a 
different cytotoxic. MTIs had at least an additive effect when combined with methotrexate 
(MTX), dexamethasone (DEX), L-asparaginase (L-ASP), etoposide (VP-16), and 
doxorubicin (DOX). ALL cell lines treated with vincristine or cytarabine showed neither 
additive benefit nor antagonism.  
 
 
 
 
 
FIGURE 1: Temsirolimus in Combination with Cytotoxic Therapy 
 


 
 
 
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Sirolimus has also been found to reverse glucocorticoid resistance in resistant lymphoid 
cell lines (Fig. 2).13 Wei et al. found that the mTOR inhibitor rapamycin sensitized lymphoid 
malignancy cells to glucocorticoid induced apoptosis via modulation of the antiapoptotic 
MCL1. MTIs also downregulate cyclin D1 leading to down-regulation of dihydrofolate 
reductase (DHFR) synthesis, possibly increasing sensitivity of ALL blasts to MTX.6 
 
FIGURE 2: Rapamycin sensitizes lymphoid malignancy cell to GC-induced 
apoptosis 
 
 
As described in Section 2.2.1, studies have shown that MTIs inhibit growth of B-precursor 
ALL lines in vitro, inducing apoptosis in both primary cell cultures 3 and NOD/SCID 
xenograft models.5  
 
 
2.2.2 
Preclinical Pharmacokinetic Studies 
Repeat dose toxicity studies have demonstrated temsirolimus related changes in multiple 
organs and systems in rodents and non-rodents. These include lymphoid atrophy, and 
decreased lymphocytes, decreases in weight, size, and/or function of male reproductive 
MTX         DEX        L-ASP       VP-16       DOX         VCR       ARA-C
Normalized to Untreated
0
0.2
0.4
0.6
0.8
1
1.2
untreated
MTI
2nd drug
both


 
 
 
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organs, increased cholesterol, and general inflammatory responses that included 
inflammation or rashes of the skin and increases in neutrophils, fibrinogen, and/or serum 
proteins. In addition, rodent-specific effects of temsirolimus included hyperglycemia, 
atrophy of female reproductive organs, myocardial degeneration and phospholipidosis. 
The pathogenesis of many of the changes is associated with the known antiproliferative 
effect of temsirolimus. The nature of changes and target organs were similar across 
studies, regardless of the duration of administration and were similar between IV and oral 
dosing. 
 
The pharmacokinetic profile of temsirolimus after IV and oral administration was 
established based on results from in vivo studies in mice, rats, monkeys, and humans. 
Temsirolimus is extensively converted to sirolimus in mice and humans. Less conversion 
occurs in rats and monkeys. Temsirolimus demonstrates 85-87% binding to plasma 
proteins at concentrations of 10-100 ng/mL, with an apparent concentration-dependent 
binding to erythrocytes. The primary metabolites of temsirolimus in rats and monkeys are 
hydroxytemsirolimus (M10) and secotemsirolimus (M4). Oral administration of 
temsirolimus resulted in a more extensive number of circulating metabolites with 
temsirolimus as the major circulating compound-related product in rat and monkey whole 
blood, followed by sirolimus as the next most abundant metabolite. There is evidence of 
more extensive metabolism in the feces of rats compared with blood and plasma, 
suggesting further biotransformation during elimination. The primary oxidative 
metabolism is via CYP3A4, indicating that inhibitors and inducers of CYP3A4 enzyme 
system may alter the metabolism of temsirolimus, although temsirolimus does not induce 
CYP3A4. 
 
2.3 
Adult Studies 
 
 
2.3.1 
Phase 1 Studies 
 
mTOR inhibitor in solid tumors: 
In a Phase 1 trial of single agent temsirolimus in adults with solid tumors, doses ranged 
from 7.5 to 220 mg/m2 weekly with no MTD determined.8 At the 34 mg/m2 and 45 mg/m2 
doses, one patient in each dose level had Grade 3 dose limiting toxicity (DLT) of 
thrombocytopenia; one also neutropenia and hypophosphatemia; the other had asthenia 
and diarrhea. Dose escalation continued to 220 mg/m2 where the DLTs included grade 3 
stomatitis, manic-depressive syndrome, transaminase elevation, and asthenia. At all 
dose levels, temsirolimus (and its hydrolysis product sirolimus) were in the range that 
inhibits cancer cell proliferation in vitro.8 
 
mTOR inhibitor in hematologic malignancies: 
A Phase 1/2 study of oral everolimus in adult patients with relapsed hematologic 
malignancies has also been reported.14 Twenty-seven patients (only 1 with ALL) received 
either 5 mg or 10 mg daily. No DLTs were noted although grade 3 toxicities occurring in 
more than 5% of patients included hyperglycemia (22%), hypophosphatemia (7%) and 
fatigue (7%).  
 
 
 
2.3.2 
Phase 1 Studies in Combination with Chemotherapy 
 
A variety of MTI’s have been studied in combination with other therapies; including 
interferon in renal cell carcinoma,15 hormonal agents in breast cancer,16 5-FU/LCV17, 
imatinib in gastrointestinal stromal tumors, gemcitabine, and sorafenib in adult tumors. 
Early data on MTI/chemotherapy combinations have sometimes shown potential 
enhancement of expected toxicities when compared to single agent use in patients with 
solid tumors. In the 5-FU/LCV/temsirolimus study, grade 4 mucositis/stomatitis was 
observed at the 45 mg/m2 level.17 Grade 3 toxicities noted in adult trials with temsirolimus 
have been rash, nausea/vomiting, cytopenias, hypophosphatemia, hypokalemia, 


 
 
 
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hyperglycemia, 
asthenia/neuropathy, 
fatigue, 
mucositis, 
hypercholesteremia/ 
hypertriglyceridemia, and dyspnea.15, 18-20 
 
The only published combination trial of an MTI and high-dose chemotherapy in leukemia 
is an adult AML Phase 1 dose escalation trial of oral daily sirolimus on a backbone of 
standard adult AML therapy consisting of 5 days each of mitoxantrone (8 mg/m2/d), 
cytarabine (1 gm/m2/d) and etoposide (100 mg/m2/d). This trial did not demonstrate an 
increased toxicity rate with the MTI/chemotherapy combination. One patient had a DLT 
attributed to prolonged aplasia (120 days) at a sirolimus dose of 15 mg load and 5 mg 
daily. In the prior 4 dose levels, the median time to ANC >500 mm3 was 27 days (range 
16-38). Overall sirolimus was well tolerated and did not increase non-hematologic toxicity 
of the backbone chemotherapy.21 
 
 
2.3.3 
Phase 2 Studies 
 
 
Phase 2 trials have also been conducted in a wide variety of tumors utilizing a flat dosing 
schedule of 25, 75 and/or 250 mg intravenously weekly with notable single agent activity 
in mantle cell lymphoma, breast cancer, and renal cell carcinoma.  Two phase 2 studies 
of single agent temsirolimus in adults with relapsed or refractory mantle cell lymphoma 
have been conducted.22, 23  Thirty-five patients were treated at a dose of 250 mg IV 
weekly. Objective responses were seen in 13 of 34 patients (one CR and 12 PR). The 
median time-to-progression in all patients was 6.5 months, and the median duration of 
response for the responders was 6.9 months. Twenty nine patients were treated at 25 mg 
IV weekly and responses were seen in 41% of patients (1 CR and 10 PR).  Hematologic 
toxicities were common, and thrombocytopenia was the most frequent cause of dose 
reductions. The thrombocytopenia was brief, however, with resolution typically observed 
within one week. Treatment at the lower dose was associated with similar response but 
less myelosuppression23  
 
A Phase 2 randomized, double-blind multicenter Phase 2 trial of temsirolimus has also 
been conducted in patients with advanced renal cell carcinoma. Patients (n=111) were 
treated with this drug as a single agent using doses of 25 mg, 75 mg or 250 mg IV 
weekly. The objective response rate was <10%, however time to progression was 
prolonged in the patients on this study compared to historical controls. Responses did not 
appear to be dose-dependent and the lowest dose was deemed capable of biologic 
activity. Therefore, the dose designated for further study was 25 mg IV weekly. The most 
frequently occurring drug related adverse events observed in patients on this study were 
rash (76%), mucositis (70%), asthenia (50%), and nausea (43%). The most frequently 
occurring > Grade 3 toxicities were hypophosphatemia (13%), anemia (9%), 
hyperglycemia (17%) and hypertriglyceridemia (6%). It has been suggested that the latter 
findings may be due to effects of the drug on signaling via insulin-associated pathways, 
and that changes in these laboratory parameters may serve as biomarkers of 
temsirolimus activity.24 
 
Subsequently, 626 patients with metastatic RCC and 3 or more adverse risk features 
were treated in a randomized Phase 2I trial with temsirolimus 25 mg intravenously weekly 
versus 18 million units IFN-α thrice weekly versus 15 mg temsirolimus intravenously 
weekly + 6 million units IFN-α thrice weekly. Patients treated with temsirolimus had a 
statistically significant longer survival than IFN-a patients (10.9 vs. 7.3 months, P= 
0.0069) with a 9% objective response rate in the temsirolimus monotherapy arm.25 Grade 
3 adverse events occurred in 67% of the temsirolimus group and included anemia, 
thrombocytopenia, hypercholesterolemia, hyperlipidemia, hyperglycemia, asthenia and 
dyspnea. Temsirolimus has also been combined with letrozole, 5 fluorouracil and 
leucovorin, and sorafenib with hyperglycemia, asthenia, rash, stomatitis, and hand-foot 
syndrome being the predominant toxicities.17, 26, 27 
 
 
2.3.4 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 


 
 
 
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In a prostate cancer clinical trial, target phosphoprotein inhibition in tumor was seen in an 
oral dosing regimen at a dose equivalent to 7 mg IV weekly.28 In the oral everolimus trial 
nine patients had biologic samples of which 6 (including one responder) showed 
decreased phosphorylation of p70S6 and/or eIF4E-binding protein.14 
 
2.4 
Pediatric Studies 
 
 
2.4.1 
Prior Experience in Children  
 
mTOR inhibitor in solid tumors: 
A Phase 1 trial of single agent once weekly IV temsirolimus in children with advanced 
solid tumors had an MTD of 75 mg/m2.30 The DLT at the 150 mg/m2 dose was grade 3 
anorexia (1 pt) and grade 4 thrombocytopenia < 7 days (1 pt). Seven patients had ≥ 
grade 3 treatment-related adverse events: neutropenia, leukopenia, anemia, anorexia, 
thrombocytopenia, and increased ALT. Cmax was comparable to adult patients; 
temsirolimus area under the curve (AUC) was higher in children. Greater exposure to 
parent drug appeared balanced by shorter half-life and commensurate lower AUC of the 
sirolimus metabolite.  
 
A Children’s Oncology Group (COG) study of temsirolimus in combination with an 
antibody directed against the Type 1 insulin-like growth factor receptor (COG ADVL0813) 
is currently in progress. Another COG study of temsirolimus in combination with 
temozolomide and irinotecan (ADVL0918) is also in progress for recurrent pediatric solid 
tumors. In this study, both agents are being administered intravenously on a weekly 
basis. Results from both studies are not yet available. 
 
On COG ADVL1114, three weekly doses of temsirolimus were given in combination with 
the UK ALL R3 re-induction treatment backbone. 31 Dose de-escalation of the 
temsirolimus from 10mg/m2/dose to 7.5mg/m2/dose was required due to the DLTs of 
hypertriglyceridemia and persistent toxicity > Grade 2 (hypertension, GGT, and mucositis 
in a non-responding patient) on day 42 of therapy. At the lower dose, DLTs of grade 5 
sepsis, grade 3 ulcer and persistent GGT elevation at day 42 were identified. Significant 
infectious toxicity was noted in the relapsed ALL population. The study has been 
amended to decrease the number of doses of temsirolimus to 2 (on days 1 and 8) and 
intensive infection prevention guidelines have been added to the protocol. Of note, 
supportive care with g-csf was not permitted in ADVL1114.  
 
mTOR inhibitor in hematologic malignancies: 
An institutional Phase 1 trial of oral sirolimus monotherapy in 9 patients with relapsed 
acute leukemia has been published in abstract form.32 The initial dose level was that 
used for pediatric renal transplant patients, 9 mg/m2 load and 3 mg/m2 daily, with one 
escalation to 12 mg/m2 load and 4 mg/m2 daily. No DLTs were noted, and 3 ALL patients 
met the criteria for stable disease, one receiving 3 full courses of sirolimus 
monotherapy.32 
 
On a Dana-Farber institutional clinical trial, pediatric and adult patients with relapsed ALL 
were treated with a combination of sirolimus and glucocorticoids for 5 days prior to 
starting multiagent reinduction chemotherapy.  Changes in gene expression as well as 
biologic markers of a pro-apoptotic state, including MCL-1 levels, were compared with 
samples from ALL patients who were treated with glucocorticoids alone.  Of the 4 
assessable patients treated with the combination of sirolimus and corticosteroid, 3 
demonstrated a marked decrease in MCL-1 protein levels after initiation of therapy which 
was evident by 6 hours.  This was accompanied by a concomitant decrease in phospho-
S6 ribosomal protein levels, suggesting successful mTOR inhibition. Of 4 patients treated 
with corticosteroids alone, three demonstrated no change in MCL-1 or phospho-S6 
ribosomal protein levels. All patients treated with sirolimus and corticosteroids 
demonstrated a decrease in circulating blasts (>80% decrease from baseline) during the 
5 days of therapy.33 


 
 
 
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2.4.2 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
 
 
In the pediatric solid tumor trial Western blot analysis of phosphorylated S6 and AKT 
proteins in peripheral blood mononuclear cells, confirmed temsirolimus 75 mg/m2 
significantly inhibited AKT pathway signaling in vivo.20 Inhibition was also seen at the 10 
and 25 mg/m2 dose levels but not in a consistently validated manner to serve as a 
pharmacodynamic endpoint.30 
 
In the pediatric hematologic malignancy single agent sirolimus trial reductions in 
phosphorylation of p70S6, AKT, STAT3 and STAT5 were seen, but did not correlate with 
dose or response in this limited number of patients.32 Similarly, while in vivo inhibition of 
target phosphoproteins was observed in several patients treated with temsirolimus on the 
COG ADVL1114 trial, these pharmacodynamic data also did not appear to correlate with 
clinical responses (Sarah Tasian, MD, private communication and Rheingold ASCO 
abstract 2015). 


 
 
 
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3.0 
PATIENT ELIGIBILITY CRITERIA AND ENROLLMENT 
 
3.1 
Patient Reservation 
 
Investigators should consult the TACL web site to determine if the study is currently open for accrual 
before approaching patients for participation.  Before enrolling a patient on study, a reservation must be 
made with the TACL Operations Center.  In order to make a reservation you may call 
 or 
send an email to 
  with the following information (if sending an email, please put 
“Reservation Request” in the subject line): 
 
 Study for which you want to make a reservation:  
 Name of the institution requesting reservation with contact information 
 Patient Initials (Last, First) 
 Patient month and year of birth 
 
If an enrollment slot is available, you will receive an email from the TACL Operations Center to confirm 
your reservation.  All reservations are good for five full calendar days starting with the next full day after 
the day the reservation is made. 
 
 
3.2 
Enrollment  
 
An enrollment guide is available on the web site (https://tacl.chla.usc.edu/tacl). Patients must be enrolled 
prior to beginning treatment on this study.  It is allowable to enroll a patient who has received IT ARA-C, IT 
MTX or triple IT therapy within seven days of enrollment as part of their evaluation to diagnose disease 
relapse.  Patients will be enrolled by contacting the TACL Operations Center at Children’s Hospital Los 
Angeles Monday through Friday, 8:30 am – 5:00 pm Pacific Time at 
 except holidays.  You 
will be asked to complete the eligibility form on the TACL RDE System prior to making your call.  In addition, 
the supporting documentation, which confirms eligibility, should be emailed or faxed to the TACL Operations 
Office at 
.   
 
Each patient will be assigned a unique TACL registration and study subject number. The dose level of 
temsirolimus will be assigned by the TACL Operations Center at the time of study registration.  An email 
confirming eligibility and assigned dose level will be sent to the treating facility and Study Co-Chairs, 
Patients should begin treatment within 3 calendar days of study enrollment.   
 
 Contact Information: 
 
 
 
 
 
TACL Operations Center 
 
 
 
 
Children’s Hospital Los Angeles 
 
 
 
 
4650 Sunset Blvd, MS #54 
 
 
 
 
Los Angeles, CA 90027 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Email: TACL@chla.usc.edu  
 
 


 
 
 
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3.3 
Inclusion Eligibility Criteria  
 
The eligibility criteria listed below are interpreted literally and cannot be waived.   
  
 
3.3.1 
Age 
 
Patients must be ≥ 12 months and ≤ 21 years of age at the time of study enrollment. 
 
3.3.2 
Diagnosis 
 
Leukemia 
Patients must have relapsed or refractory acute lymphoblastic leukemia (ALL) 
defined as below: 
 
a. Bone marrow involvement defined as ≥ 5% blasts (M2 or M3) with or without 
extramedullary involvement. 
b. Refractory bone marrow involvement defined as MRD ≥ 0.1% blasts done at 
a COG-approved MRD testing lab after most recent treatment regimen.   
c. Newly diagnosed patients (T or B-cell ALL) with refractory bone marrow 
involvement after Consolidation therapy are eligible.   
d. First relapse B-cell ALL patients are eligible with refractory disease.   
e. Second or greater relapse B-cell patients are eligible at time of relapse or 
with refractory disease. 
f. 
First or greater relapse T-cell ALL patients are eligible at time of relapse or 
with refractory disease.  
g. Isolated CNS 2 or 3 patients with < 0.1% MRD bone marrow involvement are 
not eligible. 
.   
Lymphoma 
Patient must have relapsed or refractory lymphoma with: 
a. Lymphoblastic lymphoma or peripheral T-cell lymphoma.  
b. Histologic verification of disease at original diagnosis or subsequent relapse. 
c. Evaluable or measurable disease documented by clinical or radiographic 
criteria or bone marrow disease present at study entry.   
d. Patient may have CNS 2 or 3 status.   
 
3.3.3 
Performance Level  
Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years 
of age. (See Appendix I for Performance Scales), 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 
 
3.3.4 
Prior Therapy 
Patients must have fully recovered from the acute toxic effects of all prior anti-cancer 
chemotherapy, defined as resolution of all such toxicities to ≤ Grade 2 or lower per the 
inclusion/exclusion criteria. 
 
 
a. Myelosuppressive chemotherapy:   
 
 
Patients with leukemia or lymphoma who relapse while receiving maintenance 
chemotherapy will not be required to have a waiting period before enrollment 
onto this study. 
 
 
At least 14 days must have elapsed after the completion of cytotoxic therapy, 
with the exception of hydroxyurea. Note: Cytoreduction with hydroxyurea in 
patients can be initiated and continued for up to 24 hours prior to the start of 
protocol therapy. 


 
 
 
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 
Patients who received intrathecal (IT) chemotherapy within seven days of 
therapy initiation remain eligible, but should not receive the day 1 IT 
chemotherapy. (See Section 4.1 for additional details). 
 
b. Hematopoietic growth factors: At least 14 days after the last dose of a long-acting 
growth factor (e.g. Neulasta) or 7 days for short-acting growth factor (e.g., Filgrastim).   
 
c. Biologic (anti-neoplastic agent):  At least seven days after the last dose of a biologic 
agent.  For agents that have known adverse events occurring beyond seven 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 30 days from last infusion of chimeric antigen receptor T cell (CART) 
therapy or tumor vaccines.  
d. Monoclonal antibodies: At least three half-lives of the antibody must have elapsed 
after the last dose of a monoclonal antibody with the exclusion of blinatumomab. (ie: 
Rituximab = 66 days, Epratuzumab = 69 days). Patients must have been off 
blinatumomab infusion for at least 4 days and all drug-related toxicity must have 
resolved to grade 2 or lower as outlined in the inclusion and exclusion criteria. 
 
e. XRT: At least 14 days after local palliative XRT (small port); At least 84 days must 
have elapsed if prior TBI, craniospinal XRT or if  50% radiation of pelvis; at least 42 
days must have elapsed if other substantial marrow radiation. 
 
f. 
Stem Cell Infusion:  No evidence of active graft vs. host disease and at least 84 days 
must have elapsed after transplant or stem cell infusion. 
 
 
 
3.3.6 
Organ Function Requirements 
 
3.3.6.1 Adequate Bone Marrow Function Defined as: 
 
Patients should not be known to be refractory to red blood cell or platelet 
transfusions. 
 
Blood counts are not required to be normal prior to enrollment on trial. 
However, platelet count must be  20,000/mm3 to initiate therapy (may 
receive platelet transfusions).  
 
3.3.6.2 Adequate Renal Function Defined as: 
- 
Creatinine clearance or radioisotope GFR  70ml/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this table were derived from the Schwartz 
formula for estimating GFR 34 utilizing child length and stature data published by 
the CDC. 
 


 
 
 
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3.3.6.3   Adequate Liver Function Defined as: 
- Total bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x institutional upper 
limit of normal for age  
- . SGPT (ALT) and SGOT (AST) must be less than 3 x institutional upper limit 
of normal (Grade 1 or less per CTCAE 4.03).  
- GGT must be less than 2.5 x institutional upper limit of normal (Grade 1 or 
less per CTCAE 4).  
-  Serum albumin  2 g/dL. 
- The hepatic requirements may be waived for patients with Grade 1 or 2 
elevations of hepatic transaminases clearly due to leukemic infiltration after 
consultation with a study Co-Chair.  
 
3.3.6.4  Adequate Cardiac Function Defined As: 
- Shortening fraction of   27% by echocardiogram, or 
- Ejection fraction of ≥ 50% by gated radionuclide study/echocardiogram. 
 
3.3.6.5  Adequate Pulmonary Function Defined as: 
- Pulse oximetry > 94% on room air (> 90% if at high altitude) 
- No evidence of dyspnea at rest and no exercise intolerance.  
- Baseline chest x-ray with no evidence of active infectious disease or 
pneumonitis. (See Section 3.4.3)  
 
 
3.3.6.6 Reproductive Function 
-   Female patients of childbearing potential must have a negative urine or serum  
    pregnancy test confirmed prior to enrollment. 
-   Female patients with infants must agree not to breastfeed their infants while on  
    this study. 
- Male and female patients of child-bearing potential must agree to use an   
effective method of contraception approved by the investigator during the study.  
 
 
3.3.6.7 Random or fasting glucose within the upper limits of normal for age. If the initial 
blood glucose is non-fasting and above normal limits a fasting glucose can be 
obtained and must be within the upper limits of normal for age. 
 
 
3.3.6.8 Triglyceride/Cholesterol 
 
 
Fasting or non-fasting serum triglyceride level ≤ 300 mg/dL and serum 
cholesterol level ≤ 300 mg/dL. 
 
 
 
3.4       Exclusion Eligibility Criteria 
 
 
 
3.4.1 
Concomitant Medications 
 
a. Corticosteroids:  Patients receiving corticosteroids for disease control who have not 
been on a stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment are not eligible. 
 
b. Investigational Drugs:  Patients who are currently receiving another investigational drug 
are not eligible. The definition of “investigational” for use in this protocol means any 
drug that is not licensed by the FDA, Health Canada or the Therapeutic Goods 
Administration to be sold in the countries they govern. (United States, Canada and 
Australia) 
 
c. Anti-cancer Agents:  Patients who are currently receiving or may receive while on 
therapy, other anti-cancer agents, radiation therapy or immunotherapy are not eligible 
[except leukemia patients who relapsed on Maintenance therapy or patients receiving 
hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy]. 


 
 
 
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Intrathecal chemotherapy (at the discretion of the primary oncologist) may be given up 
to one week prior to the initiation of study treatment (day 1 therapy). 
 
d. Anti-GVHD or agents to prevent organ rejection post-transplant: Patients who are 
receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host 
disease post bone marrow transplant or organ rejection post-transplant are not eligible 
for this trial. At least 3 half-lives must have elapsed after the last dose of GVHD meds. 
 
e. Anticoagulants: Patients who are currently receiving therapeutic anticoagulants 
(including aspirin, low molecular weight heparin, and others) are not eligible. At least 3 
half-lives must have elapsed after the last dose of anticoagulants.  
 
f. Angiotensin-converting enzyme (ACE) inhibitors:  Patients who are currently receiving 
ACE inhibitors are not eligible due to the development of angioneurotic edema-type 
reactions in some subjects who received concurrent treatment with temsirolimus + ACE 
inhibitors. At least 3 half-lives must have elapsed after the last dose of ACE inhibitors.  
 
g. Calcium Channel Blockers: Patients who are currently receiving Calcium Channel 
Blockers are not eligible due to the development of angioneurotic edema-type reactions 
in some subjects who received concurrent treatment with temsirolimus + Calcium 
Channel Blockers. At least 3 half-lives must have elapsed after the last dose of Calcium 
Channel Blockers. 
 
h. Enzyme inducing Anti-convulsants: Patients who are currently receiving enzyme 
inducing anticonvulsants (ie phenytoin, phenobarbitol, or carbamazepine) are not 
eligible.  Stabilizing on a non-hepatic inducing metabolizing anti-convulsant (ie: 
gabapentin or levetiracetam) prior to study entry is acceptable.  At least 3 half-lives 
must have elapsed after the last dose of enzyme inducing anti-coagulants.  
 
i. Patients receiving treatment with azoles such as fluconazole or voriconazole which are 
potent inhibitors of temsirolimus metabolism. At least three half-lives must have 
elapsed after the last dose of azoles.  
 
3.4.2 
Patients must have no pre-existing Grade 1 or higher ulcerations, fistulas, mucosal 
lesions, or skin barrier breakdown 
            
3.4.3       Patient with Burkitt’s leukemia and/or lymphoma are not eligible. 
 
3.4.4 
Infection Criteria 
 
Patients are excluded if they have:  
 
Positive blood culture within 48 hours of study enrollment;  
 
Fever above 38.2 within 48 hours of study enrollment with clinical signs of infection. 
Fever that is determined to be due to tumor burden is allowed if patients have 
documented negative blood cultures for at least 48 hours prior to enrollment and no 
concurrent signs or symptoms of active infection or hemodynamic instability.  
 
A positive fungal culture within 30 days of study enrollment. 
 
Active fungal, viral, bacterial, or protozoal infection requiring IV treatment. Chronic 
prophylaxis therapy to prevent infections is allowed.  
 
3.4.5 
Patients with Down syndrome and Fanconi Anemia are excluded. 
 
3.4.6  
Patients will be excluded if they have significant concurrent disease, illness, psychiatric 
disorder or social issue that would compromise patient safety or compliance with protocol 
treatment or required observations, interfere with consent, study participation, follow up, 
or interpretation of study results. 
 


 
 
 
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3.4.7 
Patients with known optic nerve and/or retinal involvement (because it may not be 
possible to safely delay irradiation) are not eligible. Patients presenting with visual 
disturbances by history or physical exam should have an ophthalmological exam and, if 
indicated, an MRI to determine optic nerve or retinal involvement. 
 
 
 
 
 
3.5 
Regulatory 
 
3.5.1 
Informed Consent 
All patients and/or their parents or legal guardians must sign a written informed consent. Age 
appropriate assent will be obtained per institutional guidelines. To allow non-English speaking 
patients to participate in this study, bilingual health services will be provided in the appropriate 
language when feasible. 
 
3.5.2 
Protocol Approval 
All institutional, FDA, and NCI requirements for human studies must be met. 
 
 


 
 
 
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4.0 
TREATMENT PROGRAM 
The following sections detail the treatment plan for each course of therapy.   
 
Due to a significantly increased risk of morbidity and mortality in children with multiply 
relapsed ALL undergoing intensive therapy, hospitalization from initiation of therapy until: 
1) there is evidence of ANC recovery defined as ≥ 200/microliter and increasing, and 2) 
they are afebrile and clinically stable. See Section 5.2 for highly recommended infection 
prevention guidelines. Please refer to the Drug Information section for additional administration 
guidelines. Treatment should begin within 3 calendar days of enrollment.   
 
4.1 
Treatment Course 
This is a Phase I feasibility pilot of temsirolimus in combination with five days of 
cyclophosphamide and etoposide.  After eligibility is determined, consent obtained, and 
registration occurs patients receive their first dose of temsirolimus on day 1, followed immediately 
by their first doses of etoposide and cyclophosphamide. Etoposide and cyclophosphamide are 
continued for the next four days (day 1-5). A second dose of temsirolimus is given on day 8.  A 
course is defined as 29 days. All patients should get two courses of therapy in the absence of 
progressive disease, dose limiting toxicity or investigator/subject preference to withdraw.   
 
Leukemia patients who are M1 and CNS1/2 and lymphoma patients with stable disease or better 
after the second course of therapy, may receive up to an additional six courses (for a total of eight 
courses) in the absence of relapse or progressive disease.  
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
15 
22 
29 
Temsirolimus 
● 
 
 
 
 
 
 
● 
 
 
 
 
 
 
EtoposideA 
● 
● 
● 
● 
● 
 
 
 
 
 
 
 
 
 
Cyclophosphamide 
● 
● 
● 
● 
● 
 
 
 
 
 
 
 
 
 
Intrathecal Therapy 
See detailed instructions below  
`A-available option: substitution of Etoposide Phosphate for etoposide (at 1:1 dosing) in case of 
etoposide    shortage 
 
 
Temsirolimus 
 
Dose will be assigned at study entry. Maximum dose is based on BSA of 2 m2 and 
found in Section 4.3.  Give IV over 30 minutes (+/- 10 minutes) on days 1 and 8. On day 
1 temsirolimus is given prior to etoposide and cyclophosphamide. 
 
Patients are to receive premedication with diphenhydramine (1 mg/kg, max 50 mg) prior 
to each temsirolimus dose (See Section 4.6.1.4 for Infusional Reactions). 
 
Anaphylactic precautions should be observed during temsirolimus administration. 
 
A specific supply of temsirolimus is supplied by Pfizer Pharmaceuticals for use in 
this study. Do not use commercially available drug. 
 
Etoposide 
 
100 mg/m2 IV over 1-2 hours daily x 5 on Days 1-5. Dilute per institutional standards.  To 
be given after temsirolimus on day 1 and prior to cyclophosphamide on days 1-5.  
 
Patients allergic to etoposide may be treated with Etoposide Phosphate (Etopophos): 100 
mg/m2 IV daily x 5 days on days 1-5.  
 
 
Cyclophosphamide 
 
440 mg/m2 IV daily x 5 on Days 1-5 given over 30-60 minutes. Dilute per institutional 
standards, including pre and post hydration. To be given following etoposide.  


 
 
 
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Intrathecal  Cytarabine (CNS 1) 
COURSE 1: Give intrathecally to patients with CNS1 disease at the dose defined by age below 
on day 1 of course 1 if no other IT chemotherapy is  given within 1 week of day 1 of course 1.  
Age (yrs):  
Cytarabine  Dose: 
1 – 1.99  
30 mg 
2 – 2.99  
50mg 
≥ 3 
 
70 mg 
 
 
Triple Intrathecal Therapy (CNS 2 and 3) 
 
COURSE 1: Give intrathecally to patients with CNS 2 or 3 disease at the doses defined by 
age below on day 1 if no other IT chemotherapy given within 1 week of day 1 of course 1. 
Then give weekly until the patient is CNS 1 or 2 (investigator discretion). No more than 5 
weekly doses to be given in cycle 1.   
 
COURSES 2-8: Give intrathecally to patients who were CNS 2 or 3 at study entry on day 1 of 
each course. 
 
Age (yrs):  
Dose Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC): 
1 – 1.99  
MTX: 8 mg,    
HC: 8 mg,    
ARAC: 16 mg 
2 – 2.99  
MTX: 10 mg,  
HC: 10 mg,  
ARAC: 20 mg 
3 – 8.99  
MTX: 12 mg,  
HC: 12 mg,  
ARAC: 24 mg 
≥ 9  
 
MTX: 15 mg,  
HC: 15 mg,  
ARAC: 30 mg 
 
Leucovorin Rescue 
5mg/m2/dose every 12 hours x 2 doses, starting at 48 hours post any Methotrexate containing IT 
given day 0 or after.  
 
 
Intrathecal Methotrexate (Post Course 1) 
COURSES 2, 4, 6, 8: Give intrathecally to patients who were CNS1 at study entry day 1 of each 
course. 
Age (yrs):  
Methotrexate Dose: 
1 – 1.99  
 8 mg 
2 – 2.99  
10 mg 
3 – 8.99  
12 mg 
≥ 9  
 
15 mg 
 
 
4.2 
Disease Evaluations 
 
4.2.1 
Leukemia Patients 
All patients should have a bone marrow aspirate/biopsy, lumbar puncture, and CBC to assess 
response on day 29 +/- 3 days as needed for scheduling reasons.   
 
 
A bone marrow procedure need not be performed if the patient has an absolute blast 
count (ABC) greater than or equal to 2,500/mm3 in the peripheral blood on day 29. 
 
 
If the bone marrow is hypoplastic or M1 but counts have not recovered to ANC ≥ 500 and 
PLTS ≥ 50,000 (without transfusion) obtain a weekly CBC and perform a bone marrow 
with evidence of count recovery (ANC ≥ 500 and PLTS ≥ 50,000) or day 42; whichever is 
first. A repeat bone marrow does not need to be performed if the patient subsequently 
develops an absolute blast count (ABC) greater than or equal to 2,500/mm3   
 
 
If the marrow is M2 by aspirate (assessed by morphology and/or flow cytometry) or the 
bone marrow biopsy shows 5-25% residual leukemia (assessed by morphology or 
immunohistochemistry), then proceed to course 2 regardless of ANC and PLT count after 


 
 
 
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all grade 3 or 4 non-hematologic toxicities have returned to grade 2 or less.   
 
 
If the marrow is M3 or has more blasts than the pre-study bone marrow, has progression 
in any extramedullary site, or if the patient is CNS 3 at day 29, discontinue protocol 
therapy and proceed with alternative treatment. The one exception to this is patients who 
are CNS 3 solely due to chloromas or cranial nerve findings and are CNS 1/2 by LP who 
have had at least a partial response in that area.  
 
 
A lumbar puncture with cytospin should be done on day 29 +/- 3 days to assess CNS 
status. Course 2, Day 1 Intrathecal chemotherapy can be given at this time if ANC ≥ 500 
and PLTS ≥ 50,000µL. 
 
4.2.2 
Lymphoma Patients 
All patients should have a CBC, bone marrow aspirate or biopsy (ONLY if positive at study entry), 
lumbar puncture (ONLY if positive at study entry), and imaging of known sites of disease on day 
29 +/- 3 days as needed for scheduling reasons. 
 
NHL patients who were bone marrow positive at study entry 
 
If the marrow is hypoplastic or M1, and counts have not recovered to ANC ≥ 500 and 
PLTS ≥ 50,000 (without transfusion) repeat marrow and CBC weekly until recovery or 
progression. 
 
 
If the marrow is M2 by aspirate (assessed by morphology and/or flow cytometry) or the 
bone marrow biopsy shows 5%-25% residual lymphoblasts (assessed by morphology or 
immunohistochemistry), then proceed to course 2 regardless of ANC and PLT count after 
all grade 3 or 4 non-hematologic toxicities have returned to grade 2 or less.  
  
 
If the marrow is M3 or has more blasts than the pre-study bone marrow, has progression 
in any extramedullary site, or if the patient is CNS 3 at day 29 discontinue protocol 
therapy and proceed with alternative treatment. The one exception to this is patients who 
are CNS 3 solely due to chloromas or cranial nerve findings and are CSF negative who 
have had at least a partial response in that area.  
 
 
4.3 
Dose Escalation Schedule 
The starting dose of temsirolimus (7.5 mg/m2/dose) is lower than the FDA approved adult renal cell 
carcinoma dose (25 mg) and lower than the single agent DLT found in children with solid tumors (75 
mg/m2). Temsirolimus will not be escalated beyond dose level 4.  If tolerated the dose will be escalated as 
follows:  
  
 
Dose Level 
Dose 
Maximum 
Dose 
 
 
 
1 
7.5 mg/m² 
15 mg 
2 
10 mg/m² 
20 mg 
3 
15 mg/m² 
30 mg 
4 
25 mg/m2 
50 mg 
 
 
 
4.4 
Criteria to begin Course 2 and subsequent courses 
Patients may begin the second or subsequent courses once the following criteria are met:  
 


 
 
 
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4.4.1   Course 2 Requirements 
 
Patients must be CNS 1 or 2 in order to continue on to course 2. The one exception to this is 
patients who are CNS 3 solely due to chloromas or cranial nerve findings and are CNS 1/2 by LP 
who have had at least a partial response in that area.  
 
 
Leukemia patients with an M1 marrow after the first course may proceed to Course 2 when ANC 
≥ 500/μL and platelet count ≥ 50,000 (without transfusion) as long as all grade 3 or 4 non-
hematologic toxicities have resolved to grade 2 or less.  
 
 
Leukemia patients with > 25% blasts at study entry with an M2 marrow after the first course may 
proceed to Course 2 independent of peripheral blood counts (the minimum platelet requirement to 
receive temsirolimus is 20,000). Patients with leukemia and an M2 marrow or less at study entry 
who do not have progressive disease may continue to Course 2 at the investigators discretion, 
also independent of blood counts. Patients with M3 marrow should proceed to alternative therapy.  
To proceed to Course 2 grade 3 or 4 non-hematologic toxicities have to have resolved to grade 2 
or less. The Course 2, day 1 intrathecal chemotherapy can be done up to day 8 of Course 2. 
 
 
Leukemia patients with non CNS extramedullary disease that is stable or improving and does not 
require radiation may proceed to course 2 per their BM status above.  
 
 
Lymphoma patients may proceed to Course 2 in the absence of clinical or radiographic 
progressive disease (Section 10.2.5) when ANC ≥ 500/μL and platelet count ≥ 50,000 as long as 
all grade 3 or 4 non-hematologic toxicities have resolved to grade 2 or less. Patients with 
lymphoma and marrow involvement at study entry who remain with < 25% blasts (M1 or M2)  
may continue to Course 2 at the investigators discretion.  
 
 
 
For second and subsequent courses patients must have no Grade 1 or higher ulcerations, 
fistulas, mucosal lesions, or skin barrier breakdown 
 
 
Organ function eligibility requirements:  to proceed to course 2. 
 
Adequate Renal Function Defined as: 
-Creatinine clearance or radioisotope GFR  70ml/min/1.73 m2 or 
-A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this table were derived from the Schwartz 
formula for estimating GFR 34 utilizing child length and stature data published by 
the CDC. 
 
Adequate Liver Function Defined as: 
 
Total bilirubin (sum of conjugated + unconjugated) must be less than or equal to 1.5 x 
institutional upper limit of normal (Grade 1 or less per CTCAE 4.03).  
 
SGPT (ALT) and SGOT (AST) must be less than 3 x institutional upper limit of normal 
(Grade 1 or less per CTCAE 4.03).  
 
GGT must be less than 2.5 x institutional upper limit of normal (Grade 1 or less per 


 
 
 
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CTCAE 4.03).  
 
Serum albumin  2 g/dL. 
 
 
Adequate Pulmonary Function Defined as: 
 
Pulse oximetry > 94% on room air (> 90% if at high altitude) 
 
No evidence of dyspnea at rest and no exercise intolerance.  
 
 
Random or fasting glucose within the upper limits of normal for age.  
If the initial blood glucose is non-fasting and above normal limits a fasting glucose can be 
obtained and must be within the upper limits of normal for age. 
 
 
Triglyceride/Cholesterol 
 
Fasting or non-fasting serum triglyceride level ≤ 300 mg/dL and serum cholesterol level ≤ 
300 mg/dL. 
 
 
4.4.2    Course 3-8 Requirements 
 
Patients with leukemia may receive courses 3-8 if they have an M1 marrow or MRD < 5% and an 
ANC ≥ 500 with or without platelet recovery prior to each course. The minimum platelet 
requirement to receive temsirolimus is 20,000. Patients must remain CNS 1 or 2. All other 
extramedullary involvement must be resolved. All grade 3 or 4 non-hematologic toxicities must 
have resolved to grade 2 or less prior to initiation of subsequent courses.  
 
Patients with lymphoma may receive courses 3-8 in the absence of progressive disease and an 
M1 marrow status when ANC ≥ 500/μL and platelet count ≥ 50,000 as long as all grade 3 or 4 
non-hematologic toxicities have resolved to grade 2 or less. The minimum platelet requirement to 
receive temsirolimus is 20,000. Patients must remain CNS1 or 2. All other extramedullary 
involvement must be resolved. 
 
For subsequent cycles patients must have no Grade 1 or higher ulcerations, fistulas, mucosal 
lesions, or skin barrier breakdown 
 
 
4.5 
Dose-Limiting Toxicity (DLT)   
 
Toxicity will be graded using the CTCAE criteria, version 4.03. The CTCAE provides descriptive terminology 
and a grading scale for each adverse event listed.  A copy of the CTCAE can be downloaded from the 
CTEP home page (http://ctep.cancer.gov). Any dose-limiting toxicity (DLT) should be reported 
immediately through the TACL Operations Center to the Study Chair.   
 
DLT will be evaluated during Course 1 only. 
 
DLT will be defined as any of the following events that are at least (possibly, probably or definitely) 
attributable to temsirolimus. The DLT observation period for the purposes of dose-escalation will be the 
first cycle of therapy (max 42 days). 
 
  
4.5.1 
Non-hematological dose-limiting toxicity 
 
4.5.1.1 Any grade 3, 4 or 5 non-hematologic toxicity that occurs any time after the first dose of 
temsirolimus and is at least possibly attributable to temsirolimus, with the following 
exceptions: 
 
Grade 3 or 4 fever, febrile neutropenia or infection, +/- hospitalization.  
 
Grade 3 gastrointestinal symptoms (anorexia, nausea, vomiting, and diarrhea) 
that resolve to ≤ grade 2 or baseline by day 36 of therapy. 
 
Grade 3 or 4 AST/SGOT, ALT/SGPT, or GGT that returns to ≤ Grade 2 or 
baseline within 36 days of the start of therapy.  


 
 
 
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 
Grade 3 constitutional symptoms (fatigue, malaise, weight loss, dehydration) that 
resolve to ≤ grade 2 or baseline by day 36 of therapy. 
 
Grade 3 or 4 hyperglycemia controllable by diet, oral diabetic drug and/or insulin 
that resolves to ≤ grade 2 within 96 hours of an intervention. If hyperglycemia is 
not controllable (≤ grade 2) by diet modification, insulin therapy and an oral 
diabetic agent it will be considered a DLT. 
 
Grade 3 or 4 metabolic/laboratory abnormalities (Na, K, HCO3, Ca++, PO4, 
creatinine and uric acid) attributable to tumor lysis syndrome (including tumor 
lysis syndrome itself) or its treatment that resolve to ≤ grade 2 or baseline by day 
36 with or without the use of supplementation or appropriate replacement 
therapy. 
 
Grade 3 or 4 asymptomatic electrolyte abnormalities that returns to ≤ Grade 2 or 
baseline within 36 days of the start of therapy 
 
Grade 3 or 4 hypofibrinogenemia 
 
Grade 3 albumin 
 
Grade 3 or 4 fasting hypertriglyceridemia or fasting hypercholesterolemia that 
returns to ≤ Grade 2 within 4 weeks of starting lipid lowering medication.  (See 
Section 4.6.1.7).  
 
Grade 3 or 4 non-fasting hypertriglyceridemia or hypercholesterolemia.  If Grade 
3 or 4 non-fasting hypertriglycerdemia or hypercholesterolemia is detected when 
routine (non-fasting) laboratory studies are performed, the test should be 
repeated within 3 days in the fasting state to permit accurate grading.  
 
Grade 3 hypertension that resolves to (≤ Grade 2) with appropriate use of anti-
hypertensives.  
 
Grade 3 mucositis/stomatitis. (See Section 4.6.1.6. for supportive care guidelines 
for mucositis). 
 
4.5.1.3 If a patient develops grade 3 or 4 pneumonitis attributable to temsirolimus the 
subsequent dose of temsirolimus will be held regardless of course.  This will be 
considered a DLT in Course 1 of therapy.  
 
 
 
4.5.1.4 Allergic reactions that necessitate discontinuation of study drug will not be 
 
considered a dose-limiting toxicity. 
 
4.5.1.5  Any Grade 3 or 4 toxicity that requires a dose of temsirolimus to be held in Course 1 will 
be considered a dose-limiting toxicity. Toxicities attributable to temsirolimus that do not resolve to 
≤ Grade 2 by day 36 will be considered dose-limiting toxicities. 
 
4.5.2 
Hematological dose limiting toxicity 
Bone marrow aplasia: > 42 days from Day 1 of therapy will be a DLT. Aplasia is defined as the 
failure to recover a peripheral ANC of > 500/mm3 and PLT > 20,000/mm3 in the absence of 
persistent leukemia. 
 
 
4.6 
Dose Modifications  
 
4.6.1 Dose Modifications of Temsirolimus for Non-Hematological Toxicity 
 
A Study Co- Chair must be notified of any temsirolimus dosage modification.  
 
4.6.1.1 Patients who have any dose-limiting non-hematological toxicity (as defined in Section 
4.5.1) will have subsequent doses of temsirolimus held until the toxicity resolves to  ≤ 
grade 2 or as otherwise indicated in the specific dose modifications below . The dose of 
temsirolimus will be restarted at one dose level below (or 5 mg/m2 if at dose level 1). 
Missed doses of temsirolimus should not be made up. The etoposide and 
cyclophosphamide should be continued as long as those drugs are not directly 
attributable to the toxicity.  If a DLT occurs but the patient meets requirements to receive 


 
 
 
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a subsequent course, the dose of temsirolimus will be restarted at one dose level below 
(or 5 mg/m2 if at dose level 1). If tolerated subsequently the dose can be increased back 
up to the original assigned dose. 
 
4.6.1.2 If a non-hematological toxicity recurs in a second course after one dose reduction, the 
patient will receive no further doses of temsirolimus. Patient may complete backbone 
chemotherapy as long as the other chemotherapeutic agents are not implicated in the 
toxicity or move on to other therapy per investigator choice. 
 
4.6.1.3 Dose modification for hyperglycemia: 
Therapy modifications for patients who develop hyperglycemia (based on random, non-
fasting glucose levels) should be: 
 
Hyperglycemia Grade 
Action 
Grade 1-2 
Continue temsirolimus 
Grade 3 
 
 Continue temsirolimus at same dose and initiate diet or 
TPN modification, insulin therapy and/or oral diabetic 
agent* as indicated.  
 The patient should continue to receive concomitant insulin 
and/or an oral diabetic agent for the management of 
hyperglycemia while on protocol therapy. Due to the 
residual effects of temsirolimus on blocking intracellular 
glucose uptake by inhibition of Glut1 transport and the long 
half life of temsirolimus, initial therapy with insulin may not 
work.  Early use of an oral diabetic agent is suggested. 
Grade 4 
 
 Initiate diet or TPN modifications, insulin and/or oral 
diabetic therapy as indicated. 
 Hold temsirolimus until resolves to ≤ Grade 3 
 Resume temsirolimus at same dose IF patient is 
asymptomatic AND serum glucose is consistently < 250 
mg/dL (≤ Grade 2). The patient may continue to receive 
concomitant insulin and/or an oral diabetic agent for the 
management of hyperglycemia while receiving 
temsirolimus. 
 If Grade 4 hyperglycemia recurs despite diet modification, 
and a stable dose of insulin, and an oral diabetic agent, 
then any subsequent doses of temsirolimus should be held. 
 
*Recommended guidelines for use of oral diabetic agents: Initiation of treatment 
for hyperglycemia should occur under the guidance of a pediatric endocrinologist 
at the local institution. Metformin or other oral anti-hyperglycemia agent may be used 
per local endocrinologist’s recommendations. Insulin therapy should be directed by 
specialists in pediatric diabetes, with the goal of normal fasting blood sugars < 126 mg/dL 
and HgbA1C < 8%. 
 
4.6.1.4 Dose modification for infusional reactions to temsirolimus 
 
Therapy modifications for patients who develop infusional reactions to temsirolimus should be: 
 
Grade 
Action 
Grade 1 
Transient flushing or rash, 
drug fever < 38◦ C (<100.4 ◦ F) 
And 
Grade 2 
Rash, flushing, urticaria, 
dyspnea, drug fever ≥ 
 
If a patient develops a hypersensitivity reaction despite 
diphenhydramine pretreatment, stop the infusion and wait 
30 to 60 minutes (depending upon the reaction severity). At 
the physician’s discretion, it may be possible to resume 
treatment by administering an H2 blocker approximately 30 
minutes before restarting the infusion. The manufacturer 
recommends famotidine 0.5 mg/kg IV maximum dose 20 


 
 
 
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Grade 
Action 
38◦ C (≥100.4 ◦ F) 
mg, rather than cimetidine, because it lacks reported drug 
interactions. 
If 
famotidine 
is 
unavailable, 
administer 
ranitidine 1-2 mg/kg IV maximum dose 50 mg. Re-attempt 
infusion at a slower rate, possibly over 60 minutes. 
 
 
If grade 1-2 infusion reactions recur with subsequent dose, 
add dexamethasone 0.2 mg/kg (max 10mg) IV or equivalent 
to premedications above. 
 
(Only dose interruption/discontinuation, but not dose reduction is 
required for allergic/infusional reactions) 
Grade 3 
Symptomatic 
bronchospasm with or without 
urticaria, allergy-related 
edema/angioedema, 
hypotension 
 
Stop infusion immediately and remove the infusion tube 
 
Administer diphenhydramine hydrochloride 1 mg/kg IV (max 
50 mg), dexamethasone 0.2mg/kg (max 10mg) IV (or 
equivalent), bronchodilators for bronchospasms, and other 
medications as medically indicated. Hospital admission 
should be considered. 
 
Discontinue temsirolimus treatment 
Grade 4 
Anaphylaxis 
 
Stop infusion immediately and remove the infusion tube 
 
Administer diphenhydramine hydrochloride 1 mg/kg (max 
50mg) IV, dexamethasone 0.2 mg/kg (max 10mg) IV (or 
equivalent), and other anaphylaxis medications as indicated. 
Epinephrine or bronchodilators should be administered as 
indicated. Hospital admission for observation may be 
indicated 
 
Discontinue temsirolimus treatment 
 
4.6.1.5 Dose modifications for pneumonitis 
For patients who develop pneumonitis (cough, dyspnea, fever), temsirolimus should be held 
pending investigation. If events are considered at least possibly due to treatment, discontinue 
temsirolimus therapy.  If the treating clinician determines that respiratory symptoms are not 
related to drug therapy or are infectious in nature, the patient should be retreated with the same 
dose of temsirolimus once symptoms resolve.    
 
4.6.1.6 Dose modifications for mucositis or rash 
The following guidelines should be used for patients who develop mucositis, or rash. In addition, 
stomatitis, mucositis, and/or mouth ulcers due to temsirolimus (inflammation or ulcers in the 
mouth) should be treated using local supportive care (See Section 5.2.7 for specific 
recommendations).  
 
 
Grade 
Action 
Grade 1-2 
 
Continue temsirolimus.  
Grade 3 
 
 
 If recovery to ≤ Grade 2 occurs prior to day 8 dose, 
treat with the same dose of temsirolimus. If not hold 
day 8 dose of temsirolimus. If this occurs in a second 
or subsequent course, hold temsirolimus until ≤ 
Grade 2 and restart in next cycle at one dose level 
lower (or 5mg/m2 if dose level 1)Upon retreatment, if 
Grade 3 or 4 toxicity recurs and persists >7 days, 
discontinue any further temsirolimus. 


 
 
 
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 If mucositis develops after the second dose of 
temsirolimus, initiate G-CSF daily or neulasta x 1. 
 
Grade 4  
 Discontinue temsirolimus 
 If this occurs in a second or subsequent course, hold 
temsirolimus until ≤ Grade 2 and restart in next cycle 
at one dose level lower (or 5mg/m2 if dose level 1) 
 If mucositis develops after the second dose of 
temsirolimus, initiate G-CSF daily or neulasta x 1. 
 
4.6.1.7 Dose modifications for elevated triglycerides or cholesterol 
 
Temsirolimus should not be held in cycle 1 for Grade 1-3 of elevated triglyceride or cholesterol. 
 
Dose modifications for elevated fasting cholesterol 
The following guidelines should be used for patients who develop elevated fasting cholesterol.  
 
Grade 
Action 
Grade 2 
 
 Continue temsirolimus; consider treatment with an HMG-CoA 
reductase inhibitor depending upon recommendations of 
institutional hyperlipidemia consultants 
 If on intralipids, repeat level after intralipids have been held at 
least 12 hours.  
Grade 3 
 
 If on intralipids, repeat level after intralipids have been held at 
least 12 hours.  
 An HMG-CoA reductase inhibitor should be started, and 
dosages adjusted based upon recommendations of institutional 
hyperlipidemia consultants 
 It is expected that optimal effects of the lipid lowering 
medication will be observed 2-4 weeks after its initiation.  
Treatment with temsirolimus can continue during this time 
provided that hypercholesterolemia remains ≤ Grade 3 
Grade 4 
 Hold temsirolimus until recovery ≤ Grade 3 
 An HMG-CoA reductase inhibitor should be started, and 
dosages should be adjusted based upon recommendations 
from institutional hyperlipidemia consultants 
 It is expected that optimal effect of the lipid lowering medication 
will be observed 2-4 weeks after initiation.  Temsirolimus can  
be restarted at the same dose level in subsequent courses 
when recovery to ≤ Grade 3 cholesterol is observed 
 Upon retreatment with temsirolimus concurrent with an HMG-
CoA reductase inhibitor, if Grade 4 elevations recur, 
temsirolimus should be held until recovery to ≤ Grade 3.  
Further lipid lowering medication options should be discussed 
with institutional hyperlipidemia consultants.  Upon recovery to ≤ 
Grade 3 cholesterol, temsirolimus should be restarted at the 
next lower dose level.  If the patient is being treated on the 
lowest dose level, temsirolimus therapy should be discontinued. 
 
 
 Dose modifications for elevated fasting triglycerides 


 
 
 
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The following guidelines should be used for patients who develop elevated fasting 
triglycerides.   
 
Grade 
Action 
Grade 2-3 
 
 If on intralipids, repeat level after intralipids have been held at 
least 12 hours.  
 Continue temsirolimus; if triglycerides are between 301 and 400 
mg/dL consider treatment with an HMG-CoA reductase inhibitor 
depending upon recommendations of institutional 
hyperlipidemia consultants.  HMG-CoA reductase inhibitor is 
highly recommended if triglycerides are > 400. 
 It is expected that optimal effects of the lipid lowering 
medication will be observed 2-4 weeks after its initiation.  
Treatment with temsirolimus can continue during this time 
provided that hypercholesterolemia remains ≤ Grade 3 
Grade 4 
 Hold temsirolimus until recovery to  ≤ Grade 3 
 An HMG-CoA reductase inhibitor should be started, and 
dosages should be adjusted based upon recommendations 
from institutional hyperlipidemia consultants 
 Treatment with temsirolimus can continue during this time 
provided that hypercholesterolemia remains ≤ Grade 3 
 Upon retreatment with temsirolimus concurrent with an HMG-
CoA reductase inhibitor, if Grade 4 elevations recur, 
temsirolimus should be held until recovery to ≤ Grade 3.  
Further lipid lowering medication options should be discussed 
with institutional hyperlipidemia consultants.  Upon recovery to 
≤ Grade 3, temsirolimus should be restarted at the next lower 
dose level.  If the patient is being treated on the lowest dose 
level, protocol therapy should be discontinued. 
 
 
4.6.2  Dose Modifications of Cyclophosphamide for Non-Hematological Toxicity 
 
Hematuria: Omit in the presence of macroscopic hematuria. If there is a history of previous significant 
hematuria, hydrate before cyclophosphamide until specific gravity is < 1.015 and hydrate at 
125 mL/m2/hr for 24 hours after dose. Give IV Mesna (200 mg/m2) 15 minutes before the 
cyclophosphamide and repeat at hours 3, 6, and 9. Mesna may also be given by continuous infusion. 
 
Renal Dysfunction: If creatinine clearance or radioisotope GFR is < 10 mL/min/1.73 m2, reduce dose of 
cyclophosphamide by 50%. Prior to dose adjustment of cyclophosphamide, the creatinine clearance 
should be repeated with good hydration. 
 
4.6.3  Dose Modifications of Etoposide for Non-Hematologic Toxicity 
 
Allergic Reaction: Treat per institutional protocol. Consider premedication with diphenhydramine (1-2 
mg/kg slow IV push) and/or hydrocortisone 100-300 mg/m2. Continue to use premedication before 
etoposide for subsequent doses. Also consider substituting an equimolar amount of Etoposide 
phosphate, in the face of significant allergy and/or hypotension. Etoposide phosphate is a water soluble 
prodrug that does not contain polysorbate 80 and polyethyleneglycol, the solubilizing agent in etoposide 
that may induce allergic reactions and hypotension. Etoposide phosphate is rapidly converted to 
etoposide in vivo and provides total drug exposure, as represented by AUC (0-infinity),that is statistically 
indistinguishable from that measured for etoposide at equimolar doses. 
 
Hypotension: If blood pressure decreases during infusion slow infusion rate per institutional guidelines, 
and consider normal saline bolus or other IVF.  Suggested management includes: if diastolic or systolic 
blood pressure (BP) falls 20 mm Hg during infusion, reduce infusion rate by 50%. Start a simultaneous 


 
 
 
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infusion of NS 10 mL/kg if BP fails to recover or falls further. Stop infusion if BP does not recover, 
continue NS. If the patient has had any episode of hypotension, prehydrate with 0.9% NaCl at 10 
mL/kg/hr for 2 hours prior to any subsequent infusion. 
 
Renal Insufficiency: If renal function decreases, adjust etoposide as follows: CrCl 10-50 mL/min/1.73 m2, 
decrease dose by 25%; if CrCl < 10 mL/min/1.73 m2, decrease dose by 50%. 
 
Hyperbilirubinemia: If direct bilirubin is > 2 mg/dL, decrease dose by 50%. If direct bilirubin is 
> 5 mg/dL, hold etoposide. 
 
4.6.4 Dose Modifications of Intrathecal Therapy 
 
Systemic toxicity: The dosage for IT chemotherapy will not be reduced for systemic toxicity 
(myelosuppression, mucositis, etc.) and all patients will get leucovorin rescue post intrathecals containing 
methotrexate.  
 
Dose modifications following an episode of acute neurotoxicity: 
Following an acute neurotoxic event, a history and physical exam should guide the differential diagnosis. 
A neurology consult may be of value and should be considered. Seizures and other transient events may 
be linked to fever, infection, encephalitis, meningitis, hypertension, electrolyte disturbance, hypoglycemia, 
trauma, intracranial hemorrhage or thrombosis, narcotic withdrawal, illicit drug use, or other causes in 
addition to the direct side effects of chemotherapy. Appropriate laboratory studies may include, but are 
not limited to, blood cultures, a CBC, electrolytes, including glucose, calcium, magnesium and 
phosphorus, renal and liver function studies and/or an examination of the CSF. Imaging studies may 
include a CT scan and/or an MRI. The CT is commonly normal, in the absence of stroke, but if 
calcifications are present, this finding may be indicative of a more severe mineralizing 
leukoencephalopathy.   MRI abnormalities may be pronounced, but transient. Posterior reversible 
encephalopathy may be present on MR with extensive diffusion abnormalities, but these do not appear to 
correlate with subsequent demyelination or gliosis.  Additional studies, including MR angiography and/or 
venogram should be considered, if clinically indicated (e.g. focal deficits). 
 
Many acute events are temporally related to the administration of intrathecal therapy, commonly 9 to 11 
days after the IT administration.  Following an acute event, with recovery, there are few data to support or 
guide therapeutic interventions. It is reasonable to hold the next dose of IT therapy, or, substitute IT Ara-
C/hydrocortisone for 1 dose of IT MTX, or triple IT therapy or IT MTX if the toxicity appeared attributable 
to IT AraC..  
 
Hydrocephalus, microcephaly or known abnormality of CSF flow precluding intrathecal chemotherapy via 
lumbar puncture:  Intraventricular chemotherapy via Ommaya catheter may be used in place of 
intrathecal therapy delivered by LP. Intraventricular chemotherapy should be given according to the same 
schedule, but at 50% of the corresponding age-based doses that would be given by LP. NOTE: 
Obstruction to CSF flow may be a contraindication to intrathecal and/or intraventricular therapy. 
 
Viral, bacterial, or fungal meningitis: Omit until resolved. 
 
 
4.7  
Drug Interactions 
 
4.7.1 
CYP3A4 Inducers and Inhibitors 
The use of potent inhibitors and inducers of CYP3A4 should be avoided (see below and Appendix 
II). Aprepitant is an inducer, a moderate inhibitor, and substrate of CYP3A4 and should not be 
used as an anti-emetic. Antifungal agents should be avoided unless a fungal infection is 
diagnosed. In particular, systemic imidazole antifungal agents (voriconazole, posaconazole, 
itraconazole, fluconazole, etc.) should be avoided due to their strong inhibition of temsirolimus 
metabolism, therefore leading to higher temsirolimus exposure. Azoles may be started safely 7 
days post a dose of temsirolimus, but must be stopped 5 days prior to a subsequent dose of 
temsirolimus. Topical antifungal agents, amphotericin, or caspofungin/micafungin are preferred if 
  


 
 
 
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an infection is diagnosed. Similarly, antiviral agents such as acyclovir should be avoided unless a 
viral infection is diagnosed. The macrolide group of antibiotics should be avoided. 
 
The use of enzyme inducing anticonvulsants is not permitted while on study. Neither Gabapentin 
nor Levetiracetam induce hepatic drug metabolizing enzymes and may be suitable alternative 
anticonvulsant. 
 
The use of the following medications should be discontinued prior to initiation of protocol 
therapy and should be avoided during protocol therapy if reasonable alternatives exist.  
 
Strong 
Inhibitors 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Other Inhibitors 
Inducers 
Clarithromycin 
Indinavir 
Itraconazole 
Ketoconazole 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telithromycin 
Losartan 
Voriconazole 
Aprepitant 
Diltiazem 
Erythromycin 
Fluconazole 
Grapefruit 
Juice 
Verapamil 
Cimetidine 
Amiodarone 
Chloramphenicol 
Ciprofloxacin 
Delaviridine 
Fluvoxamine 
Imatinib 
Norfloxacin 
Norfluoxetine 
(fluoxetine) 
Barbiturates 
Carbamazepine 
Efavirenz 
Glucocorticoids 
Modanfinil 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s wort 
Troglitazone 
 
 
For a more complete list of CYP 3A 4/5 Inhibitors and Inducers, see Appendix II or go to: 
http://medicine.iupui.edu/flockhart/ 
4.7.2 Other Pharmacodynamic Interactions 
 
An increased risk of angioedema is possible in pateints taking mTOR inhibitors in combination 
with Ramipril and/or amlodipine. Caution should be used whem temsirolinus is given concomitantly with a 
calcium channel blocker (i.e., amlodipine) or ACE inhibitor (i.e.ramipril).  
 


 
 
 
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5.0 
SUPPORTIVE CARE   
 
Best supportive care and treatment will be given as appropriate to each patient (antiemetics, antibiotics, 
transfusions, oxygen therapy, nutritional support, palliative treatment for pain or cough, etc.). Patients may 
experience profound myelosuppression and immune suppression during this time. Caregivers must also be 
made aware that patients may experience very rapid clinical deterioration and hospitalization for course 1 is 
highly recommended (See Section 5.2.1).  
 
5.1  
Concurrent Therapy   
 
5.1.1 
Anti-cancer Therapy 
Concurrent anti-cancer therapy not defined within this protocol, including chemotherapy, radiation 
therapy, immunotherapy, or biologic therapy may NOT be administered to patients receiving study 
drug. If these treatments are administered the patient will be removed from protocol therapy. 
 
 
5.1.2  
Investigational Agents 
No other investigational agents may be given while the patient is on protocol therapy. 
 
5.1.3 
Growth Factors 
Growth factors that support white cell number or function may be administered on day 9 or after 
at the discretion of the treating physician for infection, ICU level care, Grade 3/4 mucositis, 
ulceration, or poor wound healing. Neulasta is permitted on study.  
 
5.2  
Infection Control 
Patients with relapsed ALL have a significant risk of morbidity and mortality with intensive salvage 
therapy. Patients in first relapse have a 4-5% induction mortality rate, the majority associated with 
infection. They have also been found to have a 45% rate of Grade 3 and 4 infection during re-
induction on recent COG ALL trials 33 (and personal communication T. Horton, E. Raetz, and M. 
O’Brien), and other relapsed ALL re-induction trials.34-36 Therefore patients with multiply relapsed 
ALL require a very aggressive approach to infection prevention and treatment as outlined below: 
 
5.2.1 
Hospitalization 
Due to the substantial risk of infection in patients with relapsed ALL receiving intensive 
salvage therapy, it is strongly recommended that they remain hospitalized from the 
initiation of therapy until: 1) there is evidence of ANC recovery defined as ≥ 200/microliter 
and increasing, and 2) they are afebrile and clinically stable.  
 
5.2.2 
Bacterial Prophylaxis 
It is strongly recommended that patients receive broad spectrum gram positive and 
negative antibiotic prophylaxis at initiation of induction therapy and until they have met  
the criteria for discharge outlined in 5.2.1. The specific choice of prophylactic antibiotics 
should be guided by the individual institution, although levofloxacin is recommended.37,38 
 
5.2.3 
Fungal Prophylaxis 
Prophylactic anti-fungal therapy with IV caspofungin, micafungin or amphotericin is also 
highly recommended.  The patient should remain on prophylactic anti-fungals until their 
ANC has fallen and is 200/microliter and rising and the patient is afebrile and clinically 
stable.  Note: Azole antifungals are not permitted until 7 days after the final dose of 
temsirolimus. (See Section 4.7.1)  
 
5.2.4 
Fever and Neutropenia 
Empiric broad spectrum antibacterial and anti-fungal therapy should be initiated 
immediately for patients with an ANC < 500/microliters (or < 1000 /microliters and falling) 
and an oral temperature > 38°C on two occasions within 12  hours or ≥ 38.5°C once or as 
clinically indicated. Broad-spectrum antibacterial antibiotics and anti-fungals, once 
started, should be continued until there is evidence of ANC recovery. If clinical symptoms 
or radiographic evidence of enterocolitis or typhilitis develop, broad spectrum coverage 
for gram negatives, anaerobes and an anti-fungal is highly recommended. Surveillance 


 
 
 
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radiographic imaging surveillance for sites of infection should also be performed as 
clinically indicated. 
 
5.2.5 
Empiric Management of Pulmonary Infiltrates 
Consideration should be given to evaluating pulmonary infiltrates with bronchoscopy and 
biopsy, lavage or open lung biopsy. If a procedure cannot be tolerated, begin empiric 
treatment with antifungal therapy given the high likelihood of fungal disease. Empiric 
coverage should be initiated per local institutional guidelines with consideration of 
bacterial, fungal, Pneumocystis jiroveci pneumonia (PJP, formerly called PCP) and 
legionella etiologies pending culture results. If fungal pulmonary disease is documented, 
surveillance radiographic imaging studies of the sinuses, abdomen/pelvis and brain are 
indicated. 
 
5.2.6 
Pneumocystis jiroveci Pneumonia Prophylaxis 
It is recommended that all patients receive prophylaxis for PJP (formerly called PCP).  
Options include trimethoprim/sulfamethoxazole (TMP-SMX) for two sequential days each 
week at a dose of 2.5 mg/kg/dose TMP-SMX (maximum dose of 160 mg) twice daily 
(BID) or according to institutional policy, unless they have a documented sulfa allergy. 
Options for sulfa-allergic patients include intravenous or nebulized monthly pentamidine 
or atovaquone per institutional standards. PJP prophylaxis should be continued 
throughout the entire study period. 
 
5.2.7 
Management of Mucositis/Perirectal Cellulitis 
Based on pilot experience and the intensity of this regimen, episodes of Grade 3-4 
mucositis and perirectal cellulitis are anticipated. Mucositis should be managed with IV 
hydration and hyperalimentation if indicated, effective analgesia, broad-spectrum gram-
positive and gram-negative antibiotic therapy and empiric antiviral and antifungal therapy 
as indicated. See Section 4.6.1.6 for recommendations for early local care for 
mucositis/stomatitis. Management of perirectal cellulitis should include broad-spectrum 
antibiotic therapy with dual gram-negative coverage as well as anaerobic coverage and 
supportive care  per institutional protocol. 
 
 


 
 
 
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5.3  
Supportive Care 
 
 
Appropriate antibiotics, blood products, antiemetics (except for aprepitant, see Section 4.7.1), anti-
hypertensives, fluids, electrolytes, and tumor lysis precautions and general supportive care are to be 
used as necessary. See Section 4.6 for dose modifications of therapeutic agents based upon toxicity. 
 
 
5.3.1 
Recommendations for care of stomatitis, mucositis and/or mouth ulcers: 
 ● Grade 1 - use conservative measures such as non-alcoholic mouth wash or 
salt water (0.9%) mouth wash several times a day until resolution. 
 
● Grade 2 or 3 - topical analgesic mouth treatments (i.e., local anesthetics such as 
benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, orphenol) may be 
used with or without topical corticosteroids, such as 
triamcinolone oral paste 0.1% (e.g. Kenalog in Orabase®). Agents containing hydrogen 
peroxide, iodine, and thyme derivatives may worsen mouth ulcers and should not be 
used. 
 
● If Grade 3 or higher mucositis develops after the second dose of temsirolimus initiate 
use of G-CSF or neulasta.  
 
Topical antifungal agents (nystatin) amphotericin or echinocandins (eg, caspofungin or 
micafungin) are preferred if an oral infection is diagnosed. Similarly, prophylactic antiviral 
agents such as acyclovir should be avoided due to interaction with temsirolimus unless a 
viral infection is diagnosed. Systemic imidazole antifungal agents (ketoconazole, 
fluconazole, traconazole, etc.) should be avoided due to their strong inhibition of 
temsirolimus metabolism until 7 days post a dose of temsirolimus or 5 days prior.   
 
● If due for IT therapy when any grade mucositis is present, the use of leucovorin 5 
mg/m2/dose every 12 hours x 2 doses, beginning 48 hours after the IT therapy, is 
encouraged. 
 
 
 
 
5.3.2 
Tumor Lysis: 
It is recommended, but not mandated, that all subjects start allopurinol 150 mg/m2 
divided TID or urate oxidase (0.1mg/kg IV) prior to the initiation of therapy. Serum 
chemistries, including electrolytes, BUN, Cr, and uric acid, should be monitored at least 2 
times per week for the first week. If there is no evidence of tumor lysis the patients may 
then get routine chemistry labs as described in Section 7.0. If a patient’s peripheral 
leukemic blast count is  20,000 or if they have bulk lymphomatous disease it is highly 
recommended, although not mandated, that they are admitted to the hospital for IV 
hydration and close monitoring for metabolic abnormalities and renal insufficiency due to 
tumor lysis syndrome. 
 
 
5.3.3 
Infusional Reactions: 
Anaphylactic precautions should be observed during temsirolimus administration. 
Patients should receive premedication with diphenhydramine (1 mg/kg, max 50 mg) prior 
to each temsirolimus dose. See Section 4.6.1.4 for management and dose modification 
guidelines for infusional reactions. 
 
 
 
5.3.4 
Blood Products 
Investigators should follow institutional guidelines regarding administration of blood 
products. Platelets must be 20,000 in order to receive temsirolimus. 
 
 


 
 
 
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6.0 
DRUG INFORMATION 
 
6.1 
Temsirolimus (CCI-779, Torisel®, Rapamycin analog, WAY-130779) 
(NSC#683864, IND#61010) 
 
6.1.1 
Nomenclature and Molecular Structure 
The chemical name is Sirolimus 42-ester with 2,2-bis (hydroxymethyl)-propionic acid. The molecular 
formula is C56H87NO16. The molecular weight is 1030.30 daltons.  
 
6.1.2 
Mode of Action and Pharmacology 
Temsirolimus [an ester of the immunosuppressive compound sirolimus, (rapamycin, Rapamune®)] blocks 
cell cycle progression from the G1 to the S phase by binding to the intracellular cytoplasmic protein, 
FK506 binding protein (FKBP)12.  This complex inhibits activity of the enzyme mTOR (mammalian target 
of rapamycin), inhibiting translation of several key proteins that regulate progression through the G1 
phase in response to growth factors.  Sirolimus, temsirolimus's major metabolite, also binds to FKBP12. 
 
Classification: mTOR inhibitor 
 
Approximate Solubility (at 25ºC): Very soluble in ethanol.  Soluble in phosal 50 PG, octanol, propylene 
glycol, polyethylene glycol (PEG) 400, triacetin,  polyethylene  glycol (PEG) 200, labrosol, and 
polysorbate 80.  Insoluble in miglyol 812, olive oil and water. 
 
Incompatibilities: Avoid contact of the diluted product with polyvinyl chloride (PVC) equipment or devices 
that are plasticized with di- (2-ethylhexyl)pthalate (DEHP) to prevent DEHP leaching.  Store diluted 
temsirolimus solutions in bottles (glass) or plastic bags (polyolefin or polypropylene).   
 
Infusion sets containing polyvinyl chloride should not be used to administer temsirolimus to avoid leaching 
of plasticizer.  
 
The following are examples of in-line filters that are compaitible with temsirolimus: 
 
• 
IV 6200 Disposable I.V. Filter 0.2 micron by EPS®, Inc  
 
• 
IV 6120 Disposable I.V. Filter 1.2 micron by EPS®, Inc  
 
• 
LV 5000 Large Volume 5 micron Conical Filter by B.Braun  
 
• 
Baxter Paclitaxel Set with 0.22 micron filter  
 
• 
Codan 0.2 micron monofilter 
 
Other polyethersulfone filters may be used. 
 
Potential Drug Interactions: Temsirolimus is a CYP3A4 substrate.  Avoid concomitant treatment of 
temsirolimus with potent CYP3A4 inhibitors and agents that have CYP3A4 induction potential (See 
Appendix II).  
 
The combination of temsirolimus and sunitinib resulted in dose limiting toxicity at low doses of both 
agents.  Avoid concomitant sunitinib during temsirolimus treatment.   
In vitro, temsirolimus inhibited CYP2D6, CYP3A4, and CYP3A5 activity.  It inhibited 
 
paclitaxel metabolism, but did not significantly affect 5-fluorouracil metabolism.    
 
 
Temsirolimus and warfarin may interact to increase INR.  
 
 
Patient Care Implications:  For hypersensitivity prophylaxis, see Section 5.6.1.4. 
 
 
Vaccinations:  Avoid the use of live vaccines during temsirolimus treatment. 
 
 
6.1.3 
Toxicity/Adverse Events 
The toxicity and adverse events in the table below are derived from the Prescribing Information for 
Torisel® (temsirolimus) and Investigator’s Brochure.  The following events were reported in at least 10% 
of patients who received Torisel in a clinical trial. 


 
 
 
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 Adverse Events with Possible  
 Relationship to Temsirolimus  
 (CTCAE 4.0 Terms) 
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
 
 
GASTROINTESTINAL DISORDERS 
 
 
Diarrhea 
 
Gastrointestinal 
disorders – Other 
(Mucositis/stomatitis)1 
 
Nausea 
 
Anorexia 
 
Abdominal Pain 
 
Constipation 
 
Vomiting 
 
Gastrointestinal disorders – 
Other (Perforation, GI) 
 
 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
 
Asthenia 
 
Generalized Pain 
 
Edema2 
 
Pyrexia 
 
Weight Loss 
 
Headache 
 
Chills 
 
Chest pain 
 
 
 
 
 
 
 
IMMUNE SYSTEM DISORDERS 
 
 
 
 
 
Allergic reactions, anaphylaxis 
 
INFECTIONS AND INFESTATIONS5 
 
 
 
 
Infections3 
 
Urinary tract infection4  
 
Pharyngitis 
 
Rhinitis 
 
 
 
INVESTIGATIONS 
 
 
Platelet count 
decreased 
 
Lymphopenia  
 
Elevated alkaline 
phosphatase  
 
Elevated serum 
creatinine  
 
Elevated AST 
 
Leukopenia 
 
Hemoglobin decreased 
 
Total cholesterol 
increased 
 
 
 
ALT increased 
 
Neutrophil count 
decreased 
 
Weight loss 
 
Total bilirubin increased 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
Hyperglycemia 
 
Metabolism and nutrition 
disorders- Other 
(hyperlipidemia) 
 
Decreased potassium  
 
 
 
 
 
 


 
 
 
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 Adverse Events with Possible  
 Relationship to Temsirolimus  
 (CTCAE 4.0 Terms) 
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious  
 
 
Hypertriglyceridemia 
 
Hypophosphatemia 
 
 
 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
 
Arthralgia 
 
Back pain 
 
Myalgia 
 
 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
 
Dysgeusia5 
 
 
Intracerebral hemorrhage 
 
 
 
PSYCHIATRIC DISORDERS 
 
 
 
Depression 
 
Insomnia 
 
 
 
 
RENAL AND URINARY DISORDERS 
 
 
 
 
Renal Failure 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Dyspnea 
 
Cough 
 
 
Epistaxis 
 
Interstitial lung disease 
 
Pulmonary thromboembolism 
 
 
 
 
 
 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Rash6  
 
Dry skin 
 
Nail disorder 
 
Pruritus 
 
Acne 
 
 
 
 
 
 
 
 
 
 
 
1 Includes aphthous stomatitis, glossitis, mouth ulceration, mucositis and stomatitis 
2 Includes edema, facial edema, and peripheral edema 
3 Includes infection, not otherwise specified (NOS) and the following infections that occurred infrequently 
as distinct entities: abscess, bronchitis, cellulitis, herpes simplex and herpes zoster 
4 Includes cystitis, dysuria, hematuria, urinary frequency, and urinary tract infection 
5 Includes taste loss and taste perversion 
6 Includes eczema, exfoliative dermatitis, maculopapular rash, puritic rash, pustular rash, rash NOS and 
vesiculobullous rash 
 
The following selected adverse reactions were reported less frequently (<10%). 
 


 
 
 
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 
Gastrointestinal Disorders – Fatal bowel perforation occurred in 1 patient (1%) 
 
 
Eye Disorders - Conjunctivitis (including lacrimation disorder) occurred in 15 patients (7%). 
 
 
Immune System - Allergic/Hypersensitivity reactions occurred in 18 patients (9%). 
 
 
Angioneurotic edema-type reactions (including delayed reactions occurring two months 
following initiation of therapy) have been observed in some patients who received TORISEL and 
ACE inhibitors concomitantly.   
 
 
Infections - Pneumonia occurred in 17 patients (8%); upper respiratory tract infection occurred in 
14 patients (7%). 
 
 
General Disorders and Administration Site Conditions - Impaired wound healing occurred in 
3 patients (1%). 
 
 
Respiratory, Thoracic and Mediastinal Disorders – Interstitial lung disease occurred in 5 
patients (2%), including rare fatalities. 
 
 
Vascular - Hypertension occurred in 14 patients (7%); venous thromboembolism (including deep 
vein thrombosis and pulmonary embolus [including fatal outcomes]) occurred in 5 patients (2%); 
thrombophlebitis occurred in 2 patients (1%). 
 
 
6.1.4 
Formulation and Stability 
 
TORISEL (temsirolimus) is supplied as a commercially labeled kit consisting of the following: 
TORISEL (temsirolimus) injection (25 mg/mL).  The TORISEL vial includes an overfill of 0.2 mL. Inert 
ingredients in the drug vial include dehydrated alcohol, d,l-alpha-tocopherol, propylene glycol, and 
anhydrous citric acid.  
 
DILUENT for TORISEL.  The DILUENT vial includes a deliverable volume of 1.8 mL.  The diluent vial 
contains polysorbate 80 NF, polyethylene glycol 400 NF, and absolute alcohol USP. 
 
 
 
Stability 
 
The 10 mg/mL drug solution/diluent mixture is stable for 24 hours at room  
 
 
temperature 
 
 Administer within 6 hours of the final dilution in 0.9% NaCl.  Store at room  
 
 
temperature (20º-25ºC) and protect from light. 
 
Storage 
 
Refrigerate intact TORISEL kit at 2º-8ºC and protect from light. 
 
6.1.5  
Preparation and Administration 
 
Solution Preparation 
These mixing instructions apply to commercial TORISEL only (as is provided for this study). The 
investigationally labeled product used in other studies is mixed differently. 
 
Protect from excessive light. 
 
Follow this two steps dilution process (TORISEL should only be diluted with the supplied diluent): 
 
 
Step 1 
 
Inject 1.8 mL of DILUENT for TORISEL into the vial of TORISEL injection (25 mg/mL).  Due to the 
intentional 0.2 mL overfill in the TORISEL injection vial, the resulting drug concentration will be 10 mg/mL.  
A total volume of 3 mL will be obtained.  Mix well by gentle inversion of the vial.  DO NOT SHAKE. Allow 
sufficient time for air bubbles to subside.   
 
 


 
 
 
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Step 2 
Withdraw the required amount of TORISEL from the 10 mg/mL drug solution/diluent mixture prepared in 
Step 1.  Further dilute with 0.9% sodium chloride injection immediately in glass or polyolefin containers to 
a final concentration between 0.04 mg/mL and 1 mg/mL. 
 
Route of Administration 
Administer temsirolimus as an intravenous infusion over 30 minutes (+/- 10 minutes) with an appropriate 
in-line filter (i.e. 0.2 to 5 micron) for all temsirolimus doses equal to or greater than 10 mg.  To avoid drug 
loss, do not use an inline filter for temsirolimus doses less than 10 mg.  Protect from light during 
administration. 
 
6.1.6  Supplier: Pfizer Pharmaceuticals, Inc   
 
 
6.1.7  Drug Ordering Information:  
 
Once you have IRB approval, contact TACL Operations at TACL@chla.usc.edu to arrange for a starter 
supply of temsirolimus. 
 
Sites receiving temsirolimus will verify the drug disposition and storage conditions on receipt and 
document this verification in the pharmacy records. When a definitive expiration date is determined, study 
drug will be removed from inventory at each investigative site and replaced with a new supply of study 
drug. Questions regarding drug shipments to and from TACL sites can be addressed to TACL Operations 
at 323-361-5429 or TACL@chla.usc.edu.  
 
 
6.2 
Etoposide  (Vepesid®, Etopophos®,VP-16) NSC #141540 
 
6.2.1  
Source and Pharmacology:  
A semisynthetic derivative of podophyllotoxin that forms a complex with topoisomerase 2 and DNA which 
results in single and double strand DNA breaks. Its main effect appears to be in the S and G2 phase of 
the cell cycle. The initial t½ is 1.5 hours and the mean terminal half-life is 4 to 11 hours. It is primarily 
excreted in the urine. In children, approximately 55% of the dose is excreted in the urine as etoposide in 
24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m² or about 35% of the total body 
clearance over a dose range of 80 to 600 mg/m². Etoposide, therefore, is cleared by both renal and non 
renal processes, i.e., metabolism and biliary excretion. The effect of renal disease on plasma Etoposide 
clearance is not known. Biliary excretion appears to be a minor route of etoposide elimination. Only 6% or 
less of an intravenous dose is recovered in the bile as etoposide. Metabolism accounts for most of the 
non renal clearance of etoposide. 
 
The maximum plasma concentration and area under the concentration time curve (AUC) exhibit a high 
degree of patient variability. Etoposide is highly bound to plasma proteins (~94%), primarily serum 
albumin. Pharmacodynamic studies have shown that etoposide systemic exposure is related to toxicity. 
Preliminary data suggests that systemic exposure for unbound etoposide correlates better than total 
(bound and unbound) etoposide. There is poor diffusion into the CSF < 5%. 
 
Cmax and AUC values for orally administered etoposide capsules consistently fall in the same range as 
the Cmax and AUC values for an intravenous dose of one-half the size of the oral dose. The overall mean 
value of oral capsule bioavailability is approximately 50% (range 25-75%).  
 
Etoposide phosphate is a water soluble ester of etoposide which is rapidly and completely converted to 
etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate that etoposide phosphate is 
bioequivalent to etoposide when it is administered in molar equivalent doses.  
 
 
6.2.2 Toxicity: 
 


 
 
 
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Common 
Happens to 21-100 children out 
of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children out 
of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting 
Anorexia 
Transient hypotension 
during infusion; 
anaphylaxis (chills, fever, 
tachycardia, dyspnea, 
bronchospasm, 
hypotension) 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Myelosuppression (anemia, 
leukopenia), alopecia 
Thrombocytopenia, 
diarrhea, abdominal pain, 
asthenia, malaise, rashes 
and urticaria 
Peripheral neuropathy, 
mucositis, 
hepatotoxicity, chest pain, 
thrombophlebitis, 
congestive heart failure, 
Stevens-Johnson 
Syndrome, exfoliative 
dermatitis 
Delayed: 
Any time later 
during therapy, 
excluding the 
above conditions 
 
 
Dystonia, ovarian failure, 
amenorrhea, anovulatory 
cycles, hypomenorrhea, 
onycholysis of nails 
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy 
(preleukemic or leukemic 
syndromes) 
Unknown Frequency and Timing: Fetal toxicities and teratogenic effects of etoposide have been noted in 
animals at 1/20th of the human dose. It is unknown whether the drug is excreted in breast milk. 
 
 
6.2.3  
Formulation and Stability 
Etoposide for Injection is available as a 20 mg/mL solution in sterile multiple dose vials (5 mL, 25 mL, or 
50 mL each). The pH of the clear, nearly colorless to yellow liquid is 3 to 4. Each mL contains 20 mg 
etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg modified polysorbate 80/tween 80, 650 mg 
polyethylene glycol 300, and 30.5 percent (v/v) alcohol. Vial headspace contains nitrogen. Unopened 
vials of etoposide are stable until expiration date on package at controlled room temperature (20˚-25˚C or 
68˚-77˚F). Etoposide phosphate for injection is available for intravenous infusion as a sterile lyophilized 
powder in single-dose vials containing etoposide phosphate equivalent to 100 mg etoposide, 32.7 mg 
sodium citrate USP, and 300 mg dextran 40. Etoposide phosphate must be stored under refrigeration (2°-
8°C or 36°- 46°F). Unopened vials of etoposide phosphate are stable until the expiration date on the 
package. 
 
 
6.2.4  
Guidelines for Administration 
 
Etoposide: Dilute etoposide to a final concentration ≤ 0.4 mg/mL in D5W or NS. Etoposide infusions are 
stable at room temperature for 96 hours when diluted to concentrations of 0.2 mg/mL; stability is 24 hours 
at room temperature with concentrations of 0.4 mg/mL. The time to precipitation is highly unpredictable at 
concentrations > 0.4 mg/mL. Use in-line filter during infusion secondary to the risk of precipitate 
formation. However, the use of an in-line filter is not mandatory since etoposide precipitation is unlikely at 
concentrations of 0.1-0.4 mg/mL. Do not administer etoposide by rapid intravenous injection. Slow 
rate of administration if hypotension occurs. Leaching of diethylhexyl phthalate (DEHP) from polyvinyl 
chloride (PVC) bags occurred with etoposide 0.4 mg/mL in NS. To avoid leaching, prepare the etoposide 
solution as close as possible, preferably within 4 hours, to the time of administration or alternatively as 
per institutional policy; glass or polyethylene-lined (non-PVC) containers and polyethylene-lined tubing 
may be used to minimize exposure to DEHP.  
 


 
 
 
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Etoposide Phosphate: Reconstitute the 100 mg vial with 5 or 10 mL of Sterile Water for Injection, D5W, 
NS, Bacteriostatic Water for Injection with Benzyl Alcohol, or Bacteriostatic Sodium Chloride for Injection 
with Benzyl Alcohol for a concentration equivalent to 20 mg/mL or 10 mg/mL etoposide equivalent (22.7 
mg/mL or 11.4 mg/mL etoposide phosphate), respectively. Use diluents without benzyl alcohol for 
neonates and infants < 2 years of age or patients with hypersensitivity to benzyl alcohol. When 
reconstituted as directed, etoposide phosphate solutions can be stored in glass or plastic containers 
under refrigeration for 7 days. When reconstituted with a diluent containing a bacteriostat, store at 
controlled room temperature for up to 48 hours. Following reconstitution with SWFI, D5W, or NS store at 
controlled room temperature for up to 24 hours. Following reconstitution, etoposide phosphate may be 
further diluted to a concentration as low as 0.1 mg/mL of etoposide with D5W or NS. 
 
6.2.5  
Supplier: Commercially available. See package insert  for further information. 
 
 
6.3 
Cyclophosphamide (Cytoxan) NSC #26271 
 
6.3.1  
Source and Pharmacology  
Cyclophosphamide is an alkylating agent related to nitrogen mustard. Cyclophosphamide is inactive until 
it is metabolized by P450 isoenzymes (CYP2B6, CYP2C9, and CYP3A4) in the liver to active 
compounds. The initial product is 4-hydroxycyclophosphamide (4-HC) which is in equilibrium with 
aldophosphamide which spontaneously releases acrolein to produce phosphoramide mustard. 
Phosphoramide mustard, which is an active bifunctional alkylating species, is 10 times more potent in 
vitro than is 4-HC and has been shown to produce interstrand DNA cross-link analogous to those 
produced by mechlorethamine. Approximately 70% of a dose of cyclophosphamide is excreted in the 
urine as the inactive carboxyphosphamide and 5-25% as unchanged drug. The plasma half-life ranges 
from 4.1 to 16 hours after IV administration. 
 
 
6.3.2  
Toxicity 
 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to <5 children out of 
every 100 
Immediate: 
Within 1-2 
days of 
receiving 
drug 
Anorexia, nausea & vomiting 
(acute and delayed) 
Abdominal discomfort, 
diarrhea 
Transient blurred vision, nasal 
stuffiness with rapid 
administration, 
arrhythmias (rapid infusion), 
skin rash, anaphylaxis, SIADH 
Prompt: 
Within 2-3 
weeks, prior 
to the next 
course 
Leukopenia, alopecia, 
immune suppression 
Thrombocytopenia, 
anemia, hemorrhagic 
cystitis (L) 
Cardiac toxicity with high dose 
(acute – CHF hemorrhagic 
myocarditis, myocardial 
necrosis) (L), 
hyperpigmentation, nail 
Changes, impaired wound 
healing, infection secondary to 
immune suppression 
Delayed: 
Any time later 
during 
therapy, 
excluding the 
above 
conditions 
Gonadal dysfunction: 
azoospermia or 
oligospermia 
(prolonged or permanent)1 
(L) 
Amenorrhea1 
Gonadal dysfunction: ovarian 
failure1 (L), interstitial 
pneumonitis, 
pulmonary fibrosis2 (L) 
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy (ALL, 
ANLL, AML), bladder 
carcinoma (long term use > 2 
years), bladder fibrosis 


 
 
 
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Unknown Frequency and Timing: Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in 
combination with other antineoplastic agents) have been noted in humans. Toxicities include: chromosomal 
abnormalities, multiple anomalies, pancytopenia, and low birth weight. Cyclophosphamide is excreted into 
breast milk. Cyclophosphamide is contraindicated during breast feeding because of reported cases of 
neutropenia in breast fed infants and the potential for serious adverse effects. 
1 Dependent on dose, age, gender, and degree of pubertal development at time of treatment. 
2 Risk increased with pulmonary chest irradiation and higher doses. 
(L) Toxicity may also occur later. 
 
6.3.3  
Formulation and Stability  
Cyclophosphamide for injection is available as powder for injection or lyophilized powder for injection in 
500 mg, 1 g, and 2 g vials. The powder for injection contains 82 mg sodium bicarbonate/100 mg 
cyclophosphamide and the lyophilized powder for injection contains 75 mg mannitol/100 mg 
cyclophosphamide. Storage at or below 25ºC (77ºF) is recommended. The product will withstand brief 
exposures to temperatures up to 30ºC (86ºF). 
 
6.3.4  
Guidelines for Administration  
If the drug will be administered as undiluted drug at the 20 mg/mL concentration, then reconstitute to 20 
mg/mL with NS ONLY to avoid a hypotonic solution. If the drug will be further diluted prior to 
administration, then first reconstitute with NS, SWFI, or Bacteriostatic Water for Injection (paraben 
preserved only) to a concentration of 20 mg/mL. Following reconstitution further dilute in dextrose or 
saline containing solutions for IV use. 
 
6.3.5  Supplier: Commercially available. See package insert for further information. 
 
6.4 
IT Methotrexate (MTX, amethopterin, Trexall®) NSC #000740 
 
6.4.1 
Source and Pharmacology:  
A folate analogue which reversibly inhibits dihydrofolate reductase, the enzyme that reduces folic acid to 
tetrahydrofolic acid. Inhibition of tetrahydrofolate formation limits the availability of one carbon fragments 
necessary for the synthesis of purines and the conversion of deoxyuridylate to thymidylate in the 
synthesis of DNA and cell reproduction. The polyglutamated metabolites of MTX also contribute to the 
cytotoxic effect of MTX on DNA repair and/or strand breaks. MTX cytotoxicity is highly dependent on the 
absolute drug concentration and the duration of drug exposure. MTX is actively transported across cell 
membranes. At serum methotrexate concentrations exceeding 0.1 μmol/mL, passive diffusion becomes a 
major means of intracellular transport of MTX. The drug is widely distributed throughout the body with the 
highest concentration in the kidney, liver, spleen, gallbladder and skin. Plasma concentrations following 
high dose IV MTX decline in a biphasic manner with an initial half-life of 1.5-3.5 hours, and a terminal half 
life of 8-15 hours. About 50% is bound to protein. After oral administration, approximately 60% of a 30 
mg/m2 dose is rapidly absorbed from the GI tract, with peak blood levels at 1 hour. At doses > 30 mg/m² 
absorption decreases significantly. Even at low doses absorption may be very erratic, varying between 
23% and 95%. The elimination of MTX from the CSF after an intrathecal dose is characterized by a 
biphasic curve with half-lives of 4.5 and 14 hours. After intrathecal administration of 12 mg/m², the lumbar 
concentration of MTX is ~100 times higher than in plasma. (Ventricular concentration is ~ 10% of lumbar 
concentration). MTX is excreted primarily by the kidneys via glomerular filtration and active secretion into 
the proximal tubules. Renal clearance usually equals or exceeds creatinine clearance. Small amounts are 
excreted in the feces. There is significant entero-hepatic circulation of MTX. The distribution of MTX into 
third-space fluid collections, such as pleural effusions and ascitic fluid, can substantially alter MTX 
pharmacokinetics. The slow release of accumulated MTX from these third spaces over time prolongs the 
terminal half-life of the drug, leading to potentially increased clinical toxicity. 
 
 
6.4.2 
Toxicity 
 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to <5 children out 
of every 100 
Immediate: 
Nausea, headache 
Arachnoditis: (headache, 
Anaphylaxis, vomiting, 


 
 
 
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Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to <5 children out 
of every 100 
Within 1-2 days of 
receiving drug 
fever, vomiting, 
meningismus, nuchal 
rigidity, and pleocytosis) 
seizures(L), 
confusion, back pain, rash, 
bleeding 
into subarachnoid or 
subdural space 
(risk > with platelet counts 
< 20,000), 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
 
 
Myelosuppression, ataxia, 
somnolence, cranial nerve 
palsy, 
subacute myelopathy 
(paraparesis/paraplegia), 
speech 
disorders, pain in the legs, 
bladder 
dysfunction 
 
Delayed: 
Any time later during 
therapy, excluding 
the above conditions 
 
Learning disability (L), 
Cognitive disturbance 
Leukoencephalopathy1 (L) 
 
Late: 
Any time after 
completion of 
treatment 
 
 
Progressive CNS 
deterioration1 
 
1 May be enhanced by HDMTX and/or cranial irradiation.  
(L) Toxicity may also occur later. 
 
6.4.3 Formulation and Stability 
Methotrexate for Injection is available as a lyophilized powder for injection in 1000 mg vials. The powder 
for injection contains approximately 7 mEq sodium in the 1000 mg vial. Methotrexate for Injection is also 
available as a 25 mg/mL solution in 2, 4, 8, 10, and 40 mL preservative free vials and 2 and 10 mL vials 
with preservative. The 2, 4, 8, 10, and 40 mL solutions contain approximately 0.43, 0.86, 1.72, 2.15, and 
8.6 mEq sodium per vial, respectively. The preserved vials contain 0.9% benzyl alcohol as a preservative. 
Sterile methotrexate powder or solution is stable at 20º-25ºC (68º-77ºF); excursions permitted to 15º-30ºC 
(59º- 86 Fº). Protect from light. 
 
6.4.4 
Guidelines for Administration:  
See Treatment and Dose Modifications sections of protocol. Leucovorin rescue may be necessary with 
certain doses of methotrexate. 
 
For Intrathecal use: Use preservative free 25 mg/mL solution. For intrathecal administration, dilute with 
5-10 mL preservative free NS, lactated Ringer’s, or Elliot’s B solution as per institutional standard of 
practice. The volume of CSF removed should be equal to at least half the volume delivered. 
 
Patient Age (years) 
Methotrexate 
Dose 
Recommended 
volume 
10% CSF 
volume 
CSF Volume * 
1 – 1.99 
8 mg 
5 – 10 mL 
5 mL 
50 +/- 10 mL (babies) 
2 – 2.99 
10 mg 
5 – 10 mL 
8 mL 
80 +/- 20 mL (younger 
children) 
3 – 8.99 
12 mg 
5 – 10 mL 
10 mL 
100 +/- 20 mL (older 
children) 
9 or greater 
15 mg 
5 – 10 mL 
13 mL 
130 +/- 30 mL (adults) 


 
 
 
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*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection; N Engl J Med. 1962 Dec 
20; 267:1273-8 
 
Of Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the 
patient remaining prone after the procedure may facilitate drug distribution. These procedures have not 
been validated in clinical trials. They are allowed but not mandated for patients on TACL studies.  
 
Intrathecal cytarabine mixed in NS, lactated Ringer’s injection, or Elliot’s B solution is stable for 24 hours 
at 25ºC but contains no preservative and should be administered as soon as possible after preparation. 
 
6.4.5 Supplier: Commercially available. See package insertfor further information. 
 
 
6.5 
Leucovorin Calcium (LCV, Wellcovorin®, citrovorum factor, folinic acid) NSC #003590 
 
6.5.1 
Source and Pharmacology:  
Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF). 
The biologically active compound of the mixture is the (-)- l-isomer, known as Citrovorum factor or (-)- 
folinic acid. Leucovorin does not require reduction by the enzyme dihydrofolate reductase in order to 
participate in reactions utilizing folates as a source of ―one-carbon‖ moieties. Administration of 
leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, 
which act by inhibiting dihydrofolate reductase. In contrast, leucovorin can enhance the therapeutic and 
toxic effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil. Leucovorin is readily 
converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of 
fluorodeoxyuridylic acid (an active metabolite of 5-FU) to thymidylate synthase and thereby enhances the 
inhibition of this enzyme. Peak serum levels of 5-methyl THF (an active metabolite) were reached at 
approximately 1.3-1.5 hours (IV/IM) and 2.3 hours for the oral form. The terminal half-life of total reduced 
folates was approximately 6.2 hours. Following oral administration, leucovorin is rapidly absorbed and 
expands the serum pool of reduced folates. At a dose of 25 mg, almost 100% of the l-isomer (the 
biologically active form) but only 20% of the d-isomer is absorbed. Oral absorption of leucovorin is 
saturable at doses above 25 mg. The apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 
50 mg, and 37% for 100 mg doses. Both oral and parenteral leucovorin raise the CSF folate levels. 
 
6.5.2 Toxicity 
 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
 
Anaphylaxis, urticaria, seizure 
Unknown Frequency and Timing: Fetal toxicities and teratogenic effects of leucovorin in humans are 
unknown. It is unknown whether the drug is excreted in breast milk. 
 
6.5.3 
Formulation and Stability:  
Leucovorin calcium for injection is supplied as a sterile ready to use liquid and a sterile powder for 
injection. The 10 mg/mL preservative free liquid is available in 50 mL vials containing sodium chloride 400 
mg/vial. Store preservative free liquid in the refrigerator at 2°-8°C (36°-46°F) protected from light. The 
powder for injection is available in 50 mg, 100 mg, 200 mg, and 350 mg vials. Store at room temperature 
15°-25°C (59°-77°F) protected from light. Reconstitute the sterile powder with sterile water for injection or 
bacteriostatic water for injection to a concentration of 10 mg/mL leucovorin calcium. Do not use diluents 
containing benzyl alcohol for doses > 10 mg/m² or in infants < 2 years of age or patients with 
allergy to benzyl alcohol. When Bacteriostatic Water is used, the reconstituted solution is good for 7 
days. If reconstituted with SWFI, use solution immediately as it contains no preservative. One milligram of 
leucovorin calcium contains 0.004 mEq of leucovorin and 0.004 mEq of calcium. The oral form of 
leucovorin is available as 5 mg, 10 mg, 15 mg, and 25 mg tablets. Inactive ingredients vary depending on 


 
 
 
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manufacturer but tablet formulations may include: corn starch, dibasic calcium phosphate, magnesium 
stearate, pregelatinized starch, lactose, microcrystalline cellulose, and sodium starch glycolate.  
 
6.5.4 Guidelines for Administration:  
See Treatment and Dose Modifications sections of the protocol. 
 
 
Injection: Because of the calcium content of the leucovorin solution, no more than 160 mg of 
leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL solution per 
minute). IV leucovorin and sodium bicarbonate are incompatible.  
 
 
Oral: Oral leucovorin should be spaced evenly (e.g., every six hours) throughout the day and may 
be taken without regard to meals. Doses > 25 mg should be given IV due to the saturation of 
absorption. Leucovorin should not be administered < 24 hours after intrathecal injections which 
contain methotrexate unless there are special circumstances.  
 
Supplier: Commercially available from various manufacturers. See package insertfor further information. 
 
 
6.6 
IT Cytarabine 
 
6.6.1 Source and Pharmacology:  
Cytarabine appears to act through the inhibition of DNA polymerase. A limited, but significant, 
incorporation of cytarabine into both DNA and RNA has also been reported. It exhibits cell phase 
specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions 
blocking the progression of cells from the G1 phase to the S-phase. Cytarabine is metabolized by 
deoxycytidine kinase and other nucleotide kinases to the nucleotide triphosphate (Ara-CTP), an effective 
inhibitor of DNA polymerase. Ara-CTP is inactivated by a pyrimidine nucleoside deaminase, which 
converts it to the nontoxic uracil derivative (Ara-U). It appears that the balance of kinase and 
deaminaselevels may be an important factor in determining sensitivity or resistance of the cell to 
cytarabine. It has an initial distributive phase t½ of about 10 minutes, with a secondary elimination phase 
t½ of about 1 to 3 hours. Peak levels after intramuscular or subcutaneous administration of cytarabine 
occur about 20 to 60 minutes after injection and are lower than IV administration. Intrathecally 
administered doses are metabolized and eliminated more slowly with a t½ of about 2 hours. 
 
6.6.2 Toxicity: 
 
Cytarabine: Single Agent, Intrathecal 
 
Common 
Happens to 21-
100 children out of 
every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children out of every 
100 
Immediate: 
Within 1-2 days 
of receiving 
drug 
Nausea, vomiting, 
fever, headach 
Arachnoiditis 
Rash, somnolence, meningismus, 
convulsions, paresis 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
 
 
Myelosuppression, ataxia 
Delayed: 
Any time later 
during therapy, 
excluding the 
above 
conditions 
 
 
Necrotizing leukoencephalopathy, 
paraplegia, blindness (in combination 
with XRT & systemic therapy) 
Late: 
Any time after 
 
 
 


 
 
 
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completion of 
treatment 
Unknown Frequency and Timing: This drug may be harmful to an unborn/developing child. 
The development of an unborn baby can be affected by this drug (either alone or in combination with some 
other drugs).  Birth defects can include abnormal genetic changes, abnormal development of body 
structures, abnormal reduction of blood cells, and low birth weight. 
 
6.6.3 Formulation and Stability: 
Cytarabine for Injection is available in vials of 100 mg, 500 mg, 1 g, and 2 g containing a sterile powder 
for reconstitution. It is also available at a 20 mg/mL concentration with benzyl alcohol (25 mL per vial) or 
as a preservative free solution (5 mL, 50 mL per vial), and at a 100 mg/mL concentration with benzyl 
alcohol (20 mL vial) or as preservative free solution (20 mL vial). Hydrochloric acid and/or sodium 
hydroxide may be added to adjust the pH. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-
86°F). Cytarabine solutions should be protected from light.  
 
6.6.4 Guidelines for Administration:  
 
Intrathecal: 
Intrathecal: For intrathecal administration, dilute with 5-10mL (or volume per institutional practice) 
preservative free 0.9% sodium chloride injection, lactated Ringer’s injection,  Elliot’s B solution. The 
volume of CSF removed should be equal to at least ½ the volume delivered.  
 
Patient Age 
(years) 
Recommended volume 
10% CSF volume 
CSF Volume * 
1 – 1.99 
5 – 10 mL 
5 mL 
50 +/- 10 mL (babies) 
2 – 2.99 
5 – 10 mL 
8 mL 
80 +/- 20 mL (younger children) 
3 – 8.99 
5 – 10 mL 
10 mL 
100 +/- 20 mL (older children) 
9 or greater 
5 – 10 mL 
13 mL 
130 +/- 30 mL (adults) 
 
*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection; N Engl J Med. 1962 Dec 
20; 267:1273-8.  
 
Of Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with the 
patient remaining prone after the procedure may facilitate drug distribution. These procedures have not 
been validated in clinical trials. They are allowed but not mandated for patients on TACL studies.  
 
Intrathecal cytarabine mixed in NS, lactated Ringer’s injection, or Elliot’s B solution is stable for 24 hours 
at 25ºC but contains no preservative and should be administered as soon as possible after preparation. 
 
6.6.5 Supplier: Commercially available. See package insert for further information. 
 
 
 
6.7 
Intrathecal Triples (Methotrexate/Hydrocortisone/Cytarabine, ITT) 
 
 
 
 
 
 
 
6.7.1 
Source and Pharmacology:  
The intrathecal route of administration of a drug produces more consistent CSF drug concentrations at 
relatively smaller doses because of the volume difference between the CSF and blood compartments 
(140 mL vs. 3500 mL in an adult). (The CSF volume of children after the first 3 years is equivalent to that of 
an adult). Drug half-lives are longer as well because clearance is related to flow rather than metabolism or 
protein binding. Intrathecal methotrexate has a biphasic elimination curve from the CSF with a t½ of 4.5 and 
14 hours respectively. Following IT injection of cytarabine the elimination of the drug from the CSF is 
biphasic with a t½ of 1 and 3.4 hours respectively which is 8-fold longer than the clearance from plasma. The 
elimination of hydrocortisone is similarly prolonged.   
 
6.7.2 
Toxicity  
 


 
 
 
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Intrathecal Triple Therapy (Methotrexate/ Hydrocortisone/Cytarabine) 
 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children out 
of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, 
fever, headache 
Arachnoditis: 
(headache, fever, 
vomiting, 
meningismus and 
pleocytosis)  
Rash, anaphylaxis (L), 
paresis, bleeding into 
subarachnoid or subdural 
space (risk > with platelet 
counts <20,000), confusion, 
fatigue, disorientation, 
seizures 
Prompt: 
Within 2-3 weeks, prior 
to the next course 
 
 
Myelosuppression, 
somnolence, ataxia, cranial 
nerve palsy, transient and 
rarely permanent paraplegia 
(L), speech disorders 
Delayed: 
Any time later during 
therapy, excluding the 
above condition 
 
Cognitive 
disturbances (L), 
learning disabilities (L) 
Demyelinating 
leukoencephalopathy1 (L), 
blindness1  
Late: 
Any time after the 
completion of 
treatment 
 
 
Progressive CNS 
deterioration1 
1 May be enhanced by systemic therapy such as high dose methotrexate or cytarabine and/or cranial irradiation. 
 (L) Toxicity may also occur later. 
 
6.7.3 
Formulation and Stability:  
Methotrexate 25 mg/mL 2 mL vial preservative free or methotrexate 20 mg sterile powder for injection vial. 
Cytarabine 100 mg vial sterile powder for injection. Hydrocortisone sodium succinate100 mg vial sterile 
powder for injection.   
 
6.7.4 
Guidelines for Administration:  
See Treatment and Dose Modification sections of the protocol. For intrathecal administration, dilute with 5-
10 mL preservative free normal saline, lactated ringers or Elliot’s B solution or as per institutional standard of 
practice. The volume of CSF removed should be equal to at least half the volume delivered. 
 
 
Of Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, with 
the patient remaining prone after the procedure may facilitate drug distribution. These procedures 
have not been validated in clinical trials. They are allowed but not mandated for patients on COG 
studies. 
 
Intrathecal triples are stable in normal saline for 24 hours at 25ºC but contain no preservative and 
should be administered as soon as possible after preparation. 
Patient Age 
(years) 
Doses (MTX/HDC/Ara-C) 
 
Recommended 
volume 
10% CSF 
volume 
CSF Volume 35 
1 – 1.99 
8 mg / 8 mg / 16 mg 
5–10 mL 
5 mL 
50 + 10 mL (babies) 
2 – 2.99 
10 mg / 10 mg / 20 mg 
5-10 mL 
8 mL 
80 + 20 mL (younger 
children) 
3 – 8.99 
12 mg / 12 mg / 24 mg 
5-10 mL 
10 mL 
100 + 20 mL (older 
children) 
9 or greater 
15 mg / 15 mg / 30 mg 
5-10 mL 
13 mL 
130 + 30 mL (adults) 


 
 
 
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6.7.5 
Supplier: Methotrexate, cytarabine and hydrocortisone are commercially available from various 
manufacturers. See package insert for further information  
 
 


 
 
 
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7.0   REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
All protocol-specified hematology, blood chemistries, and bone marrow aspirations and/or biopsies are to 
be performed under the auspices of the local laboratory at each investigational site. Additional 
assessments may be obtained as needed for good patient care. 
 
7.1 
Required Clinical, Laboratory and Disease Evaluation 
 
Laboratory values used to assess eligibility (see Section 3.0) must be no older than seven (7) days at the 
time of enrollment.   
 
Imaging studies must be obtained within 14 days prior to enrollment (repeat the tumor imaging if 
necessary). Chest x-ray for eligibility, per section 3.3.6.5, may also be obtained within 14 days of 
enrollment.  The bone marrow aspirate (and/or biopsy) must be obtained within 14 days prior to the start 
of protocol therapy. Lumbar puncture must be done within 7 days prior to the start of protocol therapy or 
on day 1 of therapy.  
 
During the courses of therapy, any abnormal laboratory tests must be re-checked by day 36 to assess 
resolution. 
 
Patients who are removed from protocol therapy during course 1 should continue to have the required 
observations in Section 7.1 until the originally planned end of the course or until all adverse events have 
resolved, whichever happens LATER. The only exception is with documentation of the patient’s 
withdrawal of consent.  
 
STUDIES TO BE OBTAINED 
Pre-
Study 
During  
Course 1 
End of Course 1 
Subsequent 
Courses 
History 
X1 
--- 
--- 
--- 
Physical Exam  with vital signs 
X1 
Weekly 
X 
Once per cycle 
Height, weight, BSA 
X 
--- 
X 
Once per cycle 
Performance Status 
X1 
--- 
X 
Once per cycle 
CBC, differential, platelets 
X1 
Every 3-4 days  
X 
Every 7-14 days 
Urinalysis 
X 
--- 
--- 
--- 
Tumor Lysis Labs2 
X 
Every 3-4 days in  
Week 1 
X 
--- 
Electrolytes including glucose, 
Ca++, PO4, Mg++ 
X 
Weekly 
X 
Every 7-14 days 
Creatinine, ALT, AST, GGT, 
total bilirubin, BUN 
X1 
Weekly 
X 
Once per cycle 
Albumin 
X1 
--- 
X 
--- 
Triglyceride/Cholesterol (Total, 
HDL, LDL) 
X1 
Weekly 
X 
Once per cycle 
Lipase/Amylase 
X 
--- 
--- 
--- 
PT/PTT/Fibrinogen 
X 
--- 
--- 
--- 
Pregnancy Test 
X1 
If pregnancy is suspected 
Pulse Ox and Chest X-ray 
X1 
--- 
--- 
--- 
ECHO/MUGA 
X1 
--- 
--- 
--- 
Ophthalmologic Exam3 
X1 
--- 
--- 
--- 
Bone marrow aspirate and/or 
X1 
--- 
Day 29 +/- 3 days4 
Day 29 of 2nd 


 
 
 
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STUDIES TO BE OBTAINED 
Pre-
Study 
During  
Course 1 
End of Course 1 
Subsequent 
Courses 
Biopsy for routine morphology 
 (if positive at 
study entry) 
cycle and If not 
in CR at end of 
prior cycle or if 
suspicion of 
relapse 
Tumor imaging  
(lymphoma patients only) 
X1 
--- 
Day 29 +/- 3 days 
 
If not in CR at 
end of prior 
cycle or if 
suspicion of 
relapse5  
Lumbar puncture with cell count 
& cytospin- for all leukemia 
patients and lymphoma patients 
with CNS disease at study entry 
X1 
Perform at the time the 
lumbar puncture for IT 
therapy is done 
Day 29+/- 3 
days. May give IT 
for start of 
Course 2 
Perform at the 
time the lumbar 
puncture for IT 
therapy is done 
Minimal residual disease (MRD) 
– for leukemia patients and 
lymphoma patients with BM 
involvement at study entry 
 
--- 
 
--- 
Day 29 +/- 3 
days 
End of course 2:  
Day 29 +/- 3 
days7 
Correlative bone marrow biology 
Studies6 
X 
--- 
Day 29 +/- 3 
days 
X1,4 
Correlative peripheral blood 
biology studies6 
X 
Once, day 3-5 
Day 29 +/- 3 
days 
--- 
 
1. 
Required for verification of eligibility.  Send all results to TACL Operations Center with study registration 
eligibility.  
 
2. 
Tumor lysis labs (electrolytes, BUN, Cr, Ca, PO4, and uric acid) should be obtained two times in the first 
week . If there is no evidence of tumor lysis, obtain chemistries as outlined above. 
 
3. 
Patients presenting with visual disturbances should have an ophthalmological exam and, if indicated, an 
MRI to determine optic nerve or retinal involvement prior to enrollment per Section 3.4.6. 
 
4. 
If the bone marrow is hypoplastic or M1 but counts have not recovered to ANC ≥ 500 and PLTS ≥ 50,000 
(without transfusion) obtain a weekly CBC and perform a bone marrow with evidence of count recovery 
(ANC ≥ 500 and PLTS ≥ 50,000) or day 42; whichever is first. If still delayed repeat a bone marrow every 7-
14 days after day 42 until count recovery or relapse. A repeat bone marrow does not need to be performed if 
the patient subsequently develops an absolute blast count (ABC) greater than or equal to 2,500/mm3  
  
5. 
On subsequent cycles perform BM and tumor imaging at the end of each cycle until in a CR. Once in CR 
can perform every other cycle.  
 
6. 
See Section 8.0 for timing of correlative biology studies. 
 
7. 
Obtain sample for MRD at end of course 2 if bone marrow M1 post Course 2 but MRD was > 0.01% at end 
of Course 1. 
 
 
7.2 
Required Observations Following Completion of Protocol Therapy 
 
When a patient discontinues the study, a Final Visit will be conducted. A History and PE and labs should 
be obtained. 
 
 
CBC, differential, platelets 
 
Electrolytes including glucose, Ca++, PO4, Mg++ 
 
Creatinine, ALT, bilirubin, BUN 


 
 
 
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 
Triglyceride/Cholesterol (Total, HDL, LDL) 
 
Following discontinuation of the study drug, the patient will be treated in accordance with the 
investigator's best clinical judgment. If a patient discontinues from the study due to an adverse event 
considered possibly or probably related to study drug, a Follow-up Visit must be conducted no later than 
30 days after the last dose of anti-cancer therapy administered as part of this protocol. Safety 
assessments will be conducted at least every 30 days, until all toxicities resolve, return to baseline or 
become clinically satisfactory, stable, or are considered irreversible. 
 
Patients will be followed for life for any delayed toxicities related to protocol therapy, and secondary 
malignancies. Survival information, including disease status, alternative therapies, sites of relapse and 
the date and cause of death will be collected after the last study visit until the patient is considered off 
study.  
 
 
 


 
 
 
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8.0 
CORRELATIVE AND PHARMACOKINETIC STUDIES 
 
 
Correlative 
Study 
Sample 
Type 
Volume per 
Sample 
Tube Type 
Timing of Sample Collection 
Baseline 
Cycle 1 
Subsequent 
Cycles 
Bone 
Marrow 
MRD 
bone 
marrow 
6 mL for patients 
≥12 kg  
3 mL for patients   
< 12 kg 
conical tubes 
(SM) containing 
EDTA/RPMI as 
the anticoagulant 
and media 
diluent or EDTA 
tubes 
--- 
Day 
29+/- 3 
days 
Once CR is 
obtained 
Bone 
Marrow 
Correlative 
Biology 
Study 
bone 
marrow 
10 mL for patients 
≥10kg  
3-5 mL for patients 
<10kg 
green top 
(heparinized) 
tubes 
X 
Day 
29+/- 3 
days 
Until CR 
obtained and 
at recurrence 
PBMC* 
Correlative 
Biology 
Study 
blood 
5 mL for patients    
≥ 10 kg  
2 mL for patients < 
10 kg 
lavender-top 
(K2EDTA) tubes 
or CPT tubes 
X 
*Once 
Day 3-5 
and 29  
 
* Leukemia patients only; send baseline and subsequent samples if patient has any level of detectable 
peripheral blasts at study entry (no minimum). 
 
8.1 
Bone Marrow MRD (Required for leukemia patients)  
 
If a patient has <5% bone marrow blasts (morphologically) on their end of Course 1 and/or 2 bone 
marrow, and is not aplastic, bone marrow will be sent to determine minimal residual disease by 
immunoflow. These data will provide important correlative data regarding MRD and early response to 
combined therapy. If aplastic with subsequent non-blasts recovery MRD should be sent with the bone 
marrow that documents recovery 
 
Samples requested: 
Bone Marrow  
 
Course 1, Day 29 +/- 3 days if < 5% blasts by local morphology  
 
Course 2, Day 29 +/- 3 days if < 5% bone marrow blasts post 
Course 2 and MRD > 0.01% at end of Course 1 
 
Bone Marrow Collection 
Procedure: 
 
 
Collect 6 mL for patients ≥12 kg and 3 mL for patients < 12 kg 
of marrow into a syringe and transfer the specimen 
immediately into a conical tube with 15 ml of RPMI/EDTA. If 
the shipping media tubes are unavailable, place the marrow 
into large purple EDTA tubes that are commonly used in all 
hospitals.  The viability would be enhanced if put into 
RPMI/EDTA for shipping. 
 
Mix sample well. Up to 5 ml of marrow can be placed in one 15 
cc tube with RPMI/EDTA.   
 
Use multiple syringes and tubes as needed. Reposition marrow 
aspirate needle as least once during procedure to ensure the 
maximum quality of marrow. 
 
Specimen Labeling: 
Each tube must be labeled with the study ID number and TACL ID 
along with the date and time the sample was obtained.  No personal 
identifying patient information should be included on the specimen or 
transmittal form. 


 
 
 
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Specimen Packaging and 
Shipping: 
 
 
 
Samples are to be sent at room temperature.  
 
Include the completed TACL Specimen Shipping Form with shipment 
and email (tacl@chla.usc.edu) or FAX a copy to TACL Operations 
Center (877-904-2166).   
 
Samples can be shipped to arrive Monday-Friday. For Saturday arrivals, 
please call the lab ahead of time: Phone: 206-288-7060 
 
Please send copy of Flow Cytometry histogram done locally with day 
29 bone marrows. 
 
 
 
 
 
 
 
 
 
 
 
For specimen shipping, TACL will provide a FED-EX account. Please 
call the TACL Operations Center for any questions.  
 
 
8.2 
Bone Marrow Correlative Biology Studies (Optional) 
 
Participation in the collection of these specimens is encouraged, but is voluntary, and patients may 
still participate in the therapeutic part study if they decline correlative biology studies. Institutions are 
encouraged to talk to their patients about participation. 
 
The following description of studies applies for the bone marrow and PBMC correlative studies described 
in Section 8.2 and Section 8.3 of the protocol. 
 
1. Evaluating effect of temsirolimus on mTOR pathway proteins 
The effects of temsirolimus upon ALL cells will be assessed by comparing expression of a number of 
key mTOR signaling proteins before and after initiating treatment. The changes in activation 
(phosphorylation) of the PI3K/mTOR pathway and other signaling proteins will be determined by 
leukemia cell-specific phosphoflow cytometry analyses +/- immunoblotting using published 
techniques..5, 6, 21 Baseline and subsequent PBMC samples will be collected at designated timepoints 
from patients regardless with any level of peripheral ALL blasts present at time of study entry.  
 
2. Investigating the impact of temsirolimus on proteins involved in resistance to chemotherapy. 
ALL blasts from blood and/or bone marrow will also be studied to assess changes in proteins involved 
in chemotherapy resistance. Proteins will be studied by immunoblot using published techniques and 
may include markers of methotrexate resistance (DHFR, Rb, and cyclin D1) and corticosteroid 
resistance (MCL1, RIP-1, CYLD, beclin-1, BRG1, and GSK3).5, 6, 13  21, 42 If necessary, samples will be 
flow sorted to enrich for ALL blasts. These studies will be performed pre-study, once between Day 3-
5 if peripheral blast count is ≥2500/mm3. If peripheral blasts count is not ≥ 2500/mm3, pre-study bone 
marrow will be used and compared to end of cycle 1 bone marrow.  
 
3. Investigating the impact of temsirolimus on membrane transporters. mTOR inhibitors, including 
temsirolimus, have the potential to inhibit a number of membrane transporters, including ABCG2 
(BCRP), Pgp, and MRP. Inhibition of these transporters may affect metabolism of other medications 


 
 
 
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and chemotherapeutic agents.43,44 ABCG2, Pgp, and MRP levels, will be measured in ALL blasts by 
flow cytometry, using published techniques.44 These studies will be performed on peripheral blood if 
peripheral blasts count is ≥2500/mm3 or bone marrow if less than 2500/mm3 with time points as 
described in resistance to chemotherapy experiments. See section 8.3 for further details on 
peripheral blood biology studies. These studies will only be performed on samples that are shipped 
fresh. 
 
4. Studies of ALL blasts treated with temsirolimus alone and in combination with cytotoxics in 
pre-clinical models of ALL 
ALL blasts from pre-treatment samples will be injected into xenograft models of ALL for expansion of 
blast numbers and to assess in vivo response to treatment with temsirolimus with and without 
cytotoxic agents, using published techniques.6, 18  
 
If cells (peripheral blood and/or bone marrow) are limited, priority will be the following order: (1) MRD 
assessment, (2) studies assessing changes in mTOR pathway; (3) xenograft experiments, (4) studies 
assessing proteins involved in chemotherapy resistance, and (5). studies assessing impact of 
temsirolimus on membrane transporters 
 
Samples requested: 
Bone Marrow  
 
Pre-treatment 
 
Course 1, Day 29 +/- 3 days 
 
Course 2, Day 29 +/- 3 days (if patient was not in CR after 
course 1) 
 
Any subsequent bone marrows while on study or with 
relapse/recurrence. 
Bone Marrow Collection 
Procedure: 
10 mL for patients ≥10 kg, 3-5 mL for patients <10 kg of bone marrow  
should be collected in one to three green top (sodium heparin) tubes. 
 
No processing is required, Samples should be shipped the same day 
they are obtained.  
Specimen Labeling: 
Each tube must be labeled as bone marrow with the study ID number, 
TACL ID, and the date and time the sample was obtained.  No 
personal identifying patient information should be included on the 
specimen or transmittal form. 
 
Specimen Packaging and 
Shipping: 
 
 
 
 
Sample tubes should be placed in polypropylene tubes (for 
secondary containment) and shipped in a styrofoam box as 
appropriate for biologic material.  
 
Ship the sample at room temperature (with a cold pack if possible; 
NO DRY ICE) on the same day it was obtained with Federal 
Express overnight priority delivery for arrival on a Monday through 
Friday only. Samples must be received within 24 hours of 
obtaining the sample. Do not ship samples for delivery on a 
weekend or holiday. Bone marrow and blood samples that cannot 
be delivered on a weekday should be stored refrigerated at 4°C 
and shipped the next business day.  
 
Ship samples to: 
 
 
 
  
 
 
 


 
 
 
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For specimen shipping, TACL will provide a FED-EX account. Please 
call the TACL Operations Center for any questions.  
 
 
8.3 
PBMC Correlative Biology Studies (Optional) 
 
Participation in the collection of these specimens is encouraged, but is voluntary, and patients may 
still participate in the therapeutic part study if they decline. Institutions are encouraged to talk to their 
patients about participation. 
 
The description of these studies is described in full detail under Section 8.2.1. 
 
Samples requested: 
Peripheral Blood  
 
Pre-treatment 
 
Course 1, Day 3-5*  
 
Course 1 Day 29.  
 
*Send one sample obtained between day 3-5 (day 3 preferred if 
acceptable for the patient). Do not batch. 
Blood Collection Procedure: 
Blood samples (5 mL for patients ≥ 10 kg, 2 mL for patients < 10 kg) 
will be collected in lavender-top (K2EDTA) tubes.   
 
Sample Processing: 
Blood samples do not require any processing by the site as long as 
they are collected on Monday through Thursday (not including 
holidays) and will be shipped to the laboratory on the same day of 
collection. Please contact Dr. Tasian if other arrangements are needed.  
 
Specimen Labeling: 
Each tube must be labeled as peripheral blood with the study ID 
number, TACL ID, and the date and time the sample was obtained.  No 
personal identifying patient information should be included on the 
specimen or transmittal form. 
 
Specimen Packaging and 
Shipping: 
 
 
 
FRESH SPECIMENS 
 
Sample tubes should be placed in polypropylene tubes (for 
secondary containment) and shipped in a styrofoam box as 
appropriate for biologic material.  
 
Ship the sample at room temperature on the same day it was 
obtained with Federal Express overnight priority delivery for arrival 
on a Monday through Friday only. Samples must be received 
within 24 hours of obtaining the sample. Do not ship samples 
for delivery on a weekend or holiday.  
 
Ship samples to: 
Tasian Laboratory 
The Children's Hospital of Philadelphia 
CTRB, Room 3100  
3501 Civic Center Blvd. 
Philadelphia, PA 19104 


 
 
 
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For specimen shipping, TACL will provide a FED-EX account. Please 
call the TACL Operations Center for any questions.  
 
 
 


 
 
 
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9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY, OFF STUDY CRITERIA AND 
STUDY TERMINATION 
 
 
9.1 
Criteria for Removal from Protocol Therapy 
a. Patient is not CNS 1 or 2 after the first course of therapy (this excludes patients who are CNS 3 
due to chloromas or cranial nerve involvement with evidence of improvement).  
b. Patient remains M3 after the first course of therapy 
c. Patient remains M2 after the second course of therapy 
d. Relapse in any site following remission 
e. Progressive disease 
f. 
Completion of protocol therapy 
g. Second malignant neoplasm 
h. Patient/parent withdrawal or refusal after beginning protocol therapy 
i. 
Patient/parent withdrawal or refusal before beginning protocol therapy 
j. 
Patient off treatment for other complicating disease 
k. Non-compliance with protocol regimen and procedures 
l. 
Investigator determination 
m. Female patient becomes pregnant or begins breast-feeding 
 
Pregnancy during research participation: Information may only be collected on a 
research patient who becomes pregnant and is ≥ 18, a partner of a research participant 
who becomes pregnant and is ≥18 at the time of the pregnancy and/or the newborn infant 
provided that the proper  IRB-approved, consent forms and data collection forms contain 
provisions for collection of information on the pregnancy and outcome.  
 
Incidents of exposure during pregnancy should be reported as an SAE using the IIR 
Serious Adverse Event Report Form (and Reportable Event Fax Cover Sheet) along with 
the Exposure During Pregnancy Supplemental Form. A second Exposure During 
Pregnancy Supplemental Form should be submitted to report the outcome of the 
pregnancy. 
 
 
If the outcome of the pregnancy meets any of the criteria for seriousness, report it 
to Pfizer as an SAE if permitted by your IRB on this trial. Otherwise a separate consent 
will need to be obtained to report pregnancy outcome data.  
 
Examples of pregnancy outcomes that are SAEs: 
- Spontaneous abortion (includes miscarriage and missed abortion) 
- Stillbirth 
- Congenital anomaly (including in an aborted fetus, a stillborn infant, or neonate that dies 
shortly after birth) 
- Neonatal death (within 1 month of birth) should be reported, without 
regard to causality 
- Any infant death that is assessed as possibly related to the in utero exposure to 
temsirolimus should be reported as an SAE 
 
 
 
9.2 
Off Study Criteria 
a. Death 
b. Patient Lost to follow-up 
c. Patient withdraws consent, refuses follow-up 
 
 
9.3 
Termination of the Study by TACL 


 
 
 
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The TACL Consortium may terminate this study prematurely, either in its entirety or at an 
investigative site, for reasonable cause provided that written notice is submitted in advance of the 
intended termination.  Advance notice is not required if the study is stopped due to safety 
concerns.   
 
 


 
 
 
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9.4  
Reproductive Risks  
 
In male animal studies, fertility was decreased or absent. These effects on male fertility were 
accompanied by testicular tubular degeneration, decreased sperm concentration and motility, decreased 
reproductive organ weights, and prostate atrophy. In female animal fertility studies, there were decreased 
number of corpora lutea and increased incidences of pre- and post-implantation loss resulting in 
decreased number of live fetuses, and decreased fetal weights. 
 
In developmental animal studies, there were increased embryo/fetal mortality and decreased fetal growth 
(decreased fetal weight and delayed skeletal ossification). Also there was an increased incidence of 
intestinal protrusion through the abdomen.  
 
However, there are no adequate and well-controlled studies in pregnant women using temsirolimus nor is 
there any information available for labor and delivery. Additionally, many drugs are excreted in human 
milk but lactation studies of intravenous Temsirolimus have not been conducted and the effects of 
temsirolimus excretion in human milk have not been evaluated. 
 
The potential risk for humans is unknown. 
 
10.0 
STATISTICAL CONSIDERATIONS 
  
10.1 
Statistical Considerations for Dose Escalation Criteria 
  
The primary endpoint for dose escalation is the occurrence of a dose-limiting toxicity (DLT). A standard 3+3 
patient cohort escalation design, as described below, will be used based on the toxicity experienced in the 
first course of treatment: 
 
1. Three patients are entered at the first dose level 
2. If 0/3 experiences DLT at a given dose level, then the dose is escalated to the next higher level, if a 
higher dose level exists, and three patients are enrolled.  If a higher dose level does not exists, up 
to three more patients are accrued at the same dose level. 
3. If 1/3 experiences DLT at current dose, then up to three more patients are accrued at the same 
dose level. 
4. If 2 or more DLTs are observed in a three-patient or six-patient cohort at a given dose level, then 
the MTD has been exceeded, dose escalation will be stopped, and up to three additional patients 
will be enrolled at the next lower dose level, if a lower dose level exists (unless six patients have 
already been treated at that prior dose). 
 
10.1.1 Maximum Tolerated Dose (MTD)/Highest Tested Dose (HTD) 
The MTD is the highest dose level tested at which 0/6 or 1/6 patients experience DLT with 
at least 2/3 or 2/6 patients encountering DLT at the next higher dose.  If the highest 
specified dose level (Dose Level 4) in this study is reached with 0/6 or 1/6 patients 
experiencing DLT, i.e., the MTD has not been reached, this dose level will be referred to as 
the Highest Tested Dose (HTD).  If at least 2/3 or 2/6 patients encountering DLT at the 
lowest dose, then no MTD exists. See also section 10.2.   
 
10.1.2   Definition of a Patient Evaluable for Toxicity  
Any patient who receives at least one dose of temsirolimus and experiences DLT at any 
time during protocol therapy is considered evaluable for Adverse Effects. Patients are 
evaluable for toxicity assessment if they terminate treatment for toxicity or intolerability, or 
they experience a dose limiting toxicity, or they receive 85% of the required dose of and 
other agents without dose limiting toxicity during the first course of therapy.  Patients who 
do not satisfy one of these conditions are not evaluable for toxicity and will be replaced.  
 
10.1.3 Definition of a Patient Evaluable for Response  
A patient enrolled on the trial who receives any prescribed therapy (day 1 and later) is 
considered evaluable for response.  


 
 
 
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10.2 
Patient Accrual and Study Duration 
The proposed study will accrue a minimum of 2 and maximum of 24 patients. Estimated accrual 
is 1-2 patients a month. This is expected to take 12-36 months. Allowing for time to evaluate 
patients for DLT, slow initial accrual rate, and opening of other relapsed ALL studies, it is 
expected that this study will be open to accrual for 2-3 years. 
 
10.3 
Interim Monitoring of Toxic Death  
The occurrence of toxic death (TD) at any time will be a primary endpoint for safety monitoring. 
When a patient expires while undergoing treatment, within 30 days of receiving protocol therapy, 
or during follow-up where the death is directly attributed to toxicity experienced on the protocol, 
the study committee and statistician will be notified to review the event. No formal statistical rule 
will be employed.   Rather, if the crude proportion of patients experiencing a toxic death exceed 
5% at any time, the cause and circumstances of these deaths will be reviewed with the study 
committee and with the Data and Safety Monitoring Committee to determine whether 
modifications to or termination of the study is warranted. 
 
 
10.4 
Inclusion of Women and Minorities 
The study is open to all participants regardless of gender or ethnicity.  Review of accrual to past 
studies of new agents demonstrates the accrual of both genders and all NIH-identified ethnicities to 
such studies. The small number of patients entered into this trial will obviate any analysis of 
variation in response rate with gender or ethnicity. 
 
10.5 
Correlative Studies and Response Analysis 
A descriptive analysis of the pharmacodynamic (PD) effects of temsirolimus will be performed to 
assess inhibition of mTOR and downstream signaling in patients’ lymphoblasts.  The PD data will 
be summarized with simple summary statistics, including means, medians, ranges, and standard 
deviations (if numbers and distribution permit).   
 
While the primary aim of this study is to evaluate the toxicity of temsirolimus, patients will have 
disease evaluations performed at end of therapy.  Disease response will be assessed according 
to RECIST criteria for patients with lymphoma, and will be reported descriptively. 
 
All these analyses will be descriptive and exploratory and hypotheses generating in nature. 
 
 


 
 
 
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11.0 
RESPONSE CRITERIA 
 
11.1 
Bone Marrow Status Definitions 
 
 
M1 Marrow 
Less than 5% blasts in a bone marrow aspirate or biopsy if aspirate not available. 
 
M2 Marrow 
5-25% blasts in a bone marrow aspirate or biopsy if aspirate not available.  
 
M3 Marrow 
Greater than 25% blasts in a bone marrow aspirate or biopsy if aspirate not available. 
 
 
11.2 
Response Criteria for Patients with Leukemia  
 
11.2.1 Complete Remission (CR)  
Attainment of M1 bone marrow with no evidence of circulating blasts or extramedullary 
disease and with recovery of peripheral counts (ANC ≥ 500/µL and PLT count ≥ 50,000 
µL). Qualifying marrow and peripheral counts should be performed within 1 week of each 
other. 
 
 
11.2.2 Complete Remission with Incomplete Blood Count Recovery (CRi)  
Attainment of M1 bone marrow with no evidence of circulating blasts or extramedullary 
disease, but with insufficient recovery of absolute neutrophil count (ANC < 500/µL) or 
platelets (< 50,000/ µL). 
 
11.2.3  Minimal Residual Disease negative subset of CR/CRi 
The attainment of a bone marrow with MRD < 0.01% blasts while meeting criteria for CR 
or CRi. 
 
11.2.4 Partial Remission (PR) 
Complete disappearance of circulating blasts and achievement of M2 marrow status if M3 
originally without new sites of extramedullary disease, and with recovery of absolute 
neutrophil counts (ANC ≥ 500/µL). Complete response in the marrow without resolution of 
extramedullary sites is a PR.  
 
11.2.5 Stable Disease (SD) 
Patient does not satisfy the criteria for PD, or has recovery of ANC ≥ 500/µL and fails to 
qualify for CR, CRi, or PR.  
 
11.2.6 Progressive Disease (PD) 
An increase of at least 25% in the absolute number of bone marrow leukemic cells 
morphologically, development of new sites of extramedullary disease, or other laboratory 
or clinical evidence of PD, with or without recovery of ANC or platelets. Patients with 
MRD-only level disease (< 5% blasts) at study entry who develop ≥ 10% disease 
morphologically will be considered to have progressive disease. 
 
11.2.7 Induction Death (ID) 
Any patient who dies prior to receiving subsequent therapy.   
 
11.2.8 Not evaluable (NE) 
Patient does not satisfy the criterion for PD or ID, and either did not have a marrow 
evaluation, had inadequate marrow cell count, or had insufficient recovery of ANC to be 
classified as CR, CRi, PR, or SD.  
 
11.3 
CNS Response Criteria 


 
 
 
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11.3.1  CNS Status Definitions 
 
CNS 1: In cerebral spinal fluid (CSF), absence of blasts on cytospin preparation, 
regardless of the number of white blood cells (WBCs). 
 
CNS 2: In CSF, presence < 5/μL WBCs and cytospin positive for blasts, or ≥ 5 /μL WBCs 
but negative by Steinherz/Bleyer algorithm: 
 
CNS 2a: < 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts; 
CNS 2b: ≥ 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts; and 
CNS 2c: ≥ 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts but negative by 
Steinherz/Bleyer algorithm (see below) 
 
CNS 3: In CSF, presence of ≥ 5/μL WBCs and cytospin positive for blasts and/or clinical 
signs of CNS leukemia: 
 
CNS 3a: < 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts; 
CNS 3b: ≥ 10/μL RBCs, ≥ 5/μL WBCs and positive by Steinherz/Bleyer algorithm (see 
below) 
CNS 3c: Clinical signs of CNS leukemia/lymphoma (such as facial nerve palsy, brain/eye 
involvement or hypothalamic syndrome). 
  
METHOD OF EVALUATING INITIAL TRAUMATIC LUMBAR PUNCTURES: 
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is 
traumatic and contains ≥ 5 WBC/µL and blasts, the following Steinherz/Bleyer algorithm 
should be used 
 
CSF WBC > 2X  Blood WBC 
CSF RBC           Blood RBC 
 
A patient with CSF WBC ≥ 5/µL blasts, whose CSF WBC/RBC is 2X greater than the 
blood WBC/RBC ratio, has CNS disease at diagnosis.  
 
Example: CSF WBC = 60/µL; CSF RBC = 1500/µL; blood WBC =46000/µL;  
blood RBC = 3.0 X 106/µL: 
 
CSF calculation     Blood calculation          
  60   = 0.04            46000   = 0.015 x 2 = .03 
1500 
            3.0 X 106 
 
Therefore this patient has CNS disease because 0.04 > 0.03 
 
11.4   
Response Criteria for Patients with Lymphoma  
 
Response and progression will be evaluated in this study using the revised Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline (version 1.1).45 Key points are that 5 target lesions 
are identified and that changes in the largest diameter (unidimensional measurement) of the 
tumor lesions but the shortest diameter of malignant lymph nodes are used in the RECIST v 1.1 
criteria. 
 
11.4.1 Definitions 
 
11.4.1.2 
Evaluable for objective response: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will be considered evaluable for 
response. For all other patients, only those patients who have 
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cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for response.  
 
11.4.1.2 
Evaluable Non-Target Disease Response: Patients who have lesions 
present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for 
non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
11.4.2 Disease Parameters 
 
 
11.4.2.1 
Measurable disease: Measurable lesions are defined as those that can 
be accurately measured in at least one dimension (longest diameter to 
be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or 
>10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area 
might or might not be considered measurable.  If the investigator 
thinks it appropriate to include them, the conditions under which 
such lesions should be considered must be defined in the 
protocol. 
 
11.4.2.2 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed 
by CT scan (CT scan slice thickness no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
11.4.2.3 
Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. 
 
Bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory 
breast disease, and abdominal masses (not followed by CT or MRI), are 
considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent 
cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, 
these are preferred for selection as target lesions. 
 
11.4.2.4 
Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion that can be measured reproducibly should be 
selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be 


 
 
 
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included in the sum, then only the short axis is added into the sum.  The 
baseline sum diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the 
disease. 
 
11.4.2.5 
Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be 
identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
11.4.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or     
calipers.  
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
11.4.3.1 
Clinical lesions:  Clinical lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph nodes) 
and 10 mm diameter as assessed using calipers (e.g., skin nodules).  In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
11.4.3.2 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable 
lesions when they are clearly defined and surrounded by aerated lung.  
However, CT is preferable.  
 
11.4.3.3 
Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans). Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  
 
11.4.3.4 
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements.  However, if the site can document that 
the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer 
lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
11.4.3.5 
Tumor markers: Tumor markers alone cannot be used to assess 
response.  If markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.  
 
11.4.3.6 
Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 


 
 
 
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cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
 
Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease. 
 
11.4.3.7 
FDG-PET: While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET 
scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the 
date of the initial abnormal FDG-PET scan).  If the positive FDG-
PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
 
 Note:  A ‘positive’ FDG-PET scan lesion means one that is FDG avid 
with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image. 
 
 
11.4.4 Evaluation of Target Lesions 
 
11.4.4.1  
Complete Response (CR): Disappearance of all target and non-target 
lesions. Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to <10 mm. If immunocytology is 
available, no disease must be detected by that methodology.   
 
11.4.4.2    
Partial Response (PR): At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the baseline sum 
diameters 
 
11.4.4.3   
Progressive Disease (PD): At least a 20% increase in the sum of the  
diameters of target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progressions). Note: in presence of 
SD or PR in target disease but unequivocal progression in non-target or 
non-measurable disease, the patient has PD if there is an overall level of 
substantial worsening in non-target disease such that the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy 
 
11.4.4.4  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study 
 
11.4.5    Evaluation of Non-Target Lesions 


 
 
 
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11.4.5.1   
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-
pathological in size (<10 mm short axis) 
 
Note:  If tumor markers are initially above the upper normal limit, they 
must normalize for a patient to be considered in complete clinical 
response. 
 
11.4.5.2   
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
 
11.4.5.3  
Progressive Disease (PD): Appearance of one or more new lesions 
and/or 
unequivocal 
progression 
of 
existing 
non-target 
lesions.  
Unequivocal progression should not normally trump target lesion status.  
It must be representative of overall disease status change, not a single 
lesion increase.     
 
11.4.5.4    
Overall Best Response Assessment 
 Each patient will be classified according to his “best response” for the 
purposes of analysis of treatment effect.  Best response is determined as 
outlined in Section 11.5 from a sequence of overall response 
assessments. 
 
11.4.6 Response Criteria for Patients with Lymphoma and Evaluable (but not Measurable) 
Disease 
 
11.4.6.1 
Evaluable Disease 
The presence of at least one lesion, with no lesion that can be accurately 
measured in at least one dimension.  Such lesions may be evaluable by 
nuclear medicine techniques, immunocytochemistry techniques, tumor 
markers or other reliable measures.  
 
11.4.6.2 
Complete Response 
Disappearance of all evaluable disease. 
 
11.4.6.3 
Partial Response 
Partial responses cannot be determined in patients with evaluable 
disease 
 
11.4.6.4 
Stable Disease  
That which does not qualify as Complete Response (CR), Partial 
Response (PR), or Progressive Disease. 
 
11.4.6.5 
Progressive Disease 
The appearance of one or more new lesions or evidence of laboratory, 
clinical, or radiographic progression. 
 
11.4.6.6 
Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the 
purposes of analysis of treatment effect.  Best response is determined as 
outlined in Section 11.5 from a sequence of overall response 
assessments. 
 
11.5 
Best Response 
 
11.5.1 
Evaluation of Best Overall Response 


 
 
 
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The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Table 2: For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>28 days Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>28 days Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once 
>28 days from baseline** 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
*   See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
**   Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
Table 3: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is 
not advised 
 
Table 4.  Sequences of overall response assessments with corresponding best response. 
  1st Assessment 
  2nd Assessment 
  Best Response 
Progression 
 
Progressive disease 


 
 
 
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Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
 
11.5.2 Duration of Response 
 
11.5.2.1 
Duration of overall response:  The duration of overall response is measured   
 
from the time measurement criteria are met for CR or PR (whichever is first  
 
 
recorded) until the first date that recurrent or progressive disease is 
 
objectively documented (taking as reference for progressive disease the  
 
 
smallest measurements recorded since the treatment started). 
 
 
The duration of overall CR is measured from the time measurement criteria  
 
 
are first met for CR until the first date that progressive disease is objectively   
 
 
documented. 
 
11.5.2.2    Duration of stable disease:  Stable disease is measured from the start of the   
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started, including the 
baseline measurements.  
 
 
 


 
 
 
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12.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
12.1 
Definitions 
 
Adverse Event: An adverse event means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
 
Suspected Adverse Reaction (SAR): Any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.  Reasonable possibility means there is evidence to suggest a causal 
relationship between the drug and the adverse event. 
 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction: An adverse event or 
suspected adverse reaction is considered “unexpected” if it is not listed in the investigator brochure or is 
not listed at the specificity or severity that has been observed; or, if an investigator brochure is not 
available, is not consistent with the risk information described in the general investigational plan. 
 
Serious Adverse Events (SAE) or Serious Suspected Adverse Reactions (SSAR): An adverse event 
or suspected adverse reaction is considered serious if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes: 
 
Death of Patient 
An event that results in the death of a patient. 
Life-Threatening 
An event that, in the opinion of the investigator, would have resulted in 
immediate fatality if medical intervention had not been taken.  This does not 
include an event that would have been fatal if it had occurred in a more severe 
form. 
Hospitalization 
An event that results in an admission to the hospital for any length of time.  
This does not include an emergency room visit or admission to an outpatient 
facility. 
Prolongation of 
Hospitalization 
An event that occurs while the study patient is hospitalized and prolongs the 
patient’s hospital stay. 
Congenital 
Anomaly 
An anomaly detected at or after birth, or any anomaly that results in fetal loss. 
Persistent or 
Significant 
Disability/ 
Incapacity 
An event that results in a condition that substantially interferes with the 
activities of daily living of a study patient.  Disability is not intended to include 
experiences of relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, or accidental trauma (e.g., sprained 
ankle). 
Important 
Medical Event 
Requiring 
Medical or 
Surgical 
Intervention to 
Prevent Serious 
Outcome 
An important medical event that may not be immediately life-threatening or 
result in death or hospitalization, but based on medical judgment may 
jeopardize the patient and may require medical or surgical intervention to 
prevent any of the outcomes listed above (i.e., death of patient, life-
threatening, hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity). Examples of such 
events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
 
12.2 
Data Collection 
Adverse events and suspected adverse reactions will be collected and reported on the electronic CRFs 
beginning with the first dose of study therapy until 30 days following the last dose of study therapy. The 
investigator will evaluate all adverse events and suspected adverse reactions as to their severity and 
relationship to temsirolimus as well as the regimen as a whole. Serious adverse events and serious 
suspected adverse reactions will require expedited reporting to the TACL Operations Center as 
described below.  


 
 
 
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12.3 
Reporting Serious Adverse Events or Serious Suspected Adverse Reactions 
 
12.3.1 The following serious adverse events or serious suspected adverse reactions 
requires expedited reporting: 
 
 
All Grade 5 events regardless of causality. 
 
All Grade 4 events that are possibly, probably or definitely related to temsirolimus or 
the regimen as a whole.  Exclude reporting of hematologic toxicity as a serious 
adverse event unless the event meets the criteria of hematologic dose limiting toxicity 
per protocol section 4.5.2:  Bone marrow aplasia: > 42 days from Day 1 of therapy 
will be a DLT. Aplasia is defined as the failure to recover a peripheral ANC of ≥ 
500/mm3 and PLT ≥ 20,000/mm3 in the absence of persistent leukemia. 
 
 
All unexpected Grade 3 events that are possibly, probably or definitely related to 
temsirolimus or the regimen as a whole. 
 
Any reported pregnancy in a female study patient or partner of a male study patient 
 
12.3.2 Steps for Reporting 
 
Step 1: Identify the adverse event or suspected adverse reaction using the NCI 
Common Toxicity Criteria (CTC), version 4.03.    
 
The CTC provides descriptive terminology and a grading scale for each adverse event 
listed.  A copy of the CTC can be downloaded at  
http://evs.nci.nih.gov/ftp1/CTCAE/About.html.   
 
Step 2: Grade the event using the NCI CTCAE version 4.03. 
 
Step 3: Determine if the adverse event or suspected adverse reaction meets the 
criteria of being “serious”. 
 
 
Step 4: Determine the relationship of Temsirolimus and the regimen as a whole to 
the event 
The investigator will assess the causal relationship between the investigational product 
and the regimen as a whole and the adverse event.  The investigator will use his/her 
clinical expertise and judgment to select the attribution category below that best fits the 
circumstances of the AE. 
 
Related: There is a reasonable possibility that the drug/regimen caused the 
adverse event. Reasonable possibility means there is evidence to suggest a 
causal relationship between the drug and the adverse event. 
 
Unrelated: There is not a reasonable possibility that the drug/regimen caused 
the adverse event. There is not evidence to suggest a causal relationship 
between the drug and the adverse event. 
 
Step 5: Determine if the adverse event or suspected adverse reaction is 
“unexpected”.  
 
Step 6: Notify the TACL Operations Center by telephone or email 
 
The following information should be submitted within 24 hours of event notification by either 
phone 
, or Email TACL@chla.usc.edu 
 


 
 
 
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1. Patient TACL study ID and initials 
2. Event description 
3. Severity (NCI Grade) 
4. Onset date 
5. Reason event is considered serious 
6. Dose of study drug and dates of administration 
7. Investigator opinion of relationship to DRUG and the regimen as a whole 
8. Name and phone number of physician in charge of the case 
9. Name and phone number of CRA or Research nurse working with the case 
 
Step 7: Submit a written report to the TACL Operations Center 
 
Complete the TACL SAE Notification Form within 72 hours of learning of the event.  The 
completed form is email to TACL@chla.usc.edu The form may also be faxed to (877) 904-
2166. A follow-up SAE Notification Form must be submitted upon resolution of the event 
or as requested by the TACL Operations Center. Please confirm via email or phone that 
the TACL Operations Center has received this notification.   
 
12.4 
Institutional Reporting to the IRB 
 
All SAE’s should be reported to the treating institutions IRB or Ethics board. The TACL Operations Center 
will also report all SAE’s to the TACL IRB. The TACL Operations Center will distribute SAE’s to all TACL 
sites as appropriate for submission to their own IRB’s.  
 
 
 


 
 
 
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13.0 
DATA AND SAFETY MONITORING 
 
13.1 
Data Submission 
All study data will be submitted via electronic data capture forms using the DataLabs/TACL Website.  
Please refer to the TACL web site (https://tacl.chla.usc.edu/tacl) for T2014-001 CRF Completion Guide or 
contact the TACL Operations Center at 
 if you need assistance. 
 
The following are required to be submitted to the Operations Center for all patients entered: 
Paper copy of following:  Roadmaps and Bone Marrow Reports (include both aspirate and biopsy 
reports). These forms are to be emailed or faxed to the TACL Operations Office at 877-904-2166 at the 
end of each course during which the bone marrows are done. 
 
13.2 
Weekly Safety Review 
The TACL Operations Center (TOC) conducts weekly (as needed) patient safety and review meetings 
with the protocol co-chairs, , research coordinators and other administrative TACL team members to 
review all data submitted, non-serious adverse events and other correspondence pertaining to patients.  
Serious adverse events will be immediately evaluated by the study team and determination regarding 
notification of participating sites will be made.  All serious adverse events will be sent to the CHLA IRB 
and DSMC if required.  Any interim results that would affect patient safety would be immediately 
communicated to all participating TACL sites. All correspondence with sites will be done via email, with all 
information also being posted on a member’s only section of the TACL website. 
 
13.3 
Data Safety and Monitoring Committee (DSMC) 
The TACL Operations Center utilizes the Children’s Hospital Los Angeles Hem/Onc Data Safety and 
Monitoring Committee. DSMC meetings will occur every 6 months. Every 6 months, a DSMC report for 
each protocol will be prepared by the study statistician and study PI detailing patient accrual, toxicities, 
deaths on study, current study status, responses (responses will be blinded until study completes 
accrual), summary of amendments to protocol/consent, lists of any publications from study, and plans for 
study in coming year.  Any publications from the study (abstract or manuscript) will be attached to the 
DSMC report.  After DSMC review, the DSMC will issue a confidential report for each study to the study 
PI and TACL Operations Center. 
 
Not more than eight weeks after the DSMC meeting, a DSMC public review report will also be created for 
each protocol after approval of the confidential report and resolution of any issues by the PI The public 
report will then be emailed to the participating sites for each study.  These can be filed at the IRB at each 
site if required per local IRB guidelines. 
 
 


 
 
 
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14.0 
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46. 
Grabiner BC, Nardi V, Birsoy K, et al.  A diverse array of cancer-associated MTOR mutations are 
hyperactivating and can predict rapamycin sensitivity.  Cancer Discov. 2014 May; 4(5): 554-63 


 
 
 
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15.0 
SAMPLE INFORMED CONSENT 
 
Local IRB changes to this document are allowed. Changes within the document should not substantially 
alter the meaning or intent of the consent document.  If the institution or IRB insists on making deletions 
or more substantive modifications to the consent, especially in the risks sections, they should be reviewed 
and approved by the TACL Operations Center. 
 
 
INFORMED ASSENT*/CONSENT DOCUMENT / PARENTAL PERMISSION FOR 
PARTICIPATION IN RESEARCH 
 
 
TACL Protocol 
A Phase I Trial of Temsirolimus (CCI-779, Pfizer, Inc.) in Combination with Etoposide and 
Cyclophosphamide in Children with Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkin 
Lymphoma 
 
Subject Name: 
 
Medical Record #: 
 
Physician: 
 
 
When we say “you” in this consent form, we mean you or your child; “we” means the doctors and 
other staff. 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial to you. 
Clinical trials include only people who choose to take part. Please take your time to make your decision 
about taking part.  You may discuss your decision with your friends and family.  You can also discuss it 
with your health care team.  If you have any questions, you can ask your study doctor for more 
explanation.  
 
This study is being carried out by the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) 
Consortium. TACL is a group of Universities and Children’s Hospitals that are working together to find 
treatments for children with leukemia and lymphoma. 
 
You are being asked to take part in this research study because your ALL or Non-Hodgkin’s Lymphoma 
has come back (relapsed).  
 
This is a phase I study of a drug called temsirolimus in combination with intensive cytotoxic chemotherapy 
consisting of cyclophosphamide and etoposide. Temsirolimus is considered experimental because it has 
not been proven to work in a situation like yours. We are using temsirolimus because it seems to work 
against cancer in cells and animals. We do not know if temsirolimus will work in people. Temsirolimus has 
been used in only a small number of adults and children and there is a lot that we do not know about it 
yet. This is called a Phase I study because the goal is to find the highest dose of temsirolimus that we can 
give safely in combination with intensive chemotherapy.  
 
Patients with multiply relapsed ALL have a significant risk of severe side effects and serious infections 
with intensive salvage therapy. In an attempt to provide your child the safest care possible it is highly 
recommended that your child receive their initial course as an inpatient and be started on preventative 
antibiotics and anti-fungal medications during their stay.  
 


 
 
 
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Why is this study being done? 
 
We are testing new experimental drug combinations such as the combination of temsirolimus, 
cyclophosphamide and etoposide in the hopes of finding a drug combination that may be effective against 
relapsed leukemia and non-hodgkin’s lymphoma. 
 
The goals of this study are: 
 
 
To find the highest safe dose of temsirolimus that can be given with intensive  chemotherapy 
without causing severe side effects; 
 
To learn what kind of side effects temsirolimus can cause; 
 
To learn more about the pharmacology (how your body handles the drug) of temsirolimus; 
 
To learn how temsirolimus affects specific molecules on leukemia and lymphoma cells;   
 
To determine whether temsirolimus, combined with intensive chemotherapy is a beneficial 
treatment for your tumor. 
 
How many people will take part in this study? 
 
It is expected that up to 24 children and young adults will take part in this study. 
 
What will happen if I take part in this research study? 
 
Before you begin the study… 
 
You will need to have the following exams, tests or procedures to find out if you can be in the study.  These 
exams, tests or procedures are part of your regular cancer care and may be done even if you do not join 
the study.  If you have had some of them recently, they may not need to be repeated. The results of these 
tests will be reviewed.  It is possible that after these tests are reviewed, you will not be able to take part in 
the study.  If you are not able to take part in the study, your doctor will discuss with you the reasons why. 
 
 
A medical history 
 
Physical exam with vital signs(blood pressure, heart rate, temperature, oxygen levels) 
 
Bone marrow test to check your cancer (see Tests on the Bone Marrow, below) 
 
Lumbar puncture to test the fluid in your spinal cord (see Lumbar Punctures, below) 
 
Blood tests to check your organ function, including liver and kidneys 
 
Tests to make sure you are not pregnant (if you are a female and old enough to become 
pregnant) 
 
Urine Test 
 
Imaging study (CT, MRI, PET/CT) to determine the extent of your cancer (if you have 
lymphoma) 
 
Echocardiogram (ECHO) which uses sound waves to test heart function 
 
 
Tests on the Bone Marrow 
Examinations of the bone marrow will be performed routinely and may be done at the discretion of your 
study doctor. You have already had many tests of your bone marrow for your previous treatment of ALL.  
Many children receive some form of sedation or anesthesia during this procedure. A small area over your 
hip bone on the back will be cleaned and numbed with lidocaine and/or with an anesthetic cream. 
Approximately 2-3 teaspoons of bone marrow will be withdrawn through a needle inserted into the bone. 
The test is painful, especially when the bone marrow is withdrawn.  There is also a small risk of bleeding 
or infection from this procedure.   
 
Lumbar Punctures (“L.P.s”, “spinal taps”) 


 
 
 
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You are familiar with spinal taps since they were done during your initial therapy for ALL. Whether you 
decide to participate or not on this study, additional spinal taps will need to be done to give medicines, 
which are necessary to prevent the leukemia from spreading to the spinal fluid. Many children receive 
some form of sedation or anesthesia during this procedure. Spinal taps are painful and may cause 
headaches. The skin at the site of needle insertion is usually numbed with an anesthetic cream or 
lidocaine before the procedure is performed. Approximately 1 teaspoon of spinal fluid will be withdrawn 
prior to injection of the medicine. 
 
During the study …  
 
If the exams, tests and procedures show that it is safe for you to be enrolled on the study, and you will be 
given temsirolimus by intravenous (IV) infusion on days 1 and 8. Cyclophosphamide and etoposide will be 
given by intravenous (IV) infusion on days 1-5. You will then recover from the combined therapy. A cycle 
last approximately 4 weeks and you may get up to 8 cycles as long as you have stable or improving 
cancer.  
 
We highly recommend you remain in the hospital from the time you start the therapy (or from Day 1) until 
blood work and your medical team determine it is safe for you to be sent home. We also highly 
recommend you are started on preventative antibiotics and anti-fungals while you are hospitalized. 
 
 
Various methods will be used to give drugs: 
 
IV – Drug is given using a needle or tubing inserted into a vein,  It can be given by IV push over 
several minutes or by infusion over minutes to hours 
 
IT – Drug used to treat the brain and spinal cord is given using a needle inserted into the spinal 
canal 
 
Treatment 
 
Drug 
Days  
Dose 
Temsirolimus 
1 and 8 
As assigned, IV 
Cyclophosphamide 
1-5 
440 mg/m2 IV daily 
Etoposide 
1-5 
100 mg/m2 IV daily 
Triple IT (patients with CNS) 
(Methotrexate, Cytarabine, 
Hydrocortisone) 
Weekly during Course 1, 
then day 1 of each 
subsequent course 
IT dose depends on age 
Methotrexate IT (patients without CNS 
disease  
Day 1 of Courses 1, 2, 4, 6 
and 8 
IT dose depends on age 
Leucovorin 
Starting 48 hours after any 
Methotrexate containing IT 
given day 0 or after. 
5mg/m2/dose every 12 hours x 2 
doses 
 
Medical Tests During Treatment 
 
Whether you are on this study or not the following medical tests will be done to monitor for response to 
treatment as well as side effects related to treatment.  These include: 
 
Physical exams with vital signs 
 
 
 
 
Blood tests to check your organ function including: 
o 
CBC to look at your blood cells 
o 
Chemistries to look at elements and minerals in your blood 
o 
Blood tests to look at your liver, pancreas and kidney function 
 
Bone Marrow Tests 
 
Lumbar Punctures 
 
Radiology scans such as a CT, MRI or X-ray, if indicated 
 
 


 
 
 
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Tests for Research Purposes 
We would also like to do some extra tests called biologic studies.  These tests will help us learn more about 
temsirolimus on leukemia cells and may help children who receive this drug in the future. The information 
learned would not change the way you are treated, and the results of these tests will not be returned to you. 
Some of these tests are required and others are optional.  Although these tests are very important part of 
how we will better learn to use this drug, it is your decision as to whether or not you agree to participate.  
. 
Bone Marrow Samples for MRD testing 
When bone marrow testing is being done as part of your standard evaluation(s) on Day 29 (or a later 
cycle if not quite in a complete remission on day 29), we would like to request an extra sample [6 mL 
(slightly more than 1 teaspoon) from patients greater than or equal to 12 kg (26.5 pounds), or 3 mL (less 
than 1 teaspoon) from patients less than 12 kg (26.5 pounds)] to be collected for minimal residual disease 
(MRD) testing. This type of testing is a more sensitive way to evaluate whether there are any leukemia 
cells present after therapy.  These bone marrow samples are required from all patients who had > 5% 
blasts in their bone marrow at study entry. 
 
Biology Studies using Bone Marrow Samples (Optional) 
When bone marrow testing is being done as part of your standard evaluation(s) before you begin therapy 
and on Day 29, we would like to request an extra sample [10 mL (about 2 teaspoons) from patients 
greater than or equal to 10 kg (22 pounds), 3-5 mL (about 1 teaspoon) from patients less than 10 kg (22 
pounds)] to be collected to evaluate the effect of temsirolimus on your cells in the bone marrow and if 
sample permits to grow your cancer in a mouse to further study the effect of temsirolimus and intensive 
reinduction chemotherapy on proteins in those cells. 
 
The tests may help us to better learn how this drug may work. Please indicate by initialing below whether 
you choose to participate in the biology studies. 
 
______/______ Yes, I agree to participate in the biology studies using bone marrow samples. 
 
______/______ No, I do not agree to participate in the biology studies using bone marrow samples. 
 
Biology Studies using Blood Samples (Optional) 
During the study, additional blood samples will be collected to evaluate the effect of temsirolimus and 
intensive reinduction chemotherapy in your blood. The blood samples are 5 mL (about 1 teaspoon) for 
patients greater than or equal to 10 kg (22 pounds), and 2 mL (about ½ teaspoon) from patients less than 
10 kg (22 pounds) and will be obtained prior to therapy, once between day 3 and 5  and at the end of cycle 
1 of therapy on Day 29.  This amount of blood is safe to draw even from small children. 
 
The tests may help us to better learn how this drug may work. Please indicate by initialing below whether 
you choose to participate in the biology studies. 
 
______/______ Yes, I agree to participate in the biology studies using blood samples. 
 
______/______ No, I do not agree to participate in the biology studies using blood samples. 
 
What are my responsibilities? 
 
 
During the study you will be asked to take all your chemotherapy drugs as prescribed. It is very 
important that you follow your doctor’s instructions regarding when and how to take your study 
medications.  Be sure to ask your study doctor or nurse if you have any questions about taking your 
study medications.   
 
 
If you experience any unusual side effects as explained by your study doctor, you should contact the 
study center immediately.  You should also contact your study doctor if you are hospitalized for any 
reason during the study or within 30 days after completion of therapy. 
 


 
 
 
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How long will I be in the study?   
 
If you have stable or responding disease you may receive up to 8 cycles of therapy for up to 1 year.  After 
completing the study therapy, your doctor will discuss with you the options for additional treatment.   
These options will vary depending on whether or not your leukemia or Non-Hodgkin Lymphoma 
responded to the therapy.  
 
After completing the treatment on this study we would like to continue to collect some medical information 
about how you are doing for as long as you are willing to let us.  We will collect information on how your 
ALL or Non-Hodgkin Lymphoma is doing, what kind of therapy you may be getting and if you have any 
long term side effects.   
 
 
Can I stop being in the study? 
 
Yes.  You can decide to stop at any time.  Your clinical care will not be affected by your decision to 
withdraw.  Tell your doctor if you are thinking about stopping or decide to stop.  He or she will tell you how 
to stop safely.   You will be asked to visit the hospital or clinic for some follow-up tests to make sure all the 
side effects you may have experienced have gone away. 
 
It is important to tell your doctor if you are thinking about stopping so any risks from the study treatment 
and chemotherapy drugs can be evaluated by your doctor.  Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for you. 
 
Your doctor may stop you from taking part in this study at any time without your permission if he/she 
believes it is in your best interest; your tumor gets worse; if the side effects of temsirolimus or combination 
chemotherapy are too harmful for you; you need a treatment that is not allowed on this study; new 
information becomes available; if you do not follow the study rules; if you become pregnant or begin to 
breast feed; or if the study is stopped. 
 
 
 
What side effects or risks can I expect from being in the study?  
 
All people who receive cancer treatment are at risk of having side effects.  In addition to killing cancer 
cells, chemotherapy drugs can damage normal tissues and produce side effects.  Side effects are usually 
reversible when the medication is stopped, but occasionally can persist and cause serious complications 
or death. The therapy used in this protocol is made stronger so that it can kill cancer cells quickly before 
they can become resistant to treatment. Protocols used to treat relapsed leukemia or Non-Hodgkin 
lymphoma are more intensive than are those to treat newly diagnosed disease. It is not possible to predict 
whether the side effects listed below, or other rare side effects may occur.  Side effects can be increased 
when chemotherapy drugs are combined.  It is possible that this re-induction therapy will prove better 
than past therapies for relapsed ALL or Non-Hodgkin lymphoma, but it may be no better or worse than 
other treatments. It may be associated with more side effects, which may be life threatening. There also is 
a risk of death. We will tell you if we learn any new information that may affect your health, welfare, or 
decision to stay in this study. You should talk to your study doctor about any side effects that you have 
while taking part in the study.    
 
Common side effects include nausea, vomiting, hair loss and fatigue.  The risks from having your blood 
taken are minimal, but can include an infection or a blood clot. There may be pain and or bruising at the 
site where the needle is inserted to draw your blood. Chemotherapy causes temporary bone marrow 
depression. Bone marrow depression means that your bone marrow may make: 
 
 
Less red cells causing anemia;  
 
Less platelets, causing bruising and an increased chance of bleeding; 
 
Fewer white blood cells, causing a risk for serious infections.  
 
 


 
 
 
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Red blood cell and platelet transfusions may be required. 
 
Each drug will have a unique set of side effects.  Side effects related to drugs occur in people at different 
rates or frequencies.   The following kinds of risks and side effects may be observed from the drugs used 
in this protocol are divided into More Likely, Less Likely and Rare but Serious categories: 
 
Temsirolimus 
 
More Likely 
Less Likely 
Rare but Serious 
 
Decrease in red blood 
cells  
 
Decrease in the 
number  white blood 
cells 
 
Decrease in the 
number of a type of 
white blood cell called 
lymphocytes 
 
Decreased 
hemoglobin 
 
Diarrhea 
 
Nausea 
 
Decrease in platelets 
which can cause 
bruising and bleeding 
 
Sores in your mouth 
or other parts of your 
digestive tract  
 
Increased Cholesterol 
level 
 
Loss of appetite 
 
Rash 
 
Swelling of face, 
arms, legs 
 
Increase of fat in the 
blood  
 
Increase blood level of 
a form of fat called 
triglyceride 
 
Increased blood level 
of a liver enzyme 
(AST/SGOT) 
 
Decreased blood level 
of phosphate 
 
Increased blood level 
of creatinine (a 
substance normally 
eliminated by the 
kidneys into the urine) 
 
Stomach pain 
 
Fever 
 
Muscle weakness 
 
Infections 
 
Increased blood level 
of a live or bone 
enzyme (alkaline 
 
Increased blood level of a liver enzyme 
(ALT/SGPT) 
 
Increased blood level of a liver enzyme 
(bilirubin) 
 
Urinary tract infection 
 
Decreased blood level of potassium or 
other salts in the blood 
 
Sore throat 
 
Constipation 
 
Vomiting 
 
Chills 
 
Non-cardiac chest pain 
 
Abnormal wound healing 
 
Weight loss 
 
Joint pain, Back pain, Muscle pain 
 
Flu-like symptoms, including body aches 
 
Changes in taste 
 
Headache 
 
Feeling sad or depressed 
 
Having trouble sleeping 
 
Sneezing, runny nose, itchy and water 
eyes due to allergies 
 
Nose bleed 
 
Dry skin, itchy skin, acne 
 
Nail loss, change in nail texture and color 
 
High blood pressure  
 
Low blood pressure 
 
Decrease in the number of a type of white 
blood cell called neutrophils 
 
Pneumonia or other respiratory tract 
infections 
 
Swelling or infection of the eye 
 
Bloating, fluid collection including in lungs 
which may cause shortness of breath 
 
Allergic reaction by your body to the drug 
that can occur immediately or be delayed.  
The reaction may include hives, low blood 
pressure, wheezing, swelling of the throat 
and difficulty breathing  
 
 
A tear or hole in the wall 
of your stomach or 
intestines 
 
A blood clot that has 
dislodged from another 
part of the body and 
travelled to the lungs 
where it blocks oxygen 
from the body and may 
lead to death. 
 
Kidney failure 
 
Rupture of a blood 
vessel in the brain 
 
Damage to the lungs 
which can cause 
scarring in the lungs 
and affect the ability of 
your body get oxygen 


 
 
 
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More Likely 
Less Likely 
Rare but Serious 
phosphatase) 
 
Cough and shortness 
of breath 
 
Tiredness/fatigue 
 
Increased glucose 
(sugar) in the blood 
 
 
Cyclophosphamide 
 
More Likely 
Less Likely 
Rare but Serious 
 
Loss of appetite 
 
Nausea 
 
Vomiting 
 
Fewer white blood 
cells in the blood 
 
Hair loss 
 
Decreased ability of 
the body to fight 
infection 
 
Absence or decrease 
in the number of 
sperm which may be 
temporary or 
permanent which 
may decrease the 
ability to have 
children 
 
Abnormal hormone function which may 
lower the level of salt in the blood 
 
Abdominal pain 
 
Diarrhea 
 
Fewer red blood cells and platelets in the 
blood  
 
Bleeding and inflammation of the urinary 
bladder 
 
Absence or decrease monthly periods 
which may be temporary or permanent 
and which may decrease the ability to 
have children 
 
Temporary blurred vision 
 
Nasal stuffiness with IV infusions 
 
Skin rash 
 
Darkening of areas of the skin and finger 
nails 
 
Slow healing of wounds 
 
Infections  
 
Heart muscle damage 
which may occur with very 
high doses and which may 
be fatal 
 
Abnormal heart rhythms 
 
Damage and scarring of 
lung tissue which may 
make you short of breath 
 
A new cancer or leukemia 
resulting from this 
treatment. 
 
Damage or scarring of 
urinary bladder tissue 
 
Severe allergic reaction 
which can be life 
threatening with shortness 
of breath, low blood 
pressure, rapid heart rate 
chills and fever 
 
Infertility which is the 
inability to have children 
 
 
Etoposide 
 
More Likely 
Less Likely 
Rare but Serious 
 
Nausea and vomiting 
 
Hair Loss 
 
A feeling of weakness or 
tiredness 
 
Fewer red and white blood 
cells and platelets in the 
blood  
 
A low number of red blood 
cells can make you feel 
tired and weak 
 
A low number of white 
blood cells can make it 
easier to get infections 
 
A low number of platelets 
causes you to bruise and 
bleed more easily 
 
 
 Loss of appetite 
 Decreased blood pressure 
during the infusion which 
may require treatment 
 rashes 
 Diarrhea 
 Pain in the abdomen 
 Mouth sores 
 Tingling sensation or loss of 
sensation in fingers or toes 
 A feeling of  extreme 
tiredness or weakness 
 The finger or toe nails may 
loosen from their nail beds 
 Inflammation of the vein 
through which the 
medication was given 
 Chest pain 
 
Damage to the liver 
 
Severe allergic reaction which can 
be life threatening with shortness of 
breath, low blood pressure, rapid 
heart rate chills and fever 
 
A new cancer or leukemia resulting 
from this treatment 
 
Severe rashes which can result in 
loss of skin and damage to mucous 
membranes 
 
Absence  or decrease monthly 
periods which may be temporary or 
permanent and which may 
decrease the ability to have children 
 
Damage to the heart muscle which 
may make you feel tired, weak, feel 
short of breath, and retain fluid 
 


 
 
 
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More Likely 
Less Likely 
Rare but Serious 
 
 
 
Cytarabine 
 
Risks and side effects related to cytarabine when given into the spinal fluid include: 
 
More Likely 
Less Likely 
Rare but Serious 
 
Nausea  
 
Vomiting 
 
Fever 
 
Headache 
 
 
Inflammation of the lining that covers 
the brain which could lead to a severe 
headache, a stiff neck, fevers, 
abnormally high number of white blood 
cells in the spinal fluid 
 
 
Rash 
 
Feel tired, hard to stay awake 
 
Irritation of the lining of the 
brain leading to headache and 
neck stiffness 
 
Convulsions 
 
Slight or partial paralysis 
 
Fewer red and white blood 
cells and platelets in the blood 
o 
a low number of red 
blood cells can make 
you feel tired and 
weak 
o 
a low number of white 
blood cells can make 
it easier to get 
infections 
o 
a low number of 
platelets causes you 
to bruise and bleed 
more easily 
 
Difficulty controlling your 
muscles 
 
Damage to brain tissue which 
can lead to difficulty speaking, 
loss of mental function, lack of 
coordination, seizures, coma 
and death 
 
Loss of feeling and movement 
in your legs 
 
Blurred vision with a chance of 
blindness  
 
 
Methotrexate 
 
Risks and side effects related to methotrexate when given into the spinal fluid include: 
 
More Likely 
Less Likely 
Rare but Serious 
 
Nausea  
 
Headache 
 
 
Inflammation of the lining that covers 
the brain which could lead to a severe 
headache, a stiff neck, fevers, 
abnormally high number of white blood 
cells in the spinal fluid 
 
Difficulty learning or thinking clearly 
 
Confusion or a sense of not knowing 
where you are. 
 
Difficulty with speaking 
 
Seizures 
 
Temporary loss of function or 
feeling in the lower part of 
the body (partial paralysis) or 
which may affect bladder 
function 
 
Severe damage to brain 
tissue which could lead to 
difficulty carrying out normal 


 
 
 
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More Likely 
Less Likely 
Rare but Serious 
 
Vomiting 
 
Rash 
 
Sleepiness 
 
A feeling of extreme tiredness 
 
Unsteady walk 
 
Leg pain 
 
Fewer red and white blood cells and 
platelets in the blood 
o 
a low number of red blood cells 
can make you feel tired and weak 
o 
a low number of white blood cells 
can make it easier to get infections 
o 
a low number of platelets causes 
you to bruise and bleed more 
easily 
daily tasks or could lead to a 
coma. 
 
Severe allergic reaction 
which can be life threatening 
with shortness of breath, low 
blood pressure, rapid heart 
rate chills and fever 
 
Bleeding into the space in 
the spine where the injection 
is given.  You may need to 
receive a platelet transfusion 
before your injection to 
prevent this. 
 
 
 
Combined Intrathecal Therapy (given into the spinal fluid)  
The following toxicities may occur when methotrexate, cytarabine  hydrocortisone are given together into 
the spinal fluid: 
 
More Likely 
Less Likely 
Rare but Serious 
 
None 
 
Headache 
 
Abnormally high number of 
cells in the spinal fluid 
 
Learning disability 
 
Nausea and Vomiting 
 
Fever 
 
Rash  
 
Seizures 
 
Drowsiness 
 
Stiff neck 
 
Irritation of tissues in the 
brain/spinal cord 
 
Unsteady walk 
 
Partial paralysis 
 
Damage to brain tissue 
 
Increasingly poor nervous 
system function 
 
Fewer red and white blood cells 
and platelets in the blood 
 
 
 
Leucovorin 
 
Risks and side effects related to leucovorin include: 
 
More Likely 
Less Likely 
Rare but Serious 
NONE 
 
Hives 
 
Severe allergic reaction 
which can be life threatening 
with shortness of breath, low 
blood pressure, rapid heart 
rate chills and fever 
 
Seizure 
 
 
Risks associated with Disease Evaluation Imaging 
X-rays and CT scans expose you to radiation. For PET-CT scan you will get a radioactive sugar (FDG) by 
vein. The radiation exposure for the PET scan is about the same to about half that of a standard CT scan.  


 
 
 
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You will also get x-rays from the CT portion of the PET-CT scan. The total amount of radiation you get 
from the combined PET and CT scan will not be more than 2 to 6 times the amount of radiation that 
everyone gets in a year from natural sources like the atmosphere.  The risk from this amount of radiation 
is considered to be small when compared with other everyday risks. 
 
Reproductive risks  
Because the drugs in this study can affect an unborn baby, you should not become pregnant or father a 
baby while on this study.  You should not nurse a baby while on this study.  It is a condition of this study that 
adequate birth control methods be used by all participants and/or their sexual partners while enrolled in the 
study. Examples of these include total abstinence (no sex), oral contraceptives (“the pill”), an intrauterine 
device (IUD), Levonorgestrol implants (Norplant), or medroxyprogesterone acetate injections (Depo-provera 
shots).  If one of these methods of birth control cannot be used, contraceptive foam with a condom is 
recommended.  Ask your doctor about counseling and more information about preventing pregnancy. 
 
If you are a female patient and become pregnant or a male patient and your partner becomes pregnant 
during this study, contact your study doctor immediately. Female patients who become pregnant or male 
patients whose partner becomes pregnant will be given instructions for discontinuation of study 
medication and will be removed from study. The maker of temsirolimus (Pfizer, Inc) will be notified if study 
patients become pregnant while taking temsirolimus as part of this study. Adult patients (≥18 years old at 
the time of enrollment or their adult partners (≥18 years old at the time of pregnancy) will be approached 
about consenting to provide more information about the pregnancy if they were taking temsirolimus during 
any part of the pregnancy.  A separate pregnancy consent will be obtained at the time to report any data 
about the pregnancy. 
 
Confidential Information  
Because the sponsor of this study is outside of your medical center, there is the potential small risk of 
accidental release of confidential information when sending out any research documentation.   Please 
see the ”Will my medical information be kept private?” section of this document for more details. 
Developing a Second Cancer 
It is possible that you may develop a second form of cancer as a result of this treatment.  Experience so far 
suggests that the chance of this happening is very small. Not enough information has been gathered in 
children to be able to give an accurate prediction, although it may be in the range of one in every 50 to 800 
children treated.   
 
Are there medications, herbal remedies or foods that I should not take 
while on this study? 
 
The use of the following medications, foods and herbal remedies should be avoided while on 
temsirolimus as it can affect how your body processes the drug.  If you are taking any of these drugs or 
are prescribed these drugs, please let your study doctor know. Your doctor will help find reasonable 
alternatives if you are on one of these drugs. 
 
Amiodarone 
Aprepitant 
Atazanavir 
Barbiturates 
Carbamazepine 
Chloramphenicol 
Cimetidine 
Ciprofloxacin 
Clarithromycin 
Delaviridine 
Diltiazem 
Efavirenz 
Erythromycin 
Fluconazole 
Fluvoxamine 
Glucocorticoids 
Grapefruit  
Grapefruit Juice 
Imatinib 
Indinavir 
Itraconazole 
Ketoconazole 
Modanfinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine (fluoxetine) 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Posaconazole 
Rifabutin 
Rifampacin 
Rifampin 
Ritonavir 
Saquinavir 
St. John’s wort 
 


 
 
 
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Telithromycin 
Troglitazone 
Verapamil 
Voriconazole
The following types of medicines used to treat high blood pressure should be avoided while taking 
temsirolimus: 
 
 
Angiotensin converting enzyme inhibitor (ACE inhibitor) 
 
Calcium Channel Blockers (CCB) 
 
Your study doctor can review your medications and tell you if you are currently taking an ACE inhibitor or 
a calcium channel blocker. 
 
Are there benefits to subjects taking part in the study? 
 
Participation on this study may or may not benefit you.  Participating in this study will not cure your 
relapsed leukemia/lymphoma.  Based on experience with the drugs used in the treatment plan, 
researchers believe this therapy may cause your leukemia/lymphoma to stop growing or go into remission 
for a period of time.  Your cancer may not have any response to the therapy received while participating 
in this study.   
 
Are there benefits to society? 
 
It is hoped that the information learned from this study may help future children or young adults with 
relapsed ALL/ Non-Hodgkin Lymphoma.   
 
What other choices do I have if I do not take part in this study? 
 
You do not have to participate in this study to receive treatment for recurrent leukemia.  There is no 
“standard” therapy for recurrent leukemia. Most treatment plans have used drugs similar to those used in 
this protocol, although these drugs may be given in different combinations, and at different times.  You 
can receive other combinations of chemotherapy without participating in this study.   
 
As an alternative to this study, you may decide you don’t want additional treatment for your relapsed 
leukemia or lymphoma.  You will always receive medicines to help you feel more comfortable and deal 
with problems caused by your cancer or treatment whether you participate in this study or not. 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Will my medical information be kept private?  
 
Members of the research team and, if appropriate, your primary care physicians and nurses will know that 
you are a research subject. All results will be kept confidential, but may be made available to you, and/or 
your physician if you wish.  Because this study involves the treatment of a medical condition, a copy of 
this consent form will be placed in your medical record. This will allow the doctors that are caring for you 
to obtain information about what medications or procedures you are receiving in the study and treat you 
appropriately. You may read your medical record. The records are available to those caring for you at this 
hospital. 
 
Organizations that may inspect/or copy your research records for quality assurance and data analysis 
include: 
 
 
Therapeutic Advances in Childhood Leukemia & Lymphoma Consortium (TACL) 
 
Pfizer, Inc. (the makers of temsirolimus) and their designated representatives 
 
The U.S. Food and Drug Administration (FDA) 


 
 
 
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 
The U.S. Department of Health and Human Services (DHHS) 
 
The Institutional Review Board (IRB) of CHLA  
 
Health Canada 
As a result, these organizations may see your name; but they are bound by rules of confidentiality not to 
reveal your identity to others.   
 
Reasonable steps will be taken to protect your right to privacy. No information about you, or provided by 
you during the research will be shared with others without your written permission, except as explained 
below: 
 
If necessary to protect your rights or welfare (for example, if you are injured and need emergency care); 
or if required by law (i.e., child abuse, reports of certain infectious diseases). 
 
The information collected will be used to meet the purpose of this clinical study. In addition, this 
information may be used to support applications to market the studied drug in the United States and in 
other countries. It may also be used in reports of the study or for scientific publications and presentations 
that will not identify study participants by name.   
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov , as required by U.S. Law.  
This website will not include information that can identify you.  At most, the website will include a summary 
of the results.  You can search this website at any time. 
 
What are the costs of taking part in this study? 
 
The health care costs during your participation in this study that are considered part of the standard 
treatment of your disease will be billed to your insurance or other third-party payer.  This includes blood 
tests, hospitalizations, procedures that will be done and medications with the exception of the medication 
Temsirolimus.  The drug company, Pfizer, will provide the medication, Temsirolimus, free of charge for 
this study. Pfizer does not cover the cost of getting the Temsirolimus ready and giving it to you, so you or 
your insurance company may have to pay for this. 
 
You will not have to pay for the following tests that will be done for research purposes only: 
- Bone Marrow Biology Studies 
- Peripheral Blood Biology Studies 
 
Your family is responsible for other costs which may result from your participation in the study, such as, but 
not limited to, time off of work, car fare, baby sitter fees, food purchased while at the hospital, etc.  You will 
not receive any type of payment for participating in this study.  Taking part in this study may lead to added 
costs to your insurance company. Please ask about any expected added costs or insurance problems. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s 
Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .   You can print a copy of the 
“Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you 
a free copy. 
 
 
What happens if I am injured because I took part in this study? 
 
It is important that you tell your study doctor, _________________ if you feel that you have been injured 
because of taking part in this study.  You can tell the doctor in person or call her at  
__________________. 
 


 
 
 
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You will get medical treatment if you are injured as a result of taking part in this study.  You and/or your 
health plan will be charged for this treatment.   The study will not pay for medical treatment.   
 
 
What are my rights if I take part in this study? 
 
Taking part in this study is voluntary. You may choose not to participate in this study. If you decide not to 
participate, you will not be penalized and you will still receive the standard treatment. 
 
If you choose to participate, you may discontinue your participation in the study at any time. If you 
discontinue participation in the study, physicians and hospital personnel will still take care of you. 
 
You also have the right to know about new information that may affect your health, welfare, or your 
willingness to participate in the study. You will be provided with this information as soon as it becomes 
available. 
 
Whether you participate or not, you will continue to get the best medical care this hospital can provide. 
 
 
 
Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions or concerns you have about this study.  Contact 
your study doctor ___________________ at _____________________. 
 
For questions about your rights while taking part in this study, call the Institutional Review Board at 
________________________________________________________________________________ 
 
 
Where can I get more information? 
 
Call the National Cancer Institute’s Cancer Information Service: 
1-800-4-CANCER (1-800-422-6237) OR 1-800-332-8615 (for the hearing impaired) 
 
 
You will be given a copy of this consent form. 
 
You will be given a copy of this treatment plan upon request. 
 
Visit the TACL Consortium Website at https://tacl.chla.usc.edu/tacl 
 
 
 


 
 
 
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SIGNATURE OF RESEARCH SUBJECT  
 
Your signature below indicates:  
 
You have read this document and understand its meaning;  
 
You have had a chance to ask questions and have had these questions answered to your 
satisfaction;  
 
You agree to participate in this research study; and 
 
You will be given a copy of the signed permission form.  
 
__________________________________ 
 
________________________________ 
Name of Subject 
 
 
 
 
Signature & Date  
 
SIGNATURE OF PARENT(S)/GUARDIAN 
 
Your signature below indicates that you have read this document; understand its meaning; have had a 
chance to ask questions; have had these questions answered to your satisfaction; and agree to your 
child’s participation in this research study. You have been given a signed copy of this assent/permission 
form. 
 
__________________________________    
 
________________________________ 
Name(s) of Parent(s)/Guardian  
 
Name(s) of Parent(s)/Guardian 
 
 
_________________________________                   
________________________________ 
Signature of Parent (Guardian) &  Date        
 
Signature of Parent (Guardian) & Date 
 
 
SIGNATURE OF INVESTIGATOR 
 
I have explained the research to the subject and/or the subject’s parent(s)/guardian(s) and have 
answered all of their questions.  I believe that they understand the information described in this document 
and freely give consent/permission/assent to participate. 
 
______________________________________ 
Name of Investigator 
 
______________________________________  
________________________________ 
Signature of Investigator 
 
 
 
Date (must be same as the subject’s) 
  
 
SIGNATURE OF WITNESS (if a translator is used) 
 
My signature as witness certified that the subject and/or the subject’s parent(s)/guardian(s) signed this 
permission form in my presence as their voluntary act and deed. 
 
__________________________________ 
Name 
____________________________________ 
 
___________________________________ 
Signature of Witness 
 
 
 
 
Date (must be the same as the subject’s) 
 
 


 
 
 
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Please check appropriate box and sign below. 
 
Investigator’s Statement of Certification for Subjects less than Seven Years of Age (Assent) 
 
The undersigned investigator, _____________________________, hereby certifies that he/she has 
discussed the information contained in the study consent with the subject, including any risks that may 
reasonably be expected to occur. The undersigned further certifies that the subject was encouraged to 
ask questions, that all questions were answered, and that assent was obtained. 
 
 Assent was not obtained for a subject under 18 years of age. (Please state the reason. Examples 
include: child is an infant; child is comatose; child lacks cognitive abilities to understand the information.) 
 
___________________________________________________________________________________
___________________________________________________________________________________
_______________________________________________________________________________ 
 
 
Date:_____________Time:______________  
 
Signature_________________________________________ 
 
 
 
 
 
 
 


 
 
 
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INFORMED CONSENT: ATTACHMENT 1
 
 


 
 
 
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APPENDIX I:  PERFORMANCE STATUS SCALES/SCORES 
 
Performance Status Criteria 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
ECOG (Zubrod) 
Karnofsky 
Lansky 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry 
on all pre-disease 
performance without 
restriction. 
100 
Normal, no complaints, 
no evidence of disease 
100 
Fully active, normal. 
90 
Able to carry on normal 
activity, minor signs or 
symptoms of disease. 
90 
Minor restrictions in 
physically strenuous 
activity. 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to 
carry out work of a light 
or sedentary nature, e.g., 
light housework, office 
work. 
80 
Normal activity with 
effort; some signs or 
symptoms of disease. 
80 
Active, but tires more 
quickly 
70 
Cares for self, unable to 
carry on normal activity 
or do active work. 
70 
Both greater restriction of 
and less time spent in play 
activity. 
2 
Ambulatory and capable 
of all self-care but unable 
to carry out any work 
activities.  Up and about 
more than 50% of 
waking hours 
60 
Required occasional 
assistance, but is able 
to care for most of 
his/her needs. 
60 
Up and around, but 
minimal active play; keeps 
busy with quieter activities. 
50 
Requires considerable 
assistance and frequent 
medical care. 
50 
Gets dressed, but lies 
around much of the day; 
no active play, able to 
participate in all quiet play 
and activities. 
3 
Capable of only limited 
self-care, confined to 
bed or chair more than 
50% of waking hours.  
40 
Disabled, requires 
special care and 
assistance. 
40 
Mostly in bed; participates 
in quiet activities. 
30 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
30 
In bed; needs assistance 
even for quiet play. 
4 
Completely disabled.  
Cannot carry on any self-
care. Totally confined to 
bed or chair. 
20 
Very sick, hospitalization 
indicated.  Death not 
imminent. 
20 
Often sleeping; play 
entirely limited to very 
passive activities. 
10 
Moribund, fatal 
processes progressing 
rapidly. 
10 
No play; does not get out 
of bed. 
 
 
 
 
 


 
 
 
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APPENDIX II:  CYP3A4 INDUCERS AND INHIBITORS 
 
The use of the following medications should be discontinued prior to initiation of protocol therapy and 
should be avoided during protocol therapy if reasonable alternatives exist. This is not an inclusive list; 
please refer to other resources such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx for additional 
information. 
 
 
Strong 
Inhibitors 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Other Inhibitors 
Inducers 
Clarithromycin 
Indinavir 
Itraconazole 
Losartan 
Ketoconazole 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telithromycin 
Voriconazole 
 
Aprepitant 
Diltiazem 
Erythromycin 
Fluconazole 
Grapefruit 
Juice 
Verapamil 
Cimetidine 
Amiodarone 
Bocepravir 
Chloramphenicol 
Ciprofloxacin 
Delaviridine 
Fluvoxamine 
Imatinib 
Mifepristone 
Norfloxacin 
Norfluoxetine 
(fluoxetine) 
Star fruit 
Telaprevir  
Barbiturates 
Carbamazepine 
Efavirenz 
Glucocorticoids 
Modanfinil 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s wort 
Troglitazone 
 
 
 
DRUGS 
POTENTIAL INTERACTION 
ACTION TO BE TAKEN 
Anticonvulsants 
Induction of drug metabolizing 
enzymes 
Lowered EFS 
AVOID phenytoin, Phenobarbital, 
carbamazepine 
Consider Gabapentin or Levetiracetam 
(Keppra) as alternative 
Rifampin 
Induction of drug metabolizing 
enzymes  
DO NOT USE 
Azole Antifungals 
(fluconazole, 
itraconazole*, 
voriconazole, 
posaconazole, 
ketoconazole) 
Inhibition of drug metabolizing 
enzymes 
CONSIDER ALTERNATIVE 
MEDICATIONS such as echinocandins 
or amphotericin.  
 
Macrolide Antibiotics 
(erythromycin, 
clarithromycin, 
azithromycin, 
roxithromycin, 
telithromycin) 
Inhibition of drug metabolizing 
enzymes 
CONSIDER ALTERNATIVE 
MEDICATIONS 
 
 
For a more complete list of CYP 3A 4/5 Inhibitors and Inducers, go to: 
http://medicine.iupui.edu/flockhart/