Conditions: Adult Anaplastic Astrocytoma Adult Anaplastic Oligodendroglioma Adult Diffuse Astrocytoma Adult Giant Cell Glioblastoma Adult Glioblastoma Adult Gliosarcoma Adult Mixed Glioma Adult Oligodendroglioma Recurrent Adult Brain Neoplasm
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 36
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the side effects and best dose of temsirolimus when given together with perifosine and to see how well it works in treating patients with recurrent or progressive malignant glioma. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as perifosine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving temsirolimus with perifosine may be an effective treatment for malignant glioma.

Detailed description:
PRIMARY OBJECTIVES:

I. Define the maximum tolerated dose (MTD) of temsirolimus in combination with perifosine in patients with recurrent or progressive malignant glioma who are not taking enzyme-inducing anti-epileptic drugs (EIAEDs). (Phase I) II. Determine the efficacy of temsirolimus in combination with perifosine in patients with recurrent/progressive glioblastomas (GBMs) not taking EIAEDs as measured by 6 month progression-free survival (6mPFS) and radiographic response rates. (Phase II)

SECONDARY OBJECTIVES:

I. Characterize the safety profile of perifosine and temsirolimus. II. Estimate median overall and progression-free survival. III. Explore the association of pre-treatment molecular phenotype with response to treatment.

IV. Explore molecular effects during treatment including phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (S6K) and rat sarcoma (RAS)/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (ERK) signaling, proliferation, and apoptosis.

OUTLINE: This is a phase I dose-escalation study of temsirolimus, followed by a phase II study.

PHASE I: Patients receive temsirolimus intravenously (IV) over 30 minutes on days 1, 8, 15, and 22 and perifosine orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive temsirolimus and perifosine as in phase I. Some patients may also undergo cytoreductive surgery.

After completion of study therapy, patients are followed up every 3 months.

Arms:
arm 1: PHASE I: Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 and perifosine PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive temsirolimus and perifosine as in phase I. Some patients may also undergo cytoreductive surgery.

Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Perifosine intervention 3: Temsirolimus intervention 4: Therapeutic Conventional Surgery
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Given IV intervention 4: Undergo cytoreductive surgery

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Protocol 
 
IRB#: 09-058 A(14) 
 
Amended:  
Reviewed by OCR, JR 3/24/14 
 
i 
 
SUMMARY OF CHANGES 
 
For Protocol Amendment #14 to: Protocol Title: I/II Trial of Temsirolimus and Perifosine 
for Recurrent or Progressive Malignant Gliomas 
 
NCI Protocol #: 8249 
Local Protocol #: 09-058 
 
NCI Version Date: 04/01/2014 
Protocol Date: 04/01/2014 
 
# 
Section 
Page(s) Change 
1. 
Header 
All 
The local IRB Protocol # has been updated to A(14) 
throughout the document. 
2. 
Face Page 
1 
The NCI version date has been updated to 04/01/2014. 
3. 
Face Page 
2 
Sumera Bukhari has replaced Brian Seko as the 
Responsible Data Manager for Memorial Sloan Kettering 
Cancer Center. 
3. 
Face Page 
3 
The “Version #15/Version Date 04/01/2014” was added to 
Protocol Type/Version #/ Version Date. 
4. 
Table of Contents 
5-6 
The table of contents was updated to reflect the body of the 
protocol. 
5. 
N/A 
N/A 
In response to NCI correspondence from Shanda Finnigan, 
MPH, RN, CCRC, dated January 10, 2014, references to 
the “Adverse Event Expedited Reporting System 
(AdEERS)” have been changed to “CTEP Adverse Event 
Reporting System (CTEP-AERS)” throughout the protocol. 
6. 
N/A 
N/A 
Formatting and editorial changes were made throughout the 
protocol document. 
 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Protocol 
 
IRB#: 09-058 A(14) 
 
Amended:  
Reviewed by OCR, JR 3/24/14 
 
1 
 
NCI Protocol #:     8249 
 
Local Protocol #:  09-058 
 
NCI Version Date: 04/01/2014 
 
TITLE:  Phase I/II Trial of Temsirolimus and Perifosine for Recurrent or Progressive 
Malignant Gliomas 
 
Coordinating Center: 
 
 
Memorial Sloan Kettering Cancer Center 
 
*Principal Investigator: 
Thomas Kaley, MD 
 
Department of Neurology 
 
Memorial Sloan Kettering Cancer Center 
 
1275 York Avenue 
 
New York, NY 10065 
 
Tel 212-639-5122 
 
Fax 646-422-0626 
 
kaleyt@mskcc.org 
 
Co-Investigators: 
Elena Pentsova, MD (Neurology, Co-PI) 
Lisa DeAngelis, MD (Neurology) 
Craig Nolan, MD (Neurology: Suffolk) 
Jerome Posner, MD (Neurology) 
Igor Gavrilovic, MD (Neurology: Basking Ridge) 
 
Antonio Omuro, MD (Neurology) 
Ingo Mellinghoff, MD (Neurology) 
Christian Grommes, MD (Neurology) 
Philip Gutin, MD (Neurosurgery) 
Viviane Tabar, MD (Neurosurgery) 
Cameron Brennan, MD (Neurosurgery) 
Eric Holland, MD (Neurosurgery) 
Steven Larson, MD (Nuclear Medicine, Radiology) 
Mario Lacouture, MD (Medicine, Dermatology) 
Emmy Ludwig-Miller, MD (Medicine, Gastroenterology) 
Sasan Karimi, MD (Neuro-radiology, Radiology) 
 
Jason Huse, MD (Pathology) 
 
Marc Rosenblum, MD (Pathology) 
 
Memorial Sloan Kettering Cancer Center1275 York Avenue 
New York, NY 10065 
 


Memorial Sloan Kettering Cancer Center 
IRB Protocol 
 
IRB#: 09-058 A(14) 
 
Amended:  
Reviewed by OCR, JR 3/24/14 
 
2 
 
Consenting Professionals: 
Thomas Kaley, MD (Neurology) 
Elena Pentsova, MD (Neurology) 
Lisa DeAngelis, MD (Neurology) 
Craig Nolan, MD (Neurology) 
Jerome Posner, MD (Neurology) 
Igor Gavrilovic, MD (Neurology) 
Antonio Omuro, MD (Neurology) 
Ingo Mellinghoff, MD (Neurology) 
Christian Grommes, MD (Neurology) 
 
 
 
Statistician: 
Katherine S Panageas, DrPH 
 
 
Memorial Sloan Kettering Cancer Center 
 
 
Epidemiology-Biostatistics 
 
 
307 East 63rd Street 
 
 
New York, NY  10021 
 
 
 
Tel 646-735-8119 
 
 
Fax  646-735-0010 
 
 
panageak@mskcc.org  
 
 
Responsible Research Nurse: 
Responsible Data Manager: 
Mary Elizabeth Davis 
Sumera Bukhari 
Memorial Sloan Kettering Cancer Center 
Memorial Sloan Kettering Cancer Ctr 
 
160 East 53rd Street 5th floor 
633 3rd Avenue 
New York, NY 10022  
New York, NY  10017 
 
Tel 212-610-2662 
Tel 646-227-2269 
davism@mskcc.org 
bukharis@mskcc.org 
 
Data Analysis Site: 
Andrew B. Lassman, MD 
Columbia University Medical Center 
Department of Neurology 
710 West 168th Street 
New York, NY 10032 
Tel 212-305-5051 
Fax 212-305-6978 
Abl7@columbia.edu 
 
 
 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Protocol 
IRB#: 09-058 A(14) 
Amended: 
Reviewed by OCR, JR 3/24/14 
3 
NCI Supplied Agent(s): 
Temsirolimus (CCI-779) (NSC 683864) Perifosine 
(NSC# 639966) 
Protocol Type / Version # / Version Date: 
Original/Version #4/Version Date 11/19/2009; 
Version # 5/Version Date 1/8/2010;  
Version #6/Version Date 3/24/2010;  
Version #7/Version Date 5/5/2010;  
Version #8/Version Date 11/30/2010; 
Version #9/Version Date 3/4/2011; 
Version #10/ Version Date 8/22/2011; 
Version #11/Version Date 10/26/2011; 
Version #12/Version Date 2/13/2012; 
Version #13/Version Date 10/02/2013; 
Version #14/Version Date 12/01/2013; 
Version #15/Version Date 04/01/2014; 


Memorial Sloan Kettering Cancer Center 
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SCHEMA 
 
Dose levels and treatment schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose level 
Temsirolimus (mg/week) 
Perifosine load/maintenance (mg/day) 
-6 
5 
150/50 
-5 
10 
150/50 
-4 
15 
150/50 
-3 
15 
150/100 
-2 
15 
300/100 
-1 
15 
450/100 
1 (starting) 
15 
600/100 
2 
25 
600/100 
3 
50 
600/100 
4 
75 
600/100 
5 
115 
600/100 
6 
170 
600/100 
7 
170 
900/100 
Continue 
Temsirolimus + Perifosine 
Recurrence(s)/progression(s) 
Diagnostic surgery:  malignant glioma 
Initial treatment 
Temsirolimus + Perifosine 
Tissue for molecular predictors of 
outcome 
Tissue for molecular effects 
of treatment 
Surgery 
MRI every 8 weeks 


Memorial Sloan Kettering Cancer Center 
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5 
 
TABLE OF CONTENTS 
SCHEMA ...................................................................................................................................................................... 4 
1 
OBJECTIVES ................................................................................................................................................. 7 
1.1 
Primary: ............................................................................................................................................ 7 
1.2 
Secondary (phase I and II): ............................................................................................................... 7 
2 
BACKGROUND ............................................................................................................................................. 7 
2.1 
CTEP-Supplied Investigational Agents:  temsirolimus and perifosine ............................................. 7 
2.2 
Other Agents:  Not applicable (N/A) .............................................................................................. 14 
2.3 
Study Disease:  Malignant Gliomas ................................................................................................ 14 
2.4 
Rationale for combined temsirolimus and perifosine in malignant gliomas ................................... 15 
2.5 
Correlative Studies Background ..................................................................................................... 18 
3 
PATIENT SELECTION................................................................................................................................ 20 
3.1 
General Eligibility Criteria .............................................................................................................. 20 
3.2 
Exclusion Criteria ........................................................................................................................... 22 
3.3 
Inclusion of Women and Minorities................................................................................................ 23 
4 
REGISTRATION PROCEDURES ............................................................................................................... 24 
4.1 
Research Participant Registration ................................................................................................... 24 
4.2 
Informed Consent Procedures ......................................................................................................... 24 
5 
TREATMENT PLAN ................................................................................................................................... 24 
5.1 
Agent Administration ...................................................................................................................... 24 
5.2 
Definition of Dose Limiting Toxicity ............................................................................................. 31 
5.3 
General Concomitant Medication and Supportive Care Guidelines ............................................... 33 
5.4 
Duration of Therapy ........................................................................................................................ 35 
5.5 
Duration of Follow Up .................................................................................................................... 35 
5.6 
Criteria for Removal from Study .................................................................................................... 35 
6 
DOSING DELAYS/DOSE MODIFICATIONS ........................................................................................... 35 
6.1 
Dose Modifications ......................................................................................................................... 35 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ........................................................ 42 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ........................................... 42 
7.2 
Adverse Event Characteristics ........................................................................................................ 51 
7.3 
Expedited Adverse Event Reporting ............................................................................................... 51 
7.4 
Routine Adverse Event Reporting .................................................................................................. 54 
7.5 
Secondary AML/MDS .................................................................................................................... 54 
7.6  
Serious Adverse Event (SAE) Reporting at MSKCC ..................................................................... 54 


Memorial Sloan Kettering Cancer Center 
IRB Protocol 
 
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8 
PHARMACEUTICAL INFORMATION ..................................................................................................... 55 
8.1 
 CTEP-Supplied Investigational Agents:  temsirolimus and perifosine .......................................... 55 
8.2 
 Other Investigational Agent(s):  N/A ............................................................................................. 59 
8.3 
 Commercial Agent(s):  N/A ........................................................................................................... 59 
9 
CORRELATIVE/SPECIAL STUDIES ......................................................................................................... 59 
9.1 
Laboratory Correlative Studies ....................................................................................................... 59 
9.2 
Special Studies:  N/A ...................................................................................................................... 61 
10 
STUDY CALENDAR ................................................................................................................................... 61 
11 
MEASUREMENT OF EFFECT ................................................................................................................... 62 
11.1 
 Antitumor Effect ............................................................................................................................ 62 
11.2 
 Definitions...................................................................................................................................... 62 
11.3 
 Methods for Evaluation of Measurable Disease............................................................................. 63 
11.4 
 Response Criteria ........................................................................................................................... 63 
12 
DATA REPORTING / REGULATORY REQUIREMENTS ....................................................................... 64 
12.1 
 Data Reporting ............................................................................................................................... 64 
12.2 
 CTEP Multicenter Guidelines: N/A ............................................................................................... 65 
12.3 
 Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement  
(CTA) .............................................................................................................................................. 65 
13 
STATISTICAL CONSIDERATIONS .......................................................................................................... 66 
13.1 
 Study Design/Endpoints ................................................................................................................. 66 
13.2 
 Sample Size/Accrual Rate .............................................................................................................. 70 
13.3 
 Stratification Factors ...................................................................................................................... 71 
13.4 
 Analysis of Secondary Endpoints .................................................................................................. 72 
13.5 
 Reporting and Exclusions .............................................................................................................. 72 
14 
REFERENCES .............................................................................................................................................. 74 
 
APPENDIX A:  Performance Status Criteria ................................................................................................ 79 
APPENDIX B:  EIAEDs and Non-EIAEDs.................................................................................................. 80 
APPENDIX C:  Drugs Metabolized by Selected CYP450 Isoenzymes ........................................................ 81 
APPENDIX D:  Patient Pill Diary................................................................................................................. 86 
APPENDIX E:  Drug Reconciliation Form ................................................................................................... 88 


Memorial Sloan Kettering Cancer Center 
IRB Protocol 
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7 
1 OBJECTIVES 
1.1 Primary: 
1.1.1 
Phase I:  Define the maximum tolerated dose (MTD) of temsirolimus in combination with 
perifosine in patients with recurrent malignant gliomas who are not taking enzyme-inducing 
anti-epileptic drugs (EIAEDs). 
1.1.2 
Phase II: Determine the efficacy of temsirolimus in combination with perifosine in patients 
with recurrent/progressive GBMs not taking EIAEDs as measured by 6 month Progression-
Free Survival (6mPFS) and radiographic response rates 
1.2 Secondary (phase I and II): 
1.2.1 
Characterize the safety profile of perifosine and temsirolimus 
1.2.2 
Estimate median overall and progression-free survival. 
1.2.3 
Explore association of pre-treatment molecular phenotype with response to treatment. 
1.2.4 
Explore molecular effects during treatment including PI3K/AKT/mTOR/S6K and 
RAS/MEK/ERK signaling, proliferation, and apoptosis. 
2 BACKGROUND 
2.1 CTEP-Supplied Investigational Agents:  temsirolimus and perifosine 
Temsirolimus (CCI-779) (NSC 683864) 
Temsirolimus (CCI-779, sirolimus 42-ester with 2,2-bis(hydroxymethyl) propionic-acid), an ester of 
the macrocyclic immunosuppressive agent sirolimus (rapamycin, Rapamune™), is a cytostatic cell 
cycle inhibitor with antitumor properties.  The agent specifically inhibits the mammalian target of 
rapamycin (mTOR), a Ser/Thr kinase involved in the initiation of mRNA translation (reviewed in 
Dancey, 2002).  Temsirolimus has been shown to inhibit the growth of a wide range of histologically 
diverse tumor cells, with the greatest sensitivity shown by cells derived from the central nervous 
system (CNS) cancers, leukemia (T-cell), breast cancer, prostate cancer, and melanoma [Investigator’s 
Brochure 2008].  Temsirolimus is being developed as a cytostatic agent to delay the time to tumor 
recurrence or progression or to increase survival in patients with various malignancies.  Key features of 
this agent include its good tolerability, unique mechanism of action, ability to arrest cells in the G1 
phase, and ability to induce apoptosis.  Intermittent schedules of Temsirolimus administration have 
been evaluated in clinical studies because nonclinical data suggest such schedules minimize the agent’s 
immunosuppressive effects while maintaining antitumor activity. 
Mechanism of Action 
The observed antitumor and immunosuppressive properties of rapamycin analogs are due to their 
ability to disrupt the mTOR-dependent signaling pathway (Sekulic et al., 2000).  mTOR, a member of 
the phosphatidylinositide 3’-kinase (PI3K)-related family, is located predominantly in the nuclear 
fraction of both neoplastic and normal cells (Zhang et al., 2002).  mTOR activation triggers resting 
cells to increase the translation of a subset of mRNAs whose proteins are required for cell cycle 
progression from G1 to S phase.  mTOR regulates essential signal transduction pathways and is 
involved in the coupling of growth stimuli with cell cycle progression.  Experimental data indicate that 
mTOR acts downstream of the PI3K/Akt pathway and is phosphorylated in response to mitogenic 
signals (Sekulic et al., 2000).  Early studies reported that mTOR was dedicated to initiating mRNA 
translation in response to favorable nutrient environments (Barbet et al., 1996).  In fact, cells treated 
with rapamycin undergo changes that are strikingly similar to those observed during conditions of 


Memorial Sloan Kettering Cancer Center 
IRB Protocol 
 
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8 
 
starvation.  These include mTOR inactivation, down regulation of translation, G1 arrest, accumulation 
of glycogen stores and altered transcription patterns (Barbet et al., 1996).  More recent studies have 
demonstrated that mTOR is involved in regulating many aspects of cell growth, including organization 
of the actin cytoskeleton, membrane traffic, protein degradation, protein kinase C (PKC) signaling, 
ribosome biogenesis, and transcription (reviewed in Schmelzle and Hall, 2000). 
 
Temsirolimus reacts with the ubiquitous intracellular FK506-binding protein 12 (FKBP12), forming a 
Temsirolimus/FKBP12 complex that is a potent inhibitor of the highly conserved kinase mTOR 
(Armistead and Harding, 1993; Geoerger et al., 2001).  Inhibition of mTOR leads to suppression of 
several downstream signaling effectors, including the ribosomal subunit p70S6k and the eukaryotic 
initiation factor 4 binding protein 1 (4E-BP1) (Brown et al., 1994).  These two proteins play key roles 
in ribosomal biogenesis and cap-dependent translation, respectively (Brown and Schreiber 1996).  The 
extent of phosphorylation of these two downstream proteins (p70S6 kinase and 4E-BP1) may therefore 
serve as indicators of Temsirolimus biologic activity in vivo.  Inhibition of the synthesis of ribosomal 
proteins and elongation factors, required to accelerate the process of cell division, are thought to 
contribute to the anti-proliferative effects of rapamycin analogs (Terada et al., 1994).  While 
Temsirolimus inhibits the translation of only a subset of mRNAs, inhibition of mTOR can lead to a 
substantial decrease (~15%) in overall protein synthesis (Dudkin et al., 2001). 
 
Tumors that rely on paracrine or autocrine stimulation of receptors that constitutively stimulate the 
PI3K/Akt/mTOR pathway or tumors with mutations that activate the PI3K/Akt signal transduction 
pathway may depend on rapamycin-sensitive pathways for growth and therefore may be particularly 
sensitive to rapamycin analogs. The tumor suppressor gene PTEN is known to play a major role in 
embryonic development, cell migration, and apoptosis (reviewed in Yamada and Araki, 2001).  PTEN 
acts as a lipid phosphatase that regulates major signal transduction pathways and effectively terminates 
PI3K-mediated signaling (Podsypanina et al., 2001).  PTEN mutation is associated with constitutive 
activation of the PI3K/Akt pathway, resulting in tumors that are generally resistant to apoptosis.  
PTEN status in tumor cells may therefore be an important predictor of sensitivity to rapamycin analogs 
(Sekulic et al., 2000).  Preliminary evidence suggests that breast cancer cell lines containing PTEN 
mutations are sensitive to growth inhibition by rapamycin (Hidalgo and Rowinsky, 2000).  Additional 
studies in PTEN-deficient human tumor cell lines and PTEN knockout mice have demonstrated 
sensitivity to growth inhibition by Temsirolimus.  Temsirolimus produced remarkable sensitivity to G1 
arrest (ID50 < 1nM)  in PTEN-deficient myeloma cell lines, while myeloma cells containing wild type 
PTEN were at least 1000-fold less sensitive to the agent (Shi et al., 2002).  Also, studies of 
glioblastoma cell lines indicated that low PTEN protein expression was strongly linked with sensitivity 
to Temsirolimus-mediated growth arrest (Smith et al., 2002).  Together, these studies indicate that the 
molecular identification of PTEN mutations or other mutations that lead to constitutive activation of 
the pathway within tumor cells might be predictive of sensitivity to Temsirolimus therapy (Neshat et 
al., 2001; Mills et al., 2001). 
 
Summary of Clinical Studies 
Temsirolimus safety, pharmacokinetics, and preliminary antitumor effects were evaluated in a phase 1 
dose-escalation study with doses of 7.5-220 mg/m2 given as a weekly intravenous (IV) infusion to 24 
patients with advanced malignancies (Raymond et al., 2004).  Although the maximum tolerated dose 
(MTD) was not reached, 220 mg/m2 appeared to be the maximum acceptable dose, with 
thrombocytopenia being dose limiting with repeated dosing.  No clinically relevant 
immunosuppressive effects were observed during treatment, although herpes simplex infections were 
observed in five patients.  The most frequent drug-related adverse events were acneiform 
maculopapular rashes and mucositis/stomatitis (18 of 24 patients, 75%).  Confirmed partial responses 
(PRs) were observed in 2 of 24 patients evaluated, one each with renal cell carcinoma (RCC) and 
breast cancer.  
 


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Data from in vitro studies of A498 human renal cell lines indicated that Temsirolimus had a median 
growth inhibitory concentration (IC50) of 5 ng/mL [Investigator’s Brochure (CCI-779) 2007].  
Predicted modeling of IC50 (humans receiving doses as low as 10 mg) suggests that whole blood 
concentrations would be above the range of 1 ng/mL throughout the entire 1-week dose interval and 
above 5 ng/mL for the majority of this time period.  It is expected that mTOR inhibition would be 
attained with a 25 mg dose. 
 
Clinical pharmacokinetic data are available in patients with cancer receiving Temsirolimus both IV 
daily x 5 days every 2 weeks, once weekly schedules, and orally daily x 5 every 2 weeks.  These data 
indicate that there is no appreciable drug accumulation between cycles and that distribution is 
extensive.  With increasing dose, exposure (AUC) increases in a less than proportional fashion.  The 
mean volume of distribution at steady state (Vdss) is large (57 L after 2 mg IV dose; 900 L following a 
250 mg IV dose) and increases with dose.  Exposure to the hydrolytic product sirolimus is substantial 
with mean values of approximately 1.5-2.3-fold greater than those seen with Temsirolimus following 
IV administration.  Clearance (CL) of Temsirolimus from whole blood increases with increasing dose 
from approximately 5.2L/h after a 2 mg dose to 100L/h after a 250 mg dose.  Intersubject variability in 
CL at a given dose was modest and ranged from 16-27%.  The terminal half-life (t1/2) following 
Temsirolimus doses of 25 to 250 mg is approximately 15 hours. 
 
Pharmacokinetic results from the initial phase 1 study showed that the AUC increased proportionally 
with doses up to 150 mg, but doses higher than 300 mg yielded high AUCs and low CL in some 
patients (Raymond et al., 2004).  The mean Vdss was large with mean values of 127-384 L, while the 
Temsirolimus mean terminal t1/2 decreased from 22 hours (34 mg/m2) to 13 hours (220 mg/m2) as the 
dose increased.  Similar pharmacokinetic data were reported for 16 patients following their initial dose 
of Temsirolimus of 25, 75, or 250 mg delivered as a weekly 30-minute IV (Atkins et al., 2004). 
 
Phase II studies of single agent temsirolimus evaluating different doses of 25 mg, 75 mg, and/or 250 
mg weekly IV have been undertaken in broad range of tumor histologies.  The most promising activity 
has been seen in mantle cell lymphoma (Witzig et al., 2005; Ansell et al., 2006), other B-cell 
lymphomas (Smith et al., 2006) and endometrial carcinoma (Oza et al., 2006) with objective tumor 
response rates of 25-40%.  Moderate activity has been reported in breast (Chan et al., 2005) and renal 
cell carcinoma (Atkins et al., 2004). Minimal to modest single agent activity has been seen in SCLC 
(Pandya et al.,  2005), melanoma (Margolin et al.,  2005) and GBM (Chang et al., 2004, Galanis et al.,  
2006) and multiple myeloma (Farag et al., 2006).  In general, lower doses appear to be as active as 
higher doses with better tolerability. 
 
Recently, a phase 3 trial of temsirolimus, temsirolimus with interferon versus interferon in poor 
prognosis patients with RCC has been reported (Hudes et al., 2006). Of the 626 patients, overall 
survival of patients treated with temsirolimus was significantly prolonged compared to those treated 
with interferon (median 10.9 months versus 7.3 months, HR 0.73, p 0.0069).   The combination of 
interferon and temsirolimus did not confer greater benefit than interferon alone, possibly due to 
compromised dose delivery of the agent(s). 
 
Safety issues 
The safety profile of Temsirolimus has been similar across studies regardless of tumor type, schedule, 
or route of administration.  The most frequently reported adverse events have been gastrointestinal 
(mucositis, diarrhea, nausea, anorexia, vomiting), dermatologic (maculopapular rash, acneiform rash, 
pruritus, nail disorder), hematologic (thrombocytopenia, anemia, leukopenia), and metabolic 
(hyperglycemia, hyperlipemia).  Asthenia, headache, epistaxis, somnolence, and taste perversion have 
also been reported.  Less common but related adverse events included mucositis, depression, and 
allergic reactions [Investigator’s Brochure 2007]. 
 


Memorial Sloan Kettering Cancer Center 
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IRB#: 09-058 A(14) 
Acute hypersensitivity reactions to Temsirolimus that begin shortly after the start of the intravenous 
(IV) infusion (usually, but not always, with the first infusion) and end after stopping the infusion have 
been reported.  Signs and symptoms include flushing of the face and neck (sometimes also the 
extremities and trunk); descriptions of feeling hot, uncomfortable, and/or anxious; chest pain/tightness; 
shortness of breath; decrease in oxygen saturation and cyanosis; hypotension; lightheadedness; 
periorbital puffiness; descriptions of feeling like the head is swelling; nausea; back pain; numbness and 
tingling of hands/feet/face; and difficulty speaking.  Because of these idiosyncratic reactions, subjects 
receiving IV Temsirolimus should be premedicated with diphenhydramine 25-50 mg IV (or a similar 
antihistamine) approximately 30 minutes before the start of the Temsirolimus infusion.
Similarly to organ-transplant patients receiving sirolimus, pneumonitis/pulmonary infiltrates and 
alveolitis have been reported among oncology patients receiving intravenous Temsirolimus.  Some 
patients have been asymptomatic with pneumonitis detected on CT scan or chest x-ray, while others 
have had symptoms of dyspnea, cough and fever.  These symptomatic patients have had Temsirolimus 
discontinued and improved after receiving corticosteroids and/or antibiotics.  There have been a few 
instances of recurrence of the symptoms and signs of pneumonitis with Temsirolimus rechallenge.  
Patients with cough, dyspnea and fever should have Temsirolimus discontinued pending investigation 
and permanently discontinued if the diagnosis is confirmed and the reaction thought to be related to 
Temsirolimus. 
Subjects may be immunosuppressed and should be carefully observed for the occurrence of infections, 
including opportunistic infections.  Other serious adverse events seen in subjects treated on clinical 
studies of temsirolimus include abnormal wound healing, bowel perforation (including fatal outcome), 
renal failure (including fatal outcome) in subjects with advanced RCC and/or with pre-existing renal 
insufficiency, angioneurotic edema-type reactions have been observed in some subjects who received 
temsirolimus and ACE inhibitors concomitantly and cataracts have been observed in some subjects 
who received the combination of temsirolimus and interferon-a.  Central nervous system (CNS) 
bleeding has been reported, primarily in patients with CNS tumors.  Several of these patients were 
concurrently taking anticoagulants, so the relationship between Temsirolimus and the adverse event is 
not clear.  Increased fibrinogen has been reported among oncology patients receiving Temsirolimus.  
The clinical significance of this event is not certain, although thromboembolic events have been 
reported.  A list of Comprehensive Adverse Events and Potential Risks (CAEPR) in NCI-CTCAE 
terms is included in Section 7 of the protocol.  Reference may also be made to the Investigators’ 
Brochure. 
Potential Drug Interactions 
Temsirolimus and rapamycin are metabolized primarily by CYP3A4 in human liver microsomes.  
Since there are many agents that affect the metabolic activity of CYP3A4, there is a potential for drug-
drug interactions to occur between Temsirolimus and co-administered drugs.  Although formal drug-
drug interaction studies have not been reported, current knowledge and available data suggest that 
Temsirolimus should be used with caution in combination with enzyme inducers or inhibitors.  
Changes in treatment regimens in which CYP3A4 inducers or inhibitors are being administered, or 
initiation of such regimens during Temsirolimus treatment, should be avoided if possible, but are not 
contraindicated.  Temsirolimus can inhibit CYP2D6, suggesting a potential interaction with drugs that 
are substrates for CYP2D6. 
Perifosine (NSC 639966) 
Alkylphospholipids represent a new class of lipid-related compounds that exhibit promising anticancer 
activity and a different spectrum of toxicity than conventional cytotoxic agents.  Perifosine (1,1-
dimethyl-4[[(octadecyloxy)hydroxyphosphinyl]oxy]-piperidinium inner salt, is a synthetic, substituted 
heterocyclic alkylphospholipid, structurally related to miltefosine (NSC 60558, D-18506).  The anti-
tumor activity of miltifosine was initially evaluated in the 1980’s.  However, the agent was unsuitable 


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for intravenous administration, as it caused hemolytic anemia, or oral administration as it caused 
gastrointestinal toxicity that prevented adequate dosing to reach effective drug levels.  Further 
development of miltefosine was limited to topical applications, and the drug has recently been licensed 
in Europe as Miltex® for the treatment of patients with cutaneous metastases from breast cancer.  
Perifosine was identified as a potentially active and better tolerated analog of miltefosine.  Its spectrum 
of activity across the NCI 60 cell line screen was very similar to miltefosine (Pearson correlation 
coefficient = 0.817).  Both miltefosine and perifosine had very unique patterns of in vitro cell growth 
inhibition, unlike any "standard" chemotherapeutic agent. Perifosine has been shown to be more active 
and better tolerated than miltefosine in nonclinical models (Hilgard et al. 1997). Perifosine exhibited 
marked activity in animal and human tumor cell lines resistant to standard chemotherapeutic agents 
with relative sparing of normal cells, including macrophages and bone marrow cells. 
While intracellular actions of alkylphospholipids have been studied in detail, their exact mechanism(s) 
of antitumor activity are unclear.  Alkylphospholipids exert a broad spectrum of effects on cellular 
functions including proliferation, differentiation, invasion, and metastasis.  Alkylphospholipids in 
general are absorbed directly into cell membranes where they accumulate (reviewed in Arthur and 
Bittman 1998).  Although there is a widespread view that the plasma membrane is the primary site of 
action, alkylphospholipids may be widely distributed throughout the cytoplasm and possibly within the 
nucleus. Modulation of cell surface receptors and inhibition of lipid-mediated signal transduction 
pathways appear to play key roles in the observed anti-tumorigenic effects (Arthur and Bittman 1998; 
Ruiter et al. 1999; Maly et al. 1995; Verheij et al. 2002).  Initial studies suggested that 
alkylphospholipids interfere with phosphoinositide metabolism, leading to inhibition of phospholipase 
C and protein kinase C (Maly et al. 1995).  Treatment of head and neck squamous cell carcinoma 
(HNSCC) cell lines with perifosine led to loss of cyclin-dependent kinase (cdk) activity and 
subsequent cell cycle arrest in G1-S and G2-M phases.  Perifosine-mediated inhibition of cell cycle 
events may be mediated in part through p21WAF1 (Patel et al. 2002; Kondapaka et al. 2002) as a 
correlation was observed between inhibition of cdk activity and up regulation of p21WAF1.  Treatment 
with perifosine led to increased expression of p21WAF1, resulting in inactivation of the cdk/cyclin 
complex and subsequent cell cycle arrest.  Cells lacking p21 gene function (p21WAF-/-) were insensitive 
to perifosine-mediated inhibitory effects. Perifosine induced disruption of signal transduction pathways 
and cell cycle progression are likely to have profound effects on tumor cell growth and function. 
Nonclinical Anti-Tumor Efficacy 
 The activity of perifosine has been evaluated in numerous human and murine cell lines.  In vitro, cell 
lines demonstrating the greatest sensitivity to perifosine included KB (larynx), LNCaP (prostate), 
MAI-PaCa-2 (pancreas), DLD-1 (colon), and SK-HEP-1 (liver) (IC50 1.0 – 4.9 µg/mL) (Perifosine 
Investigator’s Brochure 1998).  In a soft agar tumor stem cell assay, the human KB (squamous) and 
murine L1210 (leukemia) cell lines were the most sensitive.(Perifosine Investigators Brochure, 1998)  
In the methylene blue exclusion assay, the five most sensitive lines include:  KB (squamous mouth), 
LU 65A (lung), LNCaP (prostate), PC-1 (lung) and Hep-2 (larynx) with IC50 values  of 0.8 – 3.4 
µg/mL.   In the SRB/metabolic capacity assay, KM12 (colon), PC3 (prostate), M14 (melanoma), HOP-
92 (lung) and SF295 (CNS) cancer cell lines were the most sensitive with IC50 values of 0.2 – 3.1 
µg/mL.  The majority of cell lines (in all assays) were more sensitive to perifosine than to miltefosine.  
Compared with malignant cells, mouse bone marrow cells were shown to be resistant to perifosine in 
vitro. 
The in vivo activity of perifosine has been evaluated via oral dosing in various schedules in several 
transplanted tumors, as well as in the dimethylbenzanthracene (DMBA) induced mammary tumor 
model of the rat.  Two generally drug resistant tumors exhibiting sensitivity were the KB tumor 
(squamous cell) and AsPC-1 (human pancreatic carcinoma).  In vivo, single oral doses of 511 mg/kg 
completely inhibited tumor growth, and higher doses (two doses of 203 or 300 mg/kg given  7 days 
apart) gave complete persisting remissions lasting >63 days in nude mice with subcutaneously 


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transplanted KB squamous cell tumors. Other xenografts in nude mice with good evidence of in vivo 
effect of orally administered perifosine include the Hep-2 laryngeal, R3327 rat prostate, SAS tongue, 
SC115 mouse breast and HCT-8 colon tumors treated on a daily x 21 day schedule.  Perifosine was 
extremely active in the Sprague-Dawley rat model of dimethylbenzanthracene (DMBA) induced 
mammary tumors.  Daily oral treatment using 21.5 mg/kg for 5 weeks led to complete regressions of 
tumors.  Notably, complete regressions over the entire study period were also achieved by combining a 
high initial dose of 68.1 mg/kg followed by lower daily doses of 2.15 mg/kg over 20 days, whereas the 
loading dose alone caused only an arrest of tumor growth for 14 days.  Even large, established DMBA 
induced mammary tumors (4-8 grams) in rats responded to daily doses of 14.7 to 68.1 mg/kg over 28 
days, with a persisting effect of more than 20 days after cessation of treatment. 
 
Nonclinical Pharmacology 
Nonclinical studies of perifosine given as a single oral dose (10 mg/kg) demonstrated near complete 
absorption, with an absolute bioavailability of 81% and 95% in male and female rats (Perifosine 
Investigator’s Brochure, 1998).  For doses ranging from 1 to 50 mg/kg, maximum plasma 
concentration (Cmax) values ranged from 0.34 to 10.5 µg/mL.  Time to achieve Cmax was reached at a 
median of 16 to 32 hours following administration of perifosine. The volume of distribution (Vd) was 
twice the physical body volume, and the terminal half-life (t1/2) was 120.5 – 171.4 hours. 
 
A study of [14C] excretion (urine, feces) done in the rat after oral dose [14C] perifosine at 10 and 50 
mg/kg revealed the following proportions of renal and fecal excretion: 
 
 
Urine 
Feces 
Dose (mg/kg) 
 
 
10 
<24 hr 1.0%, 
360 hr 20.4 % 
24 hr 24.6 %, 
360 hr 42.9% 
50 
<24 hr 1.2% 
<24 hr 22%, 
48 hr 48.5%, 
72 hr 52.6 % 
 
In vitro binding of perifosine to human serum albumin or α1-acid glycoprotein ranged from 92 to 98% 
(Perifosine Investigator’s Brochure, 1998).  No concentration dependence of protein binding was 
observed, suggesting a high binding capacity of the plasma proteins for perifosine.  
 
Nonclinical Toxicology 
In a subchronic toxicity study in rats, dose dependent toxicities were observed in the kidneys, 
gastrointestinal tract, skin, mammary glands, pituitary, hematopoietic tissue, spleen, ovaries, male 
genital tract, and eyes (Perifosine Investigator’s Brochure, 1998).  Effects on the hematopoietic tissue 
were characterized by an increase in cellularity for the bone marrow and an increased extramedullary 
hematopoiesis.  Histopathologic changes seen in other tissues included evidence of chronic 
nephropathy, atrophy of hair follicles, atrophy of mammary glands, reduction of follicular 
development in the ovaries, degeneration of the germinative epithelium of the testes, 
atrophy/inactivation of prostate and seminal vesicals, secondary hypertrophy of the Leydig cells in the 
testes, and hypertrophy/hyperplasia of mucosal epithelium cells in stomach and small intestine. All 
toxicities, except those in the male genital tract and eyes, were reversible within 13 weeks.  Most 
significant and not clearly reversible were ophthalmologic lesions, specifically, retinal degeneration 
and cataract formation.  This toxicity was seen in rat but not in dog toxicity studies. Clinical chemistry 
revealed reversible increases in CK, BUN, SGOT, SGPT and reversible decrease of red blood cell 
parameters, total cholesterol, triglycerides, inorganic phosphorus and albumin and total protein. 
 
In dogs, decreased food consumption, anorexia, diarrhea and vomiting were noted. Clinical chemistry 


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revealed reduced glucose levels in the group receiving the highest dose.  All changes were reversible 
during a 6-week recovery period.  Histopathologically, minimal to mild degeneration of proximal 
tubular cells of the kidneys were found in male animals.  
 
 
 
Reproductive Toxicity 
Perifosine impaired fertility and reproductive performance in male rats at doses of 2.37 and 8.25 
mg/kg.  Perifosine impaired the reproductive performance of female rats and possessed fetotoxic 
properties in doses of 3.16 and 21.5 mg/kg.  A dose of 0.464 mg/kg is considered to be the no-
observed-toxic-effect level on the female reproductive function and early embryonic development. 
 
Mutagenicity/Carcinogenicity 
In the assay systems employed (Salmonella typhimurium reverse mutation assay with and without S9-
Mix, the V79 gene mutation test, and the micronucleus test in vivo) only a slightly increased number of 
mutants was found in the V79 gene mutation test without activation, a finding similar to that for 
miltefosine. Carcinogenicity studies of perifosine are not available; thus, a carcinogenic potential of 
perifosine cannot be excluded. 
 
Clinical Results - Phase 1 
Asta Medica sponsored three European phase 1 trials of perifosine evaluating weekly and daily dosing, 
as well as an enteric coated formulation.  The study D-21266-3040 was a phase 1 study of escalating 
doses of perifosine given on a weekly schedule.  Thirty-six patients were treated in sequential cohorts 
at dose levels of 100, 200, 350, 450, 600 and 800 mg/week.  At 350 mg weekly, vomiting grade 3 
occurred in the first two patients.  These patients responded to anti-emetic prophylaxis with 
tropisetron, alizaprid, and dexamethasone, and all subsequent patients received anti-emetic 
prophylaxis.  Among 7 patients treated at the maximum administered dose of 800 mg/wk, grade 2 
nausea and vomiting of residual perifosine tablets and grade 4 diarrhea occurred.  Preliminary data 
from analyzed plasma samples of patients receiving perifosine in the dose range of 100 to 600 mg 
indicated a dose-linearity of Cmax and of the area under the concentration time curve (AUC) in this 
dose range.  However, at 800 mg/week, the dose-AUC and Cmax proportionality was reduced.  Cmax and 
t1/2 values ranged from 8 – 25 hours and 96 – 225 hours, respectively (Perifosine Investigator’s 
Brochure, 1998). After repeated dosing a slight accumulation of perifosine was seen, which is in 
accordance with the relatively prolonged terminal t1/2 of the agent.  Perifosine was not detectable in the 
patients' urine.  One patient with chondrosarcoma treated at 350 mg/weekly achieved a partial response 
(Asta Medica update to the NCI, 2000). 
 
In the phase 1 study D-21266-3079, 22 patients received perifosine at escalating doses of 50-350 mg 
daily x 21 days. Fatigue, nausea, vomiting and diarrhea were the most frequent toxicities experienced 
by patients on this study.  The maximum tolerated dose on this study was 200 mg/day.  Three of six 
patients treated at 250 mg/day and the one patient treated at 350 mg/day had intolerable fatigue and/or 
gastro-intestinal toxicity. (Asta Medica update to the NCI, 2000) 
 
An enteric-coated formulation was evaluated on a weekly study in the trial D-21266-3087.  A total of 
eight patients (4/dose level) were treated at 200 or 350 mg weekly.  The enteric coating did not 
improve the tolerability of the oral administration of perifosine and reduced its bioavailability. (Asta 
Medica update to the NCI, 2000) 
 
The Division of Cancer Treatment and Diagnosis, National Cancer Institute has sponsored two phase 1 
trials of perifosine evaluating a loading dose followed by daily maintenance dose schedule.  A loading 
dose/daily maintenance schedule was proposed due to improved efficacy in the DMBA-induced rat 
mammary carcinoma model with this schedule and the clinical PK data which showed a long terminal 


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t1/2 of ~ 100 hours and a slow approach to steady state.  A loading dose could potentially achieve active 
anti-tumor serum concentrations followed by tolerable daily maintenance dosing.  The loading dose 
was fractionated and administered every 6 hours to avoid potential problems with bioavailability and 
possible Cmax associated toxicity such as emesis.  Similar to the results from the Asta Medica-
sponsored studies, the most frequently observed toxicities in NCI sponsored phase 1 studies were 
gastrointestinal (nausea, vomiting, diarrhea) and fatigue.  Chronic nausea among patients receiving 
perifosine appears to resolve approximately 48 hours following discontinuation of therapy.  In contrast, 
fatigue may persist for weeks after therapy has ended. 
 
The first trial examined a loading dose on day 1 followed by a maintenance dose schedule for 20 days 
in patients with solid tumors repeated every 28 days.  In an attempt to minimize nausea, doses were 
administered with a meal or with maintenance doses at bedtime.  In addition, prior to the loading dose, 
patients were given granisetron, metoclopramide, diphenhydramine, and dexamethasone as anti-emetic 
prophylaxis.  As of June 2002, 30 patients had been treated on this study.  Dose limiting nausea and 
vomiting occurred with loading doses of 1200-1500 mg.  Persistent grade 2 nausea and vomiting 
despite anti-emetics, grade 3 arthralgias, arthritis, and fatigue occurred with a maintenance dose of 200 
mg/day.  Of note, while taking perifosine 200 mg/day two patients, one with history of gout and one 
with a history of hyperuricemia had episodes of gout.  One patient without a prior history had an 
episode of pseudogout. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) 
were established as: Cycle 1: 900/150 mg loading/maintenance dose and for > Cycle 2: 300 mg day 1 
loading dose followed by 150 mg days 2-21 in patients repeated every 28 days (Monga et al., 2002).  
Among 10 patients treated at the MTD/RP2D, no patients experienced grade 3-4 dose limiting events 
during the loading dose or maintenance dose periods in the first cycle.  Grade 1-2 fatigue occurred in 
2/10 patients and grade 2 gastrointestinal toxicity was intermittent and tolerable. No clinical responses 
have been observed; however, four patients with stable disease (duration 167-750 days) have been 
reported. 
 
The second DCTD, NCI sponsored phase 1 trial is evaluating a loading dose followed by a continuous 
maintenance dose schedule in patients with advanced cancer.  The loading dose is only given in course 
one, and maintenance dosing continues without a scheduled break.  The cohorts of patients have 
received loading/maintenance doses ranging from 400/50 – 1200/150 mg.  In this study, loading doses 
are split into 4-8 equal doses given at 6 hour intervals.  As of June 2002, 41 patients have been enrolled 
on study.  Reported severe toxicities for this trial include anorexia, fatigue, dehydration, 
nausea/vomiting, constipation, diarrhea, elevated liver function tests, and decreased hemoglobin.  One 
partial response in a patient with uterine sarcoma has been reported. The MTD/recommended phase 2 
dose for this schedule is 900 mg loading dose followed by 100 mg daily maintenance.  Among 14 
patients treated at the MTD, there were grade 3 events (fatigue, nausea and vomiting) during the first 
28 days of treatment. 
 
Pharmacokinetics 
Pharmacokinetic analyses from both NCI sponsored studies showed rapid achievement of steady state 
plasma concentrations without evidence of drug accumulation for doses ranging from 300/50 – 
900/150 (cycle 1) daily for the 21/28 days regimen and from 400/50 – 900/100 mg/day for the 
continuous treatment regimen.  Plasma concentrations were within the range (i.e., 5-10 µg/mL) found 
to have biological activity in laboratory studies. 
 
2.2 Other Agents:  Not applicable (N/A) 
 
2.3 Study Disease:  Malignant Gliomas 
Malignant gliomas are the most common type of brain tumor in adults.  It is estimated that each year 
there are approximately 12,000 new cases in the United States. Despite optimal treatment with surgery, 
radiotherapy and chemotherapy with temozolomide, the prognosis remains poor and almost all patients 


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Figure 1:  RCAS/tv-a modeled high grade gliomas 
(A,B,C) using forced PDGF overexpression 
accurately reflect their human counterparts (D,E,F) 
both histologically (A vs. D) and radiographically on 
contrast enhanced T1 (B vs. E) and T2  (C vs. F) 
weighed brain MRI. 
develop recurrent or progressive tumor.  Patients with glioblastoma (GBM) have a median survival of 
approximately 14.6 months,(Stupp, Mason et al. 2005) while those with anaplastic astrocytomas (AA) 
have a median survival of 24 to 36 months. The median survival for patients with recurrent GBM is 6 
months and for AA is 11 months. Once patients develop tumor progression, conventional 
chemotherapy is generally ineffective. 
 
Approximately 70% of GBMs exhibit abnormally activated phosphotidylinositol 3-kinase (PI3K)/AKT 
signaling, usually as a result of loss or alteration of the tumor suppressor gene phosphatase and tensin 
homolog on chromosome ten (PTEN).(reviewed in Lassman and Holland 2006)  The PI3K/AKT 
pathway activates the mammalian target of rapamycin (mTOR) which activates p70S6 Kinase (S6K) 
and stimulates multiple oncogenic processes including translation of a number of key proteins required 
for cell-cycle progression. The presence of PTEN gene alterations and the subsequent activation of 
these downstream pathways have been associated with poor prognosis in AA, anaplastic 
oligodendroglioma (AO) and GBM.  Targeting of the components of the PI3K/AKT/mTOR/S6K 
pathways can result in cell-cycle arrest, apoptosis, or reduced tumorigenicity. 
 
 
 
Modeling brain tumors using the RCAS/tv-a system 
One of the main objectives highlighted by the Brain Tumor Progress Review Group (PRG) was the 
need for animal models of brain tumors that accurately represent the histology and genetics of the 
disease in humans.  The RCAS/tv-a system 
produces gliomas that fulfill this objective by 
achieving cell type-specific gene transfer to 
somatic cells post-natally.  This system was 
developed by Dr. Eric Holland, now head of the 
Brain Tumor Center at Memorial Sloan Kettering 
Cancer Center.  Through glial-specific gene 
transfer in vivo, this system permits determination 
of the role of single and multiple mutations on 
gliomagenesis in mice.  Modeling with this system 
demonstrated that the combined activation of 
RAS/MAPK and PI3K/AKT signaling in GBMs is 
causal and not an epiphenomenon.  Murine gliomas 
modeled with this system reproduce their human 
counterparts both histologically and 
radiographically with high fidelity (Figure 
1).(Lassman and Holland 2006) 
 
2.4 Rationale for combined temsirolimus and perifosine in malignant gliomas 
 
Temsirolimus 
Temsirolimus crosses the blood-brain barrier and achieves therapeutic concentrations in brain tumor 
tissue.(Kuhn, Chang et al. 2007)   It is also reasonably well-tolerated with toxicities usually mild 
including myelosuppression (especially thrombocytopenia), hyperlipidemia, stomatitis, skin rash and 
fatigue.  However, temsirolimus has only modest antitumor activity as a single agent in recurrent high-
grade gliomas.  For example, the 6 month progression-free survival (6mPFS) rate for patients with 
recurrent GBM was approximately 2% in a North American Brain Tumor Consortium phase II trial, 
(Chang et al. 2005) and approximately 8% in a North Central Cancer Treatment Group phase II trial 
(Galanis et al. 2005).  Possible explanations for the limited efficacy include the existence of mTOR 
independent activities of AKT uninhibited by temsirolimus, and the observation in other cell types that 
mTOR inhibition leads to upstream activation of AKT itself through a feedback loop.(Sun et al. 2005; 


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O'Reilly et al. 2006)  
 
Perifosine 
There has been extensive pre-clinical testing of perifosine in glia in vitro and in modeled gliomas in 
vivo in Dr. Eric Holland’s laboratory at Memorial Sloan Kettering Cancer Center (MSKCC).  For 
example, perifosine specifically has been shown to inhibit AKT signaling in transformed glia (Momota 
et al. 2005) as well as reduce proliferation of modeled gliomas in mice.(Momota et al. 2005; also 
reviewed in Lyustikman and Lassman 2006)  
In addition, the effects of perifosine clearly extend beyond inhibition of the AKT signal transduction 
cascade.  These effects, while not totally understood, are in fact advantageous and likely critically 
important to the anti-glioma activity of perifosine.  For example, preclinical studies by Dr. Holland 
also demonstrated that perifosine potently inhibits MAPK/RAS signaling in glia.(Momota et al. 2005)  
Although this may be a cell type specific effect, this dual inhibition of AKT and MAPK/RAS signaling 
in glia is a major theoretical advantage over agents that inhibit only one but not both cascades, 
especially because these cascades are activated in ~70% and ~100% of GBMs,(Lassman and Holland 
2006) respectively and forced activation of both cascades in mice is sufficient to induce 
GBMs.(Holland et al. 2000)  Furthermore, other agents that inhibit AKT signaling can lead to 
MAPK/RAS activation through feedback loops (personal communication, Pier Paolo Pandolfi), and 
this potentially counterproductive effect is not seen with perifosine.  Moreover, perifosine increases the 
penetrability of the blood brain barrier in our modeled gliomas in vivo, an effect not achieved by 
mTOR blockade.  This may contribute to synergy with temsirolimus, allowing enhanced intratumoral 
penetration by temsirolimus over that seen in patients treated with temsirolimus monotherapy. 
 
Based on these preclinical data, as well as the promising results of numerous phase I and II trials in 
patients with sarcomas and other solid tumors, in 2006 we conceived, wrote, and opened an 
investigator (Lassman) initiated phase II trial of perifosine monotherapy at MSKCC for patients with 
recurrent malignant gliomas.  This was the first step in the translation of our extensive preclinical 
glioma data with perifosine into human glioma trials.  Toxicity was minimal among 25 patients 
enrolled to date, with 1 episode each of grade 1 diarrhea, grade 1 nausea, grade 4 joint pain, and grade 
3 difficulty walking as the only significant adverse events possibly, probably, or definitely related to 
perifosine.  The known toxicities of perifosine include nausea, diarrhea, and exacerbation of gout; the 
joint pain was likely a gouty attack in a patient without a prior known gout diagnosis.  Preliminary 
efficacy results, reported at the 2007 Society for Neuro-Oncology annual meeting, included 2 partial 
radiographic responses among 6 evaluable patients with recurrent anaplastic gliomas..  However, none 
of the first 12 patients with GBM reached 6 months of progression-free survival which was the primary 
efficacy endpoint; therefore, in accordance with the statistical design of the trial, accrual of patients 
with GBM was terminated because it was statistically unlikely (90% power) that the 6mPFS rate 
would reach or exceed 20%, the threshold to consider monotherapy with perifosine as promising for 
recurrent GBM. 
 
Although temsirolimus and perifosine have only limited activity as single agents, we explored the 
possibility that combinations of these agents could have synergistic therapeutic efficacy.  While the 
phase II trial of perifosine monotherapy for recurrent gliomas has been ongoing, further pre-clinical 
evaluation of perifosine in combination with temsirolimus has been conducted.  In modeled gliomas, 
perifosine reduces pAKT and reduces proliferation, but there is only minimal killing of tumor cells and 
only regional cell cycle arrest.  In addition, despite the reduction in pAKT, the activity of the mTOR 
effector S6RP (assayed by pS6RP) is not decreased in vivo and may actually rise during perifosine 
treatment for reasons that remain unclear at this time.  By contrast, temsirolimus reduces pS6RP levels 
and arrests proliferation, but also only causes minimal cell death.  However, when the two agents are 
administered together, the combination induces widespread cell death, arrest of surviving cells, and 
inhibition of the entire AKT signal transduction cascade including both pAKT and pS6RP.  Therefore, 
this extensive preclinical data suggests combining perifosine and temsirolimus has both superior anti-


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tumor effects and superior inhibition of the AKT signal transduction cascade than either agent alone.  
For example, three-day treatment of perifosine (30mg/kg) in combination with temsirolimus (40mg/kg) 
leads to massive necrosis and cell cycle arrest almost in all treated mice (n=13).  From the perspective 
of a clinical trial, with the exception of nausea/vomiting and diarrhea, the two agents have non-
overlapping toxicities when used alone, and may therefore allow therapeutic doses of each drug 
together without substantial side effects.   
 
The maximum tolerated dose (MTD) of combined temsirolimus and perifosine is required for a phase 
II study.  Therefore, we will conduct a phase I/II study to both determine the MTD, safety, and efficacy 
of the combined drug therapy.  We will also analyze pre-treatment archival tissue to identify molecular 
predictors of response and also assess tissue resected during therapy (through a surgical substudy as 
part of the phase II component) to determine molecular effects of the combination in human malignant 
gliomas in vivo. 
 
Study Design and Rationale 
Phase I Component 
The phase I component of the study will define the maximum tolerated dose (MTD) of temsirolimus in 
combination with perifosine in patients with recurrent malignant gliomas not on EIAED.  
Temsirolimus is metabolized by cytochrome P450 3A4 which is induced by EIAED.  As a result the 
therapeutic doses of temsirolimus, and to a lesser extent, perifosine, will be higher for patients on 
EIAED than for patients not taking these medications.  Therefore, to reduce the study complexity and 
the number of patients required, eligibility will be restricted to patients not taking EIAED.  If the 
combination of temsirolimus and perifosine shows efficacy, a separate phase I study to determine the 
MTD in patients on EIAED will be considered.  Standard dose escalation in groups of three will be 
performed.  
 
All patients will initially receive both drugs and none will receive placebo.  There is no intra-patient 
dose escalation.  The starting dose of perifosine will consist of a loading dose of 600 mg on day 1 
followed by a fixed maintenance dose of 100 mg per day for days 2-28 of each 28 day cycle. Patients 
will receive an initial dose of temsirolimus of 15 mg intravenously once weekly. Depending on patient 
tolerance, subsequent temsirolimus doses will be escalated to a maximum of 170 mg intravenously 
weekly in subsequent cohorts with one final cohort comprised of an escalated perifosine dose.  The 
maximum tolerated dose of temsirolimus will be based on the assessment of dose limiting toxicity 
DLT during the first 28 days of treatment only (cycle 1). If excessive toxicity is encountered with the 
combination of temsirolimus and perifosine, the doses will be reduced per section 6. 
 
Phase II Component 
The primary goal of the phase II component of the study is to determine the therapeutic efficacy of the 
combination of temsirolimus and perifosine in patients with recurrent malignant gliomas as measured 
by patients who obtain either a radiographic response or achieve 6-months of disease satibilization (6 
month progression free survival).  Patients will receive the dose of both agents determined from the 
phase I study. There is no intra-patient dose escalation.   
 
An important limitation of prior studies of targeted molecular agents in GBMs is the lack of tumor 
tissue to determine whether the therapeutic agents under evaluation inhibited their putative molecular 
targets.  We previously demonstrated such analyses are possible through a surgical substudy in which 
patients who undergo cytoreductive surgery for recurrent disease receive study drug pre-operatively 
and then restart the agents upon recovery from surgery.(Lassman et al. 2005)  Therefore, in this study 
up to 10 patients enrolling into the phase II component will undergo resection of their tumor as part of 
the trial.  These patients will receive temsirolimus and perifosine pre-operatively at the dose 
determined by the phase I.  Tumor specimens resected in this manner will be analyzed for evidence of 
inhibition of PI3K/AKT/mTOR/S6K and RAS/MEK/ERK signaling by immunohistochemistry of 


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paraffin embedded tissue and Western blot of flash frozen tissue.  PTEN, p-AKT, p-mTOR, total S6K, 
p-S6K, p-ERK, Ki-67, and apoptosis will be measured.  These data will be compared to similar 
analysis performed on tumor tissue not exposed to temsirolimus and perifosine obtained from each 
patient’s original or prior surgery (intra-patient comparison).  After recovery from surgery, patients 
will resume treatment with temsirolimus and perifosine. Treatment duration will be measured in 4 
week cycles.   
 
Phase I and II 
Patients will remain on treatment as long as there are no unacceptable toxicities until tumor 
progression.  Responses will be assessed by MRI scans every 8 weeks.  Fluorodeoxyglucose (FDG)-
PET will be performed in phase II patients to evaluate the effects of the drugs on tumor metabolism. 
Paraffin tumor sections from the original surgical resection will be obtained from all patients. An 
attempt will be made to correlate the genotype patient’s tumor specimens with response to treatment. 
In this way, molecular subsets of malignant gliomas that may be more or less likely to respond to 
treatment with temsirolimus and perifosine can be identified. 
 
2.5 Correlative Studies Background 
 
GBMs are molecularly heterogeneous.  For example, the oncogenic mutations driving tumor growth 
differ between “primary” (or “de novo”) GBMs which appear abruptly and “secondary” GBMs which 
arise from lower grade gliomas.(Kleihues and Ohgaki 1999)  Similarly, tumors with MGMT promoter 
methylation appear to exhibit greater sensitivity to temozolomide and are associated with longer 
overall survival regardless of therapy in comparison to tumors with unmethylated promoters.(Hegi et 
al., 2005)  Finally, recent results also suggest a tripartite distribution of high grade gliomas (with 
prognostic significance) designated proneural, proliferative, and mesenchymal. (Phillips et al., 2006) 
 
This molecular heterogeneity is of potential importance in clinical trials.  An experimental  
chemotherapy regimen may be declared ineffective during a trial involving GBMs of all molecular 
profiles despite responses in a small subset.  For example, the EGFR inhibitors erlotinib and gefinitib 
as monotherapy are ineffective in recurrent GBMs when all tumors are analyzed as one cohort, 
associated with 6mPFS rates and response rates that are no better than historic controls (Lieberman et 
al., 2003; Raizer et al., 2004; Rich et al., 2004; Vogelbaum et al., 2004; Yung et al., 2004)  However, 
analysis of archival tissue in one study demonstrated that a specific molecular profile, present in only 
10-15% of patients, strongly correlated with activity in the small subset of patients exhibiting 
radiographic responses.(Mellinghoff et al., 2005)  Although others have questioned this conclusion, 
(Brandes et al., 2008), the concept that treatment may be active in tumors with a specific molecular 
profile is important.  Molecular profiling may allow identification of a subset of tumors sensitive to a 
particular therapy that would otherwise be declared inactive.  Such identification may then allow 
individualization of therapy.  In this trial, we also propose to molecularly profile archival tissue with 
the goal of determining the subset of patients more likely to respond. 
 
Initial results from The Cancer Genome Atlas (TCGA) study of GBM (in which 200 tumors were 
analyzed for chromosomal copy number, gene expression, and large scale gene re-sequencing) 
confirmed the previously documented high incidence of PDGFRA amplification/mutation and EGFR 
amplification/mutation.(The Cancer Genome Atlas (TCGA) Research Network, submitted).  This 
analysis also identified an unexpectedly high incidence of NF1 mutation and gene deletion, found in 
>20% of primary GBMs.  NF1 silencing, PDGFRA amplification/mutation, and EGFR 
amplification/mutation are mutually exclusive genetic lesions.  Furthermore, unsupervised clustering 
of transcriptome data reveals 3 groups of GBM defined by their gene expression:  these groups are 
strongly enriched for EGFR, PDGFRA, and NF1 aberrations, respectively.  If NF1, PDGFRA, and 
EGFR mutation are associated with distinct molecular subtypes of GBM, it is possible these subtypes 
may respond differently to various therapies. 


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Of note, the “PDGF” transcriptomal group in the TCGA data set is characterized by expression of 
markers previously associated with the “Proneural” class of GBMs, such as Delta Like 3 (DLL3), 
SOX4, NCAM1, and Doublecortin (Phillips et al., 2006).  These genes are expressed in tumors with 
PDGFRA amplification, but also in tumors without PDGFR mutations which co-cluster. (TCGA data).  
In addition, unpublished data from Memorial Sloan Kettering Cancer Center also demonstrates that 
PDGF ligand is overexpressed at the protein level in tumors that harbor no PDGFR amplification, 
accounting for approximately 20% of GBMs. (Cameron Brennan and Eric Holland, personal 
communication).  
 
The PDGF group is of particular interest to this trial because the mouse model (Figure 1, reviewed in 
Lassman and Holland 2006) used to generate the GBMs for the pre-clinical data demonstrating 
synergistic activity of temsirolimus + perifosine are driven by forced PDGF overexpression in glia.  
Therefore, it may be important to identify human tumors exhibiting a PDGF-like profile, and such 
tumors may demonstrate enhanced sensitivity to temsirolimus + perifosine.  Therefore, we plan to 
molecular profile archival tissue from all patients enrolled onto this trial as an exploratory endpoint. 
 
To accomplish this, we will perform Fluorescent In-Situ Hybridization (FISH) for determination of 
EGFR amplification and PDGFRA amplification and NF1 loss, immunohistochemistry for PDGF 
ligand overexpression at the protein level (which occurs in the absence of PDGF gene amplification), 
and immunohistochemistry for NF1 under-expression.  We will also perform array based comparative 
genomic hybridization for other markers of the PDGF-like subclass including DLL3, SOX4, NCAM1, 
and Double Cortin.  Classification of tumors will be made based on results of these analyses.  The 
EGFR and NF-1 groups will be defined by amplification and loss/under-expression of EGFR and 
NF1/NF1, respectively.  The PDGF group is more complex.  Tumors will be classified as PDGF-like 
based on either:  1) PDGFRA amplification; or 2) PDGF ligand overexpression without EGFR 
amplification (Cameron Brennan and Eric Holland, personal communication).  In addition, in patients 
with available frozen tissue, tumors with neither PDGFRA amplification nor PDGF ligand 
overexpression will be tested for “Proneural” class expression markers (Phillips et al., 2006) that 
transcriptomally co-cluster with PDGFRA amplification (e.g., DLL3, SOX4, NCAM1, and 
Doublecortin).  
 
Finally, perifosine and temsirolimus both act on the PI3K/AKT/mTOR/S6K cascade, although they 
may also affect RAS/MEK/ERK signaling.  In addition, temsirolimus causes proliferation arrest.  In 
modeled mouse gliomas, combination therapy also leads to apoptotic death.  Therefore, we will assess 
archival tissue for expression and activation status of these signaling molecules using commercially 
available antibodies by immunohistochemistry for PTEN, AKT, pAKT, mTOR, p-mTOR, S6K, pS6K, 
ERK, pERK, Ki67 and assess apoptosis by TUNEL.  If flash frozen tissue is available for analysis, we 
will also perform Western Blot for PTEN, AKT, pAKT, S6K, pS6K, ERK, pERK, and proliferating 
cell nuclear antigen (PCNA).  We will also extract DNA to sequence PTEN, PI3K, and other genes 
involved in AKT signal transduction to identify mutations that may confer drug sensitivity. 
 
In addition, a subset of patients on the phase II study will receive dual drug therapy followed by 
surgical resection of tumor.  This provides an opportunity to assess the molecular effects of therapy in 
humans in vivo.  We will perform the above analysis for PI3K/AKT/mTOR/S6K and RAS/MEK/ERK 
signaling, proliferation, and apoptosis, using intrapatient comparison from pre-treatment archival tissue 
from an earlier resection as we have done in other studies.(Lassman et al., 2005) 
 
 
 
 
 


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3 PATIENT SELECTION 
 
3.1 General Eligibility Criteria  
 
3.1.1 
Patients must have unstained slides or tissue blocks available from at least one prior 
surgery.  Frozen tissue is also requested if available. 
 
3.1.2 
Patients must have received prior radiotherapy and temozolomide.  There is otherwise no 
limit on the number of prior recurrences/therapies. 
 
3.1.3 
At least 6 weeks (42 days) must have elapsed since completion of radiation therapy to 
initiation of study treatment. 
 
3.1.4 
At least 4 weeks (28 days) must have elapsed since most recent temozolomide and initiation 
of study treatment. 
3.1.5 
Patients must have recovered from the toxic effects of other prior direct inhibitors of 
VEGF/VEGFR:   4 weeks from prior therapy with agents such as bevacizumab (Avastin), 
aflibercept (VEGF-Trap), cedirinib (AZD2171), or XL-184 (BMS 907351);  any questions 
regarding the definition of a direct anti-VEGF/VEGFR therapy must be discussed with the 
PI or co-PI.  Patients must have recovered from the toxic effects of other prior therapy 
including:  4 weeks (28 days) from any investigational agent, two weeks (14 days) from 
vincristine, 6 weeks (42 days) from nitrosoureas, 3 weeks (21 days) from procarbazine 
administration, and 1 week (7 days) for non-cytotoxic agents, e.g., interferon, tamoxifen, 
thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count), and 4 weeks (28 days) 
from any other prior cytotoxic therapy .  Any questions related to the definition of non-
cytotoxic agents should be directed to the co-PI. 
 
3.1.6 
Patients must have shown unequivocal evidence for tumor progression by MRI/CT on the 
baseline MRI/CT in comparison to a prior scan OR have recently undergone resection for 
recurrent/progressive disease per 3.1.17.  The baseline brain MRI/CT must be performed 14 
days or fewer prior to treatment.  The same type of scan, i.e., MRI (or CT for patients who 
cannot undergo MRI) must be used throughout the period of protocol treatment for tumor 
measurement.  Criteria in section 11 for progression on this study are not mandatory if the 
disease progression is obvious in the opinion of the investigator.  Any questions should be 
addressed to the PI. 
 
3.1.7 
Patients must be on a stable or decreasing dose of corticosteroids for a minimum of 5 days 
before the baseline MRI/CT (and PET scans for patients on the phase II study) except 
patients undergoing surgery on the surgical substudy of phase II (section 5.1.1.7).  If the 
corticosteroid dose is increased between the date of imaging and registration a new baseline 
MR/CT is required. 
 
3.1.8 
Age >18 years.  Because no dosing or adverse event data are currently available on the use 
of temsirolimus in combination with perifosine in patients <18 years of age, children are 
excluded from this study, but will be eligible for future pediatric phase 1 combination trials. 
 
3.1.9 
Karnofsky Performance Status >60% 
 
3.1.10 
Life expectancy of greater than 8 weeks. 
 
3.1.11 
Patients must have normal organ and marrow function (WBC > 2,000/µl, ANC > 
1,500/mm3, platelet count of > 100,000/mm3, and hemoglobin > 10 gm/dl), adequate liver 


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function (SGOT, SGPT and bilirubin < 2 times ULN), adequate renal function (creatinine < 
1.5 mg/dL), calcium levels at or above the lower limit of normal, and phosphorus levels at 
or above the lower limit of normal before starting therapy.  These tests must be performed 
within 14 days prior to registration.  Eligibility level for hemoglobin may be reached by 
transfusion. 
 
3.1.11.1  Platelet count of at least 100,000/mm3 on at least 2 consecutive blood draws, at  
                                                least 1 week apart, with results stable/trending upward.  Any question  
                                                regarding the definition of stable/trending upward must be discussed with  
                                                the PI. 
 
3.1.12 
Patients must have cholesterol level < 350 mg/dl and triglycerides level < 400 mg/dl 
because temsirolimus can induce hyperlipidemia. 
 
3.1.13 
Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation because the effects of temsirolimus and perifosine on the 
developing human fetus are unknown.  Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately. 
3.1.14 
Women of childbearing potential must have a negative B-HCG pregnancy test documented 
within 7 days prior to treatment. 
 
3.1.15 
Women must agree not to breast feed. 
 
3.1.16 
Patients must have the ability to understand and the willingness to sign a written informed 
consent document. 
 
3.1.17 
As a primary efficacy endpoint is 6mPFS rate, measurable disease is not required for 
eligibility in patients who recently underwent resection as long as progressive disease led to 
the surgery, and the histology of the most recent surgery documented 
recurrent/progressive/persistent malignant glioma. 
 
3.1.17.1 
If cytoreductive surgery is planned for tumor recurrence at the time of 
enrollment, such patients may be eligible for the surgical substudy (Phase II 
only), taking temsirolimus + perifosine pre-operatively and then re-initiating 
such therapy after recovering from the effects of surgery (section 5). 
 
Phase I specific inclusion criteria: 
3.1.18 
Patients must have a EITHER 
 
Histologically confirmed intracranial malignant glioma of the following types:  
Glioblastoma, Anaplastic astrocytoma (AA), Anaplastic oligodendroglioma (AO), 
Anaplastic oligo-astrocytoma (AOA) also called anaplastic mixed gliomas, Malignant 
glioma NOS (not otherwise specified).  Patients will be eligible if the original histology was 
low-grade glioma and a subsequent histological diagnosis of a high grade (malignant) 
glioma is made. 
 
OR 
 
Histologically confirmed low grade (WHO grade II) gliomas (such as low grade 
astrocytoma, low grade oligodendroglioma, low grade oligo-astrocytoma (mixed gliomas), 


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or low grade glioma NOS) IF there is radiographic evidence by MRI or CT of malignant 
transformation but histologic confirmation of high grade (malignant) transformation would 
not be otherwise undertaken for routine clinical care.  Inclusion of patients in this group 
will allow increased accrual rapidity by enrolling patients who are otherwise ineligible for 
almost all malignant glioma trials yet whom are treated presumptively for malignant 
glioma.  The primary aim of the phase I study is not determination of efficacy.  Therefore, 
inclusion of such patients will not affect efficacy analyses. 
 
Phase II specific inclusion criteria: 
3.1.19 
Patients must have a histologically confirmed intracranial malignant glioma of the 
following types:  Glioblastoma, Anaplastic astrocytoma (AA), Anaplastic 
oligodendroglioma (AO), Anaplastic oligo-astrocytoma (AOA) also called anaplastic mixed 
gliomas, Malignant glioma NOS (not otherwise specified).  Patients will be eligible if the 
original histology was low-grade glioma and a subsequent histological diagnosis of a high 
grade (malignant) glioma is made. 
 
Phase II patients enrolling on the surgical substudy to evaluate tissue correlates. 
3.1.20 
Patients eligible for the surgical subset have been identified as candidates for cytoreductive 
surgery by the treating physician and/or based on discussion in a multidisciplinary tumor 
board, with the input of other surgeons as well as that of the neuro-oncologists involved in 
the trial.  For the patients in the preoperative component, a scan showing progression is 
required but stable corticosteroids are not required.  Following surgery, a scan should be 
done less than 96 hours after surgery.  If this is not performed, then a new baseline scan 
should be performed at least 4 weeks after surgery to avoid mis-interpretation of post-
operative changes as enhancing disease.  This scan will serve as the new baseline before 
restarting treatment post-operative, and it must be performed on a stable or decreasing dose 
of corticosteroids.  (As above, regarding the baseline MRI or CT scan prior to registration, 
patients in the Phase II component who are NOT participating in the pre-operative 
component of the study should be on a steroid dose that has been stable for at least 5 days 
prior to the scan.  If the corticosteroid dose is increased between the date of imaging and 
registration a new baseline MR/CT is required.) 
 
3.1.21 
Post-operatively, treatment with temsirolimus and perifosine must re-start no later than the 
14th day after the scan. If the 96-hour scan is more than 14 days old before treatment is 
initiated, the scan needs to be repeated on a stable or decreasing steroid dose.  Treatment 
must start no later than 56 days after surgery. 
 
 
 
Phase II patients previously treated with becacizumab or other direct inhibitors of 
VEGF/VEGFR including Aflibercept (VEGF-Trap) and cedirinib and XL-184 (BMS 907351). 
 
3.1.22 
There is no limit on such therapy for patients accrued to phase I.  For phase II, historical 
controls for this group of patients is poorly defined.  Therefore, we will accrue up to 15 
patients who received prior treatment with direct VEGF/VEGFR inhibitors in order to gain 
preliminary data for use as a comparison group in a follow up study.  See section 13.2.  All 
other inclusion/exclusion criteria also apply to this cohort.  Any question about the 
definition of a direct VEGF/VEGFR inhibitor should be addressed to the PI or co-PI prior 
to registration. 
 
3.2 Exclusion Criteria 
3.2.1 Patients may not be receiving any other investigational agents. 
 
3.2.2 Patients must not have a history of allergic reactions attributed to compounds of similar chemical 


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or biologic composition to temsirolimus or perifosine. 
 
3.2.3 Patients must not be taking EIAED.  If previously on an EIAED, the patient must be off of it for 
at least two weeks prior to treatment on study. 
 
3.2.4 Patients must not have uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.5 Pregnant women are excluded from this study because temsirolimus and perifosine are agents 
with the potential for teratogenic or abortifacient effects.  Because there is an unknown but potential 
risk for adverse events in nursing infants secondary to treatment of the mother with temsirolimus or 
perifosine, breastfeeding should be discontinued if the mother is treated with temsirolimus and 
perifosine. 
 
3.2.6 HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential 
for pharmacokinetic interactions with temsirolimus and perifosine.  In addition, these patients are at 
increased risk of lethal infections when treated with marrow-suppressive therapy.  Appropriate studies 
will be undertaken in patients receiving combination antiretroviral therapy when indicated. 
 
Phase II specific exclusion criteria 
3.2.7 Patients may not have received prior treatment with mTOR inhibitors such as temsirolimus, 
rapamycin (sirolimus), or RAD001 (everolimus).  Any question regarding the definition of mTOR 
inhibiting therapy must be discussed with the PI.  Such prior therapy is allowed for the phase I 
component. 
 
3.2.8 Patients may not have previously received perifosine or other AKT targeting agents.  Any 
question regarding the definition of AKT targeting therapy must be discussed with the PI.  Such prior 
therapy is allowed for the phase I component. 
 
 3.2.9 Patients must not have received prior treatment with convection enhanced delivery, other 
catheter based intra-tumoral treatment, or carmustine (BCNU)/Gliadel wafers because of potential 
difficulty interpreting brain scans in such patients.  Such prior therapy is allowed for the phase I 
component . 
 
 3.2.10 Patients with prior therapy that included stereotactic radiosurgery (including gamma-knife or 
cyber-knife) during therapy for newly diagnosed or recurrent disease, or re-irradiation of any type, 
must have confirmation of true progressive disease rather than radiation necrosis based upon surgical 
documentation of recurrent/progressive disease.  Imaging with MRSpectroscopy, PET, or other 
techniques is not adequate to exclude radiation necrosis for this study. (Clarke et al., 2008)  Such prior 
therapy is allowed for the phase I component and does not require surgical documentation of disease. 
 
3.2.11 Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-
situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum 
of 3 years are ineligible for the phase II study but are eligible for the phase I component. 
 
 
3.3 Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  Males and females will be recruited with no preference to gender.  
No exclusion to this study will be based on race.  


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4 REGISTRATION PROCEDURES  
 
4.1 Research Participant Registration 
Confirm eligibility as defined in the section entitled Patient Selection. 
 
Obtain informed consent by following procedures defined in section entitled Informed Consent Procedures. 
 
During the registration process, registering individuals will be required to complete a protocol specific 
Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office at Memorial 
Sloan Kettering Cancer Center. PPR is available Monday through Friday from 8:30am – 5:30pm (ET) at 
646-735-8000. Registrations must be submitted via the PPR Electronic Registration System (http://ppr/). 
 The completed signature page of the written consent/RA or verbal script/RA, a completed Eligibility 
Checklist and other relevant documents must be uploaded via the PPR Electronic Registration System. 
 
 
 
4.2 Informed Consent Procedures 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full details of 
the protocol and study procedures as well as the risks involved to participants prior to their inclusion in the 
study. Participants will also be informed that they are free to withdraw from the study at any time. All 
participants must sign an IRB/PB-approved consent form indicating their consent to participate. This 
consent form meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following:  
 
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to withdraw 
from participation at any time.  
Before any protocol-specific procedures can be carried out, the consenting professional will fully explain 
the aspects of patient privacy concerning research specific information.   
 
In addition to signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must receive a 
copy of the signed informed consent form. 
 
 
5 TREATMENT PLAN  
 
 
5.1 Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential risks for 
temsirolimus and perifosine are described in Section 7.  Appropriate dose modifications for 


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temsirolimus and perifosine are described in Section 6.   
5.1.1 
CTEP IND Agents:  temsirolimus and perifosine 
5.1.1.1 Pre-medication for temsirolimus 
Idiosyncratic hypersensitivity reactions have been seen, so patients receiving IV Temsirolimus 
should be premedicated with diphenhydramine 25 – 50 mg IV (or a similar antihistamine) 
approximately 30 minutes before the start of the Temsirolimus infusion.  If the subject begins 
to develop a hypersensitivity reaction despite pretreatment with diphenhydramine, the 
infusion should be stopped for at least 30 – 60 minutes, depending upon the severity of the 
reaction.  The infusion may be resumed by administering a histamine H2-receptor antagonist 
approximately 30 minutes before restarting the Temsirolimus infusion.  Famotidine 20 mg IV 
or ranitidine 50 mg IV are recommended rather than cimetidine because of the lack of likely 
metabolic/pharmacologic interactions with the former drugs.  The rate of the Temsirolimus 
infusion may also be slowed from 30 minutes to over an hour.  All subjects should be 
monitored while receiving the Temsirolimus infusion and emergency medical equipment and 
health care personnel must be readily available to respond to hypersensitivity reactions or 
other medical emergencies. 
Anti-emetic prophylaxis.  For the 1st dose of temsirolimus, the prophylaxis for the loading dose of perifosine (below) 
will also be used as prophylaxis for temsirolimus.  Starting with the 2nd dose of temsirolimus, nausea/vomiting 
induced by study agents should be treated initially with a serotonin type-3 (5-HT(3)) antagonist.  If this is 
inadequate, phenothiazine (prochlorperazine 10 mg q8h PO prn or promethazine 12.5-25 mg IV q6h prn should be 
added until acute nausea is controlled.  Should this prove inadequate acutely, a corticosteroid may be added (e.g., 
dexamethasone 4 mg q6h prn) but note that corticosteroid use can confound response interpretation.  Alternative or 
additional antiemetics may be prescribed at the discretion of the investigator as needed.  
5.1.1.2 Pre-medication for perifosine 
Anti-emetic prophylaxis for loading dose -- The loading dose will be administered in the adult day hospital (or 
equivalent outpatient chemotherapy unit) in divided doses with anti-emetic prophylaxis, IV if needed.  A divided 
dose that occurs in the evening can be taken by the patient at home at the discretion of the investigator. 
Administer together 0.5-1 hour before intake of the first loading dose: 
• granisetron (1 mg PO, or 10 :g/kg IV) or equivalent 5HT3 antagonist
• metoclopramide (20 mg PO or 1-2 mg/kg IV)
• diphenhydramine (25 mg, IV or PO)
• dexamethasone (8 mg, IV or PO) – Note any brain MRI scan within 5 days of the loading dose is therefore
not evaluable for best radiographic response because of the potential confounding effects of
dexamethasone on contrast enhancement. 
Three hours after intake of the first divided dose, and one hour before the next divided dose is given: 
• metoclopramide (20-40 mg, IV or PO)
• diphenhydramine (25 mg, IV or PO)
This may be repeated every 3-4 hours if needed during the loading dose period.  Alternative or additional 
antiemetics may be prescribed at the discretion of the investigator as needed.   
Diphenhydramine may be held for sedation. 
Anti-emetic prophylaxis for maintenance dose -- The daily perifosine maintenance dose will be continued at home 
without routine anti-emetic prophylaxis, but anti-emetics can be used on an as needed basis.  Maintenance doses of 
the study medication will be administered together with food at bedtime to minimize nausea not controlled by anti-


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emetics.  Nausea/vomiting requiring anti-emetic treatment during the maintenance doses may be treated with the 
following regimen: granisetron 1 mg PO or 10 :g/kg IV or equivalent 5HT3 antagonist, followed, if ineffective, by 
metoclopramide (20 mg PO or 1-2 mg/kg IV plus diphenhydramine (25 mg IV or PO).  After acute nausea has 
resolved, consideration should be given to initiation of prophylactic antiemetic therapy for subsequent doses.  If 
nausea recurs despite reasonable medical intervention (as outlined above), dose reduction will be needed as 
described in Section 6.  Alternative or additional antiemetics may be prescribed at the discretion of the investigator 
as needed.  
Hyperuricemia/gout -  Prior to beginning perifosine, all patients should be questioned about a history of 
hyperuricemia and/or gout.  Patients with a known history of hyperuricemia and/or gout should receive 
prophylactic treatment with allopurinol 300 mg orally daily.  If severe gout does occur or uric acid levels 
increase, the dose of allopurinol should be increased and/or other medications used at physician discretion. 
 
5.1.1.3 Route of administration for temsirolimus 
 
Temsirolimus is administered intravenously.  Temsirolimus is incompatible with polyvinyl chloride (PVC) 
equipment or devices that are plasticized with di- (2-ethylhexyl) pthalate (DEHP).  Administer 
Temsirolimus over approximately 30 minutes as an IV infusion via an automatic dispensing pump (e.g. 
IMED, Harvard, Travenol) using non-polyvinyl chloride (PVC) tubing with the appropriate filter.  List of 
filters for tubing with preattached filters that are permissible are found the in the pharmaceutical 
information section.  It is recommended but not mandatory that CCI-779 (temsirolimus) be administered 
through either a “long line” venous access devise such as a PICC line, a mediport, or a central venous 
catheter.  
 
5.1.1.4 Route of administration for perifosine 
 
Perifosine will be taken orally.  All doses are administered with food.  Pills should remain intact and 
should not be crushed except to administer via g-tube. 
 
5.1.1.5 Phase I treatment schedule 
 
Temsirolimus:  The starting dose for temsirolimus in the phase I component of the study is 15 mg IV 
weekly (table 1). 
 
 
 
 
 Perifosine:  The starting dose for perifosine in the phase I component of the study is a loading dose of 600 
mg orally on day 1 and then a maintenance dose of 100 mg orally daily thereafter on days 2-28.   The 
loading dose is only administered during cycle 1 unless treatment is interrupted for >7 days for which 
patients will receive a repeat loading dose upon restarting perifosine (table 1). 
 
The loading dose should be divided into doses of 150 mg each administered every 4 hours until the 
complete load has been administered.   The loading dose is given only on cycle 1 day 1.  The first 3 divided 
doses of the load should be administered under supervision in the adult day hospital (or equivalent 
outpatient chemotherapy unti) where patients will have access to intravenous antiemetics if needed.  
Patients may receive the 4th-6th doses of the load at home if they have tolerated the first 3 divided doses at 
the discretion of the investigator.  On cycle 1 days 2-28, patients take a maintenance dose every night with 
food and not on an empty stomach. 
 
Cycles >2 consist of daily maintenance doses taken every night on days 1-28 without a loading dose.  
However, if treatment is interrupted for >7 days for any reason, patients will undergo a repeat loading dose 
of perifosine upon re-starting therapy. 
 
 
 
 
 
See section 5.2 for discussion of dose escalations and maximum tolerated dose. 
 


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Table 1:  The following temsirolimus and perifosine dose levels will be used to determine dosing for 
specific cohorts in the Phase I component.  
Dose level 
Temsirolimus (mg/week) 
Perifosine load/maintenance (mg/day) 
-6 
5 
150/50 
-5 
10 
150/50 
-4 
15 
150/50 
-3 
15 
150/100 
-2 
15 
300/100 
-1 
15 
450/100 
1 (starting) 
15 
600/100 
2 
25 
600/100 
3 
50 
600/100 
4 
75 
600/100 
5 
115 
600/100 
6 
170 
600/100 
7 
170 
900/100 
 
Treatment with both agents will occur simultaneously in the following manner:  after anti-
emetic prophylaxis, patients will receive the first divided dose of the perifosine loading dose.  
Patients will be observed for 30 minutes to ensure there has been adequate anti-emetic 
prophylaxis, and then patients will receive temsirolimus at their assigned dose administered 
over 30 minutes IV.  The remaining divided doses of the perifosine loading dose will then be 
administered.  Patients will then return weekly for infusion of temsirolimus over 30 minutes 
IV.  Dosing will be continuous although for the purposes of evaluation, a cycle will be defined 
as 4 weeks (28 days).  It is expected that temsirolimus administration will occur on the same 
day of the week throughout the treatment period.  However, it may be given up to 3 days early 
or late due to holiday or other scheduling reasons.   
 
Prior to beginning cycle 3, patients undergo clinical and radiographic tumor restaging.  As 
long as the tumor is stable or smaller in size and the patient is clinically stable or improved, 
they will go on 2 more 4 week cycles of therapy with temsirolimus and perifosine.  Treatment 
will continue indefinitely as long as there are no unacceptable toxicities (DLTs) and no 
clinical or radiographic progression. 
 
5.1.1.6 Phase II treatment schedule for patients NOT participating in the surgical substudy 
 
Temsirolimus:  The starting dose for temsirolimus will be determined from the phase I 
component.  There is no intra-patient dose escalation. 
 
 
 
 
 Perifosine:   The starting dose (load and maintenance) for perifosine will be determined from 
the phase I component.  The loading dose is only administered during cycle 1 unless treatment 
is interrupted for >7 days for which patients will receive a repeat loading dose upon restarting 
perifosine (table).  There is no intra-patient dose escalation. 
 
Treatment with both agents will occur simultaneously in the following manner:  after anti-
emetic prophylaxis, patients will receive the first divided dose of the perifosine loading dose.  
Patients will be observed for 30 minutes to ensure there has been adequate anti-emetic 
prophylaxis, and then patients will receive temsirolimus administered over 30 minutes IV.  
The remaining divided doses of the perifosine loading dose will then be administered.  
Patients will then return weekly for infusion of temsirolimus over 30 minutes IV.  Dosing will 


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be continuous although for the purposes of evaluation, a cycle will be defined as 4 weeks (28 
days).  It is expected that temsirolimus administration will occur on the same day of the week 
throughout the treatment period.  However, it may be given up to 3 days early or late due to 
holiday or other scheduling reasons.   
 
Prior to beginning cycle 3, patients undergo clinical and radiographic tumor restaging.  As 
long as the tumor is stable or smaller in size and the patient is clinically stable or improved, 
they will go on 2 more 4 week cycles of therapy with temsirolimus and perifosine.  Treatment 
will continue indefinitely as long as there are no unacceptable toxicities (DLTs) and no 
clinical or radiographic progression. 
 
5.1.1.7 Phase II treatment schedule for patients who ARE participating in the surgical substudy 
 
Patients who choose to participate in this component of the study must have a contrast 
enhanced brain MRI performed within 14 days of taking pre-operative temsirolimus and 
perifosine.  Patients unable to undergo MRI will have CT scans.  A brain PET scan must also 
be performed within the 14 days before taking pre-operative temsirolimus and perifosine, and 
again (research PET) after completing the full loading dose of perifosine and 1 dose of 
temsirolimus but before surgery to correlate metabolic effects with tissue analysis.  A repeat 
PET is again requested but is not mandatory for patients with residual measurable disease 
post-operatively before restarting study drugs (research PET). 
 
 
 
Before surgery 
The loading dose of perifosine and the dose of temsirolimus will be administered on the same 
day.  This may be up to 1-4 days pre-operatively 
 
Temsirolimus:  Patients will receive one treatment of temsirolimus intravenously prior to surgery analogous to phase 
II patients NOT on the surgical substudy (section 5.1.1.6).  The dose will be determined by the phase I component of 
the study.  This dose of temsirolimus may be administered up to the 4th pre-operative day.  This dosing allows for 
some flexibility in scheduling surgery. 
 
Perifosine:   Patients will receive a loading dose of perifosine prior to surgery analogous to phase II patients NOT on 
the surgical substudy (section 5.1.1.6),  Patients will receive a loading dose of perifosine the same day they receive 
pre-operative temsirolimus.  They will receive a maintenance dose nightly starting the next day until the night before 
surgery.  If the loading dose is administered on the pre-operative day, then they will not receive a maintenance dose 
pre-operatively.  The dose will be determined by the phase I component of the study. 
 
Both agents should be administered as in section 5.1.1.6.  Both agents should be started up to 4 days before 
surgery.   If clinical or other scheduling reasons alter the plan or timing for surgery, the PI must be notified 
and best physician practice applied to care for the patient. 
 
Day of surgery 
Tissue freezer vials should be labeled with the patient’s protocol study Identifier number(s). Additionally, a thermos 
with liquid nitrogen (preferably), or if not possible, an ice bucket with dry ice should be prepared. All attempts will 
be made to obtain specimens immediately adjacent to the areas of resection taken for “permanent sections” in order 
to optimize the likelihood that the tumor seen on permanent sections is representative of that taken for analysis.  
Once the pathologist has made a diagnosis of "tumor" on frozen section at the time of surgical resection, the tumor 
tissue should be divided into 50 – 100mg pieces. 
 
 
 
At the time of surgical resection, the following specimens will be obtained: 
• 
Fresh tumor tissue frozen in liquid nitrogen for evaluation of activation status of PI3K/AKT/mTOR/S6K, 
RAS/MEK/ERK, proliferation, and gene profiling. 


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• 
Paraffin block or slides for evaluation of activation status of PI3K/AKT/mTOR/S6K, RAS/MEK/ERK, 
proliferation, apoptosis, and gene profiling. 
 
It is important that the exact times of collection of these specimens be recorded. 
 
Pre and post-operative evaluations will consist of standard clinical practice. Patients should have weekly CBC and 
differential in the postoperative period.  Once patients have recovered from the effects of surgery, they will start the 
phase II component of the study.  Patients are not required to have residual disease to continue onto the phase II 
component. 
 
Following surgery 
A post-operative MRI/CT scan should be done no later than 96 hours from surgery on a steroid dose that is stable or 
decreasing. Treatment with temsirolimus and perifosine post-operatively should start no later than 14 days after the 
scan. If the 96-hour scan is more than 14 days before treatment is initiated, the scan needs to be repeated on a stable 
or decreasing steroid dose.  The post-operative scan should be assessed for the presence of residual measurable 
disease.  A repeat PET is again requested but is not mandatory for patients with residual measurable disease post-
operatively before restarting study drugs. 
 
Treatment may be instituted starting 7 days postoperatively if patients have recovered from effects of surgery and 
demonstrated wound healing. Treatment with temsirolimus and perifosine post-operatively should start no later than 
56 days after surgery.  
 
Day 1 of treatment following surgery will represent the first day of treatment for determination of the primary 
endpoint of 6 month progression free survival.  The dose of temsirolimus and perifosine will be determined by the 
phase I component of the study.  Patients will undergo a loading dose of perifosine when re-initiating treatment post-
operatively.  Patients will receive treatment in 4 week cycles in the same manner as patients not on the surgical 
substudy.  Drug treatment will be started analogously to patients in the phase II component NOT on the surgical 
substudy. 
 
In the unlikely event that the analysis of the tissue specimen demonstrates necrosis or lack of active disease, the PI 
should be notified and the patient disenrolled from the trial as they are not eligible without recurrent/progressive 
disease.  Such patients may be replaced. 
 
5.1.2 
Other Agents:  N/A 
 
5.1.3 
Other Procedures 
 
5.1.3.1 Pre-treatment evaluations 
A complete history, physical, and neurological examination (to include documentation of the patients 
Karnofsky Performance Status per Appendix A, as well as neuro-imaging confirming tumor 
progression shall be performed on all patients.  The baseline scan should be performed within 14 days 
of treatment initiation.  Brain PET (to evaluate tumor metabolism) should be performed as well for 
patients on phase II. 
 
Prestudy laboratory tests shall include CBC, differential, platelets, PT, PTT, INR, carbon dioxide, 
BUN, creatinine, glucose, potassium, sodium, calcium, phosphorus, chloride, total protein, albumin, 
alkaline phosphatase, total bilirubin, SGOT (AST), SGPT (ALT), uric acid, cholesterol, triglycerides.  
Antiepileptic drug levels may be drawn if they are used clinically to monitor patient’s AED dose.  
These pr-study laboratory tests must be obtained within 14 days of treatment initiation. Women of 
childbearing potential must obtain a serum pregnancy test within 7 days prior to registration. 
 
Unstained paraffin tissue from surgical samples: Every reasonable effort will be made to obtain a 


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representative paraffin tissue block (at least 5 mm x 5 mm) or at least 15 unstained paraffin slides 
(preferably 30) in all patients from original surgery and/or definitive surgery and/or the surgery closest 
to initiation of this clinical trial in patients on phase I.  Prior tissue is mandatory for patients on phase 
II.  Paraffin slides will be used for DNA isolation and immunohistochemistry to evaluate molecular 
pathways described in section 2.5 and section 9.  Array comparative genomic hybridization (array 
CGH) will also be performed on these specimens. We will attempt to correlate tumor genotype with 
response to treatment. 
 
5.1.3.2 Evaluation during study:  Phase I requirements 
 
Following the 1st treatment, CBC, differential, and platelets, and serum chemistries (BUN, creatinine, 
glucose, calcium, alkaline phosphatase, phosphorus, total bilirubin, SGOT (AST), SGPT (ALT), 
fasting cholesterol and triglycerides will be performed every week for the first 4 weeks and then every 
2 weeks thereafter. All labs are permitted to be obtained up to 3 days prior to the weekly Temsirolimus 
IV infusion. AED levels (if clinically appropriate) will be measured every 2 weeks for the first 4 weeks 
and then every 4 weeks. β-HCG will be measured prior to each 4-week cycle. For patients on warfarin, 
a PT/INR will be checked every 1-2 weeks, or sooner if clinically indicated.  Uric acid will be re-
checked as clinically indicated. 
 
A head CT (wthout contrast) or MRI with gradient echo must also be performed during week 2 of 
treatment to evaluate for subclinical hemorrhage observed in mice treated with the combination of 
temsirolimus and perifosine.   
 
A brain MRI/CT will be done prior to every other cycle (up to 2 weeks prior).  An MRI/CT scan done 
at 6 months from initiation of therapy will be performed while the patient is still in the study to ensure 
assessment of the primary endpoint.   
 
A complete physical and neurologic exam (to include documentation of the patients Karnofsky 
Performance Status) will be performed up to 3 days  prior to every cycle.  
 
Phase I patients will be evaluated for adverse events at least weekly during their first cycle of therapy. 
These adverse events will be reported to the PI.  
 
Adverse events for subsequent cycles will be reported prior to the beginning of each cycle. In addition 
all serious adverse events will be reported to the NCI and the PI. 
 
All relevant information regarding drug doses, concomitant medications, and doses, measurable lesions 
with measurements, tumor response, laboratory examinations, and treatment-related toxicities shall be 
documented in the patient’s medical record and flow sheets. 
 
 
 
 
 
All patients will be followed for overall survival, when possible. 
 
 
Patients who discontinue treatment due to progression will be followed for survival every 3 
months. 
 
Patients who come off therapy for reasons other than progression should be followed until 
progression or institution of new anti-tumor therapy.  They should then be followed for survival. 
 
5.1.3.3 Evaluation during study:  Phase II requirements 
 
Following the 1st treatment, CBC, differential, and platelets, and serum chemistries (BUN, creatinine, 
glucose, calcium, alkaline phosphatase, phosphorus, total bilirubin, SGOT (AST), SGPT (ALT), 
fasting cholesterol and triglycerides will be performed every week for the first 4 weeks and then every 


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2 weeks thereafter. All labs are permitted to be obtained up to 3 days prior to the weekly Temsirolimus 
IV infusion. Patients with normal bloodwork may have these laboratory tests performed every 4 weeks 
after the first 16 weeks. AED levels (if clinically appropriate) will be measured every 2 weeks for the 
first 4 weeks and then every 4 weeks. β-HCG will be measured prior to each 4-week cycle. For 
patients on warfarin, a PT/INR will be checked every 1-2 weeks, or sooner if clinically indicated.  Uric 
acid will be re-checked as clinically indicated. 
 
A head CT (without contrast) or MRI with gradient echo must also be performed during week 2 of 
treatment to evaluate for subclinical hemorrhage observed in mice treated with the combination of 
temsirolimus and perifosine.  Note that the CT of the head performed with the PET scan (i.e., in 
patients undergoing a PET/CT) is NOT sufficient. 
 
A brain MRI/CT will be done prior to every other cycle (up to 2 weeks prior).  A brain MRI/CT 
done at 6 months from initiation of therapy will be performed while the patient is still in the study 
to ensure assessment of the primary endpoint.   
A brain PET scan for research purposes will be perfomed after 1-2 weeks of treatment.  A follow 
up PET will then be performed after every 4th cycle (approximately 16 weeks). The PET scans 
must be performed at MSKCC in order to allow easier comparison and interpretation. 
 
A complete neurologic exam (to include documentation of the patients Karnofsky Performance 
Status) will be performed up to 3 days prior to every other cycle.  
 
Phase II patients will be evaluated for adverse events at the end of each cycle. In addition all 
serious adverse events will be reported to the NCI and the PI. 
 
All relevant information regarding drug doses, concomitant medications, and doses, measurable 
lesions with measurements, tumor response, laboratory examinations, and treatment-related 
toxicities shall be documented in the patient’s medical record and flow sheets. 
 
 
 
 
 
All patients will be followed for overall survival, when possible. 
 
 
Patients who discontinue treatment due to progression will be followed for survival every 3 
months. 
 
Patients who come off therapy for reasons other than progression should be followed until 
progression or institution of new anti-tumor therapy.  They should then be followed for 
survival. 
 
Patients enrolled in surgical substudy must have a brain MRI/CT scan obtained within 96 hours 
post-operatively. Treatment with temsirolimus and perifosine post-operatively should start no less 
than 7 days and no later than 56 days after surgery. If post-operative scan (performed within 96-
hour after surgery) is more than 14 days old when treatment is re-initiated post-operatively, the 
scan needs to be repeated. 
 
5.2 Definition of Dose Limiting Toxicity 
 
5.2.1 
Definition of dose limiting toxicities (DLT): 
Toxicities will be graded according to the CTCAE version 4.0.  If multiple toxicities are seen, the presence of 
DLT should be based on the most severe toxicity experienced.  DLT will be defined as any of the following 
events occurring during treatment with temsirolimus and perifosine and attributable (possible, probable, or 
definite) to either study drug or the combined therapy: 
 
• 
Any grade 3 thrombocytopenia, grade 4 anemia, and/or grade 4 neutropenia. 


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• 
Any unacceptable grade 2 non-hematologic toxicity, despite maximal medical treatment, that results in 
dose interruption of greater than 7 days within the first 28 days,.* 
• 
Any non-hematologic grade 3 or 4 toxicity, excluding alopecia, despite maximal medical treatment.* 
• 
Failure to recover from toxicities to be eligible for re-treatment with temsirolimus and perifosine 
within 2 weeks of the last dose of temsirolimus and perifosine. 
 
*Non-hematologic toxicities diarrhea and mucositis will only be considered a DLT if they remain grade 3 or 
unacceptable grade 2, despite maximal medical therapy. 
 
*Hypercholesterolemia and hypertriglyceridemia and other Metabolism and Nutrition Disorders (such as 
hypophosphatemia and hypocalcemia) will only be considered a DLT if they remain grade 3 or unacceptable 
grade 2, despite maximal medical therapy 
. 
 
5.2.2 
Maximum Tolerated Dose (MTD) 
 
The MTD will be based on the assessment of DLT during the first 28 days of treatment only (cycle 1).  
Escalations are planned in groups of three patients, with an additional three patients to be added at the first 
indication of Dose Limiting Toxicity (DLT).  (Please see next two paragraphs).  There is NO intra-patient 
dose escalation.  The MTD of temsirolimus in combination with perifosine will be defined as the dose at which 
fewer then one-third of patients experience a DLT.  Therefore, the MTD is the dose level at which 0/3 or 1/6 (or 
up to 2/9, etc.) patients experience DLT with the next higher dose having at least 2/3 or 2/6 patients 
encountering DLT.  Up to three patients may be enrolled simultaneously at each dose level.  These patients 
should be observed for DLT for at least 4 weeks from the first day of treatment before new patients are enrolled 
at the next highest dose level (Table 2).  Patients completing 28 days of therapy or patients removed for toxicity 
earlier than 28 days are evaluable.  Patients removed from study within 28 days for reasons other than toxicity 
may be replaced. 
 
 
Table 2:  Dose levels used to determine dosing for specific cohorts in the Phase I component 
Dose level 
Temsirolimus (mg/week) 
Perifosine load/maintenance (mg/day) 
-6 
5 
150/50 
-5 
10 
150/50 
-4 
15 
150/50 
-3 
15 
150/100 
-2 
15 
300/100 
-1 
15 
450/100 
1 (starting) 
15 
600/100 
2 
25 
600/100 
3 
50 
600/100 
4 
75 
600/100 
5 
115 
600/100 
6 
170 
600/100 
7 
170 
900/100 
 
The following dose escalation rules will be used: 
• 
Three patients are studied at the first dose level 
• 
If none of these three patients experience DLT, then the dose is escalated to the next higher level in the 
three subsequent patients. 
• 
If one of the three patients experience DLT at the current dose, then three more patients are accrued at the 
same dose. If none of these three additional patients suffer DLT, then the dose is escalated in subsequent 


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patients. If one or more of these three additional patients experiences DLT, the MTD has been exceeded 
and three more patients are treated at the next lower dose (if only three patients were previously treated at 
that prior dose). 
• 
If two or more patients encounter DLT, then the MTD has been exceeded and three more patients are 
treated at the next lower dose level (if only three patients were previously treated at that prior dose). 
• 
At least 6 patients will be treated at the MTD. 
• 
All escalations will occur in separate cohorts.  There is no intra-patient dose escalation of either drug. 
  
 
Table 3:  Escalation rules 
 
5.3 General Concomitant Medication and Supportive Care Guidelines 
 
5.3.1 
Nausea/vomiting  - see 5.1.1  
 
5.3.2 
Hyperuricemia/gout – see 5.1.1 
 
5.3.3 
Hypersensitivity reactions – see 5.1.1 
 
5.3.4 
Mucositis  - Mucositis is common with CCI-779 (temsirolimus).  This can be troublesome in the 
initial few weeks but usually subsides with time. Early treatment with mouthwash is recommended 
(e.g. Magic mouth wash (Maalox, viscous lidocaine and benadryl in 1:1:1 mixture) or kaopectate/ 
diphenhydramine/ lidocaine solution in 1:1:1 mixture).  Antifungal agents should be used if oral 
candidiasis is present.  Consider GI consultation. 
 
5.3.5 
Hyperlipidemia - It is recommended that patients with hyperlipidemia be treated with pravastatin 
(which dose not affect cytochrome metabolism), extended release niacin, or gemfibrozil (Lopid), 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients were 
treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to the 
next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level if 
only 3 patients were treated previously at that dose.  
However, a cohort may be expanded to more than 6 
patients if the PI and CTEP medical monitor agree 
more information is needed to clarify whether a DLT 
has occurred or the MTD has been reached. 
<1 out of 6 at highest dose level below 
the maximally administered dose 
This is generally the recommended phase 2 dose. At least 6 
patients must be entered at the recommended phase 2 dose. 


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such as Lopid 600 mg BID. 
 
5.3.6 
Diarrhea should be managed with loperamide:  4 mg at first onset, then 2 mg every 2-4 hours until 
diarrhea is controlled (maximum = 16 mg loperamide/day).  Additional antidiarrheal measures may 
be used at the discretion of the treating physician as warranted by the patient’s condition.  Consider 
GI consultation. 
 
5.3.7 
Routine supportive measures for cancer patients such as erythropoietin, analgesics, blood 
transfusions, antibiotics, bisphosphonates, and hematopoietic colony stimulating factors for 
treatment of cytopenias are permitted. 
 
5.3.8 
CY450 metabolism -  In vitro studies with Temsirolimus in human liver microsomes indicate that 
CYP3A4 may be the primarily enzyme responsible for the agent’s metabolism, suggesting that 
compounds known to modulate CYP3A4 activity may therefore affect the metabolism of 
Temsirolimus.  Inhibitors of CYP3A4 may decrease the metabolism and increase Temsirolimus 
levels, while inducers of CYP3A4 may increase the metabolism and decrease Temsirolimus levels.  
Temsirolimus or its metabolites may also interact with the CYP450 enzyme system by inhibiting 
CYP2D6.  Because there is a potential for interaction of temsirolimus and potentially perifosine with 
other concomitantly administered drugs through the cytochrome P450 system, the case report form 
must capture the concurrent use of all other drugs, over-the-counter medications, or alternative 
therapies.  The Principal Investigator should be alerted if the patient is taking any agent known to 
affect or with the potential to affect selected CYP450 isoenzymes.  Every effort should be made to 
avoid cytochrome P450 inducing medications.  Please see Appendix B and Appendix C. 
 
5.3.9 
Therapeutic anticoagulation - Patients on therapeutic anticoagulation should have PT/INR or PTT 
(whichever is appropriate) monitored closely during therapy (e.g., weekly for the first month and 
weekly for a minimum of 2 weeks following discontinuation of the agent). Therapy should be held if 
the coagulation parameters are higher than the intended therapeutic range. 
 
5.3.10 
Corticosteroids should be used in the smallest dose to control symptoms of cerebral edema and mass 
effect, and discontinued if possible. 
 
5.3.11 
Anti-seizure medications should be used as indicated. IT IS STRONGLY RECOMMENDED 
THAT EVERY EFFORT SHOULD BE MADE TO MAINTAIN THE PATIENT ON A NON-
EIAED RATHER THAN EIAED IF ANTI-SEIZURE PROPHYLAXIS IS REQUIRED.  
(APPENDIX B). 
 
5.3.11.1 
Patients who were previously on a non-EIAED and need to change anticonvulsants, 
should be started on another non-EIAED if at all possible. No delays in treatment 
would be required. 
 
5.3.11.2 
Patients who were previously on a either no AED or a non- EIAED and started on an 
EIAED should immediately be started on another non-EIAED and the EIAED 
discontinued/tapered off as quickly as possible. The patient may continue the current 
treatment dose while a non-EIAED is re-started. 
 
5.3.11.3 
Patients who were previously on a non-EIAED and need to permanently change 
anticonvulsant, but who cannot change to another non-EIAED MUST BE 
DISCUSSED WITH THE STUDY PI OR CO-PI. These patients will be taken off-
study unless it is felt that they have benefited from the therapy following assessment by 
the investigator, PI, and CTEP medical monitor. In some cases, this may be associated 
with an increase in the dose(s) used. 


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5.3.12 
Other Concomitant Medications - Therapies considered necessary for the well being of the patient 
may be given at the discretion of the investigator.  Other concomitant medications should be avoided 
except for analgesics, chronic treatments for concomitant medical conditions, or agents required for 
life-threatening medical problems.  All concomitant medications must be recorded. 
 
5.3.13 
Surgery - If neurosurgical or other surgical management is required for reasons not due to tumor 
progression, these procedures must be documented, including the indications for surgery, the 
surgical operative note and pathology report. 
 
5.3.14 
Other Anticancer or Experimental Therapies  - No other anticancer therapy (including 
chemotherapy, radiation, hormonal treatment or immunotherapy) of any kind is permitted during the 
study period. No other drug under investigation may be used concomitantly with the study drug.  If 
patients are subsequently found to have been taking such therapy before or during initiation of study 
treatment, the patient can be replaced and will not be included in toxicity or efficacy analyses 
following discussion by the investigator, PI, and CTEP medical monitor.  
 
5.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment will continue indefinitely or until one of 
the following criteria applies: 
 
• Disease progression, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s), 
• Patient decides to withdraw from the study, or 
• General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator. 
 
Prior to cycle 3, patients undergo clinical and radiographic tumor restaging.  As long as the tumor is 
stable or smaller in size and the patient is clinically stable or improved, they will go on to another 2 
four week cycles of therapy with temsirolimus and perifosine.  Treatment will continue indefinitely 
as long as there are no unacceptable toxicities (DLTs) and no tumor progression. 
 
5.5 Duration of Follow Up 
 
Patients will be followed every 3 months for survival after removal from study.  Patients removed from study 
for unacceptable adverse events will be followed until resolution or stabilization of the adverse event.  They 
should then be followed for survival every 3 months. 
 
5.6 Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.4 applies.  The reason for 
study removal and the date the patient was removed must be documented in the Case Report Form. 
 
6 DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 Dose Modifications 
 
Patients with stable or responding disease may be retreated at the same dose or at a reduced dose level, depending 
upon the adverse events observed in the current cycle and any adverse events present on the first day of the next 
cycle.  If multiple toxicities are seen, the dose administered in a subsequent cycle should be based on the most 


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severe toxicity experienced in the current cycle. Dose modifications or delays should be made based upon whether 
toxicities occur within a 4-week treatment cycle or at the expected start of the next treatment cycle.  
 
Patients who experience dose-limiting toxicity should have laboratory testing at least weekly until the toxicity has 
resolved. 
 
6.1.1 
Within Treatment Cycle: 
If a patient experiences DLT (as defined in Section 5.2) during the current treatment cycle, the treatment 
will be immediately suspended for a minimum of 1 week.  If the toxicity resolves to less than or equal to 
grade 1 (or to within 1 grade of starting values for pre-existing laboratory abnormalities)  within 2 weeks of 
the last dose of both temsirolimus and perifosine (grade 2 for diarrhea and hyperlipidemia), the patient will 
be retreated at one or two dose levels lower (see Section 6.1.2 - 6.1.5). Patients experiencing DLT at the 
initial starting dose of temsirolimus of 15 mg i.v. weekly will have the dose reduced according to Table 4. 
No dose reduction below 5 mg i.v. weekly is allowed.  Otherwise, there is no limit on the number of dose 
level reductions.  If temsirolimus-related toxicity persists at dose level -2 (5 mg i.v. weekly), the patient 
should be taken off study. 
 
Doses that are reduced for temsirolimus or perifosine related toxicity will not be re-escalated, even if there is 
minimal or no toxicity with the reduced dose. Patients whose dose has been reduced for adverse events that 
are subsequently not felt to be related to temsirolimus or perifosine may have the dose re-escalated after 
completion of one cycle with toxicities less than or equal to grade 1. If any patient has further toxicities that 
would require additional reductions, or if treatment is held for more than 2 consecutive weeks because of 
ongoing toxicity, the investigator and the CTEP medical monitor will assess if the patient should remain in 
the study (if the patient has benefited from treatment). 
 
 
 
 
 Table 4:  Temsirolimus Dose Modifications Table: 
 
Dose Modifications 
Dose Level 
Dose of Temsirolimus (mg/week intravenously) 
 
Level -2 
 
5 mg 
 
Level -1 
 
10 mg 
 
Starting dose (Level 1) 
 
15 mg 
 
Level 2 
 
25 mg 
 
Level 3 
 
50 mg 
 
Level 4 
 
75 mg 
 
Level 5 
 
115 mg 
 
Level 6 
 
170 mg 
 
 
Table 5:  Perifosine Dose Modifications Table for Maintenance Dose 
 
Dose Modifications 
Dose Level 
Dose of perifosine 
 
Level -2 
 
50 mg every other day 


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Level -1 
 
50 mg per day 
 
Starting dose (Level 1) 
 
100 mg per day 
 
6.1.2 
Hematologic Toxicity 
 
No dose adjustment or reduction of perifosine will be made for hematologic toxicity. 
 
Dose Modifications of CCI-779 (Temsirolimus) Based on Weekly ANC and Platelet Counts: 
 
ANC (/mL)  
     Platelets (/mL) 
% of Planned temsirolimus 
> 1000            and      > 75,000 
 
100% 
 
750-999          or 50,000 to < 75,000 
hold* 
 
< 750              or        < 50,000 
 
hold**  
 
 
 
* 
Upon recovery to ANC > 1,000/mL and platelets to > 100,000/mL, one lower dose level of temsirolimus 
will be administered (See Table 4).  Patients already at the lowest dose level (5 mg i.v. weekly) will be 
removed from study. 
 
**  Upon recovery to ANC > 1,000/mL and platelets to > 100,000/mL, two lower dose levels will be 
administered. The exception will be patients at dose level -1 (10 mg i.v. weekly) who will be dose-reduced 
by only one level to 5 mg IV weekly (See Table 4).  Patients already at the lowest dose level (5 mg i.v. 
weekly) will be removed from study. 
 
6.1.3 
Non-hematologic toxicity 
 
Dose Modifications Based on perifosine and temsirolimus-related Non-Hematologic Toxicities and dose 
adjustments for each drug shown in tables 4, 5, and 6: 
 
NCI Grade 
 
% of Planned perifosine and temsirolimus dose 
0-2+ 
 
100%+  
3* 
 
 
hold**  
4 
 
 
hold***  
 
 
 
 
  
 
+   For symptomatic Grade 2 toxicity, the dose may be held until recovery to CTC Grade 0-1, then continue at the 
same dose or reduce by one level of temsirolimus and/or perifosine at the investigator's discretion.  Grade 2 
diarrhea does not require temporary discontinuation of treatment as this toxicity may improve despite continued 
treatment.  For grade 2 diarrhea that is unacceptable to the patient for symptomatic reasons, hold perifosine 
temporarily held until resolution < grade 1 and subsequently re-started at the same dose.  If symptomatic grade 
2 diarrhea recurs after re-instituting treatment at the same daily dose and require temporary discontinuation, 
treatment  of both agents should be held until resolution to < grade 1 and re-instituted at a reduced doses of both 
agents (see Table 4, 5, and 6).   
 
+ 
In addition, areas of intratumoral micro-hemorrhage were noted on necroscopy of mice harboring modeled 
GBMs following combined treatment of perifosine and temsirolimus.  Significance of this in humans is unclear, 
and it may represent an early response to therapy.  However, for patient safety, a non-contrast head CT or MRI 
with gradient echo imaging is required during the 2nd week of therapy to evaluate for such microbleeds.  
CTCAE grade 1 (asymptomatic, radiographic findings only) do not require treatment modification.  CTCAE 
grade 2 (medical intervention indicated) may require corticosteroids as treatment for associated edema or other 
intervention at the discretion of the investigator, but treatment can continue at the discretion of the investigator. 
 


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* 
Except nausea/vomiting (unless patients are on maximal antiemetic therapy) or hypercholesterolemia and 
hypertriglyceridemia and other Metabolism and Nutrition Disorders (such as hypophosphatemia and 
hypocalcemia) unless remaining grade 3 or unacceptable grade 2, despite maximal medical therapy. 
 
** Hold (no minimum time unless a DLT) until recovery to CTC Grade 0-1 (or to within 1 grade of starting values 
for pre-existing laboratory abnormalities), and then resume per table 6.  For diarrhea, and hyperlipidemia, hold 
until recovery to CTC grade 2, unless the patient cannot tolerate symptoms in which case the dose may be held 
until recovery to CTC Grade 0-1. Antilipid therapy should be initiated for hyperlipidemia such as with 
pravastatin (which dose not affect cytochrome metabolism), extended release niacin, or gemfibrozil (Lopid) 
(see 5.3.5 and 6.1.5).  Note that Subjects with toxicities that are manageable with supportive therapy do not 
require dose reductions unless they remain grade 3 or unacceptable grade 2 despite maximal medical therapy. 
 
***  Hold (no minimum time unless a DLT) until recovery to CTC Grade 0-1 (or to within 1 grade of starting values 
for pre-existing laboratory abnormalities), and then resume per table 6. The exception will be patients at dose 
level -1 of temsirolimus (10 mg i.v. weekly) who will be dose-reduced by only one level to 5 mg i.v. weekly. 
For diarrhea and hyperlipidemia, hold until recovery to CTC grade 2, unless the patient cannot tolerate 
symptoms in which case the dose the dose may be held until recovery to CTC Grade 0-1. Antilipid therapy 
should be initiated for hyperlipidemia such as with pravastatin (which dose not affect cytochrome metabolism), 
extended release niacin, or gemfibrozil (Lopid) (see 5.3.5 and 6.1.5). 
 
An important exception to this scheme are patients with symptoms suggestive of interstitial pneumonitis. Because 
pneumonitis is an anticipated toxicity for temsirolimus, patients with signs/symptoms of pneumonitis should have 
treatment held and be promptly evaluated.  Those patients subsequently diagnosed with pneumonitis thought to be 
possibly related to study agent(s) should have treatment discontinued and be removed from study. 
 
6.1.3.1 
Perifosine related toxicity 
 
Dose Modifications for Toxicity During the Loading Dose:  Nausea and vomiting are the only toxicities 
likely to occur during the loading dose that may require dose modification.  In patients who have emesis 
and are unable to retain perifosine, every attempt should be made to obtain control of nausea and vomiting 
using additional antiemetic medication.  The dose of perifosine may be repeated if emesis occurs within 30 
minutes of taking the tablet(s) OR all the tablets are seen in the emesis. 
 
Dose Modifications for Toxicity during Maintenance Dosing:  
For Grade 1 toxicity, treatment with perifosine will not be interrupted. 
 
For Grade 2 nausea, vomiting, or diarrhea: 
(a) 
For nausea, vomiting and diarrhea, maintain dosing with symptomatic treatment.  The dose of 
perifosine may be repeated if emesis occurs within 30 minutes of taking the tablet(s) OR all the tablets are 
seen in the emesis. 
(b) 
For persistent nausea, vomiting or diarrhea despite symptomatic treatment that remains 
unacceptable to the patient, hold both agents and then reduce dose of each by one dose level.  If patients are 
receiving 50 mg/day of perifosine maintenance at the time of occurrence/recurrence of toxicity, change the 
schedule of administration to 50 mg every other day (q 2 days, dose level -2)  Reductions below this 
dose/schedule will not be allowed. 
 
For grade 3 joint pain (gout): 
Hold perifosine and start allopurinol and/or other agents at the discretion of the investigator.  Reevaluate the 
patient at least weekly (more frequently is allowed) until toxicity improves to < Grade 1 or grade 2 that is 
acceptable to the patient.  Then reduce the maintenance dose of perifosine by one dose level.  If patients are 
receiving 50 mg/day at the time of occurrence/recurrence of toxicity, change the schedule of administration 
to 50 mg every other day (q 2 days, dose level -2).  Reductions below this dose/schedule will not be 


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allowed. 
 
For Unresolved Toxicity 
If a patient has unresolved toxicity (which have not returned to ≤ grade 1 or grade 2 that is acceptable to the 
patient OR to within 1 grade of starting values for pre-existing laboratory abnormalities) greater than 14 
days from the last dose of both temsirolimus and perifosine, the patient should discontinue all treatment and 
be taken off study.  However, if it is the treating physician’s opinion that the patient may benefit from 
continued treatment, the patient may continue on study with a dose reduction.  Dose reduction below 50 mg 
PO q 2 days are not allowed unless it is the opinion of the treating physician that the patient may benefit 
from continued treatment. The decision to proceed with treatment must be made in consultation with the PI 
and the CTEP Senior Investigator/Medical Monitor. 


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Table 6: Summary of Dose Modification for perifosine and temsirolimus 
Toxicity 
Perifosine 
Temsirolimus 
 
Hematologic 
 
Continue drug; no dose reduction 
 
Hold drug and reduce dose per  
Section 6.1.2 and dose levels in table 4 
 
 
Rash 
 
Continue drug; no dose reduction 
 
Hold temsirolimus and reduce dose  
per Section 6.1.3 and dose levels in  
table 4.  Consider Dermatology 
consultation. 
 
 
Diarrhea, nausea, 
vomiting 
 
Hold perifosine first.  Resume at 
same dose after improvement per 
section 6.1.3 and Table 5.  If no 
improvement, hold and reduce dose 
per section 6.1.3 and dose levels in 
Table 5.  Consider GI consultation 
 
 
If no 
 improvement after holding  
perifosine, hold temsirolimus and 
reduce dose per section 6.1.3 and dose 
levels in table 4.  Consider GI 
consultation. 
 
 
Stomatitis 
 
Continue drug; no dose reduction  
 
Hold temsirolimus and reduce  
dose per Section 6.1.3 and dose levels 
in table 4.  Consider GI consultation. 
 
Pulmonary 
 
Continue drug; no dose reduction  
 
Hold drug per Section 6.1.3 
 
 
Hepatic 
 
Continue drug; no dose reduction 
 
Hold drug and reduce dose per  
Section 6.1.3 and dose levels in table 4 
 
 
Hyperlipidemia 
 
Continue drug; no dose reduction 
 
Hold drug and reduce dose per  
Section 6.1.3 and dose levels in table 
4.  Initiate antilipid therapy 
 
 
Joint pain/gout attack 
 
Hold perifosine.  Start allopurinol 
300 mg per day or other regimen at 
discretion of investigator.  If persists, 
hold perifosine.  Reduce dose per 
section 6.1.3.1 and dose levels in 
Table 5.  Continue allopurinol at 
same or inceased dose with other 
agents at the discretion of the 
investigator to treat gout. 
 
 
 
 
Continue drug; no dose reduction  


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All other toxicities 
 
Continue drug; no dose reduction 
Hold drug and reduce dose per  
Section 6.1.3 and dose levels in table 4 
except Subjects with toxicities that are 
manageable with supportive therapy 
do not require dose reductions unless 
they remain grade 3 or unacceptable 
grade 2 despite maximal medical 
therapy 
 
6.1.4 
At the Start of the Next Treatment Cycle: 
 
Additional cycles of therapy may be administered provided that the patient meets the following criteria on 
Day 1 of each cycle (labs may be drawn up to 3 days before the start of the cycle): 
 
• 
ANC > 1,000/mcL 
• 
Platelets > 100,000/mcL 
• 
Non-hematologic toxicity recovered to < grade 1 (or tolerable grade 2) EXCEPT 
o 
Non-hematologic toxicities such as rash, diarrhea and mucositis will only be considered a 
DLT if they remain grade 3 or unacceptable grade 2, despite maximal medical therapy. 
o 
*Hypercholesterolemia and hypertriglyceridemia and other Metabolism and Nutrition 
Disorders (such as hypophosphatemia and hypocalcemia) will only be considered a DLT 
if it remains grade 3 or unacceptable grade 2, despite maximal medical therapy. 
• 
No evidence of progressive disease 
 
In the event of toxicity, the doses of temsirolimus will be adjusted according to the guidelines shown in the 
Dose Delays/Dose Modifications table7 below.  If an adverse event is not covered in the table, doses may 
be reduced or held at the discretion of the investigator for the subject’s safety.  Dose adjustments for 
hematological toxicity are based on the blood counts obtained in preparation for the day of treatment.  
 
Patients requiring dose reductions should not have the dose re-escalated with subsequent treatments. 
 
Subjects with toxicities that are manageable with supportive therapy do not require dose reductions unless 
they remain grade 3 or unacceptable grade 2 despite maximal medical therapy:  hyperlipidemia may be 
treated with statins, such as pravastatin (which does not affect cytochrome metabolism), extended release 
niacin, or gemfibrozil; nausea/vomiting may be treated with antiemetics; and diarrhea may be treated with 
loperamide rather than by dose reduction 
 
Subjects will be withdrawn from the study if they fail to recover to CTC Grade 0-1 or tolerable grade 2 (or 
within 1 grade of starting values for pre-existing laboratory abnormalities) from a treatment-related toxicity 
(EXCEPT toxicities that are manageable with supportive therapy as above) within 14 days from the last 
dose of both temsirolimus and perifosine OR  they experience agent related adverse events requiring dose 
modification despite two previous dose reductions (i.e. would require a 3rd dose reduction) unless the 
investigator, PI, and CTEP monitor agree that the subject should remain in the study because of evidence 
that the patient is/may continue deriving benefit from continuing study treatment. The appropriate reduced 
dose will be determined after discussion between the principal investigator and CTEP monitor. 
 
 
 
 
 


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Table 7 
Adverse Event 
Agent 
Treatment Modifications 
Blood/Bone Marrow 
Grade 3: 
Neutrophils 
 
ANC 500-1000 
Platelets 
 
50,000-75,000 
 
 
 
 
Temsirolimus 
• 
Delay Temsirolimus until recovery to ≤ grade 
1. 
• 
Retreat at a one dose level reduction 
• 
If recovery requires > 14 days from the last 
dose of both temsirolimus and perifosine, 
discontinue all study treatment. 
Grade 4: 
Neutrophils 
 
ANC <500 
Platelets 
 
<25,000 
• 
Delay Temsirolimus until recovery to ≤ grade 
1. 
• 
Retreat at two dose levels reduction 
• 
If recovery requires > 14 days from the last 
dose of both temsirolimus and perifosine, 
discontinue all study treatment. 
Pulmonary/Upper Respiratory 
Pneumonitis (cough, 
dyspnea, fever) 
 
 
Temsirolimus 
Discontinue Temsirolimus pending investigation.  
If diagnosis is confirmed and events are 
considered at least possibly due to Temsirolimus, 
the agent is removed from the study. 
All other non-hematologic adverse events except nausea, vomiting, and diarrhea 
Grade 0-2 
 
 
 
Temsirolimus 
Grade 2 toxicities that are persistent and 
intolerable (i.e. stomatitis) can result in dose 
delays and dose reductions to the next lower dose 
level 
Grade 3-4 
Hold dose.   
• 
Re-evaluate until AE resolved to < 1 or 
tolerable grade 2.   
• 
Re-treat at a one dose level reduction 
• 
If recovery requires > 14 days from the last 
dose of both temsirolimus and perifosine, 
discontinue all study treatment. 
• 
Patients with grade 4 AEs related to agent 
may be taken off study at investigator’s 
discretion. 
 
6.1.5 
For treatment or dose modification related questions, please contact the PI at 212-639-5122 or 
kaleyt@mskcc.org. 
 
7 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following list of AEs 
(Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine whether the event requires 
expedited (via CTEP-AERS) in addition to routine reporting.   
 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. 


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In addition to the comprehensive list, a subset, the Agent Specific Adverse Event List (ASAEL), appears in a 
separate column and is identified with bold and italicized text. This subset of AEs (ASAEL) contains events that 
are considered 'expected' for expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements'  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification. 
 
7.1.1 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
For 
Temsirolimus (CCI-779, NSC 683864) 
 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI via CTEP-AERS (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification. Frequency is provided based on 1927 patients. Below is the CAEPR for temsirolimus (CCI-
779, Torisel). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.4, July 2, 20131 
 
 Adverse Events with Possible  
 Relationship to Temsirolimus (CCI-779, Torisel) 
 (CTCAE 4.0 Term) 
[n= 1927] 
 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
ENDOCRINE DISORDERS 
  
 
Endocrine disorders - Other 
(decreased testosterone) 
 
 Endocrine disorders - Other 
(decreased testosterone) (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
 Abdominal distension (Gr 2) 
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Anal mucositis2 
 
 Anal mucositis2 (Gr 2) 
 
Constipation 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
 
Gastrointestinal fistula3 
  
 
 
Gastrointestingal perforation4  Gastrointestinal perforation4 (Gr 2) 


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Mucositis oral2 
 
 
 Mucositis oral2 (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Rectal mucositis2 
 
 Rectal mucositis2 (Gr 2) 
 
Small intestinal mucositis2 
 
 Small intestinal mucositis2 (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS   
 
Chills 
 
 Chills (Gr 2) 
 
Edema face 
 
 Edema face (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 3) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Flu like symptoms 
 
 Flu like symptoms (Gr 2) 
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 2) 
 
Pain 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction5 
 
 Allergic reaction5 (Gr 2) 
INFECTIONS AND INFESTATIONS6 
  
 
Infection7 
 
 Infection7 (Gr 3) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Wound dehiscence8 
 
 Wound dehiscence8 (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase 
increased 
 
 Alkaline phosphatase increased (Gr 
2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
Cholesterol high9  
 
 Cholesterol high9 (Gr 4) 
 
Creatinine increased 
 
 Creatinine increased (Gr 3) 
 
Fibrinogen decreased 
 
 Fibrinogen decreased (Gr 2) 
 
GGT increased 
 
 GGT increased (Gr 2) 
 
Lymphocyte count 
decreased 
 
 Lymphocyte count decreased (Gr 4) 
 
Neutrophil count decreased10  
 Neutrophil count decreased10 (Gr 4) 
Platelet count 
decreased10 
 
 
 Platelet count decreased10 (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 3) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Acidosis 
 
 Acidosis (Gr 2) 
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Glucose intolerance11 
 
 Glucose intolerance11 (Gr 2) 
 
Hyperglycemia11 
 
 Hyperglycemia11 (Gr 3) 
 
Hypertriglyceridemia9 
 
 Hypertriglyceridemia9 (Gr 4) 
 
Hypocalcemia 
 
 Hypocalcemia (Gr 3) 
 
Hypokalemia 
 
 Hypokalemia (Gr 4) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 3) 
 
Metabolism and nutrition 
disorders - Other 
(hyperlipidemia)9 
 
 Metabolism and nutrition disorders 
- Other (hyperlipidemia)9 (Gr 4) 


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MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Depressed level of 
consciousness 
 
 Depressed level of consciousness 
(Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
PSYCHIATRIC DISORDERS 
  
 
Depression 
 
 Depression (Gr 2) 
 
Insomnia 
 
 Insomnia (Gr 2) 
 
Libido decreased 
 
 Libido decreased (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury12 
  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
Erectile dysfunction 
 
 Erectile dysfunction (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
 Epistaxis (Gr 2) 
 
Laryngeal mucositis2 
 
 Laryngeal mucositis2 (Gr 2) 
 
Pharyngeal mucositis2 
 
 Pharyngeal mucositis2 (Gr 2) 
 
Pleural effusion 
 
 Pleural effusion (Gr 3) 
 
Pneumonitis13 
 
 Pneumonitis13 (Gr 3) 
 
Sinus disorder 
 
 Sinus disorder (Gr 2) 
 
Tracheal mucositis2 
 
 Tracheal mucositis2 (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash acneiform 
 
 Rash acneiform (Gr 2) 
Rash maculo-
papular 
 
 
 Rash maculo-papular (Gr 3) 
 
Skin and subcutaneous 
tissue disorders – Other (nail 
disorder/nail changes)15 
 
 Skin and subcutaneous tissue 
disorders – Other (nail disorder/nail 
changes)15 (Gr 2) 
 
Urticaria 
 
 Urticaria (Gr 2) 
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
Hypotension 
 
 Hypotension (Gr 3) 
 
 
Thromboembolic event 
 Thromboembolic event (Gr 4) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Mucositis/stomatitis:  Gingivitis, mucositis/stomatitis, ulcers in mouth and throat, pharyngitis, and 
dysphagia have been reported in subjects receiving temsirolimus. 
 


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3Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Enterovesical fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS 
SOC. 
 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC.  GI perforation (including fatal outcome) 
has been observed in subjects who received temsirolimus. 
 
5Hypersensitivity /infusion reactions (including some life threatening and rare fatal reactions), including 
and not limited to flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, 
hypersensitivity, and anaphylaxis, have been associated with the administration of temsirolimus.  These 
reactions can occur very early in the first infusion, but may also occur with subsequent infusions.  Patients 
should be monitored early during infusion and appropriate supportive care should be available.  
Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate 
medical care administered.  A risk-benefit assessment should be done prior to the continuation of 
temsirolimus therapy in patients with severe life-threatening reactions. 
 
6Infections:  Bacterial and viral infections including opportunistic infections have been reported in 
subjects. Infections may originate in a variety of organ systems/body regions and may be associated with 
normal or grade 3-4 neutropenia. Bacterial and viral infections have included cellulitis, herpes zoster, 
herpes simplex, bronchitis, abscess, pharyngitis, urinary tract infection (including dysuria hematuria, 
cystitis, and urinary frequency), rhinitis folliculitis, pneumonia, and upper respiratory tract infection. 
 
7Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.  
 
8Wound Dehiscence:  The use of temsirolimus has been associated with abnormal wound healing. 
Therefore, caution should be exercised with the use of temsirolimus in the perisurgical period. 
 
9Cholesterol High: The use of temsirolimus in subjects has been associated with increases in serum 
levels of triglycerides and cholesterol. This may require initiation of or increase in the dose of lipid-
lowering agents. 
 
10Thrombocytopenia and Neutropenia: Grades 3 and 4 thrombocytopenia and/or neutropenia have been 
observed at higher frequency in subjects with mantle cell lymphoma (MCL). 
 
11Hyperglycemia/Glucose Intolerance: The use of temsirolimus in subjects was associated with increases 
in serum glucose level. This may result in the need for an increase in the dose of, or initiation of, insulin 
and/or oral hypoglycemic agent therapy.  
 
12Acute Kidney Injury: Renal failure (including fatal outcome) has been observed in subjects receiving 
temsirolimus for advanced RCC and/or with pre-existing renal insufficiency. 
 
13Interstitial Lung Disease: There have been cases of nonspecific interstitial pneumonitis, including rare 
fatal reports. Some subjects were asymptomatic with pneumonitis detected on computed tomography 
scan or chest radiograph. Others presented with symptoms such as dyspnea, cough, and fever. Some 
subjects required discontinuation of temsirolimus or treatment with corticosteroids and/or antibiotics, while 
some subjects continued treatment without additional intervention. 
 
14Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 


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47 
 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
15Nail Disorder/Nail Changes includes Nail discoloration, Nail loss, and Nail ridging under the SKIN AND 
SUBCUTANEOUS TISSUE DISORDERS SOC. 
 
Also reported on temsirolimus (CCI-779, Torisel) trials but with the relationship to temsirolimus 
(CCI-779, Torisel) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(coagulopathy); Hemolysis; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Chest pain - cardiac; Heart failure; 
Left ventricular systolic dysfunction; Myocardial infarction; Pericardial effusion; Right ventricular 
dysfunction; Sinus tachycardia; Supraventricular tachycardia; Ventricular fibrillation; Ventricular 
tachycardia 
EAR AND LABYRINTH DISORDERS - Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (Cushing's syndrome); Endocrine disorders - 
Other (diabetes mellitus) 
EYE DISORDERS - Blurred vision; Cataract; Conjunctivitis; Dry eye; Eye disorders - Other (diplopia); Eye 
pain; Flashing lights; Photophobia; Retinopathy 
GASTROINTESTINAL DISORDERS - Anal pain; Anal ulcer; Ascites; Bloating; Colitis; Colonic 
obstruction; Colonic ulcer; Dry mouth; Duodenal ulcer; Dyspepsia; Dysphagia; Enterocolitis; Esophageal 
pain; Esophageal ulcer; Esophagitis; Flatulence; Gastritis; Gastrointestinal disorders - Other (anal 
fissure); Gastrointestinal disorders - Other (gastroenteritis); Gastrointestinal disorders - Other (mouth 
ulceration); Gastrointestinal hemorrhage14, Hemorrhoids; Ileus; Oral pain; Pancreatitis; Periodontal 
disease; Proctitis; Rectal pain; Small intestinal obstruction; Stomach pain; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema trunk; Facial pain; Gait 
disturbance; Injection site reaction; Localized edema; Malaise; Multi-organ failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatic failure 
IMMUNE SYSTEM DISORDERS - Anaphylaxis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fracture; Postoperative 
hemorrhage; Vascular access complication; Wound complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; CD4 
lymphocytes decreased; INR increased (potential interaction with Coumadin); Investigations - Other (BUN 
increased); Investigations - Other (lactic dehydrogenase increased); Lipase increased; Lymphocyte count 
increased; Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hyperuricemia; Hypoalbuminemia; Hypoglycemia; Hypomagnesemia; 
Hyponatremia; Metabolism and nutrition disorders - Other (albuminuria) ; Metabolism and nutrition 
disorders - Other (blood urea increased); 
Metabolism and nutrition disorders - Other (hypoproteinemia)  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Avascular necrosis; Bone 
pain; Chest wall pain; Generalized muscle weakness; Joint effusion; Muscle weakness lower limb; 
Musculoskeletal and connective tissue disorder - Other (muscle cramps); Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Leukemia 
secondary to oncology chemotherapy; Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) - Other (carcinoma of the lung); Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) - Other (lymphoma); Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dizziness; Dysesthesia; 
Hydrocephalus; Intracranial hemorrhage; Lethargy; Neuralgia; Paresthesia; Peripheral motor neuropathy; 


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48 
 
Peripheral sensory neuropathy; Reversible posterior leukoencephalopathy syndrome; Seizure; 
Somnolence; Spasticity; Stroke; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Mania; Psychiatric disorders - Other (bipolar 
disorder); Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Cystitis noninfective; Hematuria; 
Hemoglobinuria; Proteinuria; Renal hemorrhage; Urinary frequency; Urinary retention; Urinary tract pain; 
Urinary urgency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Female genital tract fistula; Hematosalpinx; 
Irregular menstruation; Menorrhagia; Ovarian hemorrhage; Prostatic hemorrhage; Spermatic cord 
hemorrhage; Testicular disorder; Testicular hemorrhage; Testicular pain; Uterine hemorrhage; Vaginal 
discharge; Vaginal dryness; Vaginal fistula; Vaginal hemorrhage; Vaginal inflammation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Bronchopulmonary hemorrhage; Bronchospasm; Hiccups; Hypoxia; Nasal congestion; 
Pharyngolaryngeal pain; Pleuritic pain; Productive cough; Pulmonary edema; Pulmonary fibrosis; 
Pulmonary hypertension; Respiratory failure; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Hyperhidrosis; 
Pain of skin; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Skin and subcutaneous 
tissue disorders - Other (angioneurotic edema); Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Phlebitis; Superficial thrombophlebitis; Visceral arterial ischemia 
 
 
Note:  Intracerebral Bleeding: Subjects with central nervous system (CNS) tumors (primary CNS tumors 
or metastases) and/or receiving anticoagulation therapy may be at an increased risk of intracerebral 
bleeding (including fatal outcomes) while receiving therapy with temsirolimus (CCI-779, Torisel). 
 
Note: Temsirolimus (CCI-779, Torisel) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
7.1.2  Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Perifosine (NSC 639966) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) contains events that are considered 'expected' for expedited reporting 
purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification. Frequency is provided based on 1586 patients. Below is the CAEPR for Perifosine. 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Version 2.2, June 27, 20111 
 
 Adverse Events with Possible  
 Relationship to Perifosine 
 (CTCAE 4.0 Term) 
[n= 1586] 
 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
(formerly known as ASAEL)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr. 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr. 2) 
 
Constipation 
 
 Constipation (Gr. 2) 
Diarrhea 
 
 
 Diarrhea (Gr. 2) 
 
Flatulence 
 
 Flatulence (Gr. 2) 
Nausea 
 
 
 Nausea (Gr. 2) 
Vomiting 
 
 
 Vomiting (Gr. 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS   
Fatigue 
 
 
 Fatigue (Gr. 2) 
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
 Infection2 (Gr. 2) 
INVESTIGATIONS 
  
 
Alkaline phosphatase increased  
 Alkaline phosphatase increased (Gr. 
2) 
 
Creatinine increased 
 
 Creatinine increased (Gr. 2) 
 
GGT increased 
 
 GGT increased (Gr. 2) 
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr. 2) 
 
Weight loss 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr. 2) 
 
Dehydration 
 
 Dehydration (Gr. 2) 
 
Hyperglycemia 
 
 Hyperglycemia (Gr. 2) 
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr. 2) 
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hyponatremia 
 
 
 Hyponatremia (Gr. 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Back pain 
 
 Back pain (Gr. 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Dyspnea 
 
 Dyspnea (Gr. 2) 
 
Hiccups 
 
 Hiccups (Gr. 2) 
 
 


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50 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
²Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
Also reported on Perifosine trials but with the relationship to Perifosine still undetermined: 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Cardiac disorders - Other (cardiac valve 
disorder); Conduction disorder; Myocardial infarction; Palpitations; Pericardial effusion; Sinus 
bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain; Middle ear inflammation; Tinnitus 
EYE DISORDERS - Blurred vision; Cataract; Conjunctivitis; Dry eye; Eye pain; Flashing lights; Keratitis; 
Photophobia; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Colitis; Colonic obstruction; Dry 
mouth; Dyspepsia; Dysphagia; Esophageal pain; Esophageal perforation; Esophageal stenosis; 
Esophagitis; Gastric hemorrhage; Gastritis; Gastrointestinal pain; Gingival pain; Hemorrhoids; Ileus; 
Lower gastrointestinal hemorrhage; Mucositis oral; Oral hemorrhage; Oral pain; Rectal hemorrhage; 
Rectal pain; Small intestinal obstruction; Stomach pain; Toothache; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Fever; Flu 
like symptoms; Gait disturbance; General disorders and administration site conditions - Other (visceral 
edema); Localized edema; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatic pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Bruising; Fracture 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alanine aminotransferase 
increased; Aspartate aminotransferase increased; Blood bilirubin increased; CPK increased; Carbon 
monoxide diffusing capacity decreased; Cholesterol high; INR increased; Investigations - Other 
(granulocytopenia); Lipase increased; Neutrophil count decreased; Platelet count decreased; Serum 
amylase increased; Weight gain; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Glucose intolerance; Hypercalcemia; 
Hyperkalemia; Hypernatremia; Hyperuricemia; Hypoglycemia; Hypomagnesemia; Hypophosphatemia; 
Metabolism and nutrition disorders - Other (blood bicarbonate decreased) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; Bone pain; 
Buttock pain; Chest wall pain; Generalized muscle weakness; Joint range of motion decreased; Muscle 
weakness left-sided; Muscle weakness lower limb; Muscle weakness upper limb; Musculoskeletal and 
connective tissue disorder -  Other (upper extremity dysfunction); Myalgia; Myositis; Neck pain; Pain in 
extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (incl cysts and polyps) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (massive tumor hemorrhage); Tumor 
pain 
NERVOUS SYSTEM DISORDERS - Acoustic nerve disorder NOS; Ataxia; Cognitive disturbance; 
Depressed level of consciousness; Dizziness; Dysarthria; Dysgeusia; Extrapyramidal disorder; Facial 
nerve disorder; Headache; Intracranial hemorrhage; Memory impairment; Neuralgia; Peripheral sensory 
neuropathy; Pyramidal tract syndrome; Seizure; Syncope; Tremor; Trigeminal nerve disorder; Vagus 
nerve disorder 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Libido decreased; 
Personality change; Psychosis 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Proteinuria; Urinary 
frequency; Urinary incontinence; Urinary retention; Urinary tract obstruction; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Pelvic pain; Scrotal pain; Vaginal 
discharge; Vaginal hemorrhage 


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RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Atelectasis; Bronchial 
obstruction; Bronchospasm; Cough; Epistaxis; Hypoxia; Nasal congestion; Pharyngolaryngeal pain; 
Pleural effusion; Pleuritic pain; Pneumonitis; Pneumothorax; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Pain of skin; 
Photosensitivity; Pruritus; Purpura; Rash acneiform; Rash maculo-papular; Skin atrophy; Skin 
hyperpigmentation; Skin hypopigmentation; Skin ulceration 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension; Hypotension; Superficial 
thrombophlebitis; Thromboembolic event 
 
Note: Perifosine in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
7.2 Adverse Event Characteristics  
 
• 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) for expedited 
reporting purposes only.  ‘Expected’ AEs (the ASAEL) are bold and italicized in the CAEPR (Section 
7.1.1). 
 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 Expedited Adverse Event Reporting 
 
7.3.1 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP home page (http://ctep.cancer.gov).  The reporting procedures to 
be followed are presented in the “CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements” which can be downloaded from the CTEP home page (http://ctep.cancer.gov).   
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification is to be made to 
NCI by telephone at 301-897-7497 or 301-897-7402 for CIP studies. An electronic report MUST 
be submitted immediately upon re-establishment of internet connection. Please note that all 
paper AdEERS forms have been removed from the CTEP website and will NO LONGER be 
accepted. 
 
7.4 Expedited Reporting Guidelines for Phase I – CTEP-AERS Reporting Requirements for Adverse Events 
That Occur Within 30 Days1 of the Last Dose of the Investigational Agent on Phase 1 Trials 
 
 
 
 
 


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52 
Phase 1 Trials 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 
4 & 52 
Unexpected 
and 
Expected 
Unex-
pected 
Expected 
Unexpected 
Expected 
Unexpected 
and 
Expected 
with 
Hospitali-
zation 
without 
Hospitali- 
zation 
with 
Hospitali- 
Zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
24-Hour;
5 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
24-Hour;
5 Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour;
5 Calendar
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after 
the last dose of treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
•
Grade 3 unexpected events with hospitalization or prolongation of hospitalization
•
Grade 4 unexpected events
•
Grade 5 expected events and unexpected events
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, 
a full report is required as outlined in the table. 
December 15, 2004 
7.4.1 
Expedited Reporting Guidelines for phase II– CTEP-AERS Reporting Requirements for 
Adverse Events that occur within 30 Days1 of the Last Dose of the Investigational Agent 
on Phase 2 and 3 Trials 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. 
Phase 2 and 3 Trials 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and 
Expected 
Unex-
pected 
Expected 
Unexpected 
Expected 
Unex- 
pected 
Expected 
with 
Hospitali-
zation 
without 
Hospitali- 
zation 
with 
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour;
5 Calendar
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last 
dose of treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
•
Grade 4 and Grade 5 unexpected events
CTEP-AERS 10 calendar day report: 
•
Grade 3 unexpected events with hospitalization or prolongation of hospitalization
•
Grade 5 expected events
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report 
is required as outlined in the table. 
December 15, 2004 


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•
Expedited AE reporting timelines defined:

“24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete CTEP-AERS
report within 5 calendar days of the initial 24-hour report.

“10 calendar days” - A complete CTEP-AERS report on the AE must be submitted within
10 calendar days of the investigator learning of the event.
•
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization
(or prolongation of existing hospitalization) must be reported regardless of attribution and
designation as expected or unexpected with the exception of any events identified as
protocol-specific expedited adverse event reporting exclusions.
•
Any event that results in persistent or significant disabilities/incapacities, congenital
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs
following treatment with an agent under a CTEP IND.
•
Use the NCI protocol number and the protocol-specific patient ID assigned during trial
registration on all reports.
7.3.4 
Protocol-Specific Expedited Adverse Event Reporting Exclusions
For this protocol only, certain AEs/grades are exceptions to the Expedited Reporting
Guidelines and do not require expedited reporting (i.e., CTEP-AERS).  The following
AEs must be reported through the routine reporting mechanism (Section 7.4):
AEs assessed by the investigator as possibly, probably, or definitely due to Temsirolimus:
CTCAE 
Category 
Adverse Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Comments 
Blood/Bone 
Marrow 
↓ Hemoglobin, leukocytes 
(total WBC), lymphopenia, 
 ↓ neutrophils/granulocytes 
(ANC/AGC), ↓ platelets 
1-4 
No 
These AEs do not require 
expedited reporting unless 
patient is hospitalized for 
management 
Gastro-
intestinal 
Diarrhea, nausea, vomiting, 
stomatitis 
1-3 
Yes 
Hospitalization for grade 3 
AEs does not require 
expedited reporting 
Metabolic/ 
Laboratory 
Hypercholesterolemia, 
hyperglycemia, 
hypertriglyceridemia 
1-4 
No 
These AEs do not require 
expedited reporting unless 
patient is hospitalized for 
management 
AEs assessed by the investigator as possibly, probably, or definitely due to perifosine of 
grade 1-4 unless the patient is hospitalized for management 


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Category 
Adverse Event 
Constitutional Symptoms 
Fatigue (lethargy, malaise, asthenia) 
Gastrointestinal 
Anorexia 
Gastrointestinal 
Dehydration 
Gastrointestinal 
Diarrhea 
Gastrointestinal 
Flatulence 
Gastrointestinal 
Nausea 
Gastrointestinal 
Vomiting 
Hepatic 
Alkaline phosphatase 
Hepatic 
GGT (Gamma-Glutamyl 
transpeptidase) 
Pulmonary 
Hiccoughs (hiccups, singultus) 
Renal/Genitourinary 
Creatinine 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported through CTEP-AERS 
must also be reported in routine study data submissions. 
 
Note:  as in section 12.1:  This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are due January 31, April 
30, July 31, and October 31.  Instructions for submitting data using the CDUS can be found on the CTEP web site 
(http://ctep.cancer.gov).   
 
Note:  All adverse events that have occurred on the study, including those reported through CTEP-AERS, must be 
reported via CDUS. 
 
7.5 
Secondary AML/MDS 
 
Investigators are required to report cases of secondary AML/MDS occurring on or following treatment on NCI-
sponsored chemotherapy protocols using CTEP-AERS.   Refer to 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm for additional 
information about secondary AML/MDS reporting.  
 
7.6  
Serious Adverse Event (SAE) Reporting at MSKCC 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted electronically to the 
SAE Office at sae@mskcc.org.  The report should contain the following information: 
 
Fields populated from the CRDB: 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
 
 MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 


Memorial Sloan Kettering Cancer Center 
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• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following information: 
o 
An explanation of how the AE was handled 
o 
A description of the subject's condition 
o 
Indication if the subject remains on the study 
o 
If an amendment will need to be made to the protocol and/or consent form  
 
The PI’s signature and the date it was signed are required on the completed report. 
 
8 PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial agents 
administered in this study can be found in Section 7.1. 
 
8.1 CTEP-Supplied Investigational Agents:  temsirolimus and perifosine 
 
Temsirolimus (Torisel®) (CCI-779) (NSC#683864) 
 
8.1.1 
Chemical Name:  Sirolimus 42-ester with 2,2-bis (hydroxymethyl)-propionic acid 
 
8.1.2 
Other Names:  CCI-779, Torisel®, Rapamycin analog, WAY-130779 
 
8.1.3 
Classification:  Cell cycle inhibitor 
 
8.1.4 
Molecular Formula:  C56H87NO16    MW: 1030.30 daltons 
 
8.1.5 
Mode of Action:  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. 
 
8.1.6 
How Supplied:  TORISEL (temsirolimus) is supplied as a commercially labeled kit consisting of the 
following: 
 
 
8.1.6.1 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. 
 
8.1.6.2 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. 
 
8.1.7 
Preparation:  These mixing instructions apply to commercial TORISEL only. The investigationally 
labeled product is mixed differently. 
 
8.1.7.1 Protect from excessive room light and sunlight during preparation. 


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8.1.7.2 Follow this two step dilution process (TORISEL should only be diluted with the supplied 
diluent): 
 
 
 
Step 1 
Inject 1.8 mL of DILUENT for temsirolimus into the vial of temsirolimus concentrate for injection 
(25 mg/mL). A total volume of 3 mL (10 mg/mL) will be obtained. Mix well by gentle inversion 
of the vial. DO NOT SHAKE. Allow sufficient time for air bubbles to subside. The solution 
should be clear to slightly turbid, colorless to light-yellow in color and free from visual 
particulates. 
 
Step 2 
Withdraw the required amount of temsirolimus from the 10 mg/mL concentrate/diluent mixture 
prepated in Step 1. For doses less than 10 mg, filter the concentrate/diluent mixture using a 
syringe filter unit before measuring required volume. Further dilute with 0.9% sodium chloride 
injection in glass or polyolefin containers to a final concentration between 0.04 mg/mL and 1 
mg/mL. Mix by inversion of the bag and avoid excessive shaking. Inspect for visual particulates 
and discoloration prior to administration. 
 
Route of administration: Intravenous 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, prepare doses by less 
than 10 mg by filtering the concentrate/diluent mixture as noted previously between steps 1 and 2 
using a syringe filter unit. 
 
8.1.8 
Storage:  Refrigerate intact TORISEL kit at 2º-8ºC and protect from light. 
 
8.1.9 
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. 
 
8.1.10 
Route of Administration: Intravenous with an appropriate in-line filter (i.e. 0.2 to 5 micron) for all 
temsirolimus doses equal to or greater than 10 mg.  Do not use an inline filter for temsirolimus doses less than 
10 mg.  Protect from light during administration. 
 
8.1.11 
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). 
 
Temsirolimus is compatible with most infusion sets that are acceptable with paclitaxel. 
 
Infusion sets which have been qualified for use with temsirolimus include the following:  
• 
Baxter vented paclitaxel set 
• 
Baxter unvented paclitaxel set 
• 
Abbott #11947 tubing set 
• 
Alaris #72953 tubing set   
 
Other non-PVC tubings can be used with the following in-line filters: 
• 
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  


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• 
Baxter Paclitaxel IV 0.2 micron filter set (2C7555) 
• 
Codan 5 micron monofilter 
• 
Alaris extension filter set #20350E 
• 
Other polyethersulfone filters may be used. 
 
8.1.12 
Potential Drug Interactions:  
Temsirolimus is a CYP3A4 substrate.  Avoid concomitant treatment of temsirolimus with potent CYP3A4 
inhibitors and agents that have CYP3A4 induction potential.  
 
The combination of temsirolimus and sunitinib resulted in dose limiting toxicity at low doses of both agents.  
Avoid concomitant sunitinib during temsirolimus treatment.   
 
Temsirolimus and warfarin may interact to increase INR. Monitor warfarin patient’s PT/INR after starting and 
stopping temsirolimus. 
 
The combination of temsirolimus and ACE inhibitors resulted in angioedema-type reactions (including delayed 
reactions occurring up to 2 months after initiation of therapy).  
 
8.1.13 
Patient Care Implications:  For hypersensitivity prophylaxis, give diphenhydramine 25-50 mg I.V. 
(or comparable antihistamine) approximately 30 minutes before starting temsirolimus infusion.  Infuse 
over 30 minutes.  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 20 
mg IV, rather than cimetidine, because it lacks reported drug interactions.  If famotidine is unavailable, 
administer ranitidine 50 mg IV. Re-attempt infusion at a slower rate, possibly over one hour. 
 
Vaccinations:  Avoid the use of live vaccines during temsirolimus treatment. 
 
8.1.14 
Agent Ordering:  CCI-779 (temsirolimus, Torisel®) may be requested by the Principal Investigator 
(or their authorized designee) at each participating institution.  Pharmaceutical Management Branch 
(PMB) policy requires that agent be shipped directly to the institution where the patient is to be treated.  
PMB does not permit the transfer of agents between institutions (unless prior approval from PMB is 
obtained.)  The CTEP assigned protocol number must be used for ordering all CTEP supplied 
investigational agents.  The responsible investigator at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA form 1572 (Statement of Investigator), 
Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  
If there are several participating investigators at one institution, CTEP supplied investigational agents 
for the study should be ordered under the name of one lead investigator at that institution. 
 
CCI-779 (temsirolimus, Torisel®) may be requested electronically to PMB. Active CTEP-registered 
investigators and investigator-designated shipping designees and ordering designees can submit agent 
requests through the PMB Online Agent Order Processing (OAOP) application https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx. Access to OAOP requires the establishment of a CTEP 
Identity and Access Management (IAM) account https://eapps-ctep.nci.nih.gov/iam/ and the 
maintenance of an “active” account status and a “current” password. For questions about drug orders, 
transfers, returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
8.1.15 
Agent Accountability 
Agent Inventory Records – The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the inventory and disposition of all agents received from DCTD 


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58 
using the NCI Drug Accountability Record Form (DARF).  (See the CTEP home page at 
http://ctep.cancer.gov for the Procedures for Drug Accountability and Storage and to obtain a copy of 
the DARF and Clinical Drug Request form.) 
Perifosine (NSC # 639966) 
8.1.16 
Chemical name: 1,1-dimethyl-4-[[(octadecyloxy)hydroxyphosphinyl]oxy]-piperidinium inner salt 
8.1.17 
Classification:  Alkylphospholipid 
8.1.18 
Other names:  Octadecylphosphopiperidine (OPP), D-21266 
8.1.19 
Molecular Formula: C25H52NO4P  MW:  461.66 g/mol 
8.1.20 
Approximate Solubility:  
•
Water:  300 mg/mL
•
Methanol:  >800 mg/mL
•
0.1 m HCL:  280 mg/mL
•
0.1 m NaOH:  320 mg/mL
•
1-Octanol:  200mg/mL
8.1.21 
Mode of Action: Perifosine accumulates in cellular membranes and interferes with signal transduction 
pathway(s) 
8.1.22 
How Supplied: Perifosine is supplied as a film-coated tablet containing 50 mg of active ingredient, in bottles of 30 tablets. 
8.1.23 
One film-coated tablet contains: 
•
Perifosine 50 mg
•
Other ingredients (tablet core):
o
Corn Starch 112mg
o
Microcrystalline Cellulose (Avicel PH 101)  40mg
o
Dibasic Calcium PhosphateColloidal 40mg
o
Silicon Dioxide (Aerosil V 200) 5mg
o
Magnesium Stearate 5 mg
•
Other Ingredients (film coating):  hydroxypropyl methycellulose (Pharmacoat 603),
polyethylene glycol 6000, titanium dioxide, simethicone (Silbione antimousse 70454)
8.1.24 
Storage:  Store closed containers at room temperature (20-25o C).  Perifosine is hygroscopic, so containers 
must be kept closed and dry. 
8.1.25 
Perifosine tablets must be dispensed in the original container. 
8.1.26 
Stability: Stability testing program ongoing. 
8.1.27 
Route of Administration: Oral with meal(s). 
8.1.28 
Potential Drug Interactions:  None reported.  However, perifosine is extensively bound to human serum 
proteins including albumin and alpha-acid glycoprotein. 
8.1.29 
Availability: Perifosine is an investigational agent supplied to investigators by the Division of Cancer 


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Treatment and Diagnosis (DCTD), NCI. 
 
 
Perifosine is provided to the NCI under a Cooperative Research and Development Agreement (CRADA) 
between Zentaris AG (formerly Asta Medica) and the DCTD, NCI (see Section 12.3). 
 
8.1.30 
Agent Ordering:  NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) policy requires 
that agent be shipped directly to the institution where the patient is to be treated.  PMB does not permit 
the transfer of agents between institutions (unless prior approval from PMB is obtained.)  The CTEP-
assigned protocol number must be used for ordering all CTEP-supplied investigational agents.  The 
responsible investigator at each participating institution must be registered with CTEP, DCTD through 
an annual submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental 
Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution. 
 
Agent may be requested electronically to PMB. Active CTEP-registered investigators and investigator-
designated shipping designees and ordering designees can submit agent requests through the PMB 
Online Agent Order Processing (OAOP) application https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx. Access to OAOP requires the establishment of a CTEP 
Identity and Access Management (IAM) account https://eapps-ctep.nci.nih.gov/iam/ and the 
maintenance of an “active” account status and a “current” password. For questions about drug orders, 
transfers, returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
8.1.31 
Agent Accountability 
Agent Inventory Records – The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the inventory and disposition of all agents received from DCTD 
using the NCI Drug Accountability Record Form (DARF).  (See the CTEP home page at 
http://ctep.cancer.gov for the Procedures for Drug Accountability and Storage and to obtain a copy of 
the DARF and Clinical Drug Request form.) 
 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful record of the 
inventory and disposition of all agents received from DCTD using the NCI Drug Accountability 
Record Form.  See the CTEP web site for Policy and Guidelines for Accountability and Storage of 
Investigational Drugs (http://ctep.cancer.gov/requisition/storage.html). 
 
8.2 
 
Other Investigational Agent(s):  N/A 
 
8.3 
 
Commercial Agent(s):  N/A 
 
9 CORRELATIVE/SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Studies 
 
9.1.1 
All patients – molecular profiling of archival tissue 
 
9.1.1.1 Collection of Specimen(s):   
 
Pre-treatment tissue will be collected in all patients.  If available, this will be from the surgery that 
occurred most recently in relationship to study registration.  However, specimens from other prior 
surgery(s) may also be collected if available.  For patients who develop tumor progression while 


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on study and undergo re-operation, tissue resected following disease progression will be used to 
determine molecular correlates of treatment failure.  
 
 
 A representative paraffin tissue block (at least 5 mm x 5 mm) or at least 15 unstained slides 
(preferably 30) will be requested from the Department of Pathology at Memorial Sloan Kettering 
Cancer Center (MSKCC) for patients who underwent a prior surgery at MSKCC.  For patients 
who underwent surgery elsewhere, the block (or 30 unstained slides if the block is unavailable) 
will be requested and sent as 5.1.3.1 and in 9.1.1.3. 
 
 
 
 Patients undergoing tumor resection at MSKCC routinely have tissue flash frozen in liquid 
nitrogen immediately after removal and stored at -70 degrees Celsius.  When available, such tissue 
will also be procured from the brain tumor bank of the MSKCC Brain Tumor Center. 
 
 
 
 Optional:  One tube of blood will also be collected before starting treatment and research for 
future research purposes. 
 
9.1.1.2    Handling of Specimens(s): 
 
 Paraffin blocks will be cut by the Department of Pathology into unstained slides using standard 
procedures for routine clinical testing by immunohistochemistry and FISH.  Unstained slides will 
also be handled according to routine procedures at room temperate. 
 
9.1.1.3    Shipping of Specimen(s): 
 For patients who underwent surgery at a center other than MSKCC, a representative paraffin 
tissue block (at least 5 mm x 5 mm) or at least 15 unstained slides (preferably 30) will be 
requested and shipped to the PI, Thomas Kaley, MD by overnight courier at room temperature.   
 
9.1.1.4  Site Performing Correlative Studies: 
 FISH analysis will be performed in the FISH laboratory in the Pathology Department at Memorial 
Sloan Kettering Cancer Center and other assays in the laboratories of Cameron Brennan, MD and 
Eric Holland, MD, PhD at Memorial Sloan Kettering Cancer Center or their designee(s). 
 
 
 
The following studies will be performed: 
• 
FISH for EGFR amplification, PDGFRA amplification, and NF1 loss and others 
• 
Immunohistochemistry for NF1 under-expression, PDGF ligand, PTEN, AKT, pAKT, 
mTOR, p-mTOR, S6K, pS6K, ERK, pERK, and Ki67 and others 
• 
Western blot of homogenized flash frozen tissue (when available) for NF1, PDGF 
(ligands), PTEN, AKT, pAKT, S6K, pS6K, ERK, pERK, and proliferating cell nuclear 
antigen (PCNA) and others if immunohistochemistry fails for these markers. 
• 
TUNEL 
 
If sufficient tissue is available (paraffinized and/or frozen), we will also perform 
• 
RNA extraction for RTPCR analysis of DLL3, SOX4, NCAM1, and Doublecortin 
overexpression and others 
• 
DNA extraction for mutational analysis of PTEN, AKT, PI3K, mTOR, EGFR, NF1, and 
others 
 
9.1.2             Molecular effects during treatment 
The evaluation of the in vivo biological activity of these agents will be based on a within patient 
comparison of PI3K/AKT/mTOR/S6K signaling and cell proliferation in pre-treatment archived tissue to 
the tissue acquired during treatment as part of the phase II surgical substudy.  The therapy will be 
considered molecularly effective if the phosphorylation of PI3K/AKT/mTOR/S6K is decreased by at least 
one level based on the pathology grading for those markers which are positive in the pretreatment tissue for 


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that patient. (See discussion of the assays to be used in the laboratory correlates section.)  Given the small 
number of patients who will undergo surgery, these studies will also be considered exploratory. 
 
 
 
9.1.2.1 Collection of Specimen(s): 
 
 
 
 
see section 5.1.3.2 
 
 
 
9.1.2.2 Handling of Specimens(s): 
 
 
 
 
see section 5.1.3.2 
 
 
 
9.1.2.3 Shipping of Specimen(s): 
 
 
  
Not applicable (all resections on the surgical substudy will occur at Memorial Sloan Kettering 
Cancer Center) 
 
 
 
9.1.2.4  Site Performing Correlative Study:    
 
 
  
All assays will be performed in the laboratories of Cameron Brennan, MD and Eric Holland, 
MD, PhD at Memorial Sloan Kettering Cancer Center or their designee(s). 
 
As in 9.1.1, assays for effects on AKT and RAS signaling, proliferation, and apoptosis will be 
performed including: immunohistochemistry for PTEN, AKT, pAKT, mTOR, p-mTOR, S6K, 
pS6K, ERK, pERK, Ki67; TUNEL; Western Blot for PTEN, AKT, pAKT, S6K, pS6K, ERK, 
pERK, and proliferating cell nuclear antigen (PCNA). 
 
 
9.2 Special Studies:  N/A 
 
10 
STUDY CALENDAR 
 
   
Pre-
Study Wk 
1i 
Wk 
2 
Wk 
3 
Wk 
 4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 , etc 
Off 
Study 
 
 Temsirolimus and 
perifosinea 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Concurrent meds 
 
X 
 
X----------------------------------------------------------------------------------------------X 
 
 
 
Physical/Neuro exam 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Vital signs 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Performance status 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
CBC w/diff, pltsb 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
PT, PTT, INRc 
 
X 
 
 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
 
 
 
 
 
 
 
 
Serum chemistryd,e 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 


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11 MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect 
 
The primary endpoint of this study is a hybrid of:   6-month progression free-survival (with the start date 
defined as the first treatment dose in the phase II component for patients not on the surgical substudy, and from 
the first post-operative treatment dose for patients enrolled on the phase II surgical substudy) and radiographic 
response (among patients with measurable disease at the start of treatment).  Patients enrolled to the phase I 
component who are treated at the MTD and otherwise qualify for the phase II study will be included in all phase 
II efficacy analyses.   
 
As the primary efficacy analysis includes prolonged disease stabilization as a success (6mPFS), patients without 
measurable disease are eligible whether they enroll post-operatively following a gross-total resection or whether 
they undergo a gross total resection as part of the phase II surgical substudy.  However, for patients with 
measurable disease either at the start of treatment (at study entry or post-operatively on the surgical substudy), 
radiographic responses will be measured.   
 
For the purposes of this study, patients should be re-evaluated for response approximately every 8 weeks.  The 
same technique (CT or MRI) must be used for intrapatient comparisons throughout the study. 
 
11.2 
Definitions 
Evaluable for toxicity:   All patients who receive any study treatment will be evaluable for toxicity from the 
time of their first treatment with temsirolimus and/or perifosine.   
 
Serum lipidsf 
    X 
   
  X 
  X 
   X 
   X 
 
   X 
 
   X 
 
   X 
 
     X 
 
Adverse event evaluation 
 
 
  X --------------------------------------------------------------------------------------------X 
 
X 
 
 
Tumor measurements 
 
 
X 
 
Tumor measurements are repeated every 8 weeks (May be performed up to 2 weeks 
early) 
 
 
X 
 
Radiologic evaluationg 
 
X 
 
Radiologic measurements should be performed every 8 weeks (May be performed up 
to 2 weeks early) 
 
X 
 
B-HCG 
 
Xh 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
a:     Temsirolimus administered weekly, Perifosine administered daily. 
b:     Following the 1st treatment:  Weekly for first 4 weeks and then every 2 weeks. Phase II patients with stable bloodwork after 16 weeks 
can have these laboratory tests monthly. 
c:     Following the 1st treatment:  For patients on warfarin, every 1-2 weeks, or sooner, if clincically indicated; otherwise, at the discretion of 
the treating physician. 
d.    Following the 1st treatment:  Alkaline phosphatase, total bilirubin, carbon dioxide, BUN, calcium, chloride, creatinine, glucose, 
phosphorus, sodium, potassium, total protein, SGOT[AST], SGPT[ALT] weekly for 4 weeks then every 2 weeks.  Phase II patients 
with stable bloodwork after 16 weeks can have these laboratory tests monthly.  Uric acid should be checked at baseline and then during 
treatment as clinically indicated. 
e.     Patients with diarrhea should have more frequent monitoring of electrolytes at the discretion of the investigator. 
f.     Following the 1st treatment:  Fasting triglycerides and cholesterol weekly for first 4 weeks then every 2 weeks.  Phase II patients with 
stable bloodwork after 16 weeks can have these laboratory tests monthly. 
g.     MRI or CT at baseline and every 8 weeks (may be performed up to 2 weeks early).  An FDG-PET scan should be performed after 1-2 
weeks of therapy and every 4th cycle (16 weeks).  A NON-CONTRAST HEAD CT OR AN MRI WITH GRADIENT ECHO 
SEQUENCE MUST ALSO BE PERFORMED DURING WEEK 2 TO EVALUATE FOR HEMORRHAGE (see  5.1.3). 
h:     Serum pregnancy test (women of childbearing potential).    
i.      Note: all tests and evaluations performed for baseline can also serve as those required for week 1, as long as they are within the starting 
timeframes of treatment initiation. 
NOTE:  All laboratory tests, assessments, and treatments are permitted a window of +/- 3 days to 
accommodate patient scheduling, weekends, and/or holidays 
 


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Evaluable for 6-month progression-free survival:  All patients who receive any study treatment on the phase II 
study and those on the phase I treated at the MTD who otherwise qualify for the phase II will be evaluable for 
6mPFS except those that are removed from the study before the end of cycle 1 for reasons other than clinical 
progression (such as toxicity).  Patients who suffer clinical progression without radiographic confirmation of 
progression will be considered to have progressive disease in determination of 6mPFS.  Clinical progression 
requires the absence of other causes of decline, such as anticonvulsant toxicity or overly rapid corticosteroid 
taper, and that steroids be increased to a prior level before scoring as progression. 
 
Evaluable for radiographic response (CR or PR):  Only those patients who have measurable disease (defined 
below) present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
radiographically will be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  Patients with measurable disease at study entry who suffer clinical 
progression without radiographic confirmation of progression will be considered to have progressive disease in 
determination of radiographic response rate.  Clinical progression requires the absence of other causes of 
decline, such as anticonvulsant toxicity or overly rapid corticosteroid taper, and that steroids be increased to a 
prior level before scoring as progression. 
 
Disease will be defined as either measurable or non-measurable: 
Measurable Disease:  Bi-dimensionally measurable lesions with clearly defined margins by CT or MRI scan of 
at least 1 cm by 1 cm.  For patients on the surgical substudy, the baseline study used to determine existence of 
measurable disease will be either the post-operative MRI or a later MRI used as the new baseline before re-
starting therapy post-operatively.  Note that patients who undergo gross total resection, either on the phase II 
surgical substudy or immediately pre-enrollment not as part of the protocol, have non-measurable disease.  The 
surgical cavity without a measurable mass of tumors should not be defined as measurable. 
 
Objective Status, To Be Recorded at Each Evaluation: If there are too many measurable lesions to 
measure at each evaluation, choose the largest two to be followed before a patient is entered on study.   
 
Progression-Free Survival:  Duration of time from the date of the start of treatment to the date of 
progression or death from any cause. 
 
Overall survival:  Duration of time from the date of start of treatment to date of death from any cause. 
 
Start of treatment:  Date of the first treatment dose for all patients except those on the surgical substudy 
of phase II for whom it is defined as the date of the first post-operative drug administration. 
 
11.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers or 
electronically using imaging software.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 2 weeks before the beginning of the 
treatment.  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 when both methods have been used to assess the 
antitumor effect of a treatment. 
 
11.4 
Response Criteria 
Response and progression will be evaluated in this study using standard criteria for patients with 
malignant gliomas.(Macdonald, Cascino et al. 1990)  A major difference from RECIST and other 
criteria for measuring response in solid tumors is the requirement that patients be on a stable or 
decreasing dose of corticosteroids when evaluating for response because of the potentially confounding 
impact of corticosteroids on contrast enhancement during brain tumor imaging by CT(Cairncross, 
Macdonald et al. 1988) or MRI(Watling, Lee et al. 1994) scans.  The tumor size will be measured in 


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64 
 
millimeters and is the largest cross-sectional area using perpendicular measurements of contrast 
enhancing abnormality. 
 
If there are too many measurable lesions to measure at each evaluation, choose the largest two to be 
followed before a patient is entered on study.  The remaining lesions will not be considered measurable 
for the purpose of objective status determination.  Unless progression is observed, objective status can 
only be determined when ALL measurable and sites are assessed. 
 
Complete Response (CR):  Complete disappearance of all measurable disease and all non-measurable 
disease using the same technique (MRI or CT) as baseline.  Patients must be on no steroids.  
Confirmed on follow up MRI/CT at least 1 month later. 
 
Partial Response (PR):  Greater than or equal to 50% decrease under baseline in the sum of products 
of perpendicular diameters of all measurable lesions.  No progression of non-measurable disease.  No 
new lesions.  All measurable and non-measurable lesions and sites must be assessed using the same 
techniques as baseline.  The steroid dose at the time of the scan evaluation should be no greater than 
the maximum dose used in the first 8 weeks from initiation of therapy.  Confirmed on follow up 
MRI/CT at least 1 month later. 
 
Stable/No Response: Does not qualify for CR, PR, or progression. All measurable and non-measurable 
sites must be assessed using the same techniques as baseline.  The steroid dose at the time of the scan 
evaluation should be no greater than the maximum dose used in the first 8 weeks from initiation of 
therapy. 
 
Progression: 25% increase in the sum of products of all measurable lesions over smallest sum 
observed during treatment (which may be smaller than baseline) using the same techniques as 
baseline, OR clear worsening of any non-measurable disease, OR appearance of any new lesion/site, 
OR clear clinical worsening or failure to return for evaluation due to death or deteriorating condition 
(unless clearly unrelated to this cancer). 
 
Unknown: Progression has not been documented and one or more measurable or non-measurable  
site(s) have not been assessed. 
 
Best Overall Response:  For patients with all disease sites assessed every evaluation period, the best 
response will be defined as the best objective status as measured according to Section 11.4.  If the 
response does not persist on an MRI at least 1 month later, the response will still be recorded based on 
the prior scan, but will be designated as a non-sustained response. If the response is sustained, e.g. still 
present on the subsequent MRI, it will be recorded as a sustained response, lasting until the time of 
tumor progression.  Best response is unknown if the patient did not have measurable disease either at 
study entry or post-operatively for patients on the surgical substudy of phase II or if all objective status 
determinations before progression are unknown. 
 
12 DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: 
List and Reporting Requirements). 
 
12.1 
Data Reporting  
 
Method:  This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are due 
January 31, April 30, July 31, and October 31.  Instructions for submitting data using the CDUS can be 


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found on the CTEP web site (http://ctep.cancer.gov).  Note:  All adverse events that have occurred on 
the study, including those reported through CTEP-AERS, must be reported via CDUS. 
 
Responsibility for Data Submission:  N/A (single institution study) 
 
 
12.2 
CTEP Multicenter Guidelines: N/A 
 
 
 
12.3 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement 
(CTA) 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and Diagnosis.  
Therefore, the following obligations/guidelines, in addition to the provisions in the “Intellectual 
Property Option to Collaborator” (http://ctep.cancer.gov/industry) contained within the terms of award, 
apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study.  Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the 
investigators.  The protocol documents for studies utilizing investigational Agents contain 
confidential information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member participating 
on the study, the individual should sign a confidentiality agreement.  A suitable model agreement 
can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with (an)other 
investigational Agent(s), each the subject of different collaborative agreements , the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use shall 
hereinafter be referred to as "Multi-Party Data.”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the existence and nature 
of any agreements governing their collaboration with NIH, the design of the proposed 
combination protocol, and the existence of any obligations that would tend to restrict NCI's 
participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by 
any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials must agree in 
writing prior to the commencement of the trials that it will use the Multi-Party Data solely for 
development, regulatory approval, and commercialization of its own investigational Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be 
made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order.  Additionally, all Clinical Data and Results 
and Raw Data will be collected, used, and disclosed consistent with all applicable federal statutes 
and regulations for the protection of human subjects including, if applicable, the Standards for 
Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 


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4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or 
PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC 
for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group 
office for Cooperative Group studies or by the principal investigator for non-Cooperative Group 
studies for immediate delivery to Collaborator(s) for advisory review and comment prior to 
submission for publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to an additional 30 
days in order to ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected.  Copies of abstracts must be provided 
to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably 
at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings.  Press releases and other media presentations must also be 
forwarded to CTEP prior to release.  Copies of any manuscript, abstract and/or press release/ 
media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
13 STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
Phase I:  
Up to 42 patients will be enrolled in the phase I portion of this study (6 patient X 7 cohorts= 42 total 
patients).  A standard phase I design will be used to determine the MTD of combined perifosine and 
temsirolimus.  To determine the MTD, a dose escalation scheme with patients entering in cohorts of 3 
at each dose level will be used.  The MTD will be defined as the dose at which fewer than one-third of 
patients experience a DLT.   
 
The dose of temsirolimus will be escalated in groups of 3 patients, with 3 additional patients enrolled 
at the first sign of a DLT.  There will be no intra-patient dose escalation.  If 0 of 3 patients experience a 
DLT at a dose level, then 3 patients will be enrolled at the next dose level.  If 1 of 3 patients 
experiences a DLT at a dose level, then 3 additional patients will be enrolled at the same dose level.  If 
1 of 6 patients experiences a DLT at that dose level, then 3 additional patients will be enrolled at the 
next dose level.  However, if 2 or more of 6 patients (or 3 or more of 9 patients, etc.) at a dose level 
experiences a DLT, then the MTD is defined as the previous dose level.  Six patients will be treated at 
a dose level being considered as the MTD.  A cohort may be expanded to more than 6 patients if the PI 
and CTEP medical monitor agree more information is needed to clarify whether a DLT has occurred or 
the MTD has been reached. 
 
If the first dose level exceeds the MTD, then the dose will be de-escalated to level -1.  If one-third or 
more of patients experience DLT at level -1, then the level will be reduced to level -2, etc.   Using this 


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scheme, the probability of escalating to the next higher dose level, based on the true rate of DLT at the 
current dose, is: 
 
                                              True Toxicity at a Given Dose   
                                         
10% 
20%    30%    40%    50%    60% 
Probability of Escalating         .91     .71       .49       .31       .17       .08 
 
Therefore, if the true underlying proportion of DLTs is 50% at a given dose level, then there is a 17% 
chance of escalating to the next dose.  Baseline characteristics will be summarized across all enrolled 
patients. 
 
Patients completing 28 days of therapy or patients removed for toxicity earlier than 28 days are 
evaluable. Patients removed from study within 28 days for reasons other than toxicity may be 
replaced.   
 
An accounting will be done of all patients registered in the study.  The number of patients who died or 
withdrew before treatment began will be specified.  Patients who did not meet all eligibility criteria 
will be described.  Patients who were evaluated separately due to first-cycle non-drug-related death or 
cessation of first-cycle therapy prior to DLT will be characterized.  Treatment administration will be 
described for all cycles.  Doses administered, dose modifications or delays, and duration of therapy 
will be evaluated.  Safety variables will be summarized by descriptive statistics.  Adverse events that 
occur will be reported for each dose level and described in terms of incidence and severity.  Laboratory 
data will be presented by dose level at each observation time. Values outside of normal limits will be 
identified and their frequency calculated.  Parameters will be described based on the CTCAE version 
4.0 severity grading.  Distribution by CTC severity grade (when applicable) and clinical relevance will 
be given. 
 
 
 
Phase II: 
 
The primary clinical objective of this phase of the study will be to determine if temsirolimus and 
perifosine in combination can significantly delay progression and/or induce tumor responses in patients 
with recurrent malignant gliomas.  The trial cohort will include both GBM and Anaplastic Glioma 
(AG) patients. The primary endpoint is a hybrid endpoint of progression-free survival (PFS) at 6 
months and radiographic response.  The calculation of PFS for patients will be determined from the 
first day of study drug administration except for those in the surgical substudy for whom it will be 
calculated from the first day of study drug administration following surgery. 
 
The historical values for comparison are from a database of 225 GBM patients enrolled in 8 previous 
phase II studies (in which none of the treatments were considered particularly effective).(Wong, Hess 
et al. 1999)  In this database, the 6 month PFS was 15% for GBM.  The 6 month PFS for patients 
treated with BCNU for recurrence/progression was 17.5%.(Brandes, Tosoni et al. 2004)  Therefore, we 
would expect 6 month PFS to be less than 20% in molecular unselected recurrent GBMs. 
 
However, these ineffective 6mPFS rates of 15%-20% were derived from trials that accrued patients 
without regard to molecular profiling, and without accepting radiographic responses as evidence of 
efficacy.  The modeled GBMs in mice used in the pre-clinical testing of combined therapy with 
temsirolimus and perifosine are driven by forced PDGF ligand expression.  Therefore, this therapy 
may be more effective in human tumors also exhibiting a PDGF-like signaling profile than in other 
tumors.  Molecular profiling work from The Cancer Genome Atlas and at Memorial Sloan Kettering 
demonstrates 3 main profiles of GBMs:  PDGF, EGFR, and NF1.  The accrual for this study will 
include a mixture of enriched patients that present with the PDGF-like molecular profile and 
nonenriched patients that do not have this profile. It is expected that the accrual ratio of nonenriched to 


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enriched patients will be 3:1 because tumors of other molecular profiles are approximately 3 times as 
common as those with the PDGF-like profile.  We will profile tumors in all patients (phase I and II) 
and may observe a higher level of efficacy among patients with tumors exhibiting the enriched profile. 
 
For the phase II study, a two-stage design will be used to assess treatment activity for this mixture 
patient population.  For the purpose of this study, a patient will be defined as a success if he/she 
remains alive and progression free for six months from the start of treatment or attains a radiographic 
response.  We will set the insufficient success rates at ≤0.25 for the enriched patient population and 
≤0.15 for the non-enriched patient population.  Sufficient success rates for the enriched and 
nonenriched populations are set at ≥0.45 and ≥0.35, respectively.  In the first stage, 20 patients will be 
enrolled in the study.  If ≤4 successes (either response or 6mPFS) are observed, then the trial will be 
stopped.  If ≥5 successes are observed, then 22 additional patients will be accrued, for a total of 42 
patients. 
 
At the end of the second stage, if ≤9 patients with GBM reach 6 months of progression-free survival, 
then, we will conclude that the treatment is not sufficiently active in recurrent/progressive GBMs. The 
design has power 0.90 for a population success proportion of 0.45/0.35 in the enriched/nonenriched 
populations, using a 0.10 size test for success rates of 0.25/0.15 in the enriched/nonenriched 
populations. 
 
In addition to the assessment of the population success rate in this population, the crude incidence rates 
for the probability of remaining alive and progression free for six months, patient response, and 
toxicity will be computed along with the attendant 95% confidence intervals. Kaplan-Meier estimates 
of the progression-free and overall survival distributions will be computed as a function of time in the 
whole group and stratified by molecular profile. 
 
 Although it is estimated that 25% of patients will be enriched patients, we do not stratify accrual based      
on this factor.  If the treatment regimen appears promising given the observed mixture of 
enriched/nonenriched patients then additional patients may be accrued in order to obtain 10 enriched 
patients.  Outcomes (e.g., response, progression rate, toxicity) will be summarized descriptively for 
these patients.  
 
Anaplastic gliomas 
Up to 10 patients with anaplastic gliomas will be accrued to the phase II study.  Endpoints such as 
response, median overall survival, and median progression-free survival will be computed in order to 
gain preliminary data for these other malignant glioma subtypes.  However, the historical controls for 
patients with anaplastic glioma are less well defined than for GBM; therefore, only patients with GBM 
will be included in analyses of efficacy.  Archival tissue will be profiled to explore whether profiling 
influences response in such patients.  
 
Prior treatment with bevacizumab or other direct inhibitors of VEGF/VEGFR including Aflibercept 
(VEGF-Trap) and cedirinib and XL-184 (BMS 907351). 
There is no limit on such therapy for the phase I study for which determination of MTD is the primary 
endpoint.  For the phase II study, however, the historic control data available for efficacy goals after 
treatment with bevacizumab or other similar therapy is extremely limited.  For example, the only such 
data that exists is from two retrospective analyses, currently published only in abstract form:  one of 44 
patients at Dana Farber Cancer Center (Quant et al., 2008) and the other of 14 patients at Memorial 
Sloan Kettering Cancer Center (Lassman et al., 2008).  The historic control data sets typically used for 
recurrent GBM trials (Wong et al., 1999; Lamporn, et al., 2008) did not include patients treated with 
bevacizumab or similar drugs.  Therefore, it is difficult to reasonably estimate efficacy goals for this 
population.  In addition, discontinuation of such agents can lead to rapid clinical deterioration and 
rebound contrast enhancement that can confound MRI interpretation. 


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However, it is possible that during the course of this study, the use of bevacizumab or other direct 
VEGF/VEGFR inhibitors will become routine for treatment of gliomas.  Therefore, to explore efficacy 
of the experimental regimen in this protocol following treatment with bevacizumab or other 
VEGF/VEGFR directed agents, we will accrue up to 15 patients who received prior treatment with 
direct VEGF/VEGFR inhibitors in order to gain preliminary data for use as a comparison group in a 
follow up study.  Although there are not a sufficient number of patients in each group to formally test 
treatment efficacy, the clinical outcomes for these patients will be summarized at the conclusion of the 
study.  Endpoints such as response, median overall survival, and median progression-free survival will 
be computed,.  However, only patients with GBM who are naïve to prior treatment with direct 
VEGF/VEGFR inhibitors will be included in analyses of efficacy.  Archival tissue will be profiled to 
explore whether profiling influences response in such patients. 
 
Surgical substudy 
In order to obtain specimens for study of molecular effects of drug therapy in tumor tissue, we plan to 
accrue up to 10 subjects to a preoperative treatment arm.  Although patients on the surgical substudy 
will have resections of tumor at the initiation of treatment, the natural history of recurrent GBM 
strongly supports the concept that nearly all patients will have tumor progression by 6 months if no 
further treatment or ineffective treatment is provided post-operatively.  For example, a review of 
patients with recurrent GBM treated for first relapse at the MD Anderson Cancer Center also supports 
the concept that gross total resection does not impact on 6-month PFS rate.  During the time from of 
2001-2003, 220 patients were treated at MD Anderson for first relapse or progression of GBM.  There 
was no difference in 6-month PFS between those patients who had a gross total resection at relapse 
compared with all other patients. (Mark Gilbert, personal communication).  Hence, we plan to combine 
data from patients on and not on the surgical substudy in efficacy analyses.  The calculation of PFS for 
patients enrolled in the pre-operative component of the study will be determined from the first day of 
study drug administration following surgery. 
 
Molecular profiling of pre-treatment tissue 
The analysis of the biological correlate data has the overall goal of providing an increased 
understanding of the nature of the response to temsirolimus and perifosine, and how it may be 
influenced by genetic characteristics of the tumor. The amount of data available for the various 
measures is uncertain. Assays utilizing historical paraffin tissues should be relatively complete, 
although the information may be limited by the impact of intervening treatment. The nature of the 
analyses and the strength of the conclusions from these laboratory studies depend not only on the 
amount of data available, but also on the nature of patient response to therapy. If a substantive 
response to treatment is found, there will be more opportunity to detect biological correlates. If the 
response is not favorable, the data may be used to understand better the reason for the failure. Thus it is 
difficult to pre-specify the nature of the analyses and all should be considered exploratory.  However, 
as in section 2.5, archival tissue will undergo molecular analysis for PI3K/AKT/mTOR/S6K and 
RAS/MEK/ERK signaling; proliferation; apoptosis; and categorized as PDGF, EGFR, or NF1-like if 
possible.  As above, we may observe more activity among tumors with PDGF than other profiles, and 
efficacy goals are higher for this group.   
 
Slides analyzed by immunohistochemistry will be scored for immunostaining on a 4 point scale (0-3) 
analogous to that developed by others. (Choe et al. 2003)  Band intensity on Western blot will be 
similarly scored on a 4 point scale as we have done previously (Lassman  et al. 2005).  Gene 
amplification by FISH will be defined as the presence of >4 gene copies to avoid categorizing tumors 
with polysomies as containing genes that are amplified   For example, polysomy for chromosome 7 is a 
relatively common finding in GBMs, leading to the presence of 4 copies, but does not correlate with 
EGFR amplification.  Finally, tumor DNA will be extracted from pre-treatment tissue and AKT, PI3K, 
PTEN, RAS, and ERK will be sequenced in all responders to identify mutations that may increase 


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perifosine sensitivity.  Such sequencing is crucial because it is an emerging paradigm that mutations in 
the genes encoding the targets of small molecule inhibitors can sensitize those targets to their inhibitors 
including mTOR inhibitors such as temsirolimus in myeloma (Shi et al., 2002) and GBM (Smith et al., 
2002) as MSKCC investigators have demonstrated in both non-small cell lung cancer (Pao et al., 2004) 
and glioblastoma (Mellinghoff et al. 2005; Cloughesy et al. 2007) 
 
We hypothesize that patients who respond to combination therapy of temsirolimus and perifosine or 
with at least 6 months of progression free-survival will have pre-treatment tumor tissue exhibiting high 
levels of AKT and RAS/ERK signaling because we hypothesize that these targets must be active for 
drug action, and because these signal transduction cascades are activated in the mouse GBM model 
system used in the ascertainment of the preclinical data.  As above, we hypothesize that tumors 
exhibiting a PDGF-like molecular profile may also exhibit greater sensitivity to the study treatment 
because the mouse GBM model used is a PDGF-ligand driven tumor. 
 
Molecular effects during treatment 
The evaluation of the in vivo biological activity of these agents will be based on a within patient 
comparison of PI3K/AKT/mTOR/S6K signaling and cell proliferation in pre-treatment archived tissue 
to the tissue acquired during treatment as part of the phase II surgical substudy.  The therapy will be 
considered molecularly effective if the phosphorylation of PI3K/AKT/mTOR/S6K is decreased by at 
least level by immunohistochemistry (and Western blot when sufficient frozen tissue is available for 
analysis) based on the pathology grading for those markers which are positive in the pretreatment 
tissue for that patient.  (See discussion of the assays to be used in the laboratory correlates section.)  
Effects on proliferation will be assessed by counting mitoses on standard H&E staining, and by Ki-67 
immunostaining to estimate the proliferation index (% of tumors staining per HPF).  Effects on 
apoptosis (TUNEL) will also be analyzed in paraffin embedded tissue.  Tissue data will be compared 
to data from our perifosine monotherapy trial (analysis underway) to determine molecular correlates of 
perifosine alone versus perifosine + temsirolimus.  Given the small number of patients (maximum 10) 
who will undergo surgery, these studies will also be considered exploratory. 
 
13.2 
Sample Size/Accrual Rate 
 
It is anticipated that the many dose levels of phase I will not be needed, that phase I will likely include 
patients with AG, and that patients treated on Phase I at the MTD who are otherwise eligible for Phase 
II will count toward Phase II accrual goals and be included in phase II efficacy analyses.  Therefore, 
although maximum enrollment is up to 92 patients (42 in phase I, 42 with GBM in phase II, 10 with 
AG if not already accrued to phase I and II), we anticipate the number of accrued patients will be far 
less. 
 
For phase II, we anticipate accrual of 3 patients per month.  Therefore, it is anticipated that the first 20 
on phase II stage I patients will be accrued in approximately 9 months.  In order to increase accrual 
rapidity, enrollment of patients to stage 2 will open and continue while patients on stage 1 are followed 
for response and PFS, and we will accept non-sustained radiographic responses as evidence of activity 
in stage 1 to fully accrue stage 2 (above).  However, if accrual to stage 1 is halted for lack of efficacy, 
then enrollment to stage 2 will terminate, and any patients still on trial with any histology may 
continue until progression or death at the discretion of the investigator, PI, and CTEP medical monitor. 
 
Patients removed for toxicity are evaluable.  Phase I patients removed from study within 28 days 
forreasons other than toxicity may be replaced. 
 
 
 
 


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Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
4 
+ 
4 
= 
8 
Not Hispanic or Latino 
12 
+ 
22 
=     34 
Ethnic Category: Total of all subjects 
16                      (A1) 
+ 
26 
       (B1) = 
42 
           (C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
 
Asian 
4 
+ 
4 
= 
 
Black or African American 
4 
+ 
4 
= 
 
Native Hawaiian or other Pacific Islander 
0 
+ 
0 
= 
 
White 
8 
+ 
18 
= 
 
Racial Category: Total of all subjects 
16 
      (A2) 
+ 
26 
       (B2) = 
42 
           (C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
Accrual Rate:         3 
pts/month  
Total Expected Accrual:         3 
Min 
       92 
Max 
 
 
13.3 
Stratification Factors  
 
The following cohorts will be accrued: 
Study Phase: 
Phase I or Phase II 
 
Prior direct VEGF/VEGFR inhibitor 
Yes or No 
 
histologically documented 
malignant glioma: 
Yes or No 
 
Histology at Registration: 
1) Glioblastoma (GBM), with the additional designation 
of: 
• 
GBM 
• 
Gliosarcoma (GS) 
• 
GBM with oligodendroglioma features 
• 
Giant cell GBM 
 
 
2) Anaplastic Glioma (AG) with the additional 
designation of: 
• 
Anaplastic Astrocytoma (AA) 
• 
Anaplastic Oligodendroglioma (AO) 
• 
Anaplastic Oligo-astrocytoma (AOA) 
• 
High grade glioma NOS (Difficult to subclassify) 
 


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Surgical substudy (phase II): 
Yes or No 
 
Measurable disease at registration 
Yes or No 
for non-surgical patients, post-operatively 
for surgical substudy patients: 
 
 
Molecular profile of baseline tissue: 
Enriched (PDGF) or non-enriched (other) with the 
additional designation for non-enriched of: 
• 
EGFR 
• 
NF1 
• 
Undetermined/Other 
Note this will be assessed in all patients but will not be 
determined prior to registration and treatment initiation. 
 
13.4 
Analysis of Secondary Endpoints 
 
Radiographic response rate will be reported according to the definitions above (Section 11.4).  This 
will be reported using all eligible patients who receive at least 1 dose of protocol therapy with 
temsirolimus and/or perifosine, and another section will detail the response rate for evaluable patients 
only (those with measurable disease at study entry or post-operatively among those enrolled on the 
phase II surgical substudy).  A response rate analysis on this subset will include an explanation of 
which patients were excluded from the analysis and for which reasons.  Calculations of 95% 
confidence limits will be given where applicable.  Median overall and progression-free survival will be 
calculated and include all eligible patients who received at least 1 dose of protocol therapy with 
temsirolimus and/or perifosine.  Biologic correlative goals include molecular analysis of pre-treatment 
tissue to identify both molecular predictors of response (using Fishers exact test) and molecular effects 
during treatment (using Wilcoxon rank sum test) as described in section 2.5 and section 9. 
 
13.5 
Reporting and Exclusions 
 
 
13.5.1 
Evaluation of toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with temsirolimus or perifosine. 
 
 
13.5.2 
Evaluation of efficacy.  All patients who receive any treatment with temsirolimus or 
perifosine will be assessed for the primary efficacy endpoint of 6 month progression-free 
survival, even if there are major protocol treatment deviations or if they are ineligible.  
 
 
       13.5.3 
Response rate:  All patients included in the study must be assessed for response to 
treatment, even if there are major protocol treatment deviations or if they are ineligible.   
 
Each patient will be assigned one of the following categories:  1) complete response, 2) 
partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data).  [Note:  By arbitrary convention, category 9 
usually designates the “unknown” status of any type of data in a clinical database.]  
 
All of the patients who met the eligibility criteria and who have measurable disease 
except those who received no study medication will be included in the main analysis of 
the response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 


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administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Cairncross, J. G., D. R. Macdonald, et al. (1988). Steroid-induced CT changes in patients with recurrent malignant 
glioma.  Neurology 38(5): 724-6. 
 
Chang, S.M., J. Kuhn, P. Wen, et al. (2004).  Phase I/pharmacokinetic study of CCI-779 in patients with recurrent 
malignant glioma on enzyme-inducing antiepileptic drugs.  Invest New Drugs.  22:427-435.  
 
Chang, S. M., P. Wen, et al. (2005). Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. 
Invest New Drugs 23(4): 357-61. 
 
Choe, G., S. Horvath, et al. (2003). Analysis of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma 
patients in vivo. Cancer Res 63(11): 2742-6 
 
Clarke, J. L., L. E. Abrey, et al. (2008). Pseudoprogression (PsPr) after concurrent radiotherapy (RT) and 
temozolomide (TMZ) for newly diagnosed glioblastoma multiforme (GBM) [abstract 2025]. J Clin Oncol 26(May 
20 suppl): abstr 2025. 
 
Cloughesy, T. F., K. Yoshimoto, et al. (2008). Antitumor activity of rapamycin in a Phase I trial for patients with 
recurrent PTEN-deficient glioblastoma. PLoS Med 5(1): e8. 


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Dancey, J.E.  (2002).  Clinical development of mammalian target of rapamycin inhibitors.  Hematol Oncol Clin 
North Am.  16:1101-1114. 
 
Farag, S.S., Zhang, S., Miller, M., et al. (2006) Phase II trial of temsirolimus (CCI-779) in patients with relapsed or 
refractory multiple myeloma (MM): Preliminary results. J Clin Oncol 2006  ASCO Annual Meeting Proceedings 
Part 1.  24:Abstract 7616. 
 
Dudkin, L., M.B. Dilling, P.J. Cheshire, et al.  (2001).  Biochemical correlates of mTOR inhibition by the rapamycin 
ester CCI-779 and tumor growth inhibition.  Clin Cancer Res.  7:1758-1764.   
 
Hilgard, P., T. Klenner, J. Stekar, et al. (1997).  D-21266, a new heterocyclic alkylphospholipid with antitumor 
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Hudes, G., Carducci, M., Tomczak, P., et al. (2006) A phase 3, randomized, 3-arm study of temsirolimus (TEMSR) 
or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line, poor-risk patients with 
advanced renal cell carcinoma (adv RCC). J Clin Oncol 2006 ASCO Annual Meeting Proceedings Part I. 24(8S 
(June 20 Supplement)):Abstract LBA4. 
 
Galanis, E. Buckner, J.C., Maurer, M.J., et al. (2005) Phase II trial of temsirolimus (CCI-779) in recurrent 
glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 23(23):5294-304. 
 
Geoerger, B., K. Kerr, C-B. Tang, et al. (2001).  Antitumor activity of the rapamycin analogue CCI-779 in human 
primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy.  
Cancer Res.  61:1527-1532. 
 
Hegi, M. E., A. C. Diserens, et al. (2005). MGMT gene silencing and benefit from temozolomide in glioblastoma. N 
Engl J Med 352(10): 997-1003. 
 
Hidalgo, M., and E.K. Rowinsky.  (2000).  The rapamycin-sensitive signal transduction pathway as a target for 
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Hidalgo, M., M.B. Atkins, W.M. Stadler, et al.  (2003).  A randomized double-blind phase 2 study of intravenous 
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Holland, E. C., J. Celestino, et al. (2000). Combined activation of Ras and Akt in neural progenitors induces 
glioblastoma formation in mice. Nat Genet 25(1): 55-7. 
 
Investigator's Brochure (Temsirolimus, CCI-779) 2007.  Wyeth Research. 
 
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Kondapaka, S., S. Singh, G. Dasmahapatra, et al. (2002).  Perifosine – a novel alkyllysophospholipid, modulates the 
Akt signaling pathway.  Proc Am Assoc Cancer Res.  Abstract 2977.  
 
Kuhn, J. G., S. M. Chang, et al. (2007). Pharmacokinetic and tumor distribution characteristics of temsirolimus in 
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Lamborn, K. R., W. K. Yung, et al. (2008). Progression-free survival: an important end point in evaluating therapy 


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for recurrent high-grade gliomas." Neuro Oncol 10(2): 162-70. 
Lassman, A. B., M. R. Rossi, et al. (2005). Molecular study of malignant gliomas treated with epidermal growth 
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Annual Meeting Proceedings Part 124(18S (June Suppl)):Abstract 3003. 
 
 
Pandya, K.J., Levy, D.E., Hidalgo, M., et al. (2005) A randomized, phase II ECOG trial of two dose levels of 
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http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7
010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=34&abstractID=30785 
 
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Perifosine Investigator’s Brochure, 1998.  Zentaris AG. 
 
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Shi, Y., J. Gera, L. Hu, et al.,  (2002).  Enhanced sensitivity of multiple myeloma cells containing PTEN mutations 
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Smith, S.G., C.N. Trinh, L.J. Inge, et al.,  (2002).  PTEN expression status predicts glioblastoma cell sensitivity to 
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APPENDIX A:  Performance Status Criteria 
 
 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
0 
Dead. 
 
 
 
 
 
 


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APPENDIX B:  EIAEDs and Non-EIAEDs 
 
EIAEDs: 
 
Carbamazipine  (Tegretol, Tegretol XR, Carbatrol) 
Oxcarbazepine 
(Trileptal) 
Phenytoin 
(Dilantin, Phenytek) 
Fosphenytoin 
(Cerebyx) 
Phenobarbital 
(Solfoton, and Luminal)       
Primidone 
(Mysoline) 
 
 
Non-EIAEDs: 
 
Valproic acid 
(Depakote, Depakene) 
Gabapentin  
(Neurontin) 
Lamotrigine 
(Lamictil) 
Topriamate 
(Topamax) 
Tiagabine  
(Gabatril) 
Zonisamide 
(Zonegran) 
Levatriacetam 
(Keppra) 
 
 
 
Clonazepam  
(Klonopin) 
Clobazam 
(Frisium) 


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APPENDIX C:   Drugs Metabolized by Selected CYP450 Isoenzymes 
 
 
 
Selected drugs known to be metabolized by CYP2D6 
 
CYP2D6 
 
SUBSTRATES 
 
INHIBITORS 
 
INDUCERS 
Generic Name 
Trade Name 
Generic Name 
Trade Name 
Generic Name 
Trade Name 
Methylphenidate 
Ritalin 
Methadone 
Dolophine 
None known 
 
Antidepressants:  e.g. 
    Amitriptyline 
    Clomipramine 
    Paroxetine 
 
Elavil 
Anafranil 
Paxil 
Antidepressants:  e.g. 
    Clomipramine 
    Paroxetine 
    Sertraline 
 
Thorazine 
Paxil 
Zoloft 
 
 
Antipsychotic agents: e.g. 
    Chlorpromazine 
    Haloperidol 
 
Thorazine 
Haldol 
Antipsychotic agents: e.g. 
    Chlorpromazine 
    Haloperidol 
 
Thorazine 
Haldol 
 
 
Analgesics: e.g. 
    Codeine 
    Oxycodone 
 
-- 
Oxycontin  
Antimalarials: e.g. 
    Chloroquine 
    Quinine 
 
Aralen 
Legatrin 
 
 
Anit-hypertensives: e.g. 
    Captopril 
    Metoprolol 
 
Capoten 
Lopressor 
Antifungals: e.g. 
    Ketoconazole 
    Miconazole 
 
Nizoral 
Lotramin 
 
 
Anti-neoplastics: e.g. 
    Doxorubicin 
    Tamoxifen 
 
Adriamycin 
Nolvadex  
Antihistamines: e.g. 
    Diphenhydramine 
    Tripelennamine 
 
Benadryl 
Di-delamine 
 
 
Methamphetamine 
Desoxyn  
Anti-virals: e.g. 
    Delavirdine 
    Ritonavir 
 
Rescriptor 
Norvir 
 
 
Lidocaine 
Xylocaine  
Lidocaine 
Xylocaine 
 
 
Mexiletine 
Mexitil 
Isoniazid 
Nydrazid 
 
 
Tolterodine 
Detrol 
 
Amiodarone 
Cordarone 
 
 
Dextromethorphan 
Tussin 
Methimazole 
Tapazole 
 
 
Chloroquine 
Aralen 
Cimetadine 
Tagamet 
 
 
 
 
Cocaine 
 
 
 
 
When drugs classified as ‘substrates’ are co-administered with temsirolimus, there is the potential for higher concentrations of the 
‘substrate’. When temsirolimus is co-administered with compounds classified as ‘inhibitors’, increased plasma concentrations of  
temsirolimus is the potential outcome. The coadministration of ‘inducers’ would potentially lower plasma temsirolimus concentrations. 
 
 
 
 
 
. 
 


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Comprehensive list of drugs that may have potential interactions with 
CYP2D6 
 
CYP2D6 
Substrates 
Amitryptilene 
Amoxapine 
Aripiprazole 
Atomoxetine 
Betaxolol 
Captopril 
Carvedilol 
Chloroquine 
Chlorpromazine 
Clomipramine 
Codeine 
Desipramine 
Dextroamphetamine 
Dextromethorphan 
Dihydrocodeine 
Doxepin 
Doxorubicin 
Flecainide 
Fluoxetine 
Fluphenazine 
Fluvoxamine 
Haloperidol Hydrocodone 
Imipramine 
Labetalol 
Lidocaine 
Lomustine 
Maprotiline 
Methamphetamine 
Methylphenidate 
Metoprolol 
Mexiletine 
Mirtazapine 
Nefazodone 
Nortriptyline 
Oxycodone 
Paroxetine 
Perphenazine 
Pindolol 
Procainamide 
Promethazine 
Propafenone 
Propranolol 
Risperidone 
Ritonavir  
Tamoxifen 
Tamsulosin 
Thioridazine 
Timolol 
Tolterodine 
Tramadol 
Trimipramine 
Venlafaxine 
 
 
Inhibitors 
Acebutolol 
Amiodarone 
Amitriptyline 
Amlodipine 
Amphetamine 
Azelastine 
Bepridil 
Betaxolol 
Biperiden 
Bortezomib 
Buprenorphine 
Bupropion 
Celecoxib 
Chloroquine 
Chlorpheniramine 
Chlorpromazine 
Cholecalciferol/Vitamin D3 
Cimetidine 
Cisapride 
Citalopram 
Clemastine 
Clomipramine 
Clotrimazole 
Clozapine 
Cocaine 
Codeine 
Delavirdine 
Desipramine 
Dexmedetomidine 
Dextromethorphan 
Diltiazem 
Diphenhydramine 
Disulfiram 
Dolasetron 
Doxorubicin 
Entacapone 
Escitalopram 
Felodipine 
Fexofenadine 
Flecainide 
Fluoxetine 
Fluphenazine 
Fluvastatin 
Fluvoxamine 
Gefitinib 
Halofantrine 
Haloperidol 
Hydroxyzine 
Imatinib 
Imipramine 
Indinavir 
Irbesartan 
Isoniazid 
Ketoconazole 
Labetalol 
Lansoprazole 
Lidocaine 
Lomustine 
Loratadine 
Lovastatin 
Mefloquine 
Methadone 
Methimazole 
Methotrimeprazine 
Methoxsalen 
Methylphenidate 
Metoclopramide 
Metoprolol 
Miconazole 
Mifepristone 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nortriptyline 
Olanzapine 
Omeprazole 
Ondansetron 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Perphenazine 
Pimozide 
Pindolol 
Pioglitazone 
Pravastatin 
Praziquantel 
Primaquine 
Promethazine 
Propafenone 
Propofol 
Propoxyphene 
Propanolol 
Pyrimethamine 
Quinidine 
Quinine 
Rabeprazole 
Ranitidine 
Risperidone 
Ritonavir 
Ropinirole 
Rosiglitazone 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Simvastatin  
Sulconazole 
Telithromycin 
Terbinafine 
Thioridazine 
Thiothixene 
Ticlopidine 
Timolol 
Tioconazole 
Tranylcypromine 
Trazodone 
Tripelennamine 
Triprolidine 
Valproic acid 
Venlafaxine 
Verapamil 
Vinblastine 
Vinorelbine 
Yohimbine 
Zafirlukast 
Ziprasidone 
 
Note:  There are no known CYP2D6 inducers. 
 
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In: Lacy CF, Armstrong LL, Goldman MP, Lance LL eds. Drug Information 
Handbook 12TH ed. Hudson, OH; LexiComp Inc. 2004: 1619-1631.) 
 
 


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Selected drugs known to be metabolized by CYP3A4 
 
CYP3A4 
 
SUBSTRATES 
 
INHIBITORS 
 
INDUCERS 
Generic Name 
Trade Name 
Generic Name 
Trade Name 
Generic Name 
Trade Name 
Anti-neoplastics: e.g. 
    Docetaxel 
    Gefitinib 
    Irinotecan 
 
Taxotere 
Iressa 
Camptosar 
Anti-arrhythmics: 
e.g. 
    Amiodarone 
    Diltiazem 
    Quinidine 
 
Cordarone, Pacerone 
Cardizem, Dilacor 
XR 
Cardioquin 
Aminoglutethimide 
Cytadren 
Anti-virals: e.g. 
    Amprenivir 
    Rifampin 
 
Agenerase 
Rifadin 
 
 
Anti-virals: e.g. 
    Amprenavir 
    Indinavir 
    Nelfinavir 
    Ritonavir 
 
Agenerase 
Crixivan 
Viracept 
Norvir 
Antibiotics: e.g. 
    Rifabutin 
    Rifampin 
 
Rifadin 
Mycobutin 
 
 
Anxiolytics: e.g. 
    Diazepam 
    Sertraline 
 
Valium 
Zoloft 
Cimetadine 
Tagamet 
Anticonvulsants: e.g.   
    Carbamazapine 
    Phenytoin 
    Pentobarbital 
    Phenobarbital 
 
Tegretol 
Dilantin 
Nembutal 
Luminal 
Cyclosporine 
Sandimmune 
Cyclosporine 
Sandimmune 
Hypericum perforatum 
(2) 
St. John’s 
Wort 
Anti-infectives: e.g. 
    Erythromycin 
    Tetracycline 
 
Erythrocin 
Sumycin 
Antibiotics: e.g. 
    Ciprofloxacin 
    Clarithromycin 
    Doxycycline 
    Enoxacin 
    Isoniazid 
    Telithromycin 
 
Cipro, Ciloxan 
Biaxin 
Adoxa, Periostat 
Penetrex 
Nydrazid, INH 
Ketek 
 
 
Steroids: e.g. 
    Estrogens, 
conjugated 
    Estradiol 
    Progesterone 
 
Premarin 
Climara 
Crinone 
Imatinib 
Gleevec 
  
 
Haloperidol 
Haldol 
Haloperidol 
Haldol 
 
 
Cardiovascular agents: 
e.g. 
    Digitoxin 
    Quinidine 
 
Crystodigin 
Cardioquin 
Diclofenac 
Cataflam, Voltaren 
 
 
Anti-hypertensives: e.g. 
    Nicardipine 
    Verapamil 
 
Cardene 
Calan, Chronovera 
Vasodilators: e.g. 
    Nicardipine 
    Verapamil 
 
Cardene 
Calan, Chronovera 
 
 
Anesthetics: e.g. 
    Ketamine 
    Lidocaine 
 
Xylocaine 
Diprivan 
Anesthetics: e.g. 
    Lidocaine 
    Propofol 
 
Xylocaine 
Diprivan 
 
 
Nefazodone 
     
Serzone 
Anti-depressants: 
e.g. 
    Nefazodone 
    Sertraline 
 
Serzone 
Zoloft 
 
 
Cocaine 
 
Anti-fungals: e.g. 
    Itraconazole 
    Ketoconazole 
   Miconazole 
 
Sporanox 
Nizoral 
Lotrimin, Monistat 
 
 
Ketoconazole 
Nizoral 
Caffeine 
 
 
 
Sildenafil 
Viagra 
Grapefruit juice (1) 
 
 
 
Albuterol 
Ventolin 
 
 
 
 
Carbamazapine 
Tegretol 
 
 
 
 
Lovastatin 
Mevacor 
 
 
 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Protocol 
 
IRB#: 09-058 A(14) 
 
Amended:  
Reviewed by OCR, JR 3/24/14 
 
84 
 
When drugs classified as ‘substrates’ are co-administered with  temsirolimus, there is the potential for higher concentrations of the ‘substrate’. 
When temsirolimus is co-administered with compounds classified as ‘inhibitors’, increased plasma concentrations of temsirolimus is the 
potential outcome. The coadministration of ‘inducers’ would potentially lower plasma temsirolimus concentrations. 
 
 
 
 
Comprehensive list of drugs that may have potential interactions with 
CYP3A4 
 
CYP3A4 
Substrates 
Albuterol 
Alfentanil 
Alprazolam 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Buprenorphine 
Buspirone 
Busulfan 
Carbamazapine 
Cerivastatin 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Cisapride 
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Colchicine 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Delavirdine 
Diazepam 
Digitoxin 
Dihydroergotamine 
Diltiazem 
Disopyramide 
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Efavirenz 
Eletriptan 
Enalapril 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, conj., synthetic 
Estrogens, conj., equine 
Estrogens, conj., esterified 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Felbamate 
Felodipine 
Fentanyl 
Flurazepam 
Flutamide 
Fosamprenavir 
Fulvestrant 
Gefitinib 
Halofantrine 
Haloperidol 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide dinitrate 
Isosorbide mononitrate 
Isradipine 
Itraconazole 
Ketamine 
Ketoconazole 
Lansoprazole 
Letrozole 
Levomethadyl acetate 
    hydrochloride 
Levonorgestrel 
Lidocaine 
Losartan 
Lovastatin 
Medroxyprogesterone Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methysergide 
Miconazole 
Midazolam 
Miglustat 
Mirtazapine 
Modafinil 
Montelukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Norethindrone 
Norgestrel 
Ondansetron 
Paclitaxel 
Pergolide 
Phencyclidine 
Pimozide 
Pioglitazone 
Primaquine 
Progesterone 
Quetiapine 
Quinidine 
Rabeprazole 
Repaglinide 
Rifabutin 
Rifampin 
Ritonavir 
Saquinavir 
Sertraline 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Tamsulosin 
Telithromycin 
Teniposide 
Terbinafine 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tolterodine 
Toremifene 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zolpidem 
Zonisamide 
Zopiclone 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Protocol 
 
IRB#: 09-058 A(14) 
 
Amended:  
Reviewed by OCR, JR 3/24/14 
 
85 
 
CYP3A4 
Inhibitors 
Acetominophen 
Acetazolamide 
Amioderone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffiene 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetadine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Cyclophosphamide 
Cyclosporine 
Danazol 
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit juice 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Isoniazid 
Isradapine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan 
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nitrendipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarpine 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapimil 
Vinblastine 
Vincristine 
Vinorelbine 
Zafirlukast 
Ziprasidone 
 
 
 
 
Inducers 
Aminoglutethimide 
Carbamazapine 
Fosphenytoin 
St. John’s wort 
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin 
Rifampin 
Rifapentine 
 
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In: Lacy CF, Armstrong LL, Goldman MP, Lance LL eds. Drug Information 
Handbook 12TH ed. Hudson, OH; LexiComp Inc. 2004: 1619-1631.) 
 
(1)  Malhorta et al. (2000). Clin Pharmacol Ther. 69:14-23 
 
(2)  Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249 
      Frye et al. (2004). Clin Pharmacol Ther. 76:323-329 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Protocol 
 
IRB#: 09-058 A(14) 
 
Amended:  
Reviewed by OCR, JR 3/24/14 
 
86 
 
 
APPENDIX D:  Patient Pill Diary 
 
NAME 
 
INITIALS 
 
MRN 
 
CYCLE 
For Optical Scanning: 
Document Code: RS3 – Research Patient    
Diaries 
 
DRUG NAME: ___________________________     
 
DAILY DOSE: ___________________________ 
DATE DIARY 
DISTRIBUTED 
/             / 
DATE DIARY RETURNED 
 
/             / 
 
Special Instructions: Take your medication as directed; when taking *study drug*, indicate your dose taken per day, and the time the pills were taken. Circle “no” if dose was 
missed. 
Day: 
Day: 
Day: 
Day: 
Day: 
Day: 
Day: 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: __________ 
 
 
Time:_____:_____ AM | PM  
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: __________ 
 
 
Time:_____:_____ AM | PM  
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
 
             
       
Page 1 of 2 
 
    Confirm that you took the perifosine with food :  Yes / No                                                        Patient Signature: _____________________________       Date: _____________ 
 


Memorial Sloan Kettering Cancer Center 
IRB Protocol 
 
IRB#: 09-058 A(14) 
 
Amended:  
Reviewed by OCR, JR 3/24/14 
 
87 
 
 
 
APPENDIX D:  Patient Pill Diary 
 
NAME 
 
INITIALS 
 
MRN 
 
CYCLE 
For Optical Scanning: 
Document Code: RS3 – Research Patient 
Diaries 
 
DRUG NAME: ___________________________     
 
DAILY DOSE: ___________________________ 
DATE DIARY 
DISTRIBUTED 
/             / 
DATE DIARY RETURNED 
 
/             / 
 
Special Instructions: Take your medication as directed; when taking *study drug*, indicate your dose taken per day, and the time the pills were taken. Circle “no” if dose was 
missed. 
Day: 
Day: 
Day: 
Day: 
Day: 
Day: 
Day: 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: __________ 
 
 
Time:_____:_____ AM | PM  
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: __________ 
 
 
Time:_____:_____ AM | PM  
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
Date:         
 
Pills Taken:   
YES  |  NO  
 
Daily  Dose: ___________ 
 
 
 
 
 
Time:_____:_____  AM | PM 
 
             
       
Page 2 of 2 
 
    Confirm that you took the perifosine with food :  Yes / No                                                        Patient Signature: _____________________________       Date: _____________


Memorial Sloan Kettering Cancer Center 
IRB Protocol 
 
IRB#: 09-058 A(14) 
 
Amended:  
Reviewed by OCR, JR 3/24/14 
 
88 
 
APPENDIX E: Drug Reconciliation Form 
 
 
Name 
MRN 
Cycle 
Dates Pills Taken 
 
/         /       -       /        / 
Pill Diary Returned 
 
YES      |      NO 
 
Pill Diary Completed 
 
YES      |      NO 
 
Drug Name 
Drug Lot Number 
Number of Pills 
Dispensed 
Pills Returned To 
 
PATIENT   |  PHARMACY 
Pill Bottle Returned 
 
YES      |      NO 
 
Number of Pills Returned 
Number of Pills Taken 
Number of Pills 
Missed 
Comments (If patient does not complete or return pill diary, explain and confirm patient’s compliance in the area provided) 
 
 
 
 
 
 
RN Name (please print):
 
RN signature:
 
Date/Time: Date:                                                      Time: