Conditions: Malignant Gliomas CNS Brain Cancer Cancer
Keywords: Malignant Gliomas CNS Brain Cancer Cancer Perifosine
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
The purpose of this study is to test the effectiveness of perifosine in preventing further tumor growth using the established optimal dose of the drug. A second goal is to determine if perifosine can block the molecules in the tumor that drive it to divide and grow.

Detailed description:
This is a phase II study of the small molecule inhibitor perifosine (NSC 639966, D21266, KRX-0401) in the treatment of patients with recurrent glioblastoma multiforme (GBM) and other recurrent malignant gliomas. The goal of the phase II study is to determine efficacy as measured by the progressionfree survival rate after 6 months of treatment. Secondary goals include determination of molecular and metabolic effects of perifosine by tissue analysis and PET imaging.

In addition, when cytoreductive surgery is recommended as part of the standard of care at study entry, patients will be considered for a "surgical arm." In this case, patients will receive perifosine for 5-10 days before surgery during which tumor will be aliquoted both for diagnostic purposes and for molecular effects of the drug in vivo and for analysis of drug penetration into tumor tissue.

Arms:
arm 1: Following a diagnosis of tumor recurrence or progression, all patients will receive perifosine monotherapy until toxicity, progression, or death.

Interventions: intervention 1: Perifosine
Intervention descriptions: intervention 1: Dosing will be continuous, and for the purpose of this trial a cycle will be defined as 28 days. Perifosine will be given as a 600 mg loading dose on day 1. The loading dose will be divided into 4 equal doses of 150 mg each. The first 3 doses should be given with food in the adult day hospital to allow intravenous antiemetic prophylaxis, and 4th dose at bedtime at home. The interval between doses of perifosine should be no less than 4 hours. On day 2, patients will start the maintenance dose of 100 mg daily at bedtime at home.

In addition to baseline serum, all patients will have weekly serum drawn during weeks 2-4.

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-044 A(11) 
Amended: 10/25/11 
 
 
Clinical and Molecular-Metabolic Phase II Trial of Perifosine for Recurrent/Progressive 
Malignant Gliomas 
 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator: 
Thomas Kaley, MD 
Co-Principal Investigator(s): 
Ingo Mellinghoff, MD 
Investigator(s): 
Lisa DeAngelis, MD 
Craig Nolan, MD 
Jerome Posner, MD 
Igor Gavrilovic, MD 
Philip Gutin, MD 
Viviane Tabar, MD 
Cameron Brennan, MD 
Eric Holland, MD 
Marc Rosenblum, MD 
Hilda Stambuk, MD 
Jason Huse, MD, PhD 
Eric Lis, MD 
Kathy Panageas, MD 
Antonio Omuro, MD 
Ingo Mellinghoff, MD 
Xi Chen, MD 
Timothy Akhurst, MD 
Consenting Professional(s): 
Ingo Mellinghoff, MD 
Thomas Kaley, MD 
Lisa DeAngelis, MD 
Adilia Hormigo, MD 
Craig Nolan, MD 
Jerome Posner, MD 
Igor Gavrilovic, MD 
Antonio Omuro, MD 
Ingo Mellinghoff, MD 
Xi Chen, MD 


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Collaborating Institution(s): 
Site Principal Investigator 
Site Role: 
Columbia University 
Andrew B. Lassman, MD 
Data Analaysis 
 
Clinical and Molecular-Metabolic Phase II Trial of Perifosine for Recurrent/Progressive 
Malignant Gliomas 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. 
New York, NY 10021 


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Table of Contents 
 
1.0 
PROTOCOL SUMMARY/ SCHEMA ………………………………………………….. 2 
2.0 
OBJECTIVES …………………………………………………………………………… 3 
3.0 
BACKGROUND ………………………………………………………………………... 4 
3.1 
MALIGNANT GLIOMAS…………………………………………………….….4 
3.2 
PERIFOSINE……………………….……………………………………………. 4 
3.3 
PERIFOSINE MECHANISM OF ACTION ……………………………………..5 
3.4 
PRE-CLINICAL STUDIES ………………………………………………………7 
3.5 
PERIFOSINE CLINICAL DATA……………………………………………….11 
3.6 
POTENTIAL IMPACT ON METABOLISM BY HEPATIC ENZYME 
INDUCING ANTIEPILEPTIC DRUGS (EIAEDS)…………………………….23 
4.0 
OVERVIEW OF STUDY DESIGN …………………………………………………….25 
4.1 
DESIGN …………………………………………………………………………25 
4.2 
INTERVENTION ……………………………………………………………….25 
5.0 
THERAPEUTIC/ DIAGNOSTIC AGENTS ……………………………………………26 
6.0 
ELIGIBILITY CRITERIA ………………………………………………………………27 
6.1 
INCLUSION CRITERIA ………………………………………………………..27 
6.2 
EXCLUSION CRITERIA ……………………………………………………...29 
7.0 
RECRUITMENT PLAN ………………………………………………………………...29 
8.0 
PRETREATMENT EVALUATION ……………………………………………………30 
9.0 
TREATMENT PLAN …………………………………………………………………...31 
9.1 
DOSING ………………………………………………………………………...31 
9.2 
PHARMCOKINETIC/DRUG CONCENTRATION IN TUMOR TISSUE 
(ALL PATIENTS) ………………………………………………………………31 
9.3 
TREATMENT MODIFICATIONS (ALL PATIENTS) ………………………..31 
9.4 
TREATMENT SCHEDULE FOR PATIENTS PARTICIPATING IN THE 
PRE-OPERATIVE STUDY …………………………………………………….32 
9.5 
SUPPORTIVE CARE GUIDELINES (ALL PATIENTS) ....................................33 
10.0 EVALUATION DURING TREATMENT ……………………………………………...35 
10.1 CLINICAL ………………………………………………………………………35 
10.2     LABORATORY ………………………………………………………………...35 
10.3 
IMAGING AND MOLECULAR STUDIES ……………………………………36 
11.0 
TOXICITIES …………………………………………………………………………….38 
12.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION …………………..39 
13.0 
CRITERIA FOR REMOVAL FROM STUDY …………………………………………42 
14.0 
BIOSTATISTICS ……………………………………………………………………….43 
15.0 
SUBJECT REGISTATION/ RANDOMIZATION ……………………………………..45 
15.1 
SUBJECT REGISTRATION …………………………………………………...45 
16.0 
DATA MANAGEMENT ISSUES ……………………………………………………...46 
16.1 
QUALITY ASSURANCE ………………………………………………………46 


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Clinical and Molecular-Metabolic Phase II Trial of Perifosine for Recurrent/Progressive 
Malignant Gliomas 
 
Table of Contents 
 
 
16.2 
DATA AND SAFETY MONITORING ………………………………………...46 
17.0 
PROTECTION OF HUMAN SUBJECTS ……………………………………………...47 
17.1 
PRIVACY ……………………………………………………………………….47 
17.2 
SERIOUS ADVERSE EVENT (SAE) REPORTING …………………………..47 
18.1 
INFORMED CONSENT PROCEDURES ……………………………………………...49 
18.2 
RESEARCH AUTHORIZATION ………………………………………………50 
19.0 REFERENCES ………………………………………………………………………….50 
20.0     APPENDIX ……………………………………………………………………………...51 
20.1 
KARNOFSKY PERFORMANCE STATUS, NEUROLOGICAL FUNCTION, 
AND MENTAL STATUS …………………………………………………...….51 
20.2 
EIAEDs AND NON-EIAEDs……………………………………………………52 
20.3 
Handling and Shipping of Serum and Tissue for Perifosine Measurement……..53 
20.4 
Supportive Care guidelines for Perifosine Administration 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a phase II study of the small molecule inhibitor perifosine (NSC 639966, 
D21266, KRX-0401) in the treatment of patients with recurrent glioblastoma 
multiforme (GBM) and other recurrent malignant gliomas. The sponsor of this study 
is Keryx, as well as AOI pharmaceuticals and OCOG, which are subsidiaries of Keryx. 
The goal of the phase II study is to determine efficacy as measured by the progression- 
free survival rate after 6 months of treatment.  Secondary goals include determination 
of molecular and metabolic effects of perifosine by tissue analysis and PET imaging. 
In addition, when cytoreductive surgery is recommended as part of the standard of 
care at study entry, patients will be considered for a “surgical arm.”   In this case, 
patients will receive perifosine for 5-10 days before surgery during which tumor will 
be aliquoted both for diagnostic purposes and for molecular effects of the drug in vivo 
and for analysis of drug penetration into tumor tissue.  A schema is shown on the 
following page. 


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Basline tissue 
from prior 
resection/biopsy 
(all patients) 
Recovery 
(1-2 
weeks) 
Surgery 
Yes
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
Correlate Clinical Outcome with 
Metabolic Effects 
 
Correlate Clinical Outcome with 
Molecular Effects 
Resection as part 
of 
standard of care? 
Recurrent/Progressive 
malignant glioma 
Perifosine 
Continue 
Perifosine 
Analyze Tissue for Molecular 
Impact 
• PI3K/AKT signaling 
• RAS/MAPK signaling 
Analyze Tumor for Metabolic Impact 
PET every 4 months 
MRI every 2 months 


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2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
• Primary aim: 
o Determine the efficacy of perifosine in patients with recurrent/progressive GBMs 
not taking EIAEDs as measured by 6mPFS. 
 
• Secondary aims 
o Determine molecular effects of perifosine on AKT, RAS, and proliferation in 
malignant gliomas by analysis of resected tissue in patients on the surgical 
substudy. 
o Determine metabolic effects of perifosine on malignant gliomas by PET imaging. 
o Identify molecular features that predict perifosine response. 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 Malignant gliomas 
 
The most common cancer arising from the brain is the glioblastoma multiforme 
(GBM).  It is also the most aggressive subtype among the gliomas, a collection of 
tumors including astrocytomas and oligodendrogliomas.  While the extent of 
surgical resection is an important prognostic factor [1, 2], malignant gliomas are 
diffusely infiltrative tumors; hence, all locally directed therapy (surgery, 
radiotherapy) inherently palliative.  Such tumors are also relentlessly progressive 
with the most aggressive forms carrying a dismal prognosis. For example, the 
median survival of patients with GBM is approximately 1 year.  Chemotherapy, 
typically temozolomide, is usually given either during radiotherapy (and 
continued afterward) or following radiotherapy, and a recent multinational study 
demonstrated a modest survival benefit of 2.5 months relative to radiotherapy 
alone [2].  However, only 10.7% of patients were progression-free and only 
26.5% of patients were alive 2 years following diagnosis [2].  Recurrent disease 
following radiotherapy is commonly refractory to treatment, with a 6mPFS 
following carmustine (BCNU) of only 17.5% in a recent study [3]. Therefore, 
while systemic chemotherapy improves the outcome for some patients, long term 
disease control presently remains elusive.  Novel agents that inhibit the key 
molecular pathways driving glioma growth need evaluation in malignant gliomas. 


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3.2 Perifosine (NSC 639966, D21266, KRX-0401) 
 
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 miltefosine was initially evaluated in the 
1980s, and it is licensed in Europe as a topical application for the treatment of 
patients with cutaneous metastases from breast cancer. It is also used in an oral 
formulation to treat leishmaniasis.  Because the only major toxicities of 
miltefosine are gastrointestinal --and this was thought be a local rather than a 
central effect of the drug, numerous analogues were developed to see if a less 
toxic analogue could be identified. 
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 that are distinctly different from most cytotoxic 
agents. Perifosine has been shown to be more active and better tolerated than 
miltefosine in preclinical models [4]. Perifosine exhibited marked activity in 
animal and human tumor cell lines resistant to standard chemotherapeutic agents 
with relative sparing of normal cells, including macrophages, bone marrow cells 
and normal glial cells in a glioblastoma model. 
 
Alkylphospholipids are known to affect tumor cell proliferation, differentiation, 
invasion, and metastasis. These compounds are absorbed directly into cell 
membranes where they accumulate (reviewed in [5]).  Although there is 
considerable evidence that the plasma membrane is the primary site of action, 
alkylphospholipids may be widely distributed throughout the cytoplasm and 
possibly within the nucleus.  [6, 7] 
 
3.3 Perifosine Mechanism of Action 
 
Perifosine has been shown to inhibit or otherwise modify signaling through a 
number of different signal transduction pathways including PI3K/AKT, 
RAS/MAPK which are of particular interest because these pathways are active in 
the majority of malignant gliomas and combined activation of these pathways 
induce GBMs in mice [8]. 
 
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Figure 1: RAS and AKT cascades are inhibited by perifosine. 
 
 
 
Approximately 70% of GBMs exhibit activated AKT [8, 9], typically through loss 
of the tumor suppressor PTEN[10-12] which normally represses AKT activation 
(figure 1). Modeling by Dr. Holland here at MSKCC and others has also 
demonstrated that PTEN loss is functionally equivalent to AKT activation[13], 
and that either PTEN loss or activated AKT can combine with RAS activation to 
induce GBMs[8, 13].  One downstream effector of AKT is the mammalian target 
of rapamycin (mTOR); however, treatment with mTOR inhibitors such as with 
rapamycin (sirolimus) or CCI-779 (temsirolimus) [14] for recurrent high grade 
gliomas have not shown response or survival rates that are markedly superior to 
those observed with traditional chemotherapies such as temozolomide[2, 15-17] 
or BCNU [3].  One potential explanation is that mTOR inhibitors affect only a 
subset of the pathways activated by AKT.  Therefore, inhibition of AKT itself 
may be more effective as an anti-cancer treatment.  In addition, rapamycin and its 
analogs also are associated with severe toxicity in some patients, including 
thrombocytopenia and hyperlipidemia, limiting their use.   Other direct inhibitors 
of AKT have been too toxic for clinical use.  By contrast, perifosine has been 
used with limited toxicity in humans (below). 


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3.4 Pre-clinical studies 
3.4.1 In vitro 
Prior to stimulation of the PI3K/AKT pathway, AKT is localized in the 
cellular cytoplasm.  Following stimulation and activation of PI3K, AKT is 
recruited to the cell membrane, where it then localizes. Since the long alkyl 
chain of the alkylphosphocholines can insert into the outer leaflet of the 
plasma membrane and since these agents use lipids, such as those found in 
cellular membranes, as substrates, it seemed plausible that perifosine might 
inhibit a transduction pathway component known to be dependent for its 
activity on membrane localization. 
 
Investigators at the US National Cancer Institute (NCI) first studied the effects 
of perifosine on AKT using a prostate cell line, PC-3, which is known to have 
a mutated, non-functional PTEN and thus to have constitutively activated 
AKT. [7] Their results demonstrated that very small doses of perifosine 
(5μM) blocked phosphorylation of AKT but did not decrease the total amount 
of AKT present in the cell.  These effects occurred within 30 minutes of 
exposure to perifosine, suggesting this was an initial event rather than a 
secondary phenomenon due to perifosine effects elsewhere in the cell. When 
perifosine was removed, substantial recovery of AKT phosphorylation began 
within one hour, also suggesting that perifosine’s effects are specific and not 
the result of general detergent effects.  Perifosine also blocked the effects of 
insulin, EGF (epidermal growth factor), PDGF (platelet derived growth  
factor) and other ligands known to stimulate AKT activation. By contrast, 
perifosine did not affect growth factor-mediated PI3K activation. Finally, the 
investigators showed that perifosine blocked the localization of AKT to the 
cell membrane, consistent with the observation that PI3K activation was not 
affected but AKT phosphorylation was clearly diminished, and with the initial 
hypothesis that led to the initiation of these studies. 
 
Investigators at the Netherlands Cancer Institute in Amsterdam obtained 
similar results using the epithelial cell line A431 and HeLa. [6] Three 
alkylphosphocholines, including both miltefosine and perifosine, were 
evaluated, and all appeared to inhibit AKT in a dose-dependent fashion. The 
alkylphosphocholines also blocked stimulation of AKT activity by insulin. 
 
These effects on AKT were accomplished with perifosine levels that inhibit 
the growth of tumor cells in vitro and that can be achieved in the clinic. 
 
Preclinical studies undertaken mainly by Dr. Holland’s lab at MSKCC have 
also demonstrated that perifosine is a potent inhibitor of AKT signaling in glia 
in vitro.  In addition, perifosine (PRF) inhibits the RAS cascade (reduced 
pERK) in glia, an effect not achieved by the mTOR inhibitor rapamycin 


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(Rap).  The dual inhibition of AKT and RAS signaling by PRF 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, respectively.  Furthermore, forced activation of both cascades in mice 
is sufficient to induce GBMs [8].  Therefore, combined inhibition of both 
cascades with one agent such as PRF may offer significant therapeutic 
advantage over mTOR inhibitors and over agents that inhibit only AKT or 
RAS. 
 
Figure 2: PRF inhibits both AKT and RAS (exhibited by diminished pERK); Rap 
inhibits only mTOR (exhibited by diminished pS6K) in cultured glia. 
- 
Rap 
- 
PRF 
 
pAKT 
 
pS6K 
 
pERK 
 
 
 
The activity of perifosine has been evaluated in numerous other human and 
murine cell lines.  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 2003).  In a soft agar tumor stem cell assay, the 
human KB (squamous) and murine L1210 (leukemia) cell lines were the most 
sensitive. In the methylene blue exclusion assay, the five most sensitive lines 
were:  KB (squamous mouth), LU 65A (lung), LNCaP (prostate), PC-1 (lung) 
and Hep-2 (larynx) with IC50 values of 0.8 – 3.4 g/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 g/mL.  The majority of cell lines (in 
all assays) were more sensitive to perifosine than to miltefosine.  Compared 
with leukemic cells, normal mouse bone marrow cells were shown to be 
relatively insensitive to perifosine in vitro. 
 
3.4.2 Animal studies 
 
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. 


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Two tumors resistant to conventional cytotoxics but sensitive to perifosine 
were the KB tumor (squamous cell) and AsPC-1 (human pancreatic 
carcinoma).  In vivo, single oral doses of 511 mg/kg completely inhibited the 
growth of subcutaneously transplanted KB squamous cell tumors. When 
smaller doses (203 or 300 mg/kg) were administered twice at 7 day intervals, 
complete remissions lasting >63 days were achieved. Other xenografts in nude 
mice that responded well to perifosine included the Hep-2 laryngeal, R3327 
rat prostate, SAS tongue, SC115 mouse breast and HCT-8 colon tumor. 
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 neither the loading dose nor low 
maintenance doses alone exhibited significant ant-tumor activity.  Even large 
(4-8 grams), established DMBA induced mammary tumors responded to daily 
doses of 14.7 to 68.1 mg/kg over 28 days, with a persistent effect for more 
than 20 days after cessation of treatment. 
 
Preclinical 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, 
2003).  For doses ranging from 1 to 50 mg/kg, maximum plasma 
concentration (Cmax) values ranged from 0.34 to 10.5 g/mL.  Time to achieve 
Cmax was reached at a median of 16 to 32 hours following administration of 
perifosine. It should be noted however that while there was an approximately 
linear increase in Cmax from 1 to 10 mg/kg, a 5-fold increase in dose from 10 
to 50 mg/kg led only to a 3-fold increase in Cmax.  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) in the rat after an oral dose of [14C] 
perifosine at 10 and 50 mg/kg revealed the following proportions of renal and 
fecal excretion: 


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Table 1 
 
Dose (mg/kg) 
Excretion in Urine 
Excretion in Feces 
10 
<24 hr 1.0%, 
360 hr 20.4 % 
<24 hr 24.6 %, 
360 hr 42.9% 
50 
<24 hr 1.2% 
48 hr 2.4% 
72 hr 3.6% 
<24 hr 22%, 
48 hr 48.5%, 
72 hr 52.6 % 
 
In vitro binding of perifosine to human serum albumin or 1-acid 
glycoprotein ranged from 92 to 98% (Perifosine Investigator’s Brochure, 
2003).  No concentration dependence of protein binding was observed, 
suggesting a high binding capacity of the plasma proteins for perifosine. 
 
3.4.2.1 
Activity in mouse gliomas 
 
Perifosine has been shown to cross the blood/brain barrier in the mouse as 
the Holland lab also demonstrated that PRF also causes reductions in 
mouse glioma cell proliferation (p<0.005), as measured by MIB-1 (Ki67) 
labeling commonly used in human gliomas as shown in figure 4. 
 
 
 
Fig 4: Ki-67+ cells (%)=MIB1 
 
 
 
 
 
 
 
 
3.4.3 Preclinical Toxicity 
 
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, 2003).  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 germinal epithelium of the testes, 


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atrophy/inactivation of prostate and seminal vesicles, 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 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. 
 
The no adverse effect level (NOAEL) was estimated to be < 2.15 mg/kg (12.9 
mg/m2) in rats and 2.15 mg/kg (43 mg/m2) in dogs. 
 
3.5 Perifosine Clinical Data 
 
Several Phase I and II studies of perifosine in humans have been completed and 
others are on-going in which patients experienced tumor regressions and/or 
disease stabilization.  The safety profile of perifosine is distinctly different from 
that of most cytotoxic agents.  It causes dose-related nausea, vomiting, diarrhea 
and fatigue. The gastrointestinal symptoms are thought to arise primarily because 
of direct interactions between perifosine and the gut.  Responding patients have 
been treated with months to more than a year with almost no symptoms at all. It 
does not cause myelosuppression, alopecia, or rash.  In phase I studies it has been 
administered using a variety of schedules including daily, weekly, or daily after 
an induction dose.  Responses have been seen with both the daily and weekly 
regimens.  The half-life of the drug exceeds 100 hours. 
 
In preclinical models, higher doses have been shown to be more effective than 
lower doses. The clinical responses observed thus far have been at lower doses in 
patients who have experienced no toxicity. 
Therefore, MTD may not be 
required and a lower dose may actually be superior clinically. 


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3.5.1 Clinical Results: European Phase I Trials 
 
Asta Medica/Zentaris sponsored three European phase I trials of perifosine 
evaluating weekly and daily dosing, as well as an enteric-coated formulation. 
 
Study D-21266-3040 
 
This was a phase I 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, grade 3 
vomiting occurred in the first two patients.  These patients responded to 
antiemetic prophylaxis with tropisetron, alizaprid, and dexamethasone, and all 
subsequent patients received antiemetic prophylaxis.  Among 7 patients 
treated at the maximum dose of 800 mg/wk all taken together at one time, 
grade 2 nausea and vomiting of residual perifosine tablets and grade 4 
diarrhea occurred.  In addition to nausea, vomiting and diarrhea the following 
grade 1/2 events were reported to be likely caused by the drug: gastritis, 
erythematous rash, abdominal pain, fatigue, bradycardia, increased sweating 
and arthralgia. 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, 2003). 
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. 


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Gastrointestinal toxicities for this protocol are summarized in the following 
table: 
 
Table 2 
Number of patients exhibiting nausea, vomiting, and diarrhea during the once-weekly oral 
treatment with perifosine (data from study D-21266-3040) 
Dose 
Level 
[mg/w 
k] 
No. 
of 
Patie 
nts 
Treat 
ed 
Total 
no. 
of 
doses 
(min- 
max) 
Maximum intensity (CTC grade) during any treatment course 
Nausea 
Vomiting 
Diarrhea 
0 
I 
II 
III 
0 
I 
II 
III 
IV 
0 
I 
II 
III 
IV 
100 
6 
40 
(2 - 15) 2 
1 
1 
2 
3 
1 
1 
1 
- 
4 
1 
1 
- 
- 
200 
6 
51 
(5 - 16) 2 
3 
1 
- 
4 
1 
1 
- 
- 
3 
3 
- 
- 
- 
350 
6 
37 
(4 - 8) 
3 
1 
2 
- 
4 
1 
- 
1 
- 
4 
1 
1 
- 
- 
450 
3 
28 
(5 - 16) - 
1 
2 
- 
1 
2 
- 
- 
- 
2 
- 
1 
- 
- 
600 
8 
39 
(2 - 14) 2 
3 
2 
1 
2 
4 
2 
- 
- 
- 
4 
3 
- 
1 
800 
7 
25 
(2-6) 
2 
2 
3 
- 
3 
2 
2 
- 
- 
3 
2 
1 
- 
1 
 
Efficacy was not a primary end point of this phase I study; however, indicator 
lesions were evaluated every 8 weeks, if possible.  Patient diagnoses included 
NSCLC (7 patients), melanoma (4), colorectal carcinoma (4), head and neck 
cancer (5), sarcoma (4), mesothelioma (2), hepatocellular carcinoma (1), 
esophageal carcinoma (2), SCLC (1), corpus carcinoma (1), bladder (1), breast 
(1), renal (1) and CUP syndrome (2).  No change for at least 8 weeks in the 
size of indicator lesions was found in 6/36 patients. All of these patients were 
stable for 15-16 week.  The number of patients with stable disease, the total 
number with each tumor type along with the dose administered to the patients 
with stable disease were: 
salivary gland 1/1 pt., 100 mg/wk 
mesothelioma 2/2 pts., 100 and 600 mg/wk 
hepatocellular carcinoma 1/1 pts., 200 mg/wk 
NSCLC 2/7 pts., 200 and 450 mg/wk 


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D-21266-3079 
Amended:  10/25/11 
- 17 - 
 
 
In the second phase I study, 22 patients received perifosine at escalating doses 
of 50-350 mg daily for 21 days in every 28 day cycle. Fatigue (43%), nausea 
(52%), vomiting (38%) and diarrhea (43%) 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. No patients treated at 150 mg/day experienced grade 3 or 4 
toxicity. [18] 
 
 
 
Table 3 
The gastrointestinal toxicities experienced in this protocol are summarized in 
the following table: 
Number of patients with nausea, vomiting, diarrhea during daily oral treatment with 
perifosine (data from study D-21266-3079) 
Dose 
level 
[mg/day] 
No. of 
Patien 
ts 
Treate 
d 
Total 
no. 
of 
doses 
(min- 
max) 
Maximum intensity (CTC grade) during any treatment course 
Nausea 
0 
I 
II 
III 
Vomiting 
0 
I 
II 
III IV 
Diarrhea 
0 
I 
II 
III 
IV 
50 
4 
7 
(1-2) 
2 
1 
1 
- 
2 
1 
1 
- 
- 
4 
- 
- 
- 
- 
100 
3 
5 
(1-2) 
1 
1 
1 
- 
2 
- 
1 
- 
- 
3 
- 
- 
- 
- 
150 
3 
6 
(2) 
1 
2 
- 
- 
2 
1 
- 
- 
- 
2 
1 
- 
- 
- 
200 
5 
12 
(1-4) 
2 
2 
1 
- 
3 
- 
2 
- 
- 
4 
1 
- 
- 
- 
250 
6 
11 
(1-5) 
- 
2 
3 
- 
- 
2 
3 
- 
- 
- 
2 
3 
1 
- 
350 
1 
1 
- 
- 
1 
- 
- 
- 
1 
- 
- 
- 
- 
1 
- 
- 
Efficacy is not a primary end point of this phase I study; however, indicator 
lesions were evaluated every 8 weeks, if possible.  Patient diagnoses included 
pancreatic carcinoma (1 patient), ocular melanoma (1), colorectal carcinoma 
(11), Ovarian carcinoma (1), bladder (1), hepatocellular carcinoma (1), 
esophageal carcinoma (1), and adenocarcinoma of unknown primary (5). No 
change in the size of indicator lesions was found in 2/22 patients two months 
after start of treatment. These patients were treated for the following tumor 
indications: 
hepatocellular carcinoma (1/1 pts., 200 mg/day) 
melanoma (1/4 pts., 250 mg/day) 


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D-21266-3087 
 
An enteric-coated formulation was evaluated on a weekly study in the trial. 
Thirteen patients were recruited.  The enteric coating did not improve the 
tolerability of the oral administration of perifosine and reduced its 
bioavailability. 
 
The gastrointestinal toxicities experienced by the patients are summarized in 
the following table: 
 
Table 4 
Number of patients with nausea, vomiting, diarrhea during once weekly oral treatment with 
enteric-coated perifosine (data from study D-21266-3087) 
Dose 
level 
[mg/ 
wk] 
No. of 
patien 
ts 
treate 
d 
Total 
no. 
of 
dose 
s 
(min 
- 
max) 
Maximum intensity (CTC grade) during any treatment course 
0 
Nausea 
I 
II 
III 
0 
Vomiting 
I 
II 
III IV 
0 
Diarrhea 
I 
II 
III IV 
200 
4 
17 
(1 - 
8) 
2 
- 
2 
- 
2 
1 
1 
- 
- 
2 
2 
- 
- 
- 
350 
6 
63 
(5 – 
16) 
- 
4 
1 
1 
- 
3 
3 
- 
- 
2 
1 
2 
1 
- 
450 
3 
12 
(2 - 
8) 
1 
1 
1 
- 
1 
2 
- 
- 
- 
1 
2 
- 
- 
- 
 
Patients with the following diagnoses were recruited: lung (2 patients), breast 
(2), colorectal carcinoma (1), sarcoma (2), renal (2), cervical carcinoma (1), 
esophageal carcinoma (1), ovarian (1) and pancreas (1).  One patient with 
chondrosarcoma treated at 350 mg/weekly achieved a partial response. No 
change in the size of indicator lesions was found in 2/13 patients (both 
patients had breast carcinomas) two months after start of treatment. 
(Perifosine investigators Brochure 2003)  The response in the chondrosarcoma 
patient was ongoing at 6 months. 


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3.5.2 Clinical Results: US Phase I Trials 
 
The Division of Cancer Treatment and Diagnosis, National Cancer Institute 
sponsored two phase I 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 several preclinical cancer 
models with this schedule and the fact that daily doses alone required some 
days (and possible more than a week) to reach steady state plasma levels. A 
loading dose could potentially achieve active anti-tumor serum concentrations 
followed by tolerable daily maintenance dosing. Since both preclinical 
studies and the earlier phase I studies had suggested that increases in plasma 
levels were not linear after a threshold that might be about 400 mg, the 
loading dose was fractionated and administered every 6 hours to improve 
bioavailability and decrease Cmax.  It was also anticipated that by lowering 
Cmax toxicities such as emesis might be decreased. In both studies, patients 
received antiemetic prophylaxis with dexamethasone and 5HT3 antagonist 
before initial loading dose. Similar to the results from the Asta Medica- 
sponsored studies, the most frequently observed toxicities in NCI sponsored 
phase I 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. 
 
Phase I evaluation of the “Intermittent Schedule” at the NCI 
 
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. (Because of the 7 day intervals without drug, this has been referred to 
as the “intermittent schedule.”) 
In an attempt to minimize nausea, doses 
were administered with meals or, with maintenance doses, at bedtime. In 
addition, prior to the initial loading dose, patients were given granisetron, 
metoclopramide, diphenhydramine, and dexamethasone as antiemetic 
prophylaxis. Thirty-one patients were treated on this study. Gastrointestinal 
toxicities were dose limiting. Dose limiting nausea and vomiting despite 
antiemetic prophylaxis occurred with loading doses of 1200-1500 mg.  Grade 
3 arthralgias and arthritis in the form of gout or pseudo-gout were seen in two 
patients taking perifosine 200 mg/day. One patient with a history of gout had 
reappearance of gout and one patient without a prior history had an episode of 
pseudogout. One patient with a history of hyperuricemia, had grade 2 
episodes of gout. Persistent grade 2 nausea and vomiting despite antiemetics 
and fatigue occurred with a maintenance dose of 200 mg/day. The maximum 
tolerated dose (MTD) and recommended phase II dose (RP2D) were 
established as: Cycle 1: 900/150 mg loading/maintenance dose and for 


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subsequent cycles: 300/150 mg loading/maintenance dose ([19]).  The day 1 
loading dose was divided into 2 equal doses of 450 mg taken with food, 6 
hours apart on day 1. Among 11 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. Only one other grade 3 toxicity, 
infection without neutropenia, felt to be probably due to the drug was 
recorded at dose level III. Grade 1-2 fatigue occurred in 8/11 patients and 
grade 2 gastrointestinal toxicity was intermittent and tolerable. 
 
Gastrointestinal toxicities experienced on this trial are summarized in the 
following table: 
 
Table 5 
NCI Trial I - A Phase I Trial of Oral Perifosine with Different Loading/ Maintenance Doses 
using the “Intermittent Schedule” in Patients with Refractory Neoplasms 
Dose 
Level 
Dosage - Cycle 1 
(Loading / 
Patients 
Treated 
Maximum intensity (CTC grade) during any treatment course 
Nausea 
Vomiting 
Diarrhea 
 
[mg/wk] Maintenance) 
0 
I 
II 
III 
0 
I 
II 
III 
0 
I 
II 
III 
I 
300 mg/50 mg 
3 
2 
1 
1 
1 
II 
600 mg/100 mg 
2 
2 
1 
1 
1 
1 
IIA 
600 mg/200 mg 
1 
1 
1 
1 
III 
900 mg/150 mg 
11 
4 
6 
4 
4 
4 
2 
2 
IV 
1200 mg/200 mg 
11 
5 
5 
4 
4 
6 
2 
2 
V 
1500 mg/250 mg 
3 
2 
1 
2 
1 
2 
1 
 
Patient diagnoses included head/neck (1 patient), esophagus (1), colon (6), 
pancreas (2), non-small cell lung (1), urethra (1), melanoma (2), sarcoma (3), 
breast (1), prostate (10) and renal cell (2).  No clinical responses have been 
observed; however, four patients with stable disease have been reported 
(duration 167-750 days, 3 patients with hormone refractory prostate 
carcinoma and one with melanoma). 
 
Phase I evaluation of the “Continuous Schedule” at the University of 
Wisconsin 
 
The second NCI sponsored phase I trial evaluated a loading dose followed by 
a continuous maintenance dose schedule in 42 patients with advanced cancer. 
The loading dose was only given in course one, and maintenance dosing 
continued without a scheduled break (hence the name “continuous schedule”). 
Cohorts of patients received loading/maintenance doses ranging from 400/50 
– 1200/150 mg.  In this study, loading doses were split into 4-8 equal doses 


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given at 6 hour intervals.  Patients received dexamethasone and dolasetron 
mesylate prior to each dose during the loading period with lorazepam and 
prochlorperazine prn.  Reported severe toxicities for this trial include 
anorexia, fatigue, dehydration, nausea/vomiting, constipation, diarrhea, 
elevated liver function tests, and decreased hemoglobin.  The MTD and 
recommended phase II dose for this schedule was 900 mg loading dose 
(divided into 6 equal doses of 150 mg taken with food q 6 hourly) followed by 
100 mg daily maintenance.  Among 14 patients treated at the MTD, there  
were 4 grade 3 events (fatigue in 2 patients, nausea in 1 and vomiting in 1 
patient).  Subsequently a review of the pharmacokinetics for this study 
revealed that there was only a minimal increase in plasma concentration 
between dose level 3 and dose level 4.  For this reason the actual doses used in 
subsequent phase II studies were a loading dose of 600 mg (150 x 4) and a 
maintenance dose of 100 mg.  Among the 12 patients treated at dose level 2 
there were 3 patients who experienced grade 3 fatigue and 1 patient with grade 
3 nausea. There were no additional grade 3 toxicities recorded as probably 
due to the drug. 
 
The gastrointestinal toxicities experienced on this protocol are summarized in 
the following table: 
 
Table 6 
NCI Trial II - A Phase I Trial of Perifosine with Different Loading/Maintenance Doses using 
the “Continuous Schedule” in Patients with Advanced Cancer 
Maximum intensity (CTC grade) during any treatment 
Dose 
Level 
Dosage - Cycle 
1 
(Loading / 
Patients 
Treated 
course 
Nausea 
Vomiting 
Diarrhea 
 
Maintenance) 
0 
I 
II 
III 
0 
I 
II 
III 
0 
I 
II 
III 
I 
400 mg/50 mg 
3 
3 
3 
II 
600 mg/50 mg 
7 
3 
3 
3 
2 
3 
1 
1 
III 
600 mg/100 mg 
12 
6 
2 
1 
3 
2 
6 
3 
IV 
900 mg/100 mg 
14 
7 
3 
1 
3 
2 
1 
3 
3 
V 
900 mg/150 mg 
6 
4 
1 
4 
0 
2 
3 
 
Patient diagnoses included pancreatic carcinoma (1 patient), sarcoma (5), 
colorectal carcinoma (19), ovarian carcinoma (2), renal cell (6), lung cancer 
(4), esophageal carcinoma (1), breast (1), cervical (1), glioblastoma (1) and 
tonsilar (1). One partial response in a patient with uterine sarcoma was 
reported.  The responder received 18 cycles of therapy on study and has since 
been followed for 17 months without significant progression. Seven patients 


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had stable disease lasting greater than 2 cycles (renal cell carcinoma – 2; 
sarcoma – 2; colon carcinoma – 2; ovarian carcinoma – 1).  [20] 
 
In the phase II program initiated by the National Cancer Institute trials were 
conducted with both the intermittent and continuous regimens.  Preliminary 
analysis showed that there was greater toxicity associated with the intermittent 
than the continuous regimen. 
 
Table 7 
Toxicity seen in phase II trials conducted by the NCI using either the 
‘Intermittent’ or ‘Continuous’ Regimens.  (See definitions above) 
Regimen 
Intermittent 
Continuous 
Number of patients with toxicity data available 
87 
57 
Frequency of: 
Percent 
Percent 
Nausea: 
Grade 2 
36 
9 
Grade 3 
8 
2 
Diarrhea: 
Grade 2 
28 
4 
Grade 3 
11 
2 
Vomiting: 
Grade 2 
45 
11 
Grade 3 
5 
2 
 
One additional response has been seen in a patient with sarcoma.  This 
occurred in a patient with extra-skeletal myxoid sarcoma who received 10 
cycles of therapy on study.  [21] 
 
 
Perifosine 201 
 
AOI Pharmaceuticals is currently undertaking a phase I/II trial of perifosine in 
non-small cell lung cancer.  In this study patients receive weekly doses in 
which the total dose is divided into 300 mg doses delivered at least 4 hours 
apart.  Dosing began at 900 mg (300 mg x 3) and was escalated to 1800 mg 
(300 mg x 6).  A dose limiting toxicity was defined as a grade 3 or 4 
gastrointestinal toxicity or nausea and/or vomiting lasting more than 48 hours. 
Two patients at 1800 mg experienced grade 3 diarrhea, and 1500 mg was the 
maximum tolerated dose. The GI toxicities encountered in the initial 3 
cohorts of patients are described in the following table.  The table reflects the 
first week of therapy only. 


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Table 8 
AOI Trial 201 - A Phase I Trial of Perifosine Administered Weekly in Patients with 
Metastatic Lung Cancer 
Dose 
Level  Dosage - Cycle 1 
(Loading / 
Patients 
Treated 
Maximum intensity (CTC grade) during any treatment course 
Nausea 
Vomiting 
Diarrhea 
Maintenance) 
0 
I 
II 
III 
0 
I 
II 
III 
0 
I 
II 
III 
I 
300 mg x 3 
weekly 
II 
300 mg x 4 
weekly 
III 
300 mg x 5 
weekly 
IV 
300 mg x 6 
weekly 
5 
1 
3 
1 
4 
1 
2 
3 
 
3 
2 
1 
3 
1 
1 
1 
 
5 
4 
1 
1 
4 
0 
3 
1 
1 
 
4 
1 
2 
1 
1 
3 
0 
2 
2 
3.5.3 Pharmacokinetics 
 
The pharmacokinetic data from each of the phase I studies is summarized in 
the table below. 
 
Table 9 
 
Study 
Dose Range 
Parameter 
Median Plasma 
Values (M) 
Study D-21266-3040 
100-800 mg/week 
Peak Concentration 
1.59   – 
7.97 
Concentration day 7 
0.34   – 
2.05 
Study D-21266-3079 
50 – 350 mg/day 
Peak Concentration 
3.89   –  14.58 
Concentration Day 22 
3.49   –  12.24 
Study D-21266-3087 
200- 450 mg/week 
Peak Concentration 
1.51   – 
2.42 
(enteric coated) 
Steady State Trough 
0.54   – 
2.00 
Intermittent 
300/50 – 1500/200 
Concentration Day 22 
6.87   –  22.31 
Continuous 
400/50 – 900/150 
Concentration Day 2 
9.29  - 15.14 
Steady State Concentration 
7.23   –  14.36 
 
The phase I pharmacokinetic studies showed that plasma concentrations 
similar to the IC50 values obtained for many cell lines in in-vitro studies could 
be obtained using each of the regimens with the exception of the enteric 
coated tablet.   When doses above 300 mg were administered at a single time, 
the pharmacokinetics were not linear.  Two patients on the phase I studies 
responded: one patient on the study that utilized the enteric coated tablets (D- 
21266-3087) had serum values ranging from 2.78 – 6.29 M and one patient 
on the continuous regimen had steady state levels of 12.78 ± 2.23 M. 


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3.5.4 Results of Phase II conducted by NCI 
 
The results of three of the nine NCI phase II studies have been presented at 
national and international meetings. None has yet been published in a full 
report. 
 
A multicenter Phase II Consortium organized by the Mayo Clinic and lead by 
Howard Bailey of the University of Wisconsin evaluated the continuous 
regimen in 23 patients with soft tissue sarcomas. The results were reported at 
the EORTC-NCI-AACR meeting on Molecular Targets and Cancer 
Therapeutics. The median age of the patients was 53 (range 24-77). Eight 
were male and 15 female. Thirteen had an ECOG performance status of 0 and 
10 had a PS=1. Twenty patients had received prior chemotherapy, and 5 
patients (22%) had liver metastases. Grade 3 toxicities definitely or probably 
related to the drug included fatigue in 2 patients and diarrhea, anorexia and/or 
dehydration, each in 1 patient.  One patient had a partial response and five 
patients were stable for 84-229 days. The responder was a 58-year-old man 
with an extra-skeletal myxoid chondrosarcoma.  The primary lesion on the 
thigh had been treated 8 years previously, and metastases to the lung and the 
lymph nodes had been identified 22 months prior to starting perifosine. The 
patient had previously been treated with surgery, radiotherapy and 
chemotherapy consisting of gemcitabine and cisplatin. He had not responded 
to the chemotherapy.  The patient received 10 months of perifosine therapy 
(600 mg loading dose and 100 mg/day continuously).  He had grade 1 nausea 
and diarrhea on cycle 1 only and no toxicities of any type after that point. The 
primary endpoint of the study was 6 month progression-free survival.  In 
addition to the responder, two other patients (one with a myxoid sarcoma and 
one with a desmoid tumor) had disease stabilization for more than six months. 
 
Nineteen patients with head and neck cancers were enrolled in a phase II trial 
conducted by a consortium of hospitals in Chicago, and results from this study 
were presented at the Third Chicago International Symposium on 
Malignancies of the Chest and Head and Neck.  The patients had a median age 
59 (range 46-81; 15 were male and 4 female. Five had an ECOG performance 
status of 0 and the remainder had a status of 1. Thirteen of these patients had 
received prior chemotherapy and 12 had prior radiotherapy. The continuous 
regimen was used with a starting dose of 600 mg in 4 divided doses followed 
by a daily dose of 100mg.  The investigators reported that administration by 
gastrostomy tube was feasible. Grade 3 toxicities described in their 
presentation included pain in one patient and hypercalcemia in another. 
Seventeen patients were evaluable for response. There were no objective 
responses but one patient had stable disease for 4 cycles. 


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The only phase II trial of breast cancer enrolled 18 (17 evaluable) patients. 
This trial was presented at the 2005 San Antonio Breast Cancer Symposium 
before the study was officially closed.  In this trial the intermittent regimen 
was used. The patients’ median age was 52 (range 28-69). There was 1 male 
patient.   The ECOG performance status was 0 for 10, 1 for 6, and 2 for 1 
patient.   Eight patients had tumors that were ER/PR positive, but none had 
HER2/neu positive tumors.  This was a heavily pre-treated population. 
Sixteen patients had received prior systemic therapy including neoadjuvant or 
adjuvant chemotherapy in 11, a single chemotherapy regimen for metastatic 
disease in 5 patients, and two prior chemotherapy regimens for metastases in 
9.  Fifteen patients had previously received an anthracycline and 11 a prior 
taxane.   Drug related toxicities included Grade 3 diarrhea (2 patients), 
vomiting (2 patients), nausea (1 patient) and fatigue (1 patient). One patient 
had a mixed response after 2 cycles and 2 patients were stable for 4 months. 
The mixed response occurred in a patient with extensive disease involving 
multiple organs. At the end of 2 cycles some lesions had shrunk while others 
had remained stable or increased.  Although this patient had experienced no 
major toxicities, she refused further treatment for unspecified reasons. 
 
3.5.5 Description of the responders in previous phase I/II 
trials 
 
Three patients have had clearly documented partial responses on earlier 
perifosine trials. 
 
Patient # 1 (D 21266-3079) was a 66 year old with a chondrosarcoma with a 
primary in the Xiphoid. The patient had local recurrences treated surgically at 
4 and 10 months.  At 10 months distant metastases were also documented. 
Previous chemotherapy included 2 cycles of Adriamycin, cisplatin and 
ifosfamide.  The patient received 24 weeks of enteric-coated perifosine at a 
dose of 350 mg per week and was then taken off study due to non-compliance. 
The plasma perifosine levels ranged from 2.78 – 6.29 M. Only minimal 
toxicity was observed until week 22 when the patient had grade 3 nausea and 
vomiting along with grade 2 fatigue from weeks 20-24. The sum of products 
of lesions in the lung and sternum decreased from 28.56 at on-study to 9.39 at 
the conclusion of treatment. 
 
Patient # 2 (Phase I trial of continuous regimen) was a 50 year old with a 
leiomyosarcoma with a primary in the uterus.  She developed distant 
metastases at 4 years with lesions in the scalp, lung, retroperitoneum and 
bone.  She had previously received two cycles of adriamycin and dacarbazine 
as well as strontium for bone metastases.  The patient received a loading dose 


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of 600 mg and then continuous daily perifosine at 50 mg/day for 504 days. 
The patient was taken off study at that time due to patient refusal for further 
therapy. The patient experienced absolutely no toxicity while on study. The 
patient had disease in both lungs as well as an infrasplenic mass. The 
measurements on the patient’s disease were scored by 3 independent 
observers. At the time the patient went off study the average decrease in 
measurements was scored as 62% (range 53 – 70%). The patient remains in 
partial remission after 3 years. 
 
Patient # 3 (Mayo Clinic phase II trial) was a 58 year old with an extra- 
skeletal myxoid chondrosarcoma with a primary on the thigh. The patient’s 
disease was metastatic to the lung and the lymph nodes.  The patient was 
previously treated with surgery, radiotherapy and chemotherapy consisting of 
gemcitabine and cisplatin.  The patient was treated with 10 cycles of therapy 
(600 mg loading dose and 100 mg/day continuously) and had grade 1 nausea 
and diarrhea on cycle 1 only 
 
3.6 
Potential impact on metabolism by hepatic enzyme 
inducing antiepileptic drugs (EIAEDs) 
 
There is increasing evidence that brain tumor patients receiving enzyme-inducing 
anti-epileptic drugs (EIAEDs) have markedly altered pharmacokinetics, resulting 
in accelerated drug metabolism. This may result in decreased levels of certain 
chemotherapeutic agents when administered at conventional doses. Failure to 
achieve adequate plasma levels of such agents may account for the lack of 
efficacy in past brain tumor trials. 
 
Perifosine is a potential substrate for the cytochrome P450 system, and the 
escalating concentrations of perifosine were tested for inhibition of the liver 
microsomal cytochrome P450 system in vitro (table 10). Enzyme activities 
associated with CYPlA2 (7-ethoxyresorufin 0-deethylation), CYP2A6 (coumarin 
7-hydroxylation), CYP2B6 (S-mephenytoin N-demethylation), CYP2C9 
(tolbutamide methyl-hydroxylation), CYP2C19 (S-mephenytoin 4'- 
hydroxylation), CYP2D6 (dextromethorphan 0-demethylation), CYP2E1 
(chlorzoxazone 6-hydroxylation) and CYP3A415 (testosterone 6P-hydroxylation) 
were determined using enzyme-specific probe compounds incubated with pooled 
human liver microsomal samples. 
 
In the presence of perifosine, a moderate inhibitory effect was observed on 
CYP2A6 activity (50%), and a slight inhibitory effect on CYP3A4 activity (29%), 
in both cases only at the highest concentration (100 yM). No inhibitory effect was 
observed on CYP2C19 activity by perifosine at any of the concentrations tested. 


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Enzyme activities associated with CYPIA2 (7-ethoxyresorufin 0-deethylation), 
CYP2B6 (S-mephenytoin Ndemethylation), CYP2C9 (tolbutamide methyl- 
hydroxylation), CYP2D6 (dextromethorphan 0-demethylation), and CYPZEI 
(chlorzoxazone 6-hydroxylation) were not inhibited by perifosine at any of the 
concentrations (0.25 - 100 µM). 
 
Perifosine 
Percentage of Activity Remaining 
Conc 
(µM) 
CYP1A2 
CYP2A6 
CYP2B6 CYP2C9 
CYP2C19 
CYP2D6 CYP2E1 
CYP3A4/5 
0.0 
100.0 
100.0 
100.0 
100.0 
100.0 
100.0 
100.0 
100.0 
0.25 
96.4 
97.7 
100.1 
101.3 
98.4 
96.0 
99.8 
102.2 
1 
101.2 
101.2 
100.7 
96.6 
96.8 
94.1 
100.4 
101.3 
5 
100.8 
90.8 
100.1 
95.7 
102.0 
98.5 
95.8 
103.0 
10 
98.8 
94.7 
98.0 
95.3 
97.6 
95.9 
95.0 
97.0 
25 
99.9 
88.9 
100.8 
96.0 
103.1 
98.5 
96.5 
94.5 
50 
97.8 
88.7 
101.0 
95.8 
113.9 
94.3 
89.1 
98.4 
100 
113.6 
46.1 
99.9 
98.0 
106.4 
88.1 
86.0 
71.3 
 
Table 10:  The Effect of Perifosine on CYP1A2, CYP2A6, CYP2B6, CYP2C9, 
CYP2C19, CYP2D6, CYP2E1 AND CYP3SA4/5 Activities in Pooled Human 
Liver Microsomes 
 
These data suggest that patients taking EIAEDs may have increased drug 
metabolism and a higher MTD than patients who are not taking EIAEDs. 
Therefore, to avoid the possibility of effects of EIAEDs on the metabolism of 
perifosine, and vice-versa, only patients not taking EIAEDs will be eligible for 
this trial as has become common in trials of novel agents for malignant glioma. 
(See Appendix 20.2 for a list of EIAED drugs). 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
Only patients not taking EIAEDs will be considered for this study.  If patients 
were previously on EIAEDs that have been discontinued, patients must have been 
off the agent for at least 2 weeks prior to registration.  For patients who need to 
start an AED or the AED needs to be changed, it is strongly recommended that all 
efforts should be made to use a non-EIAED. If another non-EIAED cannot be 
used, the PI or co-PI should be notified immediately. Questions regarding these 
requirements should be discussed with PI or co-PI. 
 
Surgery 
In addition, if cytoreductive surgery is recommended as part of the standard 
of care for tumor recurrence, all patients will be considered for the “surgical 


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arm” of the trial.   In this case, patients will receive perifosine for 5-10 days 
before surgery during which tumor will be aliquoted both for diagnostic 
purposes and for molecular and pharmacokinetic analyses. Ideally, tissue 
will be available from a prior surgical resection for intra-patient comparison. 
Following recovery from surgery, patients will restart perifosine until either 
tumor progression (as determined by brain imaging with CT or MRI every 2 
months) or toxicity.  All patients will be followed for overall survival after 
discontinuing perifosine. 
Biologic impact will also be determined by periodic FDG-PET imaging (see 
below). 
 
4.1.1 Patients will also be stratified as follows: 
 
Histology at Registration:  
GBM/Gliosarcoma (GBM/GS) 
Anaplastic Astrocytoma (AA) 
Anaplastic Oligodendroglioma (AO) 
Anaplastic Mixed Glioma (AMG) 
 
 
Pre-operative Candidate: 
Yes or No 
Measurable/Evaluable disease: 
Yes or No 
4.2  Intervention 
 
Following a diagnosis of tumor recurrence or progression, all patients will 
receive perifosine monotherapy until toxicity, progression, or death.  Brain 
imaging (MRI/CT) will be performed at baseline and every 2 months 
(standard of care). FDG-PET imaging will be performed at baseline, after 1- 
2 weeks of therapy, and every 4 months to assist with interpretation of tumor 
response. MR Spectroscopy and MR Perfusion may also be performed with 
every MRI to assist with interpretation of tumor response.  Patients on the 
surgical arm trial will resume perifosine after recovering from surgery and 
continue until toxicity, progression, or death. 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Perifosine (NSC # 639966; IND # 69,383) 
 
Chemical Name: 
1,1-dimethyl-4-[[(octadecyloxy)hydroxyphosphinyl]oxy]- 
piperidinium inner salt 


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Other Names: 
Octadecylphosphopiperidine (OPP), D-21266, KRX-0401 
Molecular Formula: C25H52NO4P 
M.W.: 
461.66 g/mol 
CAS No.: 
157716-52-4 
 
How Supplied: 
Perifosine is supplied as a film-coated tablet containing 50 
mg of active ingredient. 
 
Storage: 
Store closed containers at room temperature (20-25 ° C). 
Perifosine is hygroscopic, so containers must be kept 
closed and dry.  Perifosine tablets must be dispensed in the 
original container. 
 
Stability: 
Stability testing program ongoing.  Perifosine has a 
demonstrated shelf stability of at least 3 years. 
 
Route of Administration: 
Oral with meals unless otherwise specified. 
Potential Drug Interactions: None reported. 
Availability: 
Perifosine is an investigational agent supplied to 
investigators by AOI Pharmaceuticals. 
 
Agent Accountability: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 AOI 
Pharmaceuticals using the Drug Accountability Record 
Form. 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 Inclusion Criteria 
 
• Patients must have shown unequivocal evidence for tumor progression by MRI or 
CT scan. 
 
• Patients must be on a stable or decreasing dose of corticosteroids for a minimum 
of 5 days before the baseline MRI and FDG-PET scans. 


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• Patients must have failed prior radiation therapy. 
 
• Patients with prior therapy that included interstitial brachytherapy or stereotactic 
radiosurgery (including gamma-knife or cyber-knife) must have confirmation of 
true progressive disease rather than radiation necrosis based upon either PET or 
Thallium scanning, and/or MR spectroscopy, and/or MR Perfusion, and/or 
surgical documentation of disease. 
 
• All patients must sign an informed consent indicating that they are aware of the 
investigational nature of this study. Patients must have signed an authorization for 
the release of their protected health information. 
 
• Age > 18 years old, and with a life expectancy > 8 weeks. 
 
• Karnofsky Performance Status ≥ 50% 
 
• Patients must have recovered from all acute toxicities from prior therapies. At 
least 28 days must have elapsed since prior radiation. At least 28 days must have 
elapsed since prior therapy directed at VEGF/VEGFR such as bevacizumab 
(Avastin), VEGF-Trap, or AZD2171  In addition, the baseline MRI (with MR 
Perfusion if possible) and brain FDG-PET scans for this study must also be 
performed at least 28 days after discontinuation of prior therapy directed at 
VEGFR.  Any questions regarding the definition of anti-VEGF/VEGFR therapy 
must be discussed with the PI or co-PI. 
 
• Patients must have adequate bone marrow function (WBC > 3,000/µl, ANC > 
3 
3 
1,500/mm , platelet count of > 100,000/mm , and hemoglobin > 10 gm/dl), 
adequate liver function (SGOT and bilirubin < 2.5 times ULN), and adequate 
renal function (creatinine < 1.5 mg/dL before starting therapy. These tests must 
be performed within 2 weeks prior to treatment initiation.  Eligibility level for 
hemoglobin may be reached by transfusion. 
 
• Baseline MRI (with MR Perfusion if possible) must be performed within 2 weeks 
prior to treatment initiation. It also must be performed at least 28 days after 
discontinuation of prior therapy directed at VEGF/VEGFR such as bevacizumab 
(Avastin), VEGF-Trap, or AZD2171.  Any questions regarding the definition of 
anti-VEGF/VEGFR therapy should be discussed with the PI or co-PI. 


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• Baseline FDG-PET (dedicated study of the brain) must be performed within 2 
weeks prior to treatment initiation.  It also must be performed at least 28 days 
after discontinuation of prior therapy directed at VEGF/VEGFR such as 
bevacizumab (Avastin), VEGF-Trap, or AZD2171.  Any questions regarding the 
definition of anti-VEGF/VEGFR therapy should be discussed with the PI or co- 
PI. 
 
• There is no limitation on the number of prior relapses or prior therapies. 
 
• Patients must agree to practice adequate contraception. Women of childbearing 
potential must have a negative B-HCG pregnancy test documented within 7 days 
prior to registration.  Women must not be breast feeding. 
 
• If cytoreductive surgery is planned for tumor recurrence at the time of enrollment, 
such patients are eligible for the surgical arm, taking perifosine for 5-10 days pre- 
operatively and then continuing perifosine after recovering from the effects of 
surgery. 
 
• Measurable disease is not required for eligibility in patients who recently 
underwent resection as long as the following conditions are met as applicable: 
 
• Progression of disease led to the surgery 
• Gliadel wafers were not placed during the most recent surgery 
• Neither convection enhanced delivery nor catheters for infusion of 
chemotherapy were used during the most recent surgery 
• Radioactive seeds were not placed during the most recent surgery 
• The histology of the most recent surgery documented 
recurrent/persistent/progressive malignant glioma 
 
Note, however, that patients who are eligible for surgery because of 
progressive disease may be considered for the surgical arm. 
 
• Any adult patient with a recurrent/progressive malignant glioma is eligible. 
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. 


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6.2 
Subject Exclusion Criteria 
• Patients must not be taking EIAEDs. If patients were previously on EIAEDs 
that have been discontinued, patients must have been off the agent for at least 
2 weeks prior to registration. 
 
• Patients must not have any significant medical illnesses or other history that in 
the investigator’s opinion cannot be adequately controlled with appropriate 
therapy or would compromise the patient’s ability to tolerate this therapy. 
 
• 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. 
 
• Patients must not have active infection or serious intercurrent medical illness. 
 
• HIV-Positive patients receiving combination anti-retroviral therapy are 
excluded from the study due to possible retro-viral drug interactions. 
 
• Patients must not have any disease that will obscure toxicity or dangerously 
alter drug metabolism. 
 
• Surgical arm only: Patients must not have received prior therapy with signal 
transduction inhibitors (including but not limited to ZD1839/gefitinib/Iressa, 
OSI-774/erlotinib/Tarceva, rapamycin/sirolimus, CCI-779/temsirolimus, STI- 
571/imatinib/Gleevec, bevacizumab/Avastin, VEGF-Trap, AZD2171, 
sorafinib, sunitinib).  Any questions about the eligibility based on prior 
treatments should be discussed with the PI or co-PI. 
 
 
7.0 
RECRUITMENT PLAN 
 
Patients will be recruited from the neurology and neuro-surgery services at MSKCC.  All 
patients will be seen by a neuro-oncology attending.  All patients entered in the protocol 
will give written informed consent. There are no gender or racial restrictions. 
 
8.1 
PRETREATMENT EVALUATION 
 
The following studies are required within two weeks prior to starting perifosine: 
 
• Complete history and physical exam including neurologic exam and KPS. 
• Height and weight. 
• CBC including WBC differential and platelet count. 


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• Comprehensive chemistry panel. 
• Uric Acid 
• Contrast enhanced MRI (with MR Perfusion if possible) of the brain. The same 
type of scan, i.e., MRI or CT, should be used throughout the period of protocol 
treatment for tumor measurement. Patients unable to undergo an MRI will 
undergo contrast enhanced CT scans. It also must be performed at least 28 days 
after discontinuation of prior therapy directed at VEGF/VEGFR such as 
bevacizumab (Avastin), VEGF-Trap, or AZD2171.  Any questions regarding the 
definition of anti-VEGF/VEGFR therapy should be discussed with the PI or co-PI. 
• Brain FDG-PET: It also must be performed at least 28 days after discontinuation 
of prior therapy directed at VEGF/VEGFR such as bevacizumab (Avastin), VEGF- 
Trap, or AZD2171. Any questions regarding the definition of anti-VEGF/VEGFR 
therapy should be discussed with the PI or co-PI. 
• All brain PET scans must be performed on MSKCC scanners for adequate 
ability to compare scans over time. 
• For patients with histologically documented malignant gliomas who will receive 
perifosine for their 2nd or greater relapse, the date that the most recent therapy was 
started will be recorded and used to calculate the time to the prior relapse for 
comparison with time to progression on perifosine (intrapatient comparison). 
 
 
9.1 TREATMENT/INTERVENTION PLAN 
 
Dosing will be continuous, and for the purpose of this trial a cycle will be defined as 
28 days. 
 
9.2 Dosing 
Perifosine will be given as a 600 mg loading dose on day 1. The loading dose will be 
divided into 4 equal doses of 150 mg each.  The first 3 doses should be given with 
food in the adult day hospital to allow intravenous antiemetic prophylaxis, and 4th 
dose at bedtime at home. The interval between doses of perifosine should be no less 
than 4 hours.  On day 2, patients will start the maintenance dose of 100 mg daily at 
bedtime at home. 
 
9.3 Pharmacokinetics/drug concentration in tumor tissue (all patients) 
In addition to baseline serum, all patients will have weekly serum drawn during 
weeks 2-4. Patients in surgical arm of the trial will have blood drawn at baseline 
and during surgery to determine the concentration of perifosine in serum at the 
time of surgery. Tissue will also be collected for determination of the 
concentration of perifosine in tumor tissue relative to simultaneously collected 
serum.  The date and time of blood collection should be recorded. In addition, the 
date and time of the most recent dose of pre-surgical perifosine should be 
recorded. 


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9.4 Treatment modifications (all patients) 
 
For grade 1 perifosine related adverse events, treatment with perifosine will not 
be interrupted. 
 
For grade 2 perifosine related adverse events 
 
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. 
 
For persistent nausea, vomiting or diarrhea, or other persistent grade 2 adverse 
events despite symptomatic treatment, the daily dose will be reduced by 50 
mg. 
 
For grade 3 or 4 perifosine related adverse events 
 
Hold perifosine and re-evaluate the patient at least weekly until toxicity 
improves to < grade 2 (grade 0 or 1). 
 
If the toxicity resolves in 7 days or less, maintenance (daily) perifosine should 
be restarted but the daily dose will be reduced by 50 mg. 
 
If the toxicity resolves in 8-14 days, the patient will take another loading dose 
before reinitiating daily maintenance but the load will by reduced by 200 mg 
to 400 mg and the maintenance will be reduced to 50 mg. The loading dose 
will be divided into 4 equal doses of 100 mg each.  The first 3 doses should be 
given with food in the adult day hospital to allow intravenous antiemetic 
prophylaxis, and 4th dose at bedtime at home. The interval between doses of 
perifosine should be no less than 4 hours. 
 
If toxicity does not resolve within 14 days, the patient will be withdrawn from 
the study. 
 
9.5 Treatment Schedule for patients participating in the Pre-operative study: 
 
Patients who are candidates for surgical resection of recurrent disease will be 
considered for a pre-operative study to evaluate biological/tissue correlates. 
Patients who choose to participate in this component of the study must have a 
brain MRI (with MR Perfusion if possible) performed within 14 days of taking 
pre-operative perifosine.  Patients unable to undergo MRI will have CT scans.  A 
brain FDG-PET scan must also be performed within 14 days of taking pre- 
operative perifosine.  The drug will be administered for 5-10 days prior to the 


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surgery.  The last dose will be given the night before surgery.  Patients on the 
surgical arm will also undergo a pre-operative FDG-PET following at least 5 days 
of perifosine and before surgery to correlate metabolic and tissue effects during 
treatment. 
 
Day of Surgery: Prior to the surgical procedure, 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 surgery 10ml of blood will be collected for pharmacodynamic 
analysis. 
 
Following surgery: A post-operative MRI/CT scan should be done no later than 
96 hours from surgery. Once patients have recovered from the effects of surgery 
and demonstrated wound healing, they will restart perifosine (load and 
maintenance).  Patients are not required to have residual disease to continue 
perifosine. Treatment with perifosine post-operatively should start a minimum of 
7 days after surgery. If more than 14 days have passed since the post-operative 
MRI was performed, new baseline brain MRI (with MR Perfusion if possible) and 
brain FDG-PET sans must be performed. 
 
9.6 Supportive Care Guidelines (all patients) 
 
9.6.1 Antiemetic prophylaxis 
 
Patients are to be instructed that perifosine is to be taken with food. Patients 
will maintain a daily patient treatment diary to track when they take each dose 
of perifosine and return the diary to the clinic each week along with any 
remaining medication. The pills should remain intact and should not be split 
unless a gastrostomy tube is being used. 
 
All patients should have antiemetic medications prescribed and administered 
as needed, and adjusted during the cycle at the discretion of the treating 
investigator. 
 
Patients should receive an oral or IV prophylactic antiemetic regimen. The 
regimen to be used is at the discretion of the treating investigator. 


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Premedication with a 5HT3 blocker with dexamethasone is recommended. 
 
9.6.2 Diarrhea Management 
 
All patients should be instructed to take loperamide at the earliest signs of 
diarrhea and/or abdominal cramping after beginning study medication. This 
can include (a) loose stool, (b) the occurrence of 1 to 2 more bowel 
movements than usual in 1 day, or (c) an unusually high volume of stool. 
 
Loperamide should be dosed in the following manner: 4 mg at the first onset 
of diarrhea, then 2 mg every 2 hours around the clock until diarrhea free for at 
least 12 hours. Patients may take 4 mg every 4 hours during the night. 
 
Additional antidiarrheal measures may be used at the discretion of the treating 
physician as warranted by the patient’s condition. 
 
9.6.3 Hyperuricemia Prophylaxis 
 
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 po 
daily. If severe gout does occur or uric acid levels increase, the dose of 
allopurinol should be increased at physician discretion. 
 
9.6.4 G-CSF Administration 
 
Routine prophylactic use of G-CSF is not permitted. However, therapeutic 
use in patients with serious neutropenic complications, such as sepsis, may 
be considered at the investigator’s discretion 
 
9.6.5 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. 
 
9.6.6 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. 


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No other drug under investigation may be used concomitantly with the study 
drug. 
 
9.6.7 Surgery 
 
If neurosurgical 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. 
 
9.6.8 Corticosteroids should be used in the smallest dose to control symptoms of 
cerebral edema and mass effect, and discontinued if possible. 
 
Anti-seizure medications should be used as indicated.  However, only patients 
not taking EIAEDs are eligible to enroll on this trial.  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. Patients who were previously on no anticonvulsants should be 
treated with non-EIAEDs if at all possible. If for unavoidable clinical reasons 
(severe allergies, toxicities etc.) a patient is started on an EIAED, he/she 
should immediately be started on another non-EIAED and the EIAED should 
be tapered and discontinued as quickly as possible. The patient may continue 
the current treatment dose while a non- EIAED is re-started because an 
EIAED will likely increase metabolism of perifosine, reducing rather than 
increasing any potential anti-tumor effect and therefore any efficacy bias 
introduced would be negative rather than positive. 
 
Patients who were previously on a non-EIAED and need to permanently 
change anticonvulsant, but who cannot change to another non-EIAED may 
continue the current treatment dose for the next 2 weeks while an EIAED is 
started. FOLLOWING THIS PERIOD, THE SUBSEQUENT TREATMENT 
DOSE MUST BE DISCUSSED WITH THE PI OR CO-PI. Treatment may be 
allowed to continue if the patient is felt to be deriving clinical benefit.  In 
some cases this dose may be higher than the previously used dose. 
 
 
10.0  EVALUATION DURING TREATMENT/INTERVENTION 
 
10.1 
Clinical 
 
History and physical examination (including vital signs, weight and KPS) will be 
performed at each clinic visit.  Patients will have a follow up physical exam 1 week after 
the patient starts treatment and every first week of each subsequent cycle (4 week 
period). 


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A diary should be completed by the patient each week to score duration and severity of 
gastrointestinal side effects.  Patients will also maintain a weekly patient treatment diary 
to track doses of perifosine taken at home and return the diary to the clinic each week. 
 
10.2 Laboratory 
 
A CBC with differential and serum chemistry will be performed 1 week after the patient 
starts treatment, and every first week of each subsequent cycle. 
 
• 
Albumin 
• 
Alkaline phosphatase 
• 
Total bilirubin 
• 
Bicarbonate 
• 
BUN 
• 
Calcium 
• 
Chloride 
• 
Creatinine 
• 
Glucose 
• 
LDH 
• 
Phosphorus 
• 
Potassium 
• 
total protein 
• 
SGOT [AST], SGPT [ALT] 
• 
Sodium 
• 
Uric acid 
• 
Magnesium 
 
Serum pregnancy test should be obtained within 72 hours prior to the initiation of therapy 
for women of childbearing potential. 
 
10.3 
Imaging and Molecular Studies 
 
Patients not on the surgical arm will undergo imaging evaluation with brain MRI (with 
MR Perfusion and MR spectroscopy if possible) at baseline and every 8 weeks  Patients 
unable to undergo MRI will have CT scans. Patients will also undergo FDG-PET 
imaging of the brain (at MSKCC) at baseline and every 16 weeks (4 cycles) to assist with 
interpretation of MRI. Patients will also undergo a brain FDG-PET scan after 1-2 weeks 
of therapy at MSKCC to investigate potential metabolic effects of perifosine and to 
explore early FDG-PET as a predictor of response by clinical and radiographic 
evaluations performed later. 


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Patients on the surgical arm will undergo baseline imaging evaluation with brain MRI 
(with MR Perfusion and MR Spectroscopy if possible) and FDG-PET at MSKCC no 
more than 2 weeks before pre-operative perifosine.  Patients on the surgical arm will also 
undergo a pre-operative FDG-PET at MSKCC following at least 5 days of perifosine and 
before surgery to correlate metabolic and tissue effects during treatment. After surgery, a 
brain MRI must also be performed no more than 2 weeks before initiation of post- 
operative perifosine. It is expected that in most cases, the post-operative MRI (performed 
within 96 hours after surgery) will suffice and function as the new baseline scan before 
initiation of post-operative perifosine.  Patients unable to undergo MRI will have CT 
scans.  FDG-PET does not need to be repeated post-operatively before re-initiating 
perifosine. Patients will then undergo brain MRI every 8 weeks (with MR Perfusion if 
possible) and brain FDG-PET every 16 weeks (4 cycles) at MSKCC to assist with 
interpretation of MRI. 
 
Fifteen unstained paraffin slides and 100 mg of flash frozen tissue will be used to 
evaluate the effect of perifosine on PI3K/AKT and RAS/MAPK signaling, the effect on 
proliferation, and other molecular effects. In addition, 100 mg of flash frozen tissue and 
one tube of serum will be collected for pharmacokinetic analysis. 
 
All patients: The brain MRI, MR Perfusion, MR Spectroscopy and FDG-PET scans will 
be used for clinical care and be billed to insurance/patient with the exception of the FDG- 
PET performed after 1-2 weeks of therapy which is research in nature..  In addition, such 
scans will be used to determine effects of perifosine on tumor blood flow and 
metabolism. 
 
If available, 15 unstained paraffin slides and flash frozen tissue will be obtained from the 
surgery closest to initiation of this clinical trial. These will be used to evaluate molecular 
markers that could predict glioma sensitivity to perifosine such as a PI3K/AKT activity, 
RAS/MAPK activity, proliferation rate, and somatic mutations of potential oncogenes or 
tumor suppressor genes in tumor cell DNA. 
 
Dr. Eric Holland and members of his laboratory will conduct analyses of baseline tumor 
tissue for abnormalities of the RAS, AKT, and other signal transduction cascades that 
may predict tumor sensitivity to perifosine.  Dr. Holland will also conduct analyses of 
tissue resected during treatment with perifosine (surgical arm of the study) to determine 
the effects of perifosine on signaling. 
 
Jill M. Kolesar, Pharm. D. at the University of Wisconsin will conduct PK and tissue 
drug concentration analyses.  AOI Pharmaceuticals subcontracted Dr. Kolesar to perform 
such assays. Please see section 20.3 for instructions on shipping tissue/serum to Dr. 
Kolesar. 


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(Remainder of this page intentionally left blank.) 
 
 
 
 
 
 
 
 
All assessments should be obtained prior to the first dose of perifosine in each week unless otherwise specified 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Off 
Studyc 
Perifosine administrationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Concurrent meds 
X 
Physical exam 
X 
X 
X 
X 
Xf 
Vital signs 
X 
X 
X 
X 
Xf 
Height 
X 
Weight 
X 
X 
X 
X 
Xf 
Performance status 
X 
X 
X 
X 
Xf 
CBC (w/diff, pltsf) 
X 
X 
X 
X 
Xf 
Serum chemistryb 
Xd 
X 
X 
X 
Xd 
Serum pregnancye 
X 
Adverse event evaluation 
X 
X       ------------------------------------------------------------------------------------------------------------------ 
-------- 
X 
Patient Diaries 
X 
X       ------------------------------------------------------------------------------------------------------------------ 
-------- 
X 
Tumor measurements 
X 
Tumor measurements are repeated every 8 weeks. Documentation (radiological) must be 
provided for patients removed from study for progressive disease. 
Xc 
a: 
Perifosine: Dose, route, schedule as assigned. 
b: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium, uric acid, magnesium. 
c: 
Off-study evaluation. It is preferable that two consecutive measurements taken to document progressive disease if the patient is removed 
from study for this reason. 
d: 
Assessments to continue at least every 12 weeks while patient is on study. 
e: 
Within 72 hours prior to initiation of therapy for women of childbearing potential only. 
f: 
Assessments to continue at least every 4 weeks while patient is on study. 


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11.1 Toxicities/side effects 
 
The most common toxicities associate with perifosine are nausea, vomiting, and diarrhea. 
NCI CTC version 3.0 will be used to grade all toxicity. 
 
Reported Adverse Events and Potential Risks: 
• Constitutional Symptoms: fatigue (lethargy, malaise, asthenia) 
• Gastrointestinal: anorexia, dehydration, flatulence, diarrhea, nausea, vomiting 
 
The following events were reported in two or fewer of the patients treated on the 
NCI sponsored phase I trial: 
• Pulmonary: hiccoughs (hiccups, singultus) 
• Renal/Genitourinary: increased creatinine 
• Hepatic: increased alkaline phosphatase, increased GGT 
 
Also reported on the NCI phase I perifosine trials and occurring in two or fewer 
patients with the relationship to perifosine still undetermined: 
• Blood/Bone Marrow: decreased hemoglobin 
• Constitutional Symptoms: fever, sweating, weight loss 
• Dermatology/Skin: mild skin reaction 
• Gastrointestinal: mucositis, dyspepsia/heartburn 
• Neurology: lightheadedness 
• Ocular/Visual: eye symptoms, specifically blurred vision, photophobia and 
cataract formation 
• Pain: abdominal pain, headache, arthritis, arthralgia 
• Genitourinary: hyperuricemia 
 
Also from animal data: 
• Dose dependent kidney and eye events (retinal degeneration and cataracts) 
 
If hematologic toxicity grade 3 or higher occurs patients may be treated with appropriate 
growth factors. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
The primary efficacy endpoint will be progression free survival (PFS) at six months from 
registration. For this and for all other time to event analyses, if a patient is NOT registered 
on the pre-operative portion of the study (surgical arm), the start date for calculation of 
time to event will be the date of first study drug administration. For this and for all other 
time to event analysis, if a patient IS enrolled on the pre-operative portion of the study 
(surgical arm), the start date for calculation of time to event will be the date of the first 
post-operative study drug administration. 


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Objective status should be measured and recorded although this is not the primary 
endpoint.  The following definitions will be used based on standard criteria for malignant 
glioma trials [23]: 
 
Measurable Disease: Bidimensionally measurable lesions with clearly defined 
margins by CT or MRI scan. 
 
Evaluable Disease: Unidimensionally measurable lesions, masses with margins 
not clearly defined. 
 
Non-Evaluable Disease: Not Applicable for response evaluation 
 
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.  The remaining lesions will be 
considered evaluable for the purpose of objective status determination. Unless 
progression is observed, objective status can only be determined when ALL 
measurable and evaluable sites and lesions are assessed. 
 
Complete Response (CR):  Complete disappearance of all measurable and 
evaluable disease.  No new lesions. No evidence of non-evaluable disease. All 
measurable, evaluable and non-evaluable lesions and sites must be assessed using 
the same techniques as baseline.  Patients must be on no steroids. 
 
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 evaluable disease.  No new lesions. All measurable and evaluable 
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. 
 
Partial Response, Non-Measurable (PRNM): Not applicable. 
 
Stable/No Response: Does not qualify for CR, PR, or progression.  All 
measurable and evaluable 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 (over baseline if no decrease) using the same techniques as 
baseline, OR clear worsening of any evaluable 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). 


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Unknown: Progression has not been documented and one or more measurable or 
evaluable sites have not been assessed. 
 
Best Response: This will be calculated from the sequence of objective statuses. 
 
For patients with all disease sites assessed every evaluation period, the best response will 
be defined as the best objective status.  If the response does not persist at the next regular 
scheduled MRI, 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 does not qualify for a best 
response or increasing disease and if all objective status determinations before progression 
are unknown. 
 
Criteria permitting uni-dimensional response measurement have recently been adopted and 
published by an international consensus committee, Response Evaluation Criteria In Solid 
Tumors Group (RECIST).  In order to ensure comparability of data from this trial with 
data from earlier trials, this trial will retain the traditional evaluation definition above as 
primary. However, RECIST criteria that can be collected, will be used for secondary 
evaluation. 
 
Neurological Exam: Although not used for determining response, it is useful to evaluate 
improvement in the neurologic exam, (as compared to the baseline assessment), that 
should coincide with objective measurement of tumor size. 
 
+2 
Definitely better 
+1 
Possibly better 
0 
Unchanged 
-1 
Possibly worse 
-2 
Definitely worse 
 
 
Performance Status: Patients will be graded according to Karnofsky Performance Status 
(see Appendix  20.1). 
 
Time to Treatment Failure: From the treatment start date to the date of first observation of 
progressive disease, non-reversible neurologic progression or permanently increased 
steroid requirement (applies to stable disease only), death due to any cause, or early 
discontinuation of treatment. If a patient is NOT registered on the pre-operative portion of 
the study (surgical arm), the start date for calculation of time to event will be the date of 
first study drug administration. If a patient IS enrolled on the pre-operative portion of the 
study (surgical arm), the start date for calculation of time to event will be the date of the 


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first post-operative study drug administration. As an exploratory evaluation of other means 
to demonstrate clinical efficicacy, the time to treatment failure in comparison to time to the 
most recent progression for prior relapse will also be calculated for each patient; in this 
manner, each patient serves as his/her own control and an increase in the time to treatment 
failure relative to the most recent progression may also suggest clinical activity of the drug. 
 
Time to Death: From the treatment start date to date of death due to any cause. If a patient 
is NOT registered on the pre-operative portion of the study (surgical arm), the start date for 
calculation of time to event will be the date of first study drug administration. If a patient 
IS enrolled on the pre-operative portion of the study (surgical arm), the start date for 
calculation of time to event will be the date of the first post-operative study drug 
administration. 
 
 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
All patients may continue therapy unless disease progression, death, or dose limiting 
toxicity is documented. The cause of death should be recorded. 
 
The following events may be considered sufficient reason for discontinuing treatment 
with the study medication 
 
• Serious toxicity due to the study drug graded according to the NCI 
Common Terminology Criteria for Adverse Events v3.0 [22] 
• Conditions requiring therapeutic intervention not permitted by the protocol 
• Unacceptable toxicity in the opinion of the patient or investigator even if 
not specifically defined elsewhere 
• Personal preference by the patient for any reason 
• Subject non-compliance with the defined treatment plan 
• Medical or psychiatric illness or social environment which in the 
investigator's judgment renders the patient incapable of further therapy. 
• Any other situation where, in the opinion of the investigator, continued 
participation in the study would not be in the best interest of the patient 
• Treatment delay due to toxicity greater than 14 days 
• Pregnancy 
• Disease progression 
 
All reasons for discontinuation of treatment must be documented in the flow sheets. 


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14.0 
BIOSTATISTICS 
 
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.[24] 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%.[3] Therefore, we 
would expect 6 month PFS to be less than 20%. 
 
We will utilize a Simon two-stage design in which the primary endpoint is the 
progression rate at 6 months.  All patients will be followed for 6 months and progression 
or death due to disease will be considered an event.  Assuming a 6 month progression 
free survival rate of 20% is considered promising, a 6 month progression free survival 
rate of 5% is considered not promising, and the probabilities of a type I error (falsely 
accepting a non-promising therapy) and type II error (falsely rejecting a promising 
therapy) are set at 0.10 and 0.10, respectively.   In the first stage of this design, 12 
patients with GBM will be accrued. If at least 1 patient with GBM does not progress at 
the 6 month time among these 12 patients, then an additional 25 patients with GBM (for a 
total of 37) will be accrued to the second stage, otherwise the trial will be terminated. 
Note that enrollment of patients with both GBM and non-GBM malignant gliomas will 
continue while the first 12 patients with GBM are followed for PFS. However, if 0 of 
these first 12 reach 6mPFS, then enrollment will terminate; in that event, any patients still 
on trial with any histology may continue until progression or death at the discretion of the 
treating physician. At the end of the trial, if 3 or less patients with GBM are progression 
free at 6 months, the study will be declared negative.  This design yields at least a 0.90 
probability of a positive result if the true response rate is at least 20% and yields a 0.90 
probability of a negative result if the true response rate is 5%. 
 
Up to 20 patients with anaplastic glioma and evaluable disease at study entry (i.e., did not 
undergo gross total resection as the most recent therapy prior to registration) will be 
accrued.  Endpoints such as response, one-year survival probability, overall survival and 
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 and the two-stage design will be applied only to 
the GBM cohort. 
 
Surgical arm 
In order to obtain specimens for study of the tissue pharmacokinetics of perifosine in 
tumors, as well as the molecular effects of perifosine in tumor tissue, we plan to accrue 
subjects to a preoperative treatment arm.  There is no upper bound on the number of 
patients that can be entered into this substudy.  However, if the study reaches the total 
enrollment and fewer than 10 patients have entered this substudy, the trial will be kept 
open to accrue at least 10 surgical arm patients. Note, the study will only be kept open if 


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the drug is considered promising (defined above) after either the first stage enrolling 12 
patients with GBM or complete accrual of the total cohort of 37 patients with GBM. 
Any additional patients enrolled through this mechanism will be included in the primary 
analysis of efficacy (6mPFS) and the total cohort will be increased from 37 patients with 
GBM to a maximum of 47 patients with GBM (37 + 10 additional surgical patients in the 
unlikely circumstance that none of the initial 37 patients are enrolled on the surgical 
arm).  Therefore, the maximum enrollment is up to 57 patients (37 with GBM, not on 
surgical substudy; up to 10 additional patients with anaplastic glioma; up to 10 additional 
patients on surgical stubstudy if not already accrued). 
 
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.  Hence, we 
plan to combine data from patients on and not on the surgical substudy in efficacy 
analyses. 
 
Molecular and Metabolic Correlates 
Pre-treatment tissue will be used for exploration of molecular predictors of tumor 
sensitivity to perifosine (all patients).  Tissue resected during perifosine treatment 
(surgical arm) will be used to explore effects of the agent on PI3K/AKT and RAS/MAPK 
signaling as well as proliferation and other pathways. 
 
FDG-PET and MR Perfusion studies will be used for clinical care with the exception of 
the FDG-PET performed after 1-2 weeks of therapy..  However, they will also be used for 
exploration of perifosine effects on tumor metabolism and blood flow. To ensure 
adequate comparability of scans, all FDG-PET scans must be performed at MSKCC. 
 
The analysis of biological correlate data has the overall goal of providing increased 
understanding of the nature of the response to perifosine. The amount of data available 
for the various measures is uncertain. Information may also be limited by the impact of 
intervening treatment between the most recent surgery and initiation of perifosine. 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 the response is not favorable, the data may be used to better 
understand the reason for the failure. In addition, new assays may become available 
between the opening of this study and the collection and analysis of tumor tissue.  Thus, 


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it is difficult to prespecify the nature of the analyses and the list assays here is a general 
guide rather than all inclusive. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.1 Research Participant Registration 
The following person(s) can obtain informed consent: 
• Thomas Kaley, MD 
• Lisa DeAngelis, MD 
• Igor Gavrilovic, MD 
• Adilia Hormigo, MD 
• Craig Nolan, MD 
• Jerome Posner, MD 
• Eugenie Obbens, MD 
• Antonio Omuro, MD 
• Ingo Mellinghoff, MD 
• Xi Chen, MD 
 
 
Confirm with electronic medical record that the patient has received the Notice of 
Privacy Practice.  This must be obtained before the eligibility confirmation and obtaining 
of the research informed consent. 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject 
Eligibility. 
 
Obtain written informed consent, by following procedures defined in section entitled 
Informed Consent Procedures. 
 
All patients must be registered through the Protocol-Patient Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center.  PPR is available Monday through Friday from 
8:30am – 5:30pm at (646) 735-8000. The PPR fax numbers are (646) 735-0008 and (646) 
735-0003.  Registrations can be phoned in or faxed.  The completed signature page of  
the informed consent form, the completed signature page of the Research     
Authorization and a completed Eligibility Checklist must be faxed to the PPR. 
 
During the registration process registering individuals will be required to answer specific 
eligibility questions and provide the following information: 
Registering Individual 
[Last, First Name] 
Notice of Privacy Status 
[Yes, No, N/A] 


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MSKCC IRB Protocol# 
Attending of Record  (if applicable) [Last, First Name] 
Consenting Professional 
[Last, First Name] 
Informed Consent Date 
Patient's Full Name 
[Last, First Name] 
Patient MRN 
 
 
16.1 
DATA MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of 
the RSA include project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and coordinate 
the activities of the protocol study team. 
 
The data collected for this study will be entered into a secure database. Source 
documentation will be available to support the computerized patient record. 
 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data.  Routine data quality reports will be generated 
to assess missing data and inconsistencies.  Accrual rates and extext and accuracy 
of evaluations and follow-up will be monitored periodically throughout the study 
period and potential problems will be brought to the attention of the study team 
for discussion and action 
 
Random-sample data quality and protocol compliance audits will be conducted by 
the study team, at a minimum of two times per year, more frequently if indicated. 
 
16.2  Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering 
Cancer Center were approved by the National Cancer Institute in September 2001. 
The plans address thenew policies set forth by the NCI in the document entitled 
“Policy of the National Cancer Institute for Data and Safety Monitoring of 
Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research. 
The MSKCC Data and Safety Monitoring Plans can be found on the MSKCC 
Intranet at: http://mskweb2.mskcc.org/irb/index.htm 


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There are several different mechanisms by which clinical trials are monitored for 
data, safety and quality. There are institutional processes in place for quality 
assurance (e.g., protocol monitoring, compliance and data verification audits, 
therapeutic response, and staff education on clinical research QA) and 
departmental procedures for quality control, plus there are two institutional 
committees that are responsible for monitoring the activities of our clinical trials 
programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) 
for Phase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board. 
 
During the protocol development and review process, each protocol will be 
assessed for its level of risk and degree of monitoring required. Every type of 
protocol (e.g., NIH sponsored, in-house sponsored, industrial sponsored, NCI 
cooperative group, etc.) will be addressed and the monitoring procedures will be 
established at the time of protocol activation. 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
17.1 Privacy 
It is the responsibility of the Research Staff to ensure that protocol patients have 
received the Center’s Notice of Privacy Practices. If the subject has not already 
done so, MSK personnel must try to obtain acknowledgment before the patient 
participates in this study. 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form. 
The use and disclosure of protected health information will be limited to the 
individuals described in the Research Authorization form.  A Research 
Authorization form must be completed by the Principal Investigator and approved 
by the IRB and Privacy Board. 
 
 
17.2 Serious Adverse Event (SAE) Reporting 
Any SAE must be reported to the IRB as soon as possible but no later than 5 calendar 
days. The IRB requires a Clinical Research Database (CRDB) AE report to be delivered 
to the Institutional SAE Manager (307 East 63rd Street, 1st Floor) containing the following 
information: 
Fields populated from the CRDB: 
• Subject’s name 


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• Medical record number 
• Disease/histology (if applicable) 
• Protocol number 
 
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) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following information: 
o A 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. 
All serious adverse events will also be reported to AOI.  This includes serious, 
related, labeled (expected) and serious, related, unlabeled (unexpected) adverse 
experiences. 
 
These reports should be sent by FAX or E-MAIL to the Online Collaborative 
Oncology Group (OCOG), which is a subsidiary of AOI Pharmaceuticals: 
 
Online Collaborative Oncology Group 
1355 Lynnfield, Suite 245 
Memphis, TN 38119 
 
By FAX: (901)-869-3842, within 24 hours of receipt by investigator. 
FAX transmission should include Subject Number, Study Title, Study 
Number and name of Principal Investigator. 
 
By E-MAIL: ocogtrials@ocog.net, within 24 hours of receipt by 
investigator. E-Mail transmission should include Subject Number, Study 
Title, Study Number and name of Principal Investigator. 


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17.2.1 
Relationship between the adverse event and the study 
drug 
 
The Investigator must also assess the relationship of any adverse event to 
the use of study drug, based on available information, using the following 
guidelines: 
 
Unlikely - no temporal association, or the cause of the event has been 
identified, or the drug cannot be implicated. 
Possibly - temporal association, but other etiologies are likely to be the 
cause; however, involvement of the drug cannot be excluded. 
Probably - temporal association, other etiologies are possible, but unlikely. 
 
17.2.2 
Definition of Adverse Event 
Adverse events are illnesses, signs, or symptoms that appear or worsen 
during the course of a study.  Adverse events occurring in association with 
study drug administration, whether believed by the investigator to be 
related or unrelated to the drug should be recorded on the case report form. 
When the investigator is confident of the diagnosis, he should group 
together as a single illness all related signs, symptoms, and abnormal 
laboratory results, e.g. cough; rhinitis, and sneezing can be reported as 
"upper respiratory infection." 
 
Abnormal laboratory results should be noted on the case report form if 
they are associated with an overdose, require or prolong inpatient 
hospitalization or are otherwise considered significant by the investigator. 
 
17.2.3 
Definition of Serious Adverse Event 
 
A serious adverse event is one that meets any of the following criteria: 
• life-threatening (all grade 4 events except myelosuppression, nausea, 
emesis, and hyperglycemia) or fatal 
• substantial or permanent disability 
• requires or prolongs inpatient hospitalization (this does not include 
hospitalization for elective treatment or emergency room visits) 
• cancer (2 malignancy) 
• a congenital anomaly in the offspring of a patient who received trial 
medication 
• an event resulting from an overdose (overdoses without clinical 
sequelae are not serious adverse events) 
• an event (not mentioned in a-f) that may jeopardize the patient or may 
require intervention to prevent one of the outcomes listed above. 


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18.1 
INFORMED CONSENT PROCEDURES 
 
All patients must provide written informed consent prior to registration and 
treatment. Those physicians authorized to obtain informed consent are listed on the title 
page of this document. 
 
18.2 Research Authorization:  Procedures for obtaining Research Authorization: 
Before any protocol-specific procedures are carried out, investigators and/or designated 
staff will fully explain the details of the protocol, study procedures, and the aspects of 
patient privacy concerning research specific information. In addition to signing the IRB 
Informed Consent, all patients must sign the Research Authorization component of the 
informed consent form.  The Research Authorization requires a separate set of signatures 
from the patient. The original signed documents will become part of the patient’s medical 
record, and each patient will receive a copy of the signed documents. 
 
19.0 
REFERENCE(S) 
 
1. 
Jelsma, R.K. and P.C. Bucy, The treatment of glioblastoma multiforme. Trans Am Neurol 
Assoc, 1967. 92: p. 90-3. 
2. 
Stupp, R., et al., Radiotherapy plus concomitant and adjuvant temozolomide for 
glioblastoma. N Engl J Med, 2005. 352(10): p. 987-96. 
3. 
Brandes, A.A., et al., How effective is BCNU in recurrent glioblastoma in the modern 
era? A phase II trial. Neurology, 2004. 63(7): p. 1281-4. 
4. 
Hilgard, P., et al., D-21266, a new heterocyclic alkylphospholipid with antitumour 
activity. Eur J Cancer, 1997. 33(3): p. 442-6. 
5. 
Arthur, G. and R. Bittman, The inhibition of cell signaling pathways by antitumor ether 
lipids. Biochim Biophys Acta, 1998. 1390(1): p. 85-102. 
6. 
Ruiter, G.A., et al., Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 
3-kinase-Akt/PKB survival pathway. Anticancer Drugs, 2003. 14(2): p. 167-73. 
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Kondapaka, S.B., et al., Perifosine, a novel alkylphospholipid, inhibits protein kinase B 
activation. Mol Cancer Ther, 2003. 2(11): p. 1093-103. 
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Holland, E.C., et al., Combined activation of Ras and Akt in neural progenitors induces 
glioblastoma formation in mice. Nat Genet, 2000. 25(1): p. 55-7. 
9. 
Rajasekhar, V.K., et al., Oncogenic Ras and Akt signaling contribute to glioblastoma 
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Sano, T., et al., Differential expression of MMAC/PTEN in glioblastoma multiforme: 
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Choe, G., et al., Analysis of the phosphatidylinositol 3'-kinase signaling pathway in 
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Ermoian, R.P., et al., Dysregulation of PTEN and protein kinase B is associated with 
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13. 
Hu, X., et al., PTEN loss is equivalent to Akt and cooperates with Ras in the formation of 
GBMs. Neoplasia, 2005: p. In Press. 
14. 
Chang, S.M., et al., Phase II study of CCI-779 in patients with recurrent glioblastoma 
multiforme. Invest New Drugs, 2005. 23(4): p. 357-61. 
15. 
Yung, W.K., et al., A phase II study of temozolomide vs. procarbazine in patients with 
glioblastoma multiforme at first relapse. Br J Cancer, 2000. 83(5): p. 588-93. 
16. 
Brada, M., et al., Multicenter phase II trial of temozolomide in patients with glioblastoma 
multiforme at first relapse. Ann Oncol, 2001. 12(2): p. 259-66. 
17. 
Chang, S.M., et al., Temozolomide in the treatment of recurrent malignant glioma. 
Cancer, 2004. 100(3): p. 605-11. 
18. 
Crul, M., et al., Phase I and pharmacological study of daily oral administration of 
perifosine (D-21266) in patients with advanced solid tumours. Eur J Cancer, 2002. 
38(12): p. 1615-21. 
19. 
Monga, M., et al. A phase 1 trial of oral perifosine in patients with refractory neoplasma. 
in American Society of Clinical Oncology. 2002: Journal of Clinical Oncology. 
20. 
Van Ummersen, L., et al., A phase I trial of perifosine (NSC 639966) on a loading 
dose/maintenance dose schedule in patients with advanced cancer. Clin Cancer Res, 
2004. 10(22): p. 7450-6. 
21. 
Bailey, H., et al. Tolerability and limited activity of perifosine in patients with advanced 
soft tissue sarcoma (STS): a multicenter phase 2 consortium (P2C) Study. in 16th 
EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. 2004. 
Geneva Switzerland: European Journal of Cancer Supplements. 
22. 
Common Toxicity Criteria for Adverse Events v3.0 (CTCAE)  
http://www.accessdata.fda.gov/scripts/cder/onctools/toxicity.cfm. 2003, National Cancer 
Institute, Cancer Therapy Evaluation Program (CTEP). 
23. 
Macdonald, D.R., et al., Response criteria for phase II studies of supratentorial 
malignant glioma. J Clin Oncol, 1990. 8(7): p. 1277-80. 
24. 
Wong, E.T., et al., Outcomes and prognostic factors in recurrent glioma patients enrolled 
onto phase II clinical trials. J Clin Oncol, 1999. 17(8): p. 2572-8. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-044 A(11) 
Amended:  10/25/11 
- 54 - 
 
 
20.1 
APPENDICES 
 
20.2 Karnofsky Performance Status, Neurological Function, and Mental Status 
Patient's performance status will be graded according to the following scale: 
 
Karnofsky Performance Status 
KPS 100 Normal; no complaints; no evidence of disease 
KPS 90 Able to carry on normal activity; minor signs or symptoms of disease 
KPS 80 Normal activity with effort; some sign or symptoms of disease 
KPS 70 Cares for self; unable to carry on normal activity or do active work 
KPS 60 Requires occasional assistance, but is able to care for most personal 
needs 
KPS 50 Requires considerable assistance and frequent medical care 
KPS 40 Disabled; requires special care and assistance 
KPS 30 Severely disabled; hospitalization is indicated, although death not 
imminent 
KPS 20 Very sick; hospitalization necessary; active support treatment is 
necessary 
KPS 10 Moribund; fatal processes progressing rapidly 
KPS 0 Dead 
 
 
20.3 EIAEDs and Non-EIAEDs 
 
EIAEDs: 
Carbamazipine (Tegretol, Tegretol XR, Carbatrol) 
Oxcarbazepine (Trileptal) 
Phenytoin (Dilantin, Phenytek) 
Fosphenytoin (Cerebyx) 
Phenobarbital 
Primidone (Mysoline) 
 
Non-EIAEDs: 
Valproic acid (Depakote, Depakene) 
Gabapentin (Neurontin) 
Lamotrigine (Lamictil) 
Topriamate (Topamax) 
Tiagabine (Gabatril) 
Zonisamide (Zonegran) 
Levatriacetam (Keppra) 
Clonazepam (Klonopin) 
Clonozam (Frisium) 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-044 A(11) 
Amended:  10/25/11 
- 55 - 
 
 
20.4 Handling and Shipping of Serum and Tissue for Perifosine Measurement: 
 
A. Serum 
At each time point, heparinized blood is collected into a plastic vacutainer to minimize 
adhesion of perifosine. Plasma is separated by centrifugation and stored in 
polypropylene cryovials at -70°C until assayed. Perifosine in plasma is measured by a 
validated reversed phase liquid chromatography/electrospray mass spectrometry method 
by Jill M. Kolesar, Pharm.D at the University of Wisconsin, Comprehensive Cancer 
Center who has been subcontracted by AOI Pharmaceuticals to perform these analyses. 
An LC/MS analytical method used in NCI sponsored phase I trials (Woo EW, Messmann 
R, Sausville EA, Figg WD. Quantitative determination of perifosine, a novel 
alkylphosphocholine anticancer agent, in human plasma by reversed-phase liquid 
chromatography-electrospray mass spectrometry. J Chromatogr B Biomed Sci Appl. 
2001 Aug 15;759(2):247-57), is currently available for plasma samples at the Univ. of 
Wisconsin, and will be used for this study. The pharmacokinetic characteristics of 
perifosine in patients will be evaluated using WinNonlin modeling software. 
 
Sample processing and handling outline: 
 
1) A pharmacokinetic sample will be obtained from each patient, at the times outlined. 
One sodium heparin 10cc green top with >7ml of blood will be obtained and shipped to 
the Jill M. Kolesar, Pharm.D at the University of Wisconsin for further analysis. 
 
2) Pharmacokinetic samples will be obtained in association with perifosine administration 
at pretreatment, and weekly during weeks 2-4. 
 
3) Peripheral blood is to be drawn into heparinized vacutainer (green top) provided in the 
sample collection kit.  The Patient’s initials, time sample obtained, date sample was 
obtained should be recorded on each green top tube. 
 
4) Within 20 minutes of collection, centrifuge the blood samples at 900g for 15 minutes 
(or use the local laboratory Standard Operating Procedure) to separate plasma. 
 
5) For each sample collected, pipet duplicate aliquots of plasma, 2 ml each, in 
polypropylene cryovials (Nunc) provided in the sample collection kit.  Aliquot 1 is the 
sample and aliquot 2 is the duplicate. 
 
6) Place the appropriate labels, included in the sample collection kit, onto the tubes and 
freeze at -70°C until shipped. 
 
7) Sample Shipping: 
• Samples are to be shipped overnight in sufficient dry ice to keep samples 
frozen using the airbill and shipping box provided in the kit. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-044 A(11) 
Amended:  10/25/11 
- 56 - 
 
 
 
• Please place all 6 nunc sample tubes into the plastic bag provided. Do not 
ship samples and duplicates in the same box. Save the duplicates and ship 
them with your next patient. 
 
• Place the patient flowsheets in a separate plastic bag and then place it in 
the shipping box. 
 
• Please contact the central lab before shipping samples 
Amy Dresen (608) 263-5369 or 
Jill Kolesar (608) 262-5549 
 
• The laboratory is open to receive samples Monday through Friday. NOTE: 
DO NOT ship samples on Thursdays, Fridays or on days prior to 
holidays. 
 
• Ship to: Jill M. Kolesar, Pharm.D 
Analytical Instrumentation Laboratory for Pharmacokinetics, 
Pharmacodynamics and Pharmacogenetics (3P) 
University of Wisconsin 
Comprehensive Cancer Center Room K6/570 
600 Highland Avenue 
Madison, WI 53792-5669 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-044 A(11) 
Amended:  10/25/11 
- 57 - 
 
 
B. Tumor tissue Perifosine Assay 
 
IMPORTANT NOTE: THESE INSTUCTIONS PERTAIN ONLY TO THE 
DETERMINATION OF PERIFOSINE CONCENTRATION IN TISSUE THAT WILL 
BE PERFORMED BY JILL M. KOLESAR, PHARM. D. AT THE UNIVERSITY OF 
WISCONSIN. 
A SEPARATE ALIQUOT OF TISSUE FLASH FROZEN IN LIQUID NITROGEN 
SHOULD BE STORED AT -70 DEGREES CECLIUS AT MSKCC FOR 
MOLECULAR ANALYSIS OF THE EFFECTS OF PERIFOSINE THAT WILL BE 
PERFORMED BY DR. ERIC HOLLAND. 
 
To determine intracellular perifosine levels, samples will be drawn under the same 
conditions and timepoints as for pharmacokinetics studies. Tissues without processing 
will be frozen at -70O C until shipment. Specimens will be shipped to: 
 
University of Wisconsin Comprehensive Cancer Center 3P Lab 
600 Highland Ave K6/571 CSC 
Madison, WI 53792 
608-263-5369 
Attn: Amy Dresen 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-044 A(11) 
Amended:  10/25/11 
- 58 - 
 
 
20.4. Supportive Care Guidelines for Controlling Side Effects Associated with the 
Administration of Perifosine 
 
 
REMINDERS 
Patients should take all medication with food, and not on an empty stomach. 
Pills should remain intact and should not be crushed except to administer via g-tube. 
 
NAUSEA AND VOMITING 
Loading dose schedule 
• Patients should divide the loading dose of perifosine into 150mg every 6 hours until the 
total loading dose is administered. Please note that administering the total dose could 
take longer than 24 hours, but it must be taken within a 48-hour period. 
• 5HT3 antagonist—such as, but not limited to, ondansetron and granisetron—can be 
administered every 12 hours on the day of therapy and every 12 hours for 24 hours after 
the day of therapy. 
• Dexamethasone 4mg po in conjunction with the 5HT3 antagonist unless otherwise 
contraindicated. 
If the above steps are ineffective, the frequency of the 5HT3 antagonist can be increased. 
• Metoclopramide 5mg Q.I.D. can be added if needed. 
• If the nausea could be related to anticipation, the use of lorazepam can be initiated. 
• Patients should have some medication on hand for breakthrough nausea—such as 
promethazine or prochlorperazine. 
If nausea and/or vomiting remains uncontrollable after following the recommendations listed 
above, the perifosine dose can be reduced as detailed in the Dose Modifications section of the 
relevant perifosine protocol(s). 
 
Daily dosing schedule 
• Patients should take medication at bedtime – with food and not on an empty stomach. 
• Although the use of prophylactic antiemetics should not be necessary for patients on 
daily dosing, they should have antiemetics on hand—such as promethazine or 
prochlorperazine—if they do encounter nausea and/or vomiting. If these antiemetics 
are not effective, the treating physician may escalate the antiemetics to the ones listed 
above for the loading dose. 
If nausea and/or vomiting continue after following the recommendations above, dose 
reductions can be initiated in accordance to the Dose Modifications section of the relevant 
perifosine protocol(s). 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-044 A(11) 
Amended:  10/25/11 
- 59 - 
 
 
 
DIARRHEA 
For both Loading and Daily Dose Schedules 
At the first sign of change in stool or bowel function initiate recommendations 
• Imodium 4mg at the first onset of diarrhea. 
• Repeat Imodium 2mg every 2 hours until diarrhea subsides for 12 hours. 
• Patients can take Imodium 4mg every 4 hours during the night to minimize interruption 
of sleep. 
• Drink plenty of fluids. 
• Avoid foods and liquids that can aggravate diarrhea—such as dairy products, seeds, 
nuts, etc.. 
• The treating physician may use other antidiarrhea medications at his/her discretion. 
For diarrhea that cannot be controlled by following these recommendations, refer to the Dose 
Modification section of the relevant perifosine protocol(s). 
 
 
GOUT AND/OR HYPERURICEMIA 
For both Loading and Daily Dose Schedules 
• All patients should be asked about the possible prior history of gout or hyperuricemia. 
• Patients with prior history of gout or elevated uric acid levels should receive allopurinol 
300mg by mouth daily for prophylaxis. 
• The treating physician may increase the dose of allopurinol or change medications at 
his/her discretion as warranted by the individual patient’s status. 
 
 
NOTE ABOUT THIS INFORMATION 
• Treating physicians may use other agents at their discretion. 
• These recommendations are based on current information obtained from clinical 
studies—that have either been completed or are underway—examining the efficacy and 
safety of perifosine.