Clinical trial NCT02301364
Conditions: Lymphoma Primary Central Nervous System Lymphoma Recurrent/Refractory Secondary Central Nervous System Lymphoma
Keywords: Buparlisib (BKM120) 14-177
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2014-11-20; Completion date: 2016-10-11
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out what effects, good and/or bad, Buparlisib (also known as BKM120) has on lymphoma and the central nervous system.

Detailed description:

Arms: arm 1: This is an open-label, phase II trial of the pan-PI3K inhibitor buparlisib (BKM120) for patients with recurrent or refractory primary central nervous lymphoma (PCNSL) and recurrent or refractory secondary central nervous lymphoma (SCNSL).
Interventions: intervention 1: Buparlisib (BKM120)
Intervention descriptions: intervention 1: Buparlisib 100 mg once daily.

Protocol documents:
Prot_SAP_000.pdf: 
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 1 of 58
 
 
 
A Phase II Trial Of Buparlisib (BKM120) In Patients With Recurrent/Refractory Primary 
Central Nervous System Lymphoma (PCNSL) and 
Recurrent/Refractory Secondary Central Nervous System Lymphoma (SCNSL) 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
Principal Investigator/Department: 
Christian Grommes, MD 
Neurology 
Co-Principal Investigator(s)/Department: 
Ingo Mellinghoff, MD 
Neurology 
Investigator(s)/Department: 
Lisa DeAngelis, MD 
Antonio Omuro, MD 
Thomas Kaley, MD 
Craig Nolan, MD 
Igor Gavrilovic, MD 
Elena Pentsova, MD 
Eli Diamond, MD 
Mariza Daras, MD 
Adrienne Boire, MD 
Richard Phillips, MD PhD 
Jacqueline Stone, MD 
Bianca Santomasso,MD PhD 
Vaios Hatzoglou, MD 
Ariela Noy, MD 
David Straus, MD 
John Gerecitano, MD PhD 
Paul Hamlin, MD 
Steven Horwitz, MD 
Craig Moskowitz, MD 
Matthew Matasar, MD 
Alison Moskowitz, MD 
M. Lia Palomba, MD 
Carol Portlock, MD 
Andrew Zelenetz, MD PhD 
Anas Younes, MD 
Katherine Panageas, DrPH 
Alison Gilgan, NP 
Eileen Tiernan, NP 
Marcel Smith, NP 
Jessica Hansen, RN 
Mary Elizabeth-Davis, RN 
Neurology 
Neurology Neurology 
Neurology/Manhattan, CMK 
Neurology/Manhattan, BSK 
Neurology 
Neurology 
Neurology/ Manhattan, WH 
Neurology 
Neurology 
Neurology/ Manhattan, WH 
Neurology 
Radiology 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Biostatistics 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Consenting Professional(s)/Department: 
Christian Grommes, MD 
Ingo Mellinghoff, MD 
Lisa DeAngelis, MD 
Antonio Omuro, MD 
Thomas Kaley, MD 
Craig Nolan, MD 
Igor Gavrilovic, MD 
Elena Pentsova, MD 
Eli Diamond, MD 
Mariza Daras, MD 
Adrienne Boire, MD 
Richard Phillips, MD PhD 
Jacqueline Stone, MD 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology/Manhattan, CMK 
Neurology/Manhattan,BSK 
Neurology 
Neurology 
Neurology/Manhattan, WH 
Neurology 
Neurology 
Neurology/ Manhattan, WH 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 2 of 58
 
 
Bianca Santomasso,MD PhD 
Neurology 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 3 of 58
 
 
Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 3 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 4 
 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 5 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION............................................................ 9 
 
4.1 
Design............................................................................................................................. 9 
 
4.2 
Intervention ..................................................................................................................... 9 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ......................................................................... 10 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ......................................................................... 13 
 
6.1 
Subject Inclusion Criteria............................................................................................... 13 
 
6.2 
Subject Exclusion Criteria ............................................................................................. 14 
 
7.0 
RECRUITMENT PLAN ..................................................................................................... 17 
 
8.0 
PRETREATMENT EVALUATION .................................................................................... 17 
 
9.0 
TREATMENT/INTERVENTION PLAN.............................................................................. 18 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ................................................. 20 
 
11.0 TOXICITIES/SIDE EFFECTS ........................................................................................... 25 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..................... 39 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ..................................................................... 42 
 
14.0 BIOSTATISTICS .............................................................................................................. 43 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES44 
 
15.1 Research Participant Registration ................................................................................. 44 
 
15.2 Randomization .............................................................................................................. 45 
 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 45 
 
16.1 Quality Assurance ......................................................................................................... 45 
 
16.2 Data and Safety Monitoring ........................................................................................... 45 
 
17.0 PROTECTION OF HUMAN SUBJECTS .......................................................................... 45 
 
17.1 Privacy .......................................................................................................................... 45 
 
17.2 Serious Adverse Event (SAE) Reporting ....................................................................... 46 
 
18.0 INFORMED CONSENT PROCEDURES .......................................................................... 47 
 
19.0 REFERENCES ................................................................................................................. 48 
 
20.0 APPENDICES .................................................................................................................. 51 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 4 of 58
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is an open-label, phase II trial of the pan-PI3K inhibitor buparlisib (BKM120) for patients 
with recurrent or refractory primary central nervous lymphoma (PCNSL) and recurrent or 
refractory secondary central nervous lymphoma (SCNSL). Patient will be treated with single 
agent, daily dosed buparlisib and followed to assess efficacy and toxicity. 
 
Figure 1: Study Design Overview 
 
 
 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1 Primary Objective: 
 
• 
To explore the therapeutic efficacy of buparlisib in patients with PCNSL and SCNSL 
as measured as progression free survival at 24 weeks (PFS24w) 
 
2.2 Secondary Objectives: 
 
• 
To explore the safety and tolerability of buparlisib in PCNSL and SCNSL patients by 
assessing the frequency and severity of adverse events 
• 
To assess overall response rate (ORR) on MR imaging in patients with PCNSL and 
SCNSL receiving buparlisib 
• 
To assess progression free survival at 12 weeks (PFS12w) and 48 weeks (PFS48w) 
in patients with PCNSL and SCNSL receiving buparlisib 
• 
To assess the duration of response (DoR) and overall survival (OS) in patients with 
PCNSL and SCNSL receiving buparlisib 
• 
To evaluate CSF pharmacokinetics of buparlisib by measuring  drug concentration in 
serum and CSF samples 
 
2.3 Exploratory Objectives: 
 
• 
To correlate differences in drug response to PI3K pathway activation status through 
mutational and  immunohistochemical analysis of PI3K pathway members such as 
but not limited to phospho-AKT, phospho-S6, phospho-4EBP1 
• 
To characterize mutational abnormalities in paired tumor/germline DNA in 
PCNSL/SCNSL patients and correlated with drug response 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 5 of 58
 
 
• 
To correlated changes on ADC/DWI/perfusion MRI imaging to drug response 
• 
To assess neurologic functioning using the Neurologic Assessment in Neuro- 
Oncology (NANO) 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 Primary central nervous system lymphoma (PCNSL) 
 
PCNSL is an aggressive subtype of diffuse large B-cell lymphoma (DLBCL) with increasing 
incidence over the last decade (Deangelis, 2006). PCNSL usually develops in the brain but can also 
involve other compartments of the CNS including spinal cord, meninges, cerebrospinal fluid, and 
eyes. Compared to systemic DLBCL, PCNSL has a poorer prognosis (Ferreri 2011) with a cure rate 
of around 20-30% (Reni, Ferreri et al. 1997; Gavrilovic, Hormigo et al. 2006). Prognosis is especially 
poor for patients over age of 60 and patients with relapsed/refractory disease. The management of 
this disease poses a difficult challenge in neuro-oncology. Median survival for patients with 
progressive disease without treatment is two months. Unfortunately, the optimal salvage regimen is 
not known and only a few prospective clinical trials have addressed this patient population.  In 
contrast to other CNS malignancies, patients with PCNSL are mainly treated with conventional 
methotrexate-based chemotherapy and targeted agents have not been introduced into the treatment 
regimen of PCNSL. Even in patients with treatment resistant PCNSL, further chemotherapy or 
radiation is used. Targeting molecular abnormalities has not been advanced in PCNSL mainly 
because the molecular pathogenesis of PCNSL remains still largely unknown due to the relative 
rarity of this disease and the fact that tumor tissue is usually collected in only small quantities for 
diagnostic purposes. In systemic lymphoma, gene expressions profiling has identified two major 
subgroups: germinal center type and activated B cell (ABC) the latter being associated with a poorer 
clinical prognosis (Alizadeh et al., 2000) but ABC DLBCL cell lines have shown to respond 
remarably well to targeted inhibition of the phosphatidylinositol-3-kinase (PI3K) pathway (Kloo, 
2010). More than 95% of PCNSL cases are of the ABC/non-germinal center subtype (Camilleri- 
Broet, Criniere 2006). Therefore, the use of PI3K inhibitors could be promising in PCNSL, 
particularly in patients that have failed conventional methotrexate-containing chemotherapy 
regimens. 
 
3.2 Secondary CNS Lymphoma (SCNSL) 
SCNLS represents CNS involvement through direct invasion by a systemic non-Hodgkin lymphoma. 
SCNSL incidence has increased with more effective first-line therapy of systemic DLBCL. SCNSL 
most commonly presents with concurrent systemic progression of lymphoma and carries a poor 
prognosis with a median survival of 1-5 months (Grier and Batchelor, 2005). Involvement of the CNS 
may include the brain and leptomeninges. Like PCNSL, SCNSL therapy is challenging and usually 
involves methotrexate-based chemotherapy. For patients failing chemotherapy, palliative radiation 
can be offered but prognosis is dismal. 
 
3.3 Relapsed/refractory PCNSL 
Patients who relapse after initial therapy have an especially poor prognosis (Tyson, Siegal et al. 
2003; Ferreri 2011) with a rapidly downhill and aggressive clinical course (Ferreri 2011). Based on 
long-term follow-up data, the relapse rate after high-dose methotrexate-based therapy with or 
without consolidation whole-brain radiation is 44% (Gavrilovic, Hormigo et al. 2006). The site of 
relapse is frequently in the brain but can also be in other compartments of the CNS or more than 
one compartment (Gavrilovic, Hormigo et al. 2006). 
 
3.4 Current management of relapsed/refractory PCNSL 
Chemotherapy treatments for relapsed/refractory CNS lymphoma are not efficacious and are 
associated with short progression-free survival (Table 1). Whole brain radiation therapy is used if 
radiation to the CNS has not been given previously but is associated with increased risk of 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 6 of 58
 
 
neurotoxicity (Ferreri 2011). HDC/ASCT has also been studied in this setting (Table 2). Clearly, new 
agents are urgently needed for relapsed/refractory CNS lymphoma. 
 
3.5 The Phosphatidylinositol-3-kinase (PI3K Pathway) 
The PI3K signaling pathway regulates diverse cellular functions including cell proliferation, survival, 
translational regulation of protein synthesis, glucose metabolism, cell migration, and angiogenesis 
(Katso, 2001). PI3K signaling also serves a central role in the pathogenesis of numerous forms of 
neoplasia.  At the structural level, the enzyme PI3K is composed of a 110-kDa catalytic subunit and 
an 85-kDa adaptor subunit. The PI3K signaling is modulated by multiple regulators, including 
growth factors (such as EGF, IGF-1, and FGF), hormones (such as estrogen and thyroid hormone), 
integrins, intracellular calcium levels, and RAS signaling. PI3K signaling is negatively regulated at 
the level of PIP3 clearance by phospholipid phosphatases, such as the phosphatase and tensin 
homologue (PTEN) protein and the inositol 5-phospatase-2 (SHIP2) protein. 
 
 
Table 1: Salvage treatment for relapsed/refractory primary CNS lymphoma (NR: not reported) 
 
 
 
References 
 
 
No. 
 
 
Treatment 
Prior XRT 
(%) 
 
ORR   (%) 
3m 
PFS 
(%) 
6m 
PFS 
(%) 
 
 
PFS (m) 
 
OS (m) 
Arellano-Rodrigo et al. 
2003 
 
16 
 
VP16/IFOS/AraC 
100% 
37 
60 
30 
 
4.5 
6 
 
Plotkin et al. 2004 
 
22 
 
Methotrexate 
58% 
91 
NR 
NR 
 
26 
26 
 
Enting et al. 2004 
 
15 
 
Temozolomide + 
Rituximab 
13% 
53 
NR 
NR 
 
2.2 
10.5 
 
Fischer et al. 2006 
 
27 
 
Topotecan 
52% 
33 
NR 
NR 
 
2 
8.4 
 
Reni et al. 2007 
 
36 
 
Temozolomide 
85% 
26 
NR 
NR 
 
2.8 
4 
 
Raizer et al., 2012 
 
11 
 
Pemetrexed 
18% 
55 
60 
45 
 
5.7 
10.1 
 
Batchelor et al. 2011 
 
9 
 
Rituximab 
9% 
36 
NR 
NR 
 
3.7 
NR 
 
Nguyen et al. 2005 
 
27 
 
Radiation 
- 
74 
77 
62.5 
 
9.7 
10.9 
 
 
 
 
 
Table 2: Phase II trials of high-dose chemotherapy followed by autologous stem cell 
transplantation for relapsed/refractory primary CNS lymphoma 
 
 
References 
No. 
Pre-transplant induction 
High-dose Chemotherapy 
Outcome 
 
Soussain et al. 2001 
 
22 
 
AraC + VP16 
TT/Bu/Cy (TBC) 
 
3Y OS – 64% 
 
Soussain et al. 2008 
 
43 
 
AraC + VP16 
TT/Bu/Cy (TBC) 
 
2Y OS – 45% 
 
Constitutive activation of PI3K signaling is known to be a critical step in mediating the transformation 
potential of oncogenes and tumor suppressors in many tumor types (Liu 2009).  Resistance to a 
variety of therapeutic interventions, including chemotherapy, hormonal therapy and anti-HER2 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 7 of 58
 
 
therapies, can also be linked to constitutive activation of the PI3K pathway (McCubrey 2006). 
Moreover, preliminary data suggest that activation of the PI3K pathway may be a predictor of poor 
prognostic outcome in many cancers. 
Molecular changes leading to constitutive activation of the PI3K pathway are diverse and include, 
but not limited to, 
• 
Gait-of-function mutation of PI3K subunits (PIK3CA encoding the PI3K at the catalytic 
subunit p110alpha; genes encoding the p85 regulatory subunit) or oncogenes encoding 
positive regulators of PI3K (e.g. HER2, EGFR, RAS. Src-family proteins) or 
• 
Loss of function mutations or epigenetic alterations affecting negative regulators of PI3K 
signaling (e.g. loss of PTEN expression or function) (Chow 2006, Cully 2006) 
Together these observations suggest that PI3K pathway could be a critical therapeutic target for the 
treatment of patients with advanced solid malignancies who often have limited therapeutic options 
beyond institutional standard of care.  Hence, the pan-PI3K inhibitor buparlisib potentially addresses 
an unmet medical need in such patients. 
 
3.6 The PI3K/mTOR/Akt Pathway in Lymphoma 
The  early  experience  with  PI3K  inhibitors  in  systemic  lymphoma  is  very  encouraging 
(Fruman 2011). Systemic lymphomas,  and its most  common  subtype  diffuse large B-cell 
lymphoma (DLBCL)  can  be distinguished  based  on their  gene  expression profiling into 
germinal center type and activated B cell center (ABC) type (Alizadeh 2000). ABC- type DLBCLs 
have a poorer clinical outcome but ABC cell lines respond remarkably well to PI3K inhibition 
(Kloo 2010). Inhibition of the PI3Kdelta isoform seems to be particularly effective in ABC 
DLBCL, consistent with the prominent role of PI3Kdelta-mediated signaling in lymphocyte 
biology (Fruman 2011). 
 
3.7 The PI3K/mTOR/Akt Pathway in PCNSL 
Utilizing  12  patient-derived  xenograft  models  from  patients  with  intracranial  lymphoma;  9/12 
xenograft models are from patients with PCNSL, 3/12 xenograft models are from patients with 
SCNLS, we were able to demonstrate PI3K pathway activation. Using immunohistochemical staining 
and western blotting we observed increased phosphorylation of both 4EBP1 and ribosomal protein 
S6 (234/235) in all examined patient-derived orthotopic xenograft models (compared to normal 
mouse brain) (Fig. 2). These xenograft models also exhibited higher levels of AKT phosphorylation 
(Ser308 and Ser473) than intracranial xenografts from other cancer types (Fig. 2), suggesting that 
aberrant activation of the PI3K signaling pathway may occur upstream of AKT in PCNSL. 
 
Fig. 2: PI3K-mTOR 
activation in 
PCNSL. Left panel: 
Increased 
phosphorylation of 
4EBP1  and S6RP in 
all PCNSL  xenograft 
models  compared to 
normal  brain (1. line: 
H&E, 2. line: CD20;  3. 
line: Ki67; 4. line: 
p4EBP1, 5. line: 
pS6RP). Right panel: 
Protein  levels in 
PCNSL  xenografts 
(line 6-9) compared to 
normal  mouse  brain 
(line 1) and orthotopic 
xenografts from other 
cancer  types (line 2- 
5). TS543  and TS676: 
GBM; RL95-2: 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 8 of 58 
 
 
endometrial CA; Raji: Burkitt  Lymphoma. SC=subcutaneous; IC=intracranial. 
 
We also established a pre-clinical ex-vivo animal model (slice cultures) to explore the effects of PI3K 
pathway inhibition. The pan-class I PI3K inhibitor buparlisib reduced phosphorylation levels of AKT 
(Ser473) dose-dependently and also induced cell death as measured by increased cleaved caspase 
-3 and cleaved PARP levels (Fig. 3). 
 
 
Fig. 3: Ex vitro Slice Culture confirm activation of 
PI3K pathway and inhibition through the pan-PI3K 
inhibitor buparlisib. Vibratome slices were treated with the pan- 
class I PI3K inhibitor buparlisib for 24 hours. Western blot analysis is 
shown for pAKT (SER473) pS6 (SER235), p4EBP1 (THR37/46), cleaved 
caspase-3 and cleaved PARP. Vinculin served as a loading control. 
 
It is well known that the majority of PCNSL are of the 
non-germinal center or ABC subtype. We examined 
138 PCNSL patient samples and observed that 88% 
are of the non-germinal center or ABC subtype and 
therefore should respond well to PI3K inhibitors. To 
further investigate the activation status of the PI3K pathway in PCNSL, we examined the same 138 
formalin-fixed, paraffin-embedded (FFPE) human PCNSL tissue samples for PI3K pathway 
activation using phosphorylated 4EBP1 (phospho-site threonine 37/46) as readout. 79.1% of patient 
samples were positive for phospho-4EBP1 staining (Fig 4). 
 
Fig. 4: The majority 
of PCNSL is of the 
ABC subtype and 
shows activation of 
the PI3K pathway. 
Left panel: IHC staining of 
two representative PCNSL 
samples for CD10 (top), 
BCL-6 (middle), and MUM- 
1 (bottom) . Overall, 88% 
of PCNSL in our sample 
set were of the non- 
germinal center type 
(according to the Hans 
classification).  Right 
panel: 
Immunohistochemical 
(IHC) staining of the PI3K 
downstream target 
phospho-4EBP1 
(Thr37/46). Representative 
images of no, weak or 
strong IHC signal (from top 
to bottom) with pie chart 
representing the 
distribution of no, weak or 
strong phospho-4EBP1 
ICH signal in 138 PCNSL 
patient samples. 
 
The PI3K/AKT/mTOR pathway has been the focus of recent advances in cancer therapeutics in the 
lymphoma field.  Buparlisib is a potent and highly specific pan-class I PI3K inhibitor and has been 
extensively studied in non-clinical animal models.  A maximal tolerated dose has been established 
and is currently being evaluated in clinical trials with oncologic indication including non-Hodgkin 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 9 of 58 
 
 
lymphoma (MSK Protocol IRB # 13-072).  Buparlisib is of additional interest as it has good CNS 
penetration and is currently being studied in a phase II trial in recurrent glioblastoma patients. 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
Buparlisib is a potent and highly specific oral pan-class I PI3K inhibitor and has been studied 
extensively in non-clinical models and is currently being evaluated in clinical trials for several 
oncologic indications including non-Hodgkin's lymphoma and glioblastoma. 
 
As already stated in previous sections, inhibitors of the PI3K/Akt/mTOR pathway, including 
buparlisib, may be therapeutically effective in PCNSL and SCNSL patients based on the 
observations from pre-clinic studies with inhibitors of the PI3K pathway as well as clinical 
trials in non-Hodgkin lymphoma. Buparlisib, a pan-class I PI3K inhibitor with established CNS 
permeability, presents a particular intriguing compound to be used in the treatment of 
relapsed/refractory PCNSL/SCNSL. 
 
4.1.1 Rationale for the study design 
 
An open label, single arm, phase II study has been selected to explore the efficacy and 
safety of buparlisib in patients with relapsed/refractory PCNSL and relapsed/refractory 
SCNSL. Twenty-one patients will be enrolled of which at least 10 will have 
relapsed/refractory PCNSL. 
 
No clear data exist on the effect of targeted therapy in either PCNSL or SCNSL.  Additionally, 
no clear data exist that activation of the PI3K pathway in PCNSL or SCNSL is predictive for 
response to a PI3K inhibitor. Thus, enrollment of patients with activated as well as non- 
activated PI3K pathway is considered appropriate. 
 
In the absence of a comparative arm but based on historical data, PFS24w is considered an 
appropriate primary endpoint to objectively measure anti-tumor activity. 
 
A single arm study will be performed due to lack of approved agents as well as small patient 
population. 
 
The protocol specific assessments, treatment and follow-up are consistent with a standard 
procedures applied in this disease setting. 
 
4.2 
Intervention 
 
Buparlisib 100 mg once daily has been established as the maximal tolerated dose (MTD) in 2 
single agent trials (CBKM120X2101 and CBKM120X1101) and one combination trial 
(CBKM120x2107 with trastuzumab). 
 
Accordingly, buparlisib will be dosed at 100 mg/day (see Table 3). 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 10 of 58
 
 
 
 
  Table 3: Dose and treatment schedule  
 
Pharmaceutical form and route of 
Study treatments 
administration 
Dose2 
Frequency and/or Regimen 
Buparlisib 
Oral gelatin capsules 
100 mg 
(2x 50mg capsules1) 
Once daily 
1 Buparlisib may be taken to consume a dose of 100 mg/day (or dose reduction level) in 50mg or 10 mg capsules, where supplied. 
 
2 Dose reduction levels for buparlisib will be administered according to Table 5. 
 
For example, buparlisib 80 mg should preferentially be administered as 1x 50mg size capsule, and 3x10 mg size capsules. 
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Buparlisib 
 
5.1.1 Study drug packaging and labeling 
The investigational drug to be used in the course of this trial is buparlisib.  Novartis Drug 
Supply Management or its designee will provide buparlisib as 10 mg and 50 mg hard gelatin 
capsules as individual patient supply, package in bottles.  The capsules are packaged in 
HDPE bottles with a plastic child resistant closure. 
The storage conditions for study drug will be described on the medication label. Buparlisib 
will be dosed on a flat scale of mg/day and not be adjusted to body weight or body surface 
area. The investigator needs to instruct the patient to take the study drug as per the 
protocol. 
 
 
Buparlisib will be supplied as 10-mg and 50-mg hard gelatin capsules, packaged in 
bottles, and will be given orally on a flat scale of mg/day (see Table 4). 
 
 
  Table 4: Packaging and labeling  
 
 
Study treatments 
Packaging 
Labeling (and dosing frequency) 
Buparlisib 
Capsules in bottle 
10 mg 
50 mg 
Labeled as “BUPARLISIB” 
Once daily dosing 
 
 
5.1.2 Drug supply and storage 
Study drug must be received by a designated person at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the 
investigator and designated assistants have access. 
Upon receipt, buparlisib should be stored according to the instructions specified on 
the drug labels. These instructions should also be made clear to the patient for 
storage and self-administration of buparlisib at home. 
 
 
5.1.3 Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each 
patient visit using pills counts and information provided in the pill diary. Records of 
study medication used, dosages administered, and intervals between visits and the 
completion of the study will be captured in the Drug Accountability Form. This 
information must be captured in the source document at each patient visit. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 11 of 58
 
 
 
5.1.4 Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and 
dispensing of study treatment in a Drug Accountability Form. Patients will be asked 
to return all unused study treatment and packaging on a regular basis, at the end of 
the study or at the time of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the 
investigator  will  return  all  used  and  unused  study  treatment,  packaging,  drug 
labels, and a copy of the completed Drug Accountability Form to the Novartis 
monitor or to the Novartis address provided in the investigator folder at each site. 
 
 
5.1.5 Disposal and destruction 
The drug supply can be destroyed at the local Novartis facility, Drug Supply group 
or third party, as appropriate. Study drug destruction at the investigational site will 
only be permitted if authorized by Novartis in a prior agreement and if permitted by 
local regulations. 
 
5.1.6 Buparlisib Administration 
All participants will initiate treatment within 96 hours of registration. Buparlisib will be self- 
administered on a continuous once daily dosing schedule.  There will be no breaks between 
dosing schedules. 
 
The following general guidelines should be followed for buparlisib administration: 
• 
Patient should be instructed to take the dose of buparlisib once daily in the morning, at 
approximately the same time each day. 
•   Buparlisib should be taken at least 1 hour following a light breakfast. 
•   Patient should not eat for 2 hours after the administration of each buparlisib dose. 
• 
Buparlisib should be taken with a glass of water.  Patient should swallow the capsules as 
a whole and not chew them. 
• 
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting during a 
treatment cycle must be noted. 
• 
If the patient forgets to take the dose before 18:00 (6PM), then the dose should be 
withheld that day and buparlisib should be restarted the following day. 
• 
Patient should avoid consumption of Seville orange (and juice), grapefruit or grapefruit 
juice, grapefruit hybrids, pummelos, star fruit and cranberry juice from 7 days prior to the 
first dose of study drug and during the entire study treatment periods due to potential 
CYP3A interaction. Regular orange juice (Citrus X sinensis) is allowed. 
• 
Patient must avoid concomitant intake of strong and moderate CYP3A inhibitors and 
induces.  Detailed information on potential drug interactions and a list of prohibited 
concomitant CYP3A interfering medication is provided in Appendix 1. 
 
 
5.1.7 Supportive care guidelines and concomitant medications 
 
Participants must be instructed not to take any additional medications, including over-the- 
counter products, during the trial without prior consultation with the investigator.  All 
medications taken within 30 days of screening should be recorded. If concomitant therapy 
must be added or changed, including over-the-counter medications or alternative therapies, 
the reason and name of the drug/therapy should be recorded. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 12 of 58
 
 
In general, the use of any concomitant medications/therapies deemed necessary for the care 
of the participant are allowed, including drugs given prophylactically (e.g. antiemetics) with 
the following exceptions: 
 
• 
Strong CYP3A inhibitors and CYP3A inducers are prohibited.  Moderate CYP3A inhibitor 
and inducers may be used with caution. In vitro studies suggest that buparlisib is a 
sensitive CYP3A4 substrate.  Co-administration of buparlisib with strong and moderate 
CYP3A4 inhibitors is predicted to increase the systemic exposure to buparlisib; likewise 
CYP3A4 inducers can be expected to decrease systemic exposure to buparlisib, possibly 
resulting in sub-therapeutic drugs levels.  Please refer to Appendix 1 for a list of 
prohibited drugs.  Please note that this list may not be comprehensive. 
• 
CYP3A and CYP2C substrates are discouraged but may be used with caution and 
monitoring.  Particularly, caution is advised when buparlisib is co-administered with drugs 
that are sensitive substrate or have a narrow therapeutic index.  Participants receiving 
such medications must be monitored for potentiation of toxicity due to any individual 
concomitant medications, and my require dose titration or reduction of the drug substrate. 
Please refer to Appendix 2 for a list of drugs.  Please note that this list may not be 
comprehensive. 
• 
QT interval prolonging medications known to induce Torsades de Pointes or to promote 
QT prolongation are prohibited (see Appendix 3). If a participant, after initiating study 
drug, requires the concomitant use of a drug known to prolong the QT interval, then 
investigators, at their discretion, may co-administer such medications with appropriate 
monitoring. The Primary Investigator should be consulted as soon as possible 
• 
Concomitant use of QT prolonging medications that have a conditional or possible risk to 
induce Torsades de Pointes is allowed with caution and monitoring (see Appendix 4) 
• 
Medications with the potential to alter serum electrolytes (e.g. diuretics) should be 
monitored very closely for electrolyte abnormalities as these can contribute to the risk of 
QT prolongation and ventricular arrhythmias 
• 
Herbal preparations and medications are not allowed throughout the study.  These herbal 
medications include, but are not limited to: St. John’s wart, Kava, ephedra (ma huang), 
gingko biloba, dephydroepiandosterone (DHEA), yohimbe, saw palmetto, gingseng. 
Participants should stop using any herbal medications 7 days prior to first dose of study 
drug. 
• 
Corticosteroids should be used in the smallest possible dose to control symptoms or 
cerebral edema and mass effect, and discontinued if possible. 
• 
Anti-seizure medications should be used as indicated. Only participants receiving non- 
enzyme-inducing anti-epileptic drugs (EIAED) are eligible.  If for unavoidable clinical 
reasons (emergency department visit, severe allergies, toxicities, etc) a participant’s AED 
is switched to another AED, the following guideless must be followed: 
o Participants should be started on another non-EIAED if at all possible 
o Participants who are inadvertently and temporarily changed to an EIAED should 
be immediately changed to an alternative non-EIAED 
o Participants who need to permanently change anticonvulsant, but who cannot 
change to another non-EIAED must be discussed with the Principal Investigator. 
• 
Febrile neutropenia may be managed according to the Memorial Sloan-Kettering Cancer 
Center guidelines.  Measures include appropriate laboratory testing, including blood and 
urine cultures and the institution of broad-spectrum antibiotics. If a source for the fever is 
not identified or the fever resolves when the neutrophil count recovers, antibiotics will be 
discontinued and the participant observed. 
• 
Routine prophylactic use of G-CSF is not permitted.  However, therapeutic use in 
participants with serious neutropenic complications, such as sepsis, may be considered 
at the investigator’s discretion. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 13 of 58
 
 
• 
The use of antiemetics will be left to the investigators’ discretion. The preferred 
antiemetic is metoclopramide, which is not known to prolong the QT interval. 
• 
Since some patients with CNS lymphoma are at increased risk of developing 
pneumocystis jirovecii pneumonia (PJP), especially if they are on corticosteroids, 
prophylaxis for PJP may be considered. 
• 
Participants who develop diabetes mellitus during the study should be treated according 
to the American Diabetes Association guidelines. It is recommended to start treatment 
with metformin in the outpatient setting and sliding scale insulin in the inpatient setting. 
• 
Because of the potential for its interaction with study medications, warfarin sodium 
(Coumadin), or any other Coumadin-derived anticoagulant is not permitted at any dose. 
Low-molecular weight heparin is permitted. If for unavoidable clinical reasons 
(emergency department visit, severe allergy, toxicity, etc) a participant is started on 
Coumadin, they must change to a low molecular weight heparin immediately in the 
interest of subject safety. 
• 
Hormonal contraceptives may be affected by cytochrome P450 interactions, and are 
therefore not considered effective birth control for this study.  In addition, hormonal 
contraceptives may also decrease the metabolic clearance of  buparlisib via CYP3A4 
inhibition. 
• 
No other anticancer therapy of any kind is permitted during the study treatment period. 
No other drug under investigation may be used concomitantly with the study drug. 
• 
Therapies considered necessary for the well-being of the participant may be given at the 
discretion of the investigator.  Other concomitant medications should be avoided except 
for analgesics, chronic treatments for concomitant medication conditions, or agents 
required for life-threatening medical problems.  All concomitant medications must be 
recorded. 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
The population consists of adult patients with relapsed or refractory primary central nervous 
system lymphoma (PCNSL) or secondary central nervous system lymphoma (SCNSL). 
 
The investigator or designee must ensure that only patients who meet all of the following 
inclusion and none of the exclusion criteria are offered treatment in the study. 
 
6.1 
Subject Inclusion Criteria 
 
Patients eligible for inclusion in this study have to meet all the following criteria: 
 
• 
Participants must be able to understand and be willing to sign a written informed 
consent document. 
• 
Subjects must be at least 18 years of age on the day of consenting to the study. 
• 
Histologically documented PCNSL or SCNSL. Patients with SCNSL need to have 
cytology or tissue biopsy documenting  lymphomatous involvement of the CNS 
• 
Patients must have relapsed/refractory PCNSL or relapsed/refractory SCNSL 
• 
All patients need to have received at least one prior CNS directed therapy. There 
is no restriction on the number of recurrences. 
• 
Patients with parenchymal lesions must have unequivocal evidence of disease 
progression on imaging (MRI of the brain or head CT) 21 days prior to study 
registration. For patients with leptomeningeal disease only, CSF cytology must 
document lymphoma cells and/or imaging findings consistent with CSF disease 
21 days prior to study registration. 
• 
Participants must have a Karnofsky performance status (KPS) of ≥ 50. 
• 
Participants must have adequate bone marrow and organ function shown by: 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 14 of 58
 
 
o Absolute neutrophil count (ANC) ≥ 1.5x 109/L 
o Platelets ≥ 100 x 109/L and no platelet transfusion within the past 14 days 
prior to study registration 
o Hemoglobin (Hgb) ≥ 9 g/dL and no red blood cell (RBC) transfusion within 
the past 14 days prior to study registration 
o International Normalized Ratio (INR) ≤ 1.5 
o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 
1.5 times the ULN. 
o Serum bilirubin ≤ upper limit of normal; or total bilirubin ≤ 2.0x the ULN 
with direct bilirubin within the normal range in patients with well 
documented Gilbert Syndrome. 
• 
Participants must be able to take oral medication. 
• 
Patients must be able to tolerate MRI scans. 
• 
Patients must be able to tolerate lumbar puncture and/or Ommaya taps. 
• 
Participants must have recovered to grade 1 toxicity from prior therapy. 
• 
Participates must be able to submit 20 unstained slides from the initial tissue 
diagnosis for confirmation of diagnosis and correlative studies 
• 
Life expectancy of > 3 months (in the opinion of the investigator) 
 
Note: Prior autologous stem cell transplant as well as radiation to the CNS is  NOT an 
exclusion criterion. Prior allogenic stem cell transplant  IS an exclusion criterion. 
 
6.2 
Subject Exclusion Criteria 
 
Patients eligible for this study must not meet any of the following criteria: 
 
• 
Patients with SCNSL actively receiving treatment for extra-CNS disease are 
excluded. Patient should have complete resolution of their systemic disease not 
requiring additional systemic therapy (e.g. maintenance rituximab or decadron). 
• 
The patient has received prior treatment with a PI3K inhibitor, AKT inhibitor, or 
mTOR inhibitor (e.g. rapamycin, MK2206, perifosine, etc.). 
• 
Patient is concurrently using other approved or investigational antineoplastic 
agents 
• 
Patient has received chemotherapy or targeted anticancer therapy, monoclonal 
antibodies ≤ 4 weeks or 5 half-lives, whichever is shorter, or 6 weeks for 
nitrosourea or mitomycin-C prior to starting the study drug, or the patient has not 
recovered side the side effects of such therapy 
• 
Patient who has received wide field radiotherapy ≤ 4 weeks or limited 
field radiation for palliation ≤ 2 weeks prior to starting study drug or who 
have not recovered to grade 1 or better from related side effects of such 
therapy (except alopecia) 
• 
Patient requires more than 8 mg of dexamethasone daily or the equivalent 
• 
Patient is taking an enzyme inducing anti-epileptic drug (EIAED), including 
phenobarbital, phenytoin, fosphenytoin, primidone, carbamazepine, 
oxcarbazepine, eslicarbazepine, rufinamide, and felbamate.  Participates must be 
off of any EIAED for a least two weeks prior to starting the study drug 
• 
Patient is taking a drug known to be a strong inhibitor or inducers of the 
isoenzyme CYP3A. Participants must be off a strong CYP3A inhibitors and 
inducers for at least two weeks prior to starting the study drug. 
• 
Patient is taking a drug with known risk to promote QT prolongation and Torsade 
de Pointes 
• 
Patient is currently using herbal preparations or medications.  Participants should 
stop using herbal medications 7 days prior to the first dose of the study drug. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 15 of 58
 
 
• 
Patient is using warfarin or any other Coumadin-derivative anticoagulant. 
Patients must be off Coumadin-derivative anticoagulants for at least seven days 
prior to starting the study drug.  Low molecular weight heparin is allowed 
• 
Patient has a history of allergic reactions to compounds of similar chemical or 
biological composition to buparlisib 
• 
Patient has an uncontrolled intercurrent illness, including, but not limited to, 
ongoing or active infection, chronic liver disease, chronic renal disease, 
pancreatitis, chronic pulmonary disease, or psychiatric illness or social situations 
that would limit compliance with the study requirements 
• 
Patient has acute viral hepatitis or a history of chronic or active HBV or HCV 
infection 
• 
Patient has an active concurrent malignancy requiring active therapy. 
• 
Patient is known to have human immunodeficiency virus (HIV) infection 
• 
Patient has any severe psychiatric disease that would interfere with participation 
in the trial as determined by the study investigator 
• 
Patient has ≥ CTCAE grade 3 anxiety 
• 
Patient has ≥ CTCAE grade 2 diarrhea 
• 
Patient has a score ≥12 on the PHQ-9 questionnaire 
• 
Patient selects a response of “1, 2 or 3” to question number 9 on the PHQ-9- 
questionaire regarding potential for suicidal thoughts or ideation (independent of 
the total score of the PHQ-9). 
• 
Patient has a GAD-7 mood scale score ≥15. 
• 
Patient has a medically documented history of or active major depressive 
episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a 
history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing 
harm to self or others). 
• 
Patient has active cardiac disease or cardiac dysfunction including any of the 
following: 
o Left ventricular ejection fraction (LVEF) ,50% as determined by Multiple 
Gated Acquisition (MUGA) scan or echocardiogram (ECHO) 
o QTc>480msec on screening ECG (using the QTcF formula) 
o Angina pectoris that requires the use of anti-anginal medications 
o Ventricular arrhythmias except for benign premature ventricular 
contractions 
o Supraventricular and nodal arrhythmias requiring a pacemaker or not 
controlled with medication 
o Conduction abnormality requiring a pacemaker 
o Valvular disease with documented compromise in cardiac function 
o Symptomatic pericarditis 
o Myocardial infarction within the last 6 months, documented by persistent 
elevated cardiac enzymes or persistent regional wall motion abnormalities 
on assessment of left ventricular ejection fraction function 
o History of documented congestive heart failure (New York Heart 
Association functional classification III-IV) 
o Documented cardiomyopathy 
o Congenital long QT syndrome 
• 
Patient is currently receiving treatment with QT prolonging medication known to 
have a risk to induce Torsades de Pointes, and the treatment cannot be 
discontinued or switched to a different medication prior to starting study drug. 
• 
Patient has impaired gastrointestinal function or gastrointestinal disease affecting 
absorption of buparlisib (e.g. ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, or extensive small bowel resection). 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 16 of 58
 
 
• 
Patient has poorly controlled diabetes mellitus with a glycosylated hemoglobin 
>8% or poorly controlled steroid-induced diabetes mellitus with a glycosylated 
hemoglobin of >8%. 
• 
Patient underwent major systemic surgery ≤ 2 weeks prior to starting the trial 
treatment or who has not recovered from the side effects of such surgery. 
• 
Women who are pregnant or nursing (lactating), where pregnancy is defined as a 
state of a female after conception until the termination of gestation, confirmed by 
a positive serum hCG laboratory test of > 5 mIU/mL. 
• 
Patients who have received allogenic stem cell transplants. 
 
6.3 Pregnancy and Reproduction 
 
 
 
6.3.1 Women: 
 
• 
Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (i.e. age appropriate, history of vasomotor symptoms) or six months 
of spontaneous amenorrhea with serum FSH levels >40 mIU/mL and estradiol < 
20 pg/mL or have had surgical bilateral oophorectomy with our without 
hysterectomy at least six weeks prior to enrollment in the study.  In the case of 
oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up of hormone level assessment is she considered not of 
child bearing potential. 
• 
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, must use highly effective contraception during study 
treatment and for 16 weeks after study discontinuation.  Highly effective 
contraception is defined as either 
o True abstinence: When this is the line with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception 
o Sterilization: Surgical bilateral oophorectomy, with or without 
hysterectomy, or tubal ligation at least six weeks prior to study enrollment. 
In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment. 
o Male partner sterilization (with appropriate post-vasectomy documentation 
of the absence of sperm in the ejaculate).  For female patients 
participating in the study, the vasectomized male partner should be the 
sole partner for that patient. 
o Use of a combination of any two of the following: 
 
Placement of an intrauterine device (IUD) or intrauterine system 
(IUS) 
 
Barrier methods of contraception: Condom or occlusive cap 
(diaphragm or cervical vault caps) with spermicidal 
form/gel/film/cream/vaginal suppository 
 
NOTE: Oral contraception as well as injected, implanted, or local hormonal 
methods of contraception are not acceptable methods of contraception for 
women of child bearing potential as buparlisib potentially decreases the 
effectiveness of hormonal contraceptives 
 
• 
Women of child-bearing potential must have a negative serum pregnancy test at 
screening 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 17 of 58
 
 
• 
In addition to having a negative pregnancy test confirmed at screening, all female 
participants of child bearing potential must have a negative serum pregnancy test 
confirmed within 48 hours prior to dosing with the study drug. 
 
6.3.2 Men: 
 
• 
Fertile males, defined as all male subjects physiologically capable of conceiving 
offspring, must use a condom during study treatment and for 16 weeks after study 
discontinuation and should not father a child in this period 
• 
Female partner of a male study subject should use a highly effective method of 
contraception while the male partner is receiving the study agent and for 16 
weeks after the final dose of the study therapy 
 
6.2.1.3 Inclusion of women, minorities or other underrepresented populations 
 
Buparlisib is not known to differentially affect subpopulations, including women, 
minorities, or other underrepresented groups. The eligibility and exclusion criteria are 
not expected to differentially impact recruitment or retention of these subpopulations. 
 
 
 
7.0 
RECRUITMENT PLAN 
 
MSKCC has long been a center of clinical excellence in PCNSL and is a nationally renowned 
referral center for patient with PCNSL. Additionally, we will work closely with the MSKCC 
Lymphoma service to enroll patients with SCNSL.   Patients will be recruited from the 
neurology and lymphoma clinics at Memorial Sloan-Kettering Cancer Center.  All patients will 
be seen by an attending physician who is an investigator on the trial.  All patients enrolled on 
the trial must sign written informed consent.   There is no gender or racial restriction. If 
accrual is inadequately slow, then we will reach out and collaborate with other centers. 
 
 
 
8.0 
PRETREATMENT EVALUATION 
 
8.1 General Requirements 
 
All participant need to fulfill inclusion and exclusion criteria and have signed an informed 
consent form. 
 
A complete history, vital signs (including blood pressure, pulse, respiratory rate, temperature, 
weight and height), physical, and neurological examination (to include documentation of the 
patients Karnofsky performance status; Appendix 6) and NANO score as well as neuro- 
imaging (including contrast-enhanced MRI/CT brain and total spine) and/or CSF evaluation 
(including cell count, total protein and glucose as well as cytology) confirming tumor 
progression will be performed on all patients. All patients will need a PET body and brain for 
staging purposes prior to study enrollment. The scans done prior to study entry documenting 
progression will be reviewed by the principal investigator. The baseline scan or CSF 
evaluation should be performed 21 days of registration. Prestudy laboratory tests need to 
included CBC with differential, platelets, coagulation panel (including PT, PTT, INR), sodium, 
potassium, calcium, AST, ALT, alkaline phosphatase, total bilirubin, fasting plasma glucose, 
creatinine, lipid panel, HbA1c, 8 hour fasting C-peptide, amylase, lipase, LDH, a screening 
hepatitis B and C serology, a screening HIV serology, serum pregnancy test for women of 
childbearing potential. Prestudy laboratory tests must be obtained within 21days of 
registration. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 18 of 58
 
 
Documentation of tumor diagnosis. Following registration, slides from the most recent pre- 
registration biopsy and/or CSF cytology must be submitted for review and confirmation of 
diagnosis. Additionally, 20 unstained slides from the initial tissue diagnosis must be 
submitted for exploratory studies. 
 
A contrast enhanced CT scan of the chest, abdomen and pelvis, ophthalmologic evaluation 
including slit lamp exam, 12-lead ECG, ECHO/MUGA, as well as a bone marrow aspirate 
must be performed for staging purposes. These staging tests must be obtained within 21 
days of registration. 
 
Patient need to complete the PHQ-9 and GAD7 self rating mood scale within 21 days of 
registration (see Appendix 6). 
 
Please also see Table 6 for an overview of testing required prior to enrollment into the trial. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
All participant will initiate treatment at 100 mg Buparlisib PO within 96 hours of registration. 
The study drug will be administered with a flat-fixed dose, and not by body weight or body 
surface area. For the purpose of this trial a cycle will be defined as 28 days. There will be no 
breaks between dosing cycles. The study drug buparlisib will be self-administered. The 
investigator will instruct the participant to take the study drug exactly as specified in the 
protocol. Buparlisib will be administered on a continuous once daily schedule. Patients will be 
asked to keep a pill diary. Treatment will continue until one of the events in Section 13 
occurs. 
 
9.1 Dose Modifications/Delays 
 
For participants who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the participant on study drug.  If administration of 
buparlisib must be interrupted because of unacceptable toxicity, drug dosing will be 
interrupted or modified according to the rules described in Table 11.  Any planned variance 
from these guidelines in the view of patient safety must be previously discussed with the 
sponsor unless there is an urgent need for action. Any changes in buparlisib administration 
must be recorded in the pill diary. 
 
All dose modifications, interruptions, or discontinuations must be based on the worse 
preceding toxicity as graded using the CTEP Version 4.0 of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), which can be found on the website at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. In the case of 
toxicity, appropriate medical treatment should be used, including anti-emetics, anti- 
diarrheals, etc. 
 
All adverse events experienced by participants will be collected from the time of the first dose 
of study treatment through the study until the final study visit. Participants continuing to 
experience toxicity at the end of treatment visits may be contacted for additional 
assessments until the toxicity has resolved or is deemed irreversible. 
 
All participants will be initially treated at Dose Level 0. A buparlisib dose reduction will be 
administered at 20 mg below the current dose. The dose reduction steps are outlined in 
Table 5. 
 
 
 
Table 5: Dose reduction steps for Buparlisib 


Amended:08/25/15 
Page 19 of 58
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
 
 
  
IRB#: 14-177 A(5)   
 
Buparlisib dose levels and dose reductions* 
 
Starting dose level – 0 
100 mg/day continuously 
Dose level – 1 
80 mg/day continuously 
Dose level – 2 
100 mg/day 5 days out of 7 
Dose level – 3 
60 mg/day continuously 
 
Dose level – 4 
80 mg/day 5 days out of 7 
 
*Dose reduction should be based on the worst preceding toxicity 
 
 
 
 
Table 11 should be adhered to for all toxicities as noted below, regardless of suspected 
attribution unless otherwise specifically noted within the table.  For situations where a 
participant experiences a toxicity which the treating investigator feels is unrelated to 
treatment with buparlisib, but which requires a hold or reduction of the study drug according 
to Table 11, maintaining treatment with the study drug is allowable following discussion with 
the Principal Investigator. 
 
When treatment must be held pending resolution of toxicity to grade 1 or return to baseline, 
and the toxicity is a lab abnormality, in cases where the participant had a pre-existing 
laboratory abnormality at baseline, the toxicity can be considered “resolved from a hold 
perspective when it has resolved to within 1 grade of the baseline value. 
 
NOTE: For the purposes of data entry, value from screening assessments should be entered 
in as “baseline values.”  However, true “baseline values” for the purpose of dose 
modifications on study will be considered the last assessments or tests performed prior to 
initiation of study therapy. 
 
Exception: In instances where the value within 1 grade of the baseline value would still 
require a hold, continue to hold until resolution of toxicity to grade 1 or return to baseline. 
 
Participants who experience an adverse event that requires a treatment delay or dose 
reduction should be monitored with appropriate laboratory testing or other clinical evaluation 
at least weekly until resolution. 
 
Following a dose delay which resumes mid cycle, day 1 procedures not associated with the 
adverse event do not need to be repeated. 
 
No more than 4 levels of dose reduction are permitted in this study.  Participants cannot be 
treated below dose level -4. If a participant whose buparlisib dose has been reduced by 4 
dose levels requires another dose reduction, treatment on study must be stopped unless the 
participant has benefited from the study, in which case the investigator will contact the 
Principal Investigator to determine if the participant will remain in the study. 
 
A treatment delay of up to 28 days is permitted.  If the toxicity has not resolved after a 4 
week delay, the participant must be removed from study treatment unless the participant has 
benefited from the study, in which case, the investigator may contact the Principal 
Investigator to determine if the participant will remain in the study. 
 
Dose re-escalation is never permitted in this study. 


Amended:08/25/15 
Page 20 of 58
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
 
 
Cycle length will be 4 weeks (28 days), even if treatment is held for toxicity. There is no 
stopping in counting cycles/days for those periods where a subject’s drug is withheld.  All 
study evaluations and treatments should continue as if study treatment is not being held. 
 
Participants whose treatment is interrupted or permanently discontinued due to an adverse 
event or clinically significant laboratory value must be followed as outlined in Table 11 at 
least once a week for 4 weeks and subsequently at 4-week intervals until resolution or 
stabilization of the event, whichever comes first. All participants must be followed for 
adverse events and serious adverse events for 30 days following the last dose of buparlisib. 
 
9.2 Treatment interruption and treatment discontinuation 
 
If the study drug is being held due to toxicity, scheduled visits and all assessments should 
continue to be performed, with the exception of the dosing of the held study drug.  If 
treatment with the study drug is withheld for ≥ 28 days, then the study drug must be 
permanently discontinued.  Patients who permanently discontinue the study drug should 
have a follow up at approximately 30 days after discontinuation of all study treatment or 
resolution of the adverse event to ≤ grade 1, whichever occurs first, that includes all study 
assessments appropriate to monitor the event. 
 
 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
10.1 General Requirements 
 
Table 6 describes the required procedures. All procedures may increase in frequency if 
clinically indicated or oriented following a toxicity/adverse event. 
 
A complete history, vital signs (including blood pressure, pulse, respiratory rate, temperature, 
weight and height), physical and neurological examination (to include documentation of the 
patients Karnofsky performance status (Appendix 6) and NANO score as well as a serum 
pregnancy test for women of childbearing potential will be performed on day 1 (+/- 4 days) of 
each cycle. 
 
Neuro-imaging (including contrast-enhanced MRI/CT brain and total spine) and/or CSF 
collection (for patients with CSF disease; through Ommaya or spinal tap; including cytology) 
will need to be performed on all patients on day 1 cycle 3, and each additional odd 
numbered cycle (+/- 4 days). Imaging will include only the side of active disease (MRI brain 
for patients with brain disease; MRI total spine for patients with intraspinal disease; MRI brain 
and total spine for patients with brain and spine disease as well as leptomeningeal disease) 
or sides suggested by new neurologic symptoms and signs. All MRI imaging will included MR 
perfusion . If MRI spectroscopy is additionally performed, we will collect the additional data. 
 
CBC with differential, platelets, sodium, potassium, calcium, AST, ALT, alkaline 
phosphatase, total bilirubin, fasting plasma glucose, creatinine, will need to be performed at 
day 1 and day 15 of each cycle and at the end of the treatment (+/- 4 days). 
 
Amylase and lipase need to be assessed at the end of the treatment (+/- 4 days). 
 
Chest X-ray and 12-lead ECG need to be done every other cycle starting at day 1 of cycle 3 
(+/- 4 days) 
 
Participants need to complete the PHQ-9 and GAD7 self rating mood scale (see Appendix 
6).at day 1 and day 15 of cycle 1 and 2. On each consecutive cycle only on day 1 and at the 


Amended:08/25/15 
Page 21 of 58
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
 
 
end of treatment (+/- 4 days). Questionnaires can be performed over the phone on Cycle 2 
Day 15 by research staff, if the participant is not able to physically attend to clinic. 
 
 
 
 
Table 6: Required Activity Calendar 
 
 
 
Tests and procedures 
Screening 
On trial 
 
Prior to 
Registration 
Cycle 1 
Subsequent 
cycles 
End of 
treatment 
30-day 
post 
drug 
Day
1 
Day 
15 
Day 
1 
Day 
15 
Informed consent 
X 
 
Inclusion/exclusion criteria 
X 
 
History, Physical and neuroexam 
X 
X 
X 
 
X 
X 
Vital signs (blood pressure, pulse, respiration rate, 
temperature, height, weight) and KPS (Appendix 6) 
X 
X  
X 
 
X 
X 
Serum pregnancy test (if applicable) 
X 
X 
X 
 
X 
Adverse event assessment 
X 
X 
 
X 
X 
Hematology group (CBC & diff) 
X 
X 
X 
X 
X 
X 
Chemistry group (Sodium, Potassium, Calcium, AST, 
ALT, Alk Phos, Total Bilirubin, Glucose, Creatinine) 
X 
X 
X 
X 
 
X 
X 
 
Fasting plasma glucose 
X 
X 
X 
X 
X 
X 
Coagulation (PT, PTT, INR) 
X 
X 
X 
 
X 
HbA1c 
X 
 
8h fasting C-peptide 
X 
 
Lipid panel 
X 
X*  
Amylase, lipase 
X 
 
X 
LDH 
X 
 
Hepatitis B and C screen 
X 
 
12-lead EKG 
X 
X$ 
 
Chest X-ray 
X$ 
 
MUGA/ECHO 
X 
 
HIV screen 
X 
 
Bone marrow aspirate and biopsy 
X 
 
PET brain and body 
X 
 
PHQ-9 Patient self-rating mood scale 
X 
X 
X 
X (1) 
X 
GAD7 Patient self-rating mood scale 
X 
X 
X 
X (1) 
X 
NANO Score Assessment 
X 
X$ 
 
X 
Cerebrospinal fluid (CSF) Analysis including cytology 
X 
X(2)  
X(2) 
Contrast-enhanced MRI/CT of the brain and total spine 
with perfusion 
X 
 
 
X(3)  
X(3) 
 
Response evaluation 
X (4)  
X 
Computed tomography of chest, abdomen, pelvis 
X 
 
Ophthalmologic evaluation including slit lamp exam 
X 
 
PK BKM120 CSF 
X(5) 
 
PK BKM120 Blood 
X(6) 
 
Blood collection for genomic DNA 
X 
 
Collection of archival FFPE tumor samples 
X 
 
X(7) 
 
(1): PHQ-9 and GAD7 will be collected on day 15 of cycle 1 and day 1 and day 15 during cycle 2; then only on day 1 on 
subsequent cycles 
(2): Collection on day1 of all odd cycles starting on cycle 3; for patients with CSF disease only; response to treatment will be 
measured in CSF (+/- 4 days) 
(3): Imaging on day 1 of all odd cycles starting with cycle 3; MRI brain for patients with brain disease, MRI total spine for patients 
with intraspinal disease; MRI brain and total spine for patients with brain and spine disease as well as leptomeningeal disease (+/- 
4 days) 
(4): Response will be evaluated on day 1 of all odd cycles starting with cycle 3 
(5): Patients with Ommaya reservoir: CSF collection at 1h, 2h, 4h after drug administration; no Ommaya: CSF collection through 


Amended:08/25/15 
Page 22 of 58
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
 
 
lumbar puncture 2h after drug administration (+/- 30 min) 
(6): Patients with Ommaya reservoir: Blood collect parallel to CSF collection at 1h, 2h, 4h after drug administration; no Ommaya: 
blood collection parallel to CSF collection through lumbar puncture 2h after drug administration (+/- 30 min) 
(7): If there is a re-resection, FFPE material will be collected 
* Every 3 cycles starting day 1 of cycle 3 (+/- 4 days); 
$ Every other cycle starting at day 1 of cycle 3 (+/- 4 days) 
% Every MRI Visit 
 
 
 
 
10.2 Pharmacokinetic analysis and evaluation of study drug penetration into the CSF 
space 
 
In phase I clinical trials with buparlisib, preliminary PK data showed that buparlisib 
accumulated ~3 fold in achieving steady state, consistent with an effective half-life of ~ 40 
hours. Steady state can be reached after approximately 7-10 days of daily dosing in most 
participants. 
 
On day 15 of cycle 1, patients will undergo CSF and plasma pharmacokinetic analysis. At day 
15, the study drug has reached steady state. Patients with an Ommaya reservoir will undergo 
taps of their reservoir at 1h, 2h and 4h after drug administration. Patients without an Ommaya 
reservoir will undergo a single spinal tap at 2h after study drug administration. The patient will 
have plasma collection in parallel (patients with Ommaya reservoir: plasma collection at 1h, 
2h, and 4h post drug administration; patients without Ommaya reservoir: plasma collection at 
2h post drug administration. Each draw should be collected at +/- 30 min of each time point. 
CSF and plasma concentrations of the drug will be measured by liquid chromatography with 
tandem mass spectrometry to derive a CSF/plasma concentration. Samples will be stored in 
the Mellinghoff laboratory and analyzed at the end of the study. 
 
10.3 End of treatment visit, including premature withdrawal and study safety 
follow up 
All patients who discontinue study treatment, including those who refuse to return 
for a final visit, will be contacted for safety evaluations (i.e., assessment of AEs 
and/or SAEs, concomitant medications) 30 days after the last dose of study 
treatment. Patients whose treatment is interrupted or permanently discontinued 
due to an adverse event, including abnormal laboratory value, must be followed at 
least  once  a  week  for  4  weeks  and  subsequently  at  4-weeks  intervals  until 
resolution or stabilization of the event, whichever comes first. 
If patients refuse to return for safety evaluation visits or are unable to do so, every 
effort should be made to contact them by telephone to determine their status. 
Attempts to contact the patient should be documented in the source documents 
(e.g., dates of telephone calls, registered letters, etc.). 
 
 
10.4 Patient self-rating mood questionnaires 
The Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 
(GAD-7) will be collected to screen patients for the study and to aid in the 
identification and severity assessment of potential mood alterations. The PHQ-9 
and GAD-7 are validated (Kroenke 2001, Spitzer 2006, Spitzer 1999), patient self- 
administered questionnaires developed for use in clinical practices. 
The PHQ-9 consists  of  9 questions that  assess  anhedonia,  depressed  mood, 
sleep,  energy,  appetite,  guilt  and  worthlessness,  concentration,  feeling  slowed 
down or restlessness, and suicidal thoughts. For each of these questions, patients 
are asked to rate how much over the past 2 weeks they have been bothered by the 
symptom. Scoring of the PHQ-9 is based on a Likert-type scale from 0 to 3 (0 


Amended:08/25/15 
Page 23 of 58
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
 
 
indicates not at all; 1, several days; 2, more than half the days; 3, nearly every 
day). The sum of all nine questions is used to determine a total PHQ-9 score 
ranging from 0 to 27. 
The GAD-7 is a one-dimensional questionnaire consisting of 7 questions. Similarly 
to the PHQ-9, in the GAD-7, patients are asked to indicate how often, over the past 
2 weeks, they have been bothered by each of the seven core symptoms of 
generalized anxiety disorder as referenced in the DSM IV. Response options are 
‘‘not at all’’ ‘‘several days’’ ‘‘more than half the days’’ and ‘‘nearly every day’’ scored 
as 0, 1, 2, and 3, respectively. The sum of all seven questions calculates the total 
GAD-7  score.  Therefore,  GAD-7 scores  range from  0 to  21.The  patient  must 
complete two different mood questionnaires, (PHQ-9 and GAD-7) at Screening, at 
collection on day-1 or within the screening, then on day 15 of cycle 1 and day 1 
and 15 of cycle 2 and on day 1 of  subsequent cycles, as well as at  end of 
treatment.  Additional assessments may be done according to the clinical judgment 
of the investigator. All questionnaires should be administered in the patient’s local 
language at the beginning of the study visit prior to any interaction with the study 
investigator including any tests, treatments or receipt of results from any tests to 
avoid biasing the patient’s perspective. This is to avoid potentially biasing patients 
or their responses to study questionnaires. 
Patients should be given sufficient space and time to complete all study 
questionnaires and all administered questionnaires should be reviewed for 
completeness. If missing responses are noted, patients should be encouraged to 
complete any missing responses. Attempts should be made to collect responses to 
all questionnaires for all patients, including from those who discontinue prior to the 
study evaluation completion visit, however, if patients refuse to complete 
questionnaires, this should be documented in study source records. 
Completed questionnaires, including both responses to the questions and any 
unsolicited comments written by the patient, must be reviewed and assessed by 
the investigator before the clinical examination for responses which may indicate 
potential AEs or SAEs. This review should be documented in study source records. 
If an AE or SAE is confirmed then the physician should record the event as 
instructed in section “safety monitoring and reporting” of this guidance document. 
The severity classification table described in Table 7 for the PHQ-9 and GAD-7 will 
be used in this study to increase the sensitivity of identifying potential anxiety 
and/or depression disorders. During the study, questionnaire scores and 
corresponding  severity  classification  can  be  used  to  aid  the  investigator  in 
identifying new or worsening of events. Importantly, grading must be based on the 
clinical interpretation of severity according to the NCI-CTCAE (v 4.03). 
 
 
Table 7 
Classification of severity based on mood questionnaire scores 
 
PHQ-9 (depression) 
GAD-7 (anxiety) 
Score 
Severity 
Score 
Severity 
0-4 
None 
0-4 
None 
5-9 
Mild 
5-9 
Mild 
10-19 
Moderate 
10-14 
Moderate 
20-27 
Severe 
≥ 15 
Severe 
 
 
At Screening, a patient may be judged by the investigator or a psychiatrist to be 
ineligible based on medical mental health history as listed in the exclusion criteria. 
Alternatively, patients who score ≥ 12 on the PHQ-9 or ≥ 15 on the GAD-7 mood 


Amended:08/25/15 
Page 24 of 58
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
 
 
scale, respectively, or select a positive response of ‘1, 2, or 3’ to question number 
9 regarding suicidal thoughts or ideation will be excluded from the study. 
During the treatment phase, patients who indicate a positive response by selecting 
‘1, 2, or 3’ to question number 9 in the PHQ-9 must omit treatment with study drug 
buparlisib and must be referred for psychiatric consultation for optimal 
management regardless of the total questionnaire score or CTCAE grading to 
confirm if study drug should be interrupted or permanently discontinued. In this 
specific  case,  the  psychiatric  advice  can  overrule  the  patient  PHQ-9  self- 
assessment. 
Investigators must not encourage the patients to change responses reported in 
questionnaires. Guidelines on how to instruct the patient to complete the 
questionnaires as well as how to determine the scores will be provided with each 
instrument. Guidance on scoring questionnaires is also provided in Appendix 5. 
Dosing  modification  guidelines  for  buparlisib  are  provided  in  Table  11.  For 
additional information on AE reporting, please refer to Section Safety monitoring 
and reporting. 
 
 
10.5 Correlative/special studies 
Correlative studies are mandatory for all participants. 
 
 
10.5.1 Correlation of drug response to PI3K pathway activation status 
For pathway response studies we will assess activation of the PI3K pathway 
members in archival FFPE tissue. Previous studies and our own data have 
demonstrated the reliability of pathway members pAKT, pS6, and p4EBP1 in 
readouts of pathway modulation. The level of PI3K pathway activation will be 
determined by semi-quantitative immunohistochemical scoring for pAKT, pS6, and 
p4EBP1. All pathway modulation scores will be correlated with response to study 
drug. The studies will be performed in the Mellinghoff laboratory (MSKCC). 
 
 
10.5.2 Characterization of mutational abnormalities 
Participants tumor tissue will be assess for mutational abnormalities, DNA will be 
extracted from FFPE tumor tissue. We will also collect germline DNA from whole 
blood collection (See 10.5.5). DNA extraction, quantification, and quality control will 
be performed according to established protocols in the Mellinghoff laboratory. 
Through target sequencing using the Miseq technology (performed at the MSKCC 
Geoffrey Beene Translational Oncology facility) mutational abnormalities including 
but not limited to CD79a, CD79b, PIK3Ca, PIK2CB, PIK3CD, MYD88, CARD11, 
and TNFAIP2 will be assessed and correlated with response to study drug 
treatment. 
10.5.3 Correlation of MR spectroscopy changes to buparlisib as a potential biomarker 
 
Research on cancer metabolism has identified a link between deregulated signaling 
pathways and altered cellular metabolism. These changes in cancer cell metabolism can be 
measured by magnetic resonance spectroscopy (MRS) and might serve as a possible 
biomarker of therapeutic effect. Using 1H MRS in orthotopic glioblastoma models, Koul et al 
(2010) have demonstrated that inhibition of the PI3K pathway results in a decrease in total 
choline-containing metabolite levels, composed of choline, phosphocholine, and 
glycerophosphocholine. Therefore 1H MRS could be used as a powerful tool to probe the 
change in cellular metabolism before and after initiation of study drug. 
 
10.5.4 Correlation of ADC/DWI/perfusion MRI imaging to changes to buparlisib 


Amended:08/25/15 
Page 25 of 58
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
 
 
ADC signal on MRI is inversely correlated with cell density in PCNSL. Therefore a high ADC 
correlates with a low cell number and was associated with better outcome (Barajas, 2009). 
We want to further investigate MRI changes in ADC, DWI, and perfusion imaging in response 
to study drug and PI3K pathway inhibition and plan to correlate MR imaging changes with 
clinical outcome. 
 
10.5.5 Germline DNA collection 
Whole blood will be collected on cycle 1 day 15 (+/- 4 days). Blood will be collected 
in an K2EDTA containing blood collection tube (lavender top tube). Blood will be 
stored in the Mellinghoff lab prior to DNA isolation. 
 
 
11.0 TOXICITIES/SIDE EFFECTS 
 
11.1. Anticipated toxicities 
 
In order for an event to be expected (known correlation to the study drug) for the purposes of 
adverse event reporting, the event must be included in this section. 
 
A list of adverse events of all grades suspected to be buparlisib treatment related in phase I 
studies, organized by CTCAE v4.0 category includes: 
 
• 
Cardiovascular: Hypertension 
• 
Gastrointestinal: Diarrhea, dyspepsia, mucosal inflammation, nausea 
• 
General disorders: Asthenia, fatigue, pyrexia 
• 
Investigations: Aminotransferase elevation/transaminitis, GGT elevation, 
hyperbilirubinemia, lymphopenia, elevated lipase 
• 
Metabolism and nutritional disorders: Hyperglycemia, hypophosphatemia, anorexia 
• 
Nervous system disorders: Dizziness 
• 
Psychiatric disorders: Mood alterations including depression and anxiety 
• 
Pulmonary: Pneumonitis 
• 
Skin: Rash, pruritis. 
 
The safety experience for single agent buparlisib in trial CBKM120X2101 is summarized in 
Table 10 
 
 
 
Table 10: Most frequent Adverse Event (≥15%) related to study drug in study CBKM120X2101 
(n=81) 
 
Event 
All grades
Grade 3/4 
Fatigue/asthenia 
31 (38.3%)
3 (3.7%) 
Decreased appetite 
24 (29.6%) 
- 
Diarrhea 
24 (29.6%) 
3 (3.7%) 
Hyperglycemia 
24 (29.6%) 
4 (4.9%) 
Nausea 
24 (29.6%) 
- 
Rash 
22 (27.2%) 
4 (4.9%) 
Mood altered/emotional 
disorder/affective disorder 
17 (21%) 
4 (4.9%) 
Transaminases increased 
16 (19.8) 
9 (11.1%) 
Anxiety 
14 (17.3%) 
1 (1.2%) 
Depression 
14 (17.3%) 
1 (1.2%) 


Amended:08/25/15 
Page 26 of 58
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
 
 
11.2 Toxicity Management 
 
Routine supportive care is recommended.  Routine prophylactic use of G-CSF is not 
permitted.  Please refer to Table 11 for toxicity specific modifications. 
 
Table 11: Criteria for interruption and re-initiation of buparlisib treatment 
 
Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for Buparlisib 
HEMATOLOGICAL 
 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1.5 x 109/L) 
Grade 2 (ANC < 1.5 - 1.0 x 109/L) 
Maintain dose level 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
Grade 4 (ANC < 0.5 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Febrile neutropenia 
(ANC < 1.0 x 109/L, with a single 
temperature of ≥ 38.3 °C or a sustained 
temperature of ≥ 38 °C for more than one 
hour ) 
Omit dose until resolved, then  1 dose level 
Thrombocytopenia 
 
Grade 1 (PLT < LLN - 75 x 109/L) 
Grade 2 (PLT < 75 - 50 x 109/L) 
Maintain dose level 
Grade 3 (PLT < 50-25 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 4 (PLT < 25 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
RENAL 
 
Serum creatinine 
Grade 1 (< 2 x ULN) 
Maintain dose level 
Grade 2 (2 – 3 x ULN) 
Omit dose until resolved to ≤ grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 3 (> 3.0 – 6.0 x ULN) 
Permanently discontinue patient from buparlisib 
Grade 4 (> 6.0 x ULN) 
Permanently discontinue patient from buparlisib 
HEPATIC 
 
Bilirubin 
(*for patients with Gilbert Syndrome these 
dose modifications apply to changes in direct 
bilirubin only) 
will be fractionated if elevated 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level with LFTs* monitored as per protocol 
Grade 2 (> 1.5 - 3.0 x ULN) with ALT or AST 
≤ 3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 3 (> 3.0 - 10.0 x ULN) with ALT or 
AST ≤ 3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days,  1 dose level 
If resolved in > 7 days discontinue patient from buparlisib 
Grade 4 (> 10.0 x ULN) 
Permanently discontinue patient from buparlisib 
AST or ALT 
 
Grade 1 (> ULN – 3.0 x ULN) 
Maintain dose level with LFTs* monitored per protocol 


Amended:08/25/15 
Page 27 of 58
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
 
 
Grade 2 (> 3.0 - 5.0 x ULN) without total 
bilirubin elevation to > 2.0 x ULN 
Can continue treatment at  1 dose level 
Grade 3 (> 5.0 - 20.0 x ULN) without total 
bilirubin elevation to > 2.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then 
 1 dose level** 
If no recovery in ≤28 days, discontinue buparlisib 
permanently 
Grade 4 (> 20.0 x ULN) without bilirubin 
elevation to > 2.0 x ULN 
Discontinue buparlisib permanently 
AST or ALT and concurrent Bilirubin 
 
AST or ALT > 3.0 x ULN and total bilirubin > 
2.0 x ULN 
Permanently discontinue buparlisib*** 
*(LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), alkaline 
phosphatase (fractionated if alkaline phosphatase is grade 2 or higher) and GGT) 
**In case of recurring Grade 3 or higher toxicity after re-challenge, patient should be permanently 
discontinued 
***All patients with ALT or AST>3.0x ULN and total bilirubin >2.0x ULN in the absence of cholestasis must 
immediately be withdrawn from buparlisib and every attempt should be made to carry out the liver event 
follow-up assessments as described below in section 11.11.1.2: Management of Hepatotoxicity (ALT 
and/or AST> 3.0x ULN and total bilirubin >2.0x ULN) in patients receiving buparlisib and Viral 
Serology and other tests for hepatotoxicity follow-up. 
Hepatic toxicity monitoring (*for patients with Gilbert Syndrome: total and direct bilirubin must be 
monitored, intensified monitoring applies to changes in direct bilirubin only; the monitoring includes the 
following LFTs: albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), alkaline 
phosphatase (fractionated if alkaline phosphatase is grade 2 or higher) and GGT): 
Cycle 1 and 2: every other week (if visit schedule allows a more frequent monitoring this should be 
considered) or more frequently if clinically indicated especially for patients with borderline acceptable AST/ 
ALT, or bilirubin* values 
Cycle 3 and onward: monthly or more frequently if clinically indicated 
In case of any occurrence of ALT/AST, or bilirubin* increase ≥ grade 2 the liver function tests must be 
monitored weekly or more frequently if clinically indicated until resolved to ≤ grade 1 
In case of any occurrence of ALT/ AST, or bilirubin* increase ≥ grade 3 the liver function tests must be 
monitored weekly or more frequently if clinically indicated until resolved to ≤ grade 1; hereafter the 
monitoring should be continued every other week or more frequently if clinically indicated until the end 
of treatment with study medication 
Patients who discontinued study treatment should be monitored weekly, including LFTs* or more 
frequently if clinically indicated until resolved to ≤ grade 1 or stabilization (no CTCAE grade change 
over 4 weeks). 
ENDOCRINE/METABOLIC 
 
Fasting Plasma Glucose (FPG) 
Grade 1 (> ULN - 160 mg/dL) (> ULN - 8.9 
mmol/L) 
Maintain dose level, check FPG every week 
● initiate or intensify medication with appropriate anti- 
diabetic treatment as per investigator’s discretion 
● instruct patient to follow dietary guidelines according to 
local and/or institutional standards for management of 
diabetes mellitus (such as those provided by the American 
Diabetes Association) during the study 
● consider use of oral anti-hyperglycemic therapy such 
as metformin (or intensify existing medications), 
● check FPG at least weekly for 8 weeks, then continue 
checking at least every 2 weeks 
Grade 2 (>160 - 250 mg/dL) (> 8.9 - 13.9 
mmol/L) 
● If signs or symptoms of hyperglycemia (for example, 
mental status changes, excessive thirst, polyuria), manage 
as for Grade 3 hyperglycemia (see below) 
● If asymptomatic, maintain dose and re-check FPG 


Amended:08/25/15 
Page 28 of 58
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
 
 
 
within 24 hours. If grade worsens or improves then follow 
specific grade recommendations. If FPG remains at 
Grade 2: 
○ maintain dose level and monitor FPG at least 
weekly until FPG resolves to ≤ Grade 1 
○ initiate or intensify medication with appropriate 
anti-diabetic treatment such as metformin; consider adding 
a second oral agent if not improvement after several days. 
○ instruct patient to follow dietary guidelines 
according to local and/or institutional standards for 
management of diabetes mellitus (such as those provided 
by the American Diabetes Association) during the study 
○ if FPG does not resolve to ≤ Grade 1 within 14 
days after institution of appropriate anti-diabetic treatment 
reduce buparlisib by 1 dose level 
● Continue with anti-diabetic treatment and check FPG at 
least weekly for 8 weeks, then continue checking at least 
every 2 weeks 
Grade 3 (> 250 - 500 mg/dL) (> 13.9 - 27.8 
mmol/L) 
Omit buparlisib, initiate or intensify medication with 
appropriate anti-diabetic treatment, re-check FPG within 
24 hours. If grade worsens or improves then follow specific 
grade recommendations. If FPG remains at Grade 3: 
● administer intravenous hydration and intervention for 
electrolyte/ketoacidosis/hyperosmolar disturbances as 
clinically appropriate 
● continue to omit buparlisib 
● monitor FPG at least twice weekly until FPG resolves 
to ≤ Grade 1 
● If FPG resolves to < Grade 1 in 7 days or less, then re- 
start buparlisib and  1 dose level 
● If FPG remains greater than Grade 1 severity for more 
than 7 days, then discontinue patient from buparlisib 
● initiate or continue anti-diabetic treatment as 
appropriate 
○ instruct patient to follow dietary guidelines 
according to local and/or institutional standards for 
management of diabetes mellitus (such as those provided 
by the American Diabetes Association) during the study 
○ consider use of oral anti-hyperglycemic therapy 
such as metformin 
● check FPG at least weekly for 8 weeks, then continue 
checking at least every 2 weeks 
For non-fasting plasma glucose >250-500 mg/dL (> 13.9 - 
27.8 mmol/L) accompanied by signs/symptoms of 
hyperglycemia (for example, mental status changes, 
excessive thirst, polyuria), or presence of blood or urine 
ketones, omit buparlisib and following guidance for 
management of Grade 3 fasting plasma glucose (FPG) 
Grade 4 (> 500 mg/dL) (≥ 27.8 mmol/L) 
Immediately omit buparlisib, initiate or intensify medication 
with appropriate anti-diabetic treatment, re-check within 24 
hours. If grade improves then follow specific grade 
recommendations. If FPG is confirmed at Grade 4: 
● administer intravenous hydration and intervention for 
electrolyte/ketoacidosis/hyperosmolar disturbances as 
clinically appropriate 
● discontinue patient from buparlisib 


Amended:08/25/15 
Page 29 of 58
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
 
 
 
● instruct patient to follow dietary guidelines according to 
local and/or institutional standards for management of 
diabetes mellitus (such as those provided by the American 
Diabetes Association) during the study 
● consider use of oral anti-hyperglycemic therapy such 
as metformin 
● check FPG at least weekly for 8 weeks, then continue 
checking at least every 2 weeks if clinically indicated 
For non-fasting plasma glucose >500 mg/dL (> 27.8 
mmol/L) accompanied by signs/symptoms of 
hyperglycemia (for example, mental status changes, 
excessive thirst, polyuria), or presence of blood or urine 
ketones, discontinue buparlisib and following guidance for 
management of Grade 4 fasting plasma glucose (FPG). 
CARDIAC 
 
Cardiac - Left Ventricular systolic 
dysfunction 
Asymptomatic, 
resting ejection fraction 40-50%; 
or 10-20% drop from baseline 
Maintain dose level, and continue buparlisib with caution 
Repeat LVEF within 4 weeks or as clinically appropriate 
Symptomatic, 
responsive to intervention, 
ejection fraction 20-39% 
or > 20% drop from baseline 
● Omit buparlisib until resolved* (as defined below), then 
 1 dose level 
● LVEF measurement to be repeated, if not resolved* 
within 21 days, permanently discontinue patient from 
buparlisib treatment 
Refractory or poorly controlled, 
ejection fraction < 20% 
● Permanently discontinue patient from buparlisib 
*the event is considered resolved when the patient is asymptomatic, has a resting ejection fraction ≥ 40% 
and ≤20% decrease from baseline. 
Cardiac – QTc prolongation 
 
QTcF > 500 ms (≥ Grade 3) 
or > 60 ms change from baseline 
on at least two separate ECGs 
First Occurrence: 
● omit buparlisib 
● Perform an analysis of serum potassium and 
magnesium, and if below lower limit of normal, correct with 
supplements to within normal limits. Concomitant 
medication usage must be reviewed. 
● Perform a repeat ECG within one hour of the first QTcF 
of > 500 ms or >60ms from baseline 
● If QTcF remains > 500 ms or >60ms from baseline, 
repeat ECG as clinically indicated, but at least once a day 
until the QTcF returns to < 480 ms. Seek cardiologist 
input. 
● Once QTcF prolongation has resolved, buparlisib may 
be restarted at a one lower dose level 
Second Occurrence: 
● Permanently discontinue patient from buparlisib 
Other Cardiac Events 
 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Grade 4 
Permanently discontinue patient from buparlisib 
OTHER 
 
Mood alteration/Psychiatric Disorders 
* Note: For all grades, if question 9 on the PHQ-9 has a positive response (as indicated by selecting "1", 


Amended:08/25/15 
Page 30 of 58
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
 
 
"2", or "3"), omit study drug and refer patient for psychiatric consult regardless of the total questionnaire 
score or CTCAE grading to confirm if study drug should be interrupted or permanently discontinued. 
Grade 1* 
● Maintain dose level 
● Consider psychiatric consultation at the investigator’s 
discretion and introduce optimal management (e.g. as per 
local guidelines and/or psychiatric/expert consultation) 
Grade 2* 
● Omit dose until resolved to ≤ Grade 1 or baseline 
status 
● Consider psychiatric consultation at the investigator’s 
discretion and introduce optimal management (e.g. as per 
local guidelines and/or psychiatric/expert consultation) 
 
● First event: if the condition resolved to Grade ≤ 1 or to 
baseline status, continue to co-medicate and then 
maintain the dose level 
● Second and further events: if the condition resolved to 
Grade ≤ 1 or to baseline status, continue to co-medicate 
and then ↓ 1 dose level 
Grade 3* 
Omit dose until resolved to ≤ Grade 1 or baseline status 
● Psychiatric consultation is required and introduce 
optimal management 
● if the condition resolved to Grade ≤1 or to baseline 
status, continue to co-medicate and then  1 dose level 
Grade 4* 
Permanently discontinue patient from buparlisib 
● Psychiatric consultation is required 
● Introduce optimal management (e.g. as per local 
guidelines) 
Rash 
 
Grade 1 
Maintain dose level. Consider to initiate appropriate skin 
toxicity therapy (such as antihistamines, topical 
corticosteroids) 
Grade 2 
First occurrence: Omit dose until resolved to grade ≤ 1 
then: 
● If resolved in ≤ 2 weeks, maintain dose level. 
● If resolved in more than 2 weeks,  1 dose level. 
Second occurrence:  1 dose level. 
Initiate/intensify appropriate skin toxicity therapy (such as 
antihistamines, topical corticosteroids) 
Grade 3 
First occurrence: omit dose until resolved to CTCAE 
Grade ≤ 1; then  1 dose level. 
Second occurrence: permanently discontinue patient from 
buparlisib. 
Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation. 
According to the investigators discretion, a paired skin 
biopsy could be obtained (from both an affected and an 
unaffected skin area for local histopathology assessment) 
if clinical appropriate. 
Grade 4 
Permanently discontinue patient from buparlisib. 
Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation. 
According to the investigators discretion, a paired skin 


Amended:08/25/15 
Page 31 of 58
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
 
 
 
biopsy could be obtained (from both an affected and an 
unaffected skin area for local histopathology assessment) 
if clinical appropriate. 
Fatigue (asthenia) 
 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then: 
● If resolved in ≤ 7 days, maintain dose level 
● If resolved in > 7 days,  1 dose level 
Pneumonitis 
please see section for additional follow up for selected 
toxicities 
Other non- hematological adverse events  
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Grade 4 
Permanently discontinue patient from buparlisib 
Note: Omit dose for ≥ Grade 3 vomiting or Grade 3 
nausea only if the vomiting or nausea cannot be controlled 
with optimal antiemetic 
Stomatitis/Oral mucositis 
 
Grade 1 / Tolerable Grade 2 
Maintain dose level. 
Non-alcoholic or salt water mouth wash (see also section 
for additional follow up for selected toxicities) 
Intolerable Grade 2 or Grade 3 
First occurrence: hold until resolved to grade ≤ G1 and 
1 dose level (if stomatitis is readily manageable with 
optimal management, re-introduction at the same level 
might be considered at the discretion of the investigator). 
Second occurrence: hold until resolved to grade ≤ G1 and 
 1 dose level. 
Grade 4 
Permanently discontinue patient from buparlisib. 
** Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
11.3 Management of Pneumonitis in patients receiving Buparlisib 
All patients participating in clinical trials with buparlisib will be routinely asked about 
and observed for the occurrence of adverse events which could include new or 
changed pulmonary symptoms (consistent with lung abnormalities). Additionally, 
chest X-rays will be performed every other cycle to further assess the development 
of  pneumonitis.  CT  scans  and  pulmonary  function  tests  should  be  done,  as 
clinically indicated, or if there are symptoms that indicate that the patient has 
developed pneumonitis. In case of a documented pneumonitis, the guidelines 
(including dose modifications) in Table 12 should be followed. Consultation with a 
pulmonologist is highly recommended for any pneumonitis case during the study 
treatment. 
 
 
Table 12 Management of Pneumonitis 
Worst Grade 
Pneumonitis 
 
Required Investigations 
Management of 
Pneumonitis 
Buparlisib Dose Adjustment 
Grade 1 
CT scans with lung windows. Repeat 
at least every 8 weeks, (or as per local 
practice) until return to within normal 
limits. 
No specific therapy 
is required 
Administer 100% of Buparlisib dose. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 32 of 58
 
 
Worst Grade 
Pneumonitis 
 
Required Investigations 
Management of 
Pneumonitis 
Buparlisib Dose Adjustment 
Grade 2 
CT scan with lung windows. Consider 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Repeat at least 
every 8 weeks, (or as per local 
practice) until return to within normal 
limits. Consider a bronchoscopy with 
biopsy and / or BAL. 
Symptomatic only. 
Consider 
corticosteroids if 
symptoms are 
troublesome. 
Reduce buparlisib dose by 1 dose 
level (see Table 5) until recovery to ≤ 
Grade 1. Study treatment may also 
be interrupted if symptoms are 
troublesome. Patients will discontinue 
study treatment if they fail to recover 
to ≤ Grade 1 within 28 days. 
Grade 3 
CT scan with lung windows and 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Repeat at least 
every 6 weeks, (or as per local 
practice) until return to within normal 
limits. Bronchoscopy with biopsy and / 
or BAL is recommended. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Hold treatment with buparlisib until 
recovery to ≤ Grade 1. May restart 
study treatment within 28 days at a 
reduced dose (by one level) if 
evidence of clinical benefit. 
Grade 4 
CT scan with lung windows and 
required pulmonary function testing, if 
possible, includes: spirometry, DLCO, 
and room air O2 saturation at rest. 
Repeat at least every 6 weeks, (or as 
per local practice) until return to within 
normal limits. Bronchoscopy with 
biopsy and / or BAL is recommended if 
possible. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Discontinue treatment with 
buparlisib. 
 
 
11.4 Guidelines for the treatment of buparlisib induced hyperglycemia 
Buparlisib  may  affect  glucose  homeostasis  which  could  result  in  increases  of 
plasma glucose and insulin levels. Optimal glucose control should be achieved 
before starting a patient on study treatment and patients requiring insulin should be 
treated with caution. Patients with hyperglycemia should be instructed to follow 
dietary guidelines provided by the American Diabetes Association. They may also 
need  to  initiate,  continue  or  intensify  medication  with  appropriate  anti-diabetic 
treatment including insulin or oral agents. (Note: some oral antidiabetic drugs are 
CYP2C9 substrate and should be used with caution; others are CYP3A inducers or 
inhibitors and are prohibited; See Appendix 1 and Appendix 2, respectively, for 
more details). Patients who develop Grade 3 or 4 hyperglycemia should be 
managed urgently as per standard clinical practice, with the goal of stabilizing 
glycemic control within 24 hours. 
 
 
11.5 Guidelines for the treatment of study drug induced stomatitis/oral 
mucositis 
General guidance and management include patient awareness and early 
intervention. 
Evaluation for herpes virus or fungal infection should be considered. 
Patients should be informed about the possibility of developing mouth ulcers/ oral 
mucositis and instructed to report promptly any signs or symptoms to their 
physician, Patients should be educated about good oral hygiene, instructed to 
avoid spicy/acidic/salty foods, and should follow the following guidelines: 
• 
For mild toxicity (grade 1), use conservative measures such as non-alcoholic 
mouth wash or salt water (0.9%) mouth wash several times a day until 
resolution. 
• 
For more severe toxicity (grade 2 in which case patients have pain but are able 
to maintain  adequate  oral  alimentation,  or grade  3  in which  case  patients 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 33 of 58
 
 
cannot maintain adequate oral alimentation), the suggested treatments are 
topical analgesic mouth treatments (i.e., local anesthetics such as benzocaine, 
butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol) with or 
without topical corticosteroids, such as triamcinolone oral paste 0.1% (Kenalog 
in Orabase®), or as per local practice. 
• 
Agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives 
may tend to worsen mouth ulcers. It is preferable to avoid these agents. 
Antifungal agents should be avoided unless a fungal infection is diagnosed as they 
may interfere with buparlisib metabolism. 
 
 
11.6 Guidelines for the treatment of buparlisib induced diarrhea 
The investigator should consider/investigate potential concomitant medication, food 
or comorbidity driven causes of diarrhea (including infectious causes) and remedy 
these causes if possible (e.g. discontinuation of concomitant medication, dietary 
modification, treatment of comorbidity). 
The patient should be monitored for signs of dehydration and instructed to take 
preventive measures against dehydration as soon as diarrhea occurs. Concomitant 
medication for the treatment of diarrhea should be considered, as per local practice 
and best investigator’s judgment and may consist for example, as per “the 
recommended guidelines for the treatment of cancer treatment-induced diarrhea” 
(Benson 2004), of loperamide given at a standard dose (e.g. initial administration of 
4mg, then 2mg every 4 hours, maximum of 16 mg/day), along with oral hydration 
and dietetic measures could be considered for Grade 1-2 diarrhea. More severe 
diarrhea  should  be  treated  appropriately  according  to  investigator  discretion, 
including for example IV fluids. 
Dose adaptations of buparlisib in case of treatment related diarrhea should follow 
the guidelines presented above for other non-hematological adverse events. 
 
 
11.7 Guidelines for the treatment of buparlisib induced psychiatric disorders 
Psychiatric  adverse  events  will  be  closely  monitored  and  evaluated  at  each 
planned  visit  until  recovery  to  Grade  ≤  1  or  baseline  status.  The  grading  of 
psychiatric  adverse  events/mood  alterations  must  be  based  on  the  clinical 
interpretation of severity according to the NCI- CTCAE (v 4.03) guidelines. 
For patients who experience new or worsening of existing psychiatric AEs of Grade 
≥1, psychiatric consultation should be considered as described in Table 11. 
Patient self-reported mood questionnaires (GAD-7 and PHQ-9) will be used for 
screening and during the study treatment phase to aid the investigator in identifying 
new or worsening of events. For additional information regarding safety 
assessments based on patient self-reported mood questionnaires, please refer to 
Section Patient self-rating mood questionnaires. 
If question 9 in the PHQ-9 has a positive response (as indicated by selecting "1", 
"2", or "3"), omit treatment with buparlisib and refer the patient for psychiatric 
consultation for optimal management regardless of the total questionnaire score or 
CTCAE grading to confirm if study drug should be interrupted or permanently 
discontinued. In this specific case, the psychiatric advice can overrule the patient’s 
PHQ-9 self-assessment. During the study, subjects will be monitored at regular 
scheduled visits (e.g., Day 15 of Cycle 1, Day 1 and Day 15 of each subsequent 
cycle, and at the End of Treatment visit) by the investigator/site staff through 
personal interaction and the two self-reported questionnaires. Additional 
assessments may be done according to the clinical judgment of the investigator if 
desired. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 34 of 58
 
 
 
11.8 Guidelines for the treatment of study drug induced skin toxicity 
Close monitoring of potential skin reactions is recommended at each planned visit 
and should be recorded be reported as adverse event. 
Although preclinical experiments demonstrated that buparlisib has no potential 
phototoxic effect, it is recommended to caution patients to avoid sun exposure 
during treatment with buparlisib, especially when they already have experienced 
rash or other skin toxicities. Patients should be advised to take measures to protect 
themselves from direct exposure to sunlight, including the wearing of sunglasses 
as well as the use of hats, long-sleeve shirts and long pants when outdoors. 
 
 
11.9 Concomitant medications 
In general, the use of any concomitant medication/therapies deemed necessary for 
the care of the patient is permitted (see Section Permitted concomitant therapy), 
except as specifically prohibited (see Section Prohibited concomitant therapy). 
All medications (excluding study treatment and prior antineoplastic treatments), 
procedures  and  significant  non-drug  therapies  (including  physical  therapy  and 
blood transfusions) administered within 28 days prior to the administration of 
buparlisib through 30 days after the last dose of buparlisib will be recorded in the 
Concomitant medications. Medications include not only physician prescribed 
medications, but also all over-the counter medications, herbal medications 
(prohibited, see Section below) and food or vitamin supplements. The investigator 
should instruct the patient to notify the investigational site about any new 
medications she takes after the start of the study drug. 
The  patient  must  be  told  to  notify  the  investigational  site  about  any  new 
medications he/she takes after the start of the study drug. All medications (other 
than study drug) and significant non-drug therapies (including physical therapy and 
blood   transfusions)   administered  during  the  study  must  be  listed   on  the 
Concomitant Medications Sheet. 
 
 
11.10 Permitted concomitant therapy 
 
 
11.10.1 Corticosteroids 
Corticosteroids may be used a limited doses, as they have limited impact on 
buparlisib metabolism.   We recommend using corticosteroids at the smallest 
possible dose to control symptoms or cerebral edema and mass effect, and 
discontinue if possible.    Please also refer to the Investigator‘s Brochure for the 
latest recommendations and findings. 
Caution is also warranted for potential interaction with hyperglycemia. 
 
 
11.10.2 Drugs that are metabolized by CYP450 enzymes 
In vitro metabolism studies performed to examine the reversible and metabolism- 
dependent inhibition of CYPP450 enzymes showed that buparlisib is a weak, 
reversible inhibitor of CYP3A4/5, CYP2C8, CYP2C9 and CPY2C19. Note that with 
the data available, it is not possible to confirm whether such interactions will occur 
in patients. Therefore, investigators, at their discretion, may administer concomitant 
medications known to be metabolized by CYP3A4/5, CYP2C8, CYP2C9 and 
CYP2C19. Patients receiving such medications must be monitored for potentiation 
of toxicity due to any individual concomitant medications, and may require dose 
titration or reduction of the drug substrate. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 35 of 58
 
 
Refer  to  Appendix  2:  List  of  CYP450  substrates  to  be  used  with  caution. 
Particularly, caution is advised when buparlisib is co-administered with drugs that 
are sensitive substrates and/or have a narrow therapeutic index (e.g., SSRI). 
Concomitant treatment of buparlisib with weak or moderate inducers of CYP3A4 is 
permitted, however, duration of concomitant treatment should be kept as short as 
possible (e.g., less than 1 week), or fully avoided whenever possible. Note that 
coadministration of buparlisib with strong inducers is prohibited (see below). 
 
 
11.10.3 Non-enzyme Inducing Anti-epileptic drugs 
Non-enzyme inducing anti-epileptic medication (Non-EIAED) is allowed, except for 
those listed in Appendix 1. 
 
 
11.10.4 Bisphosphonates 
The use of bisphosphonates for bone metastatic disease is allowed. 
 
 
11.10.5 Palliative radiotherapy 
Local radiotherapy for analgesic purposes or for lytic lesions at risk of fracture may 
be carried out if required. Radiation to the central nervous system is NOT allowed 
during the trial. If a patient required palliative radiation involving the CSF space 
(vertebral spine radiation) prior authorization through the principal investigator is 
needed. Whenever possible, these patients should have a tumor assessment of 
the lesion(s) before receiving the radiotherapy in order to rule out progression of 
disease. No dose modification of study treatment is needed during radiotherapy but 
should be monitored with caution. 
 
 
11.10.6 Drugs with a conditional or possible risk to induce Torsades de 
Pointes 
If a patient, after enrollment in the study, requires the concomitant use of any QT 
prolonging medication with a possible or conditional risk for Torsades de Pointes 
included in Appendix 4, then investigators, at their discretion, may co-administer 
such medications. Patients receiving such medications must however be closely 
monitored. 
 
 
11.10.7 Gastric protection agents 
Buparlisib is characterized by a pH-dependent solubility. Medicinal products that 
alter the pH of the upper Gastro-Intestinal (GI) tract may alter the solubility of 
buparlisib and hence its bioavailability. These agents include, but are not limited to, 
proton-pump inhibitors (e.g., omeprazole), H2-antagonists (e.g., ranitidine) and 
antacids.  Buparlisib should be dosed in a staggered manner at least 1 hour before 
or 10 hours after dosing with medicinal products that may alter the pH of the upper 
GI tract. 
 
 
11.10.8 Prohibited concomitant therapy 
 
 
11.10.8.1 Other anticancer therapy 
Anticancer therapy (chemotherapy, endocrine, biologic or radiation therapy, and 
surgery) other than the study treatments must not be given to patients while the 
patient is enrolled in the treatment portion of the trial. If such agents are required 
for a patient then the patient must be permanently discontinued from the treatment 
portion of the study. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 36 of 58
 
 
 
11.10.8.2 Other investigational therapies 
Other investigational therapies must not be used while the patient is on the study. 
 
 
11.10.8.3 Hematopoietic growth factors 
Prophylactic use of hematopoietic growth factors (e.g. erythropoietins, granulocyte 
colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating 
factor (GMCSF)) are not permitted. However, in the event of an emergency (e.g. 
acute myelosuppression with infection), a patient may be given hematopoietic 
growth factors according to the investigator’s judgment, and the sponsor should be 
notified as soon as possible. Subsequent secondary prevention use is permitted at 
investigator’s discretion. 
Patients who begin erythropoietin or darbepoetin therapy before randomization 
may continue this treatment at the discretion of the investigator. 
 
 
11.10.8.4 Warfarin and coumarin derivatives 
Therapeutic doses of warfarin sodium or any other coumarin-derivative 
anticoagulants are not permitted. 
Buparlisib is a weak inhibitor of CYP2C8 and 2C9, the major metabolizing enzyme 
of warfarin. Despite the fact that the inhibitory signal was weak, an increase of 40- 
50% of warfarin exposure is possible and for a drug like warfarin, this might be 
clinically relevant. 
 
 
11.10.8.5 Enzyme-inducing anti-epileptic drug (EIAED) 
Use  of  enzyme-inducing  anti-epileptic  drug  (EIAED)  is  not  permitted.  Refer  to 
Appendix 1 for a list of prohibited EIAED. 
If a patient is currently taking EIAED, they must have discontinued the EIAED 
therapy for at least two weeks prior to starting study drug. 
If a patient is previously on a non-EIAED and needs to permanently change the 
anticonvulsant agent, but cannot change to another non-EIAED, the patient will be 
taken off buparlisib. 
 
 
11.10.8.6 Drugs with a known risk for Torsades de Pointes 
If a patient requires the concomitant use of any medication included in Appendix 3 
entitled “List of Prohibited QT prolonging drugs” (i.e., drugs that are generally 
accepted by the Qtdrugs.org Advisory Board of the Arizona CERT to have a risk of 
causing Torsade de Pointes), study treatment must be delayed. Note that Appendix 
3 lists drugs with a known risk for Torsades de Pointes (TdP) as well as sensitive 
CYP3A substrates (with narrow therapeutic index) with a possible or conditional 
risk for TdP. Study treatment administration must be interrupted as long as the 
patient requires therapy with the QT prolonging agent. 
 
 
11.10.8.7 Moderate and strong CYP3A inhibitors and inducers 
In vitro metabolism studies suggest that oxidative metabolism of buparlisib is 
predominantly mediated by CYP3A4 and UGT1A4. Coadministration of buparlisib 
with strong and moderate CYP3A4 inhibitors and inducers is predicted to 
respectively increase or decrease the systemic exposure to buparlisib. 
Please refer to Appendix 1 for a list of prohibited drugs. Please note that this list 
may not be comprehensive. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 37 of 58
 
 
11.10.8.8 Herbal medications 
Herbal  preparations/medications  are  not  allowed  throughout  the  study,  as  a 
potential  drug-drug  interaction  is  always  possible.  These  herbal  medications 
include, but are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko 
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. 
Patients should stop using these herbal medications at least 7 days prior to first 
dose of study treatment. 
 
 
11.10.8.9 Hormonal contraception 
Hormonal contraceptives may be affected by cytochrome P450 interactions, and 
are therefore not considered effective for this study, since induction of CYP3A4 
may not be excluded in patients receiving buparlisib. 
 
 
11.11 Liver Toxicity 
 
11.11.1 Liver Toxicity Findings 
A recent liver safety review across Novartis-sponsored trials with BKM120 
identified several potentially drug-induced liver toxicity (DILI) cases (e.g. AST/ALT 
>3.0 x ULN and TBL >2.0 x ULN at any time during the treatment, regardless of 
causality. Upon medical review, most of these cases occurred in the context of 
disease progression in terminally ill, advanced cancer patients and/or were 
confounded by other causes. However, six of these DILI candidates were 
consistent with Hy’s law criteria (e.g. AST/ALT >3.0x ULN and TBL >2.0xULN in 
the absence of cholestasis and other explanatory causes) with probable causal 
relationship to study treatment. Five of these cases were enrolled in study 
CBKM120F2302 in combination with fulvestrant, and one in combination with the 
investigational drug LDE225 (sonidegib). All patients have recovered upon 
treatment discontinuation except one patient for whom no data is available since 
the patient refused to return for safety follow-up. 
 
Approximately 25 to 45% of patients treated with single agent BKM120 reported 
liver toxicity (all grades, regardless of study drug relationship, 100 mg/d dose) 
based on a search of multiple MedDRA event terms (e.g. SMQ preferred terms). 
The incidence of grade 3 and 4 events was approximately 10 to 30%. Liver function 
test (LFT) alterations observed during ongoing and completed studies have been 
mostly transaminase enzyme increases (ALT and/or AST). Data suggest a slightly 
higher rate of grade 3 and 4 liver enzyme elevations in Japanese patients (44%) in 
the [CBKM120X1101] study, however, the number of patients treated at 100 mg in 
this study was limited (n=9). Transaminase elevations typically occur during the 
first 6 to 8 weeks of treatment start. 
 
Although transaminase increases are relatively common, only a few of the patients 
had other simultaneous observations related to impaired liver function (e.g. bilirubin 
increase or clinical symptoms). 
 
Based on these findings, conservative inclusion criteria and guidelines to monitor 
and follow patients with LFT alterations (including dose and schedule 
modifications) have been implemented. Please refer to the respective 
inclusion/exclusion criteria and Table 11.0 in this protocol for more detailed 
guidelines. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 38 of 58
 
 
11.11.1.2 Management of Hepatotoxicity (ALT and/or AST ≥ 3.0x ULN and 
total bilirubin ≥2.0x ULN) in patients receiving Buparlisib 
Criteria for interruption and re-initiation of buparlisib treatment in case of the 
occurrence of AST, ALT or bilirubin increase are detailed in Section 11.2, Toxicity 
Management (Table 11). 
 
Patients with clinically significant liver test abnormalities should perform liver- 
directed medical history, physical examination and other tests as medically 
indicated to assess potential relationship with study treatment and rule out other 
underlying causes (e.g. disease progression/obstruction, infection/hepatitis or other 
liver diseases, sepsis, metabolic diseases including diabetes, concomitant 
medications including herbals, alcohol, drug-drug interaction, cardiovascular 
disease/ischemia, other organ injuries, etc.). Any pre-existing liver conditions or 
risk factors should be reported in the respective medical history and concomitant 
medication CRF pages (if not done already). 
 
All patients with ALT or AST >3.0 x ULN and total bilirubin > 2.0 x ULN in the 
absence of cholestasis (elevation of ALP in patients without bone metastasis or if 
bone metastasis are present elevation of 5’-nucleotidase and ALP liver fraction) 
must be immediately withdrawn from buparlisib, and every attempt should be made 
to carry out locally the liver event follow-up assessments as described below: 
• 
Inform the sponsor about the event immediately after its occurrence by 
reporting the event immediately in the clinical database if it meets the 
criteria for an AE or SAE. 
• 
Evaluate if associated with the appearance or worsening of clinical 
symptoms of hepatitis or hypersensitivity such as fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash or eosinophilia, or other 
organ involvement. 
• 
Obtain fractionated bilirubin, serum Alkaline Phosphatase (ALP), creatine 
phosphokinase (CPK), lactate dehydrogenase (LDH), and blood count with 
differential to assess eosinophilia. 
• 
Perform liver imaging (ultrasound, magnetic resonance, or computerized 
tomography) to evaluate liver disease including metastasis or new lesions, 
obstruction/compression, etc. 
• 
Perform viral hepatitis and other serology tests:: 
o Hepatitis C (HCV) serology and viral RNA, Hepatitis B (HBV) serology 
and viral DNA, Hepatitis A (HAV) Immunoglobulin M (IgM) and HAV 
total 
o Hepatitis E (HEV) serology: IgM and IgG, viral RNA 
o Herpes Simplex Virus (HSV), Cytomegalovirus (CMV), Epstein-Barr 
viral (EBV) serology 
• 
Verify and record the use of concomitant medications, acetaminophen, 
herbal remedies, and other over the counter medications, or putative 
hepatotoxins, on the concomitant medications report form. 
• 
Consultation with a specialist(s) or a hepatologist(s) is recommended. 
• 
Liver biopsy as clinically indicated to assess pathological change and 
degree of potential liver injury 
• 
LFTs should be followed-up weekly until resolve to ≤ grade 1, baseline or 
stabilization (no CTCAE grade change over 4 weeks) and outcome 
documented on the respective AE and lab chemistry pages. 
 
11.11.1.3 Laboratory Evaluations 
Hepatotoxicity follow-up testing will be performed when needed (refer to section 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 39 of 58
 
 
11.11.1.2) in patients receiving buparlisib. 
 
Table 13 Clinical laboratory parameters collection plan 
 
Test Category 
Test Name 
*Viral hepatitis serologic tests and other tests 
for hepatotoxicity follow-up * 
HAAb, HBsAg, HBsAb HBcAb, HCV RNA or 
HDV RNA (where needed), HEAb, CMVAb, 
EBcAb, ALP, CPK, LDH, WBC 
(eosinophilia), and others. 
* Hepatotoxicity follow-up testing/procedures will be performed locally (refer to Section 
11.11.1.2: Management of hepatotoxicity (ALT and/or AST >3.0x ULN and total 
bilirubin >2.0x ULN) in patients receiving buparlisib and Viral hepatitis serology and 
other tests for hepatotoxicity follow-up. 
 
 
Viral Hepatitis serology and other tests for hepatotoxicity follow-up 
Viral hepatitis serologic tests are performed confirm patient’s eligibility when needed per 
clinical judgment and specific patient’s clinical circumstances. 
 
 
During study treatment, viral hepatitis serologic and other tests will be performed as per 
the guidelines of management of hepatotoxicity (ALT or AST >3.0x ULN and total bilirubin 
> 2.0x ULN) in patients receiving buparlisib, refer to Section 6.2.4.X Management of 
hepatotoxicity (ALT and/or AST >3.0x ULN and total bilirubin >2.0x ULN) in patients 
receiving buparlisib for details. 
 
 
Viral hepatitis serology includes the following: 
• 
Hepatitis B surface antigen, Hepatitis B Core Antibody (IgM) and viral DNA 
• 
Hepatitis C serology and viral RNA 
• 
Hepatitis D RNA (where needed) 
• 
Hepatitis E IgM and IgG antibody and viral RNA 
 
Obtain fractionated bilirubin, serum Alkaline Phosphatase (ALP), creatine phosphokinase (CPK), 
lactate dehydrogenase (LDH), and blood count with differential to assess eosinophilia. 
 
Additional viral serology tests may include: 
 
• 
Cytomegalovirus IgM antibody 
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody 
or monospot testing) 
• 
Herpes Simplex Virus 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1 Definitions of response 
 
This study will use the Macdonald criteria (Macdonald, et al. 1990). Specific lesions must be 
evaluated serially, and comparative analysis of changes in the area of contrast 
enhancement, as well as the non-enhancing component, should be performed. As with the 
Macdonald criteria (Macdonald, et al. 1990), the product of the maximal cross-sectional 
enhancing diameters will be used to determine the size of the contrast-enhancing lesions. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 40 of 58
 
 
a.  Measurable disease: Measurable lesions are defined as enhancing lesions that can be 
accurately measured in at least two dimensions ≥ 10mm. All tumor measurements must 
be reported in millimeters. 
b.  Non-measurable disease: All other lesions (or sites of disease), including small lesions 
(<10mm with conventional techniques) are considered non-measurable disease. 
c.   Cytologic Complete Response (CCR): Complete clearing of all malignant cells from 
ventricular or lumbar source based on cytology. A cytologic CR must be documented by 
two negative cytologies from ventricular or lumbar sources on consecutive occasions at 
least 4 weeks apart. 
 
12.2 Guidelines for evaluation of measurable disease 
 
1.  Complete Response (CR): Complete disappearance of all measurable and non- 
measurable disease. No new lesions. All measurable and non-measurable lesions 
and sites must be assessed using the same techniques as baseline. Patients must be 
on no steroids. 
2.  Partial Response (PR): Greater than or equal to 50% decrease over the baseline in 
the sum of products of perpendicular diameters of all measurable lesions. No 
progression of non-measurable disease. No new lesions. All measurable and non- 
measurable lesions and sites must be assessed using the same techniques as 
baseline. The steroid dose at the time of the scan evaluation should be no greater 
than the maximum dose used in the first 8 weeks from initiation of therapy. 
3.  Stable/no response: Does not qualify for CR, PR, or progression. All measurable and 
non-measurable sites must be assessed using the same techniques as baseline. The 
steroid dose at the time of the scan evaluation should be no greater than the 
maximum dose used in the first 8 weeks from initiation of therapy. 
4.  Progression: 25% increase in the sum of products of all measurable lesions over 
smallest sum observed (or baseline if no decrease) using the same techniques as 
baseline, OR clear worsening of any non-measurable disease, OR appearance of any 
new lesion/site, OR clear clinical worsening or failure to return for evaluation due to 
death or deteriorating condition (unless clearly unrelated to this cancer). 
 
12.3 Guidelines for patients with CSF disease 
 
1.  Complete Response (CR): Combination of CCR and complete disappearance of all 
measurable and non-measurable disease (if the participant had imaging 
abnormalities at enrollment). No new lesions. All measurable and non-measurable 
lesions and sites must be assessed using the same techniques as baseline. Patients 
must be on no steroids. 
2.  Partial Response (PR): Combination of CCR and stable size of all measurable and 
non-measurable disease (if the participant had imaging abnormalities at enrollment). 
No new lesions. All measurable and non-measurable lesions and sites must be 
assessed using the same techniques as baseline. Patients should be on a stable or 
reduced does of steroids. 
3.  Stable/no response: Tumor cells still present in CSF cytology and stable size of all 
measurable and non-measurable disease (if the participant had imaging 
abnormalities at enrollment). No new lesions. All measurable and non-measurable 
lesions and sites must be assessed using the same techniques as baseline. Patients 
should be on a stable or reduced does of steroids. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 41 of 58
 
 
4.  Progressive Disease (PD): 25% increase in the sum of products of all measurable 
lesions over smallest sum observed (or baseline if no decrease) using the same 
techniques as baseline, OR clear worsening of any non-measurable disease, OR 
appearance of any new lesion/site on imaging, OR clear clinical worsening or failure 
to return for evaluation due to death or deteriorating condition (unless clearly 
unrelated to this cancer) regardless of CSF cytology status. 
 
12.4 Best response and objective response rate (ORR) 
 
For patients with all disease sites assessed every evaluation period, the best response 
will be defined as the best objective status as measured according to section 12.2/12.3. If 
the response does not persist at the next regular scheduled MRI/CT, 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/CT, it will 
be recorded as a sustained response, lasting until the time of tumor progression. 
 
The objective response rate (ORR) is defined as the portion of patients with a best 
response of CR plus PR according to section 12.2/12.3divided by the total number of 
patients included in the study. 
 
12.5 Neurological exam 
 
Although not used for determining response, it is useful to evaluate changes in the 
neurological exam compared to the previous exam. The following scale may be used: 
 
+2 
Definitely better 
 
+1 
Possibly better 
 
0 
Unchanged 
 
-1 
Possibly worse 
 
-2 
Definitely worse 
 
Additionally the participant will be evaluated for neurologic functioning by the 
investigator and according to the NANO scale (). Assessments will be performed at 
baseline and will each treatment response assessment (every MRI visit). The NANO 
is an objective, quick, user-friendly and quantifiable evaluation of nine major domains 
for subjects with brain tumors. The domains include: gait, strength, ataxia, sensation, 
visual field, facial strength, language, level of consciousness, behavior and overall. 
Each domain is rated on a scale of 0 to 3 where 0 represents normal and 3 
represents the worst severity. A given domain should be scored non-evaluable if it 
cannot be accurately assessed due to pre-existing conditions, co-morbid events 
and/or concurrent medications. The evaluation is based on direct observation/testing 
performed during routine office visits. The NANO scale will be completed by the 
investigator or designated study physician prior to day 1 cycle 1 (baseline) and then 
with each MRI). 
 
 
 
12.6 Performance status 
 
Participants will be graded according to Karnofsky Performance Status Scale (KPS) 
(Appendix 6). 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 42 of 58
 
 
12.7 Overall survival time (OS) 
 
Overall survival time (OS) is defined as the time from treatment start to the date of 
death due to any cause. Patients not known to have died will be censored at the time 
of their last available assessment or at the analysis cut-off whichever comes earlier. 
 
OS will be described using Kaplan-Meier curves with appropriate summary statistics. 
 
12.8 Progression-free survival (PFS) 
 
Progression-free survival (PFS) is defined as the time from the date of treatment start 
to the date of the first documented PD or death due to any cause. If a patient is not 
known to have progressed or died at the date of the analysis cut-off or when he/she 
receives any further anti-cancer therapy, PFS is censored at the time of the last tumor 
assessment before the cut-off date and before the anti-cancer therapy date. PFS will 
be based on the investigator’s assessment of MRI, CSF studies and clinical 
presentation. 
 
PFS will be described using Kaplan-Meier curves with appropriate summary statistics. 
Additionally, we will report PFS at 12 weeks (PFS12w), PFS at 24 weeks (PFS24w) 
and at 48 weeks (PFS48w). 
 
12.9 Duration of response 
 
Duration of response is defined as the time from the date of first occurrence of CR or 
PR to the date of the first documented PD or death due to any cause. If a patient is 
not known to have progressed or died at the date of the analysis cut-off or when 
he/she receives any further anti-cancer therapy, duration of response is censored at 
the time of the last tumor assessment before the cut-off date and before the anti- 
cancer therapy date. 
 
Duration of response will be described using Kaplan-Meier curves with appropriate 
summary statistics. 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. The absence of treatment delays due to adverse events, treatment may continue 
until one of the following criteria applies: 
 
• 
Disease progression 
• 
Intercurrent illness that prevent further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Participant decides to withdraw from the study 
• 
General or specific changes in the participant’s condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 
The participant will be removed from study treatment when any one of the criteria listed above 
applies. The reason for study treatment removal and the date the participant was removed 
must be documented in the study-specific case report form. Alternative care options will be 
discussed with the participant. 
 
In the event of unusual or life-threatening complications, investigators must immediately 
notify the Principal Investigator. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 43 of 58
 
 
Patients will be treated until disease progression, death, unacceptable toxicity or other 
discontinuation criteria are met. 
 
After patients are removed from the trial they will represent after 30 days for a clinical follow- 
up visit. Thereafter, they will be followed for 12 months. The frequency of clinical follow-up 
visits is at the discretion of the investigator but we recommend a frequency of every 3-4 
months. Thereafter, patients will be contacted over the telephone once a year. 
 
 
 
14.0 
BIOSTATISTICS 
 
As outlined in Table 1 Section 3, prior trials in patients with recurrent PCNSL have observed 
PFS6m of 35-45% with conventional chemotherapy regimens. The primary objective of this 
phase II study is to assess the efficacy of the targeted therapy buparlisib. PFS24w rate of 
patients receiving buparlisib will be estimated along with a 95% confidence interval. 
Progression-free survival at 24 weeks (PFS24w) is defined as the percentage of patients that 
have not developed progression of disease or died without progression at 24 weeks from the 
start of treatment.  All patients will be followed for 6 months. 
 
Twenty-one patients will be entered in this trial with an anticipated accrual rate of 1- 
2/months. The therapy will be considered worth pursuing if ≥12 out of 21 participants are 
progression free at 6 months (lower bound of the 95% confidence interval exceeds 34%, the 
approximate PFS24w rate with conventional chemotherapy). 
 
Based on an accrual of 21 participants, two-sided 95% binominal confidence intervals for a 
range of overall response rate are as follows: 
 
 
 
 
 
 
 
 
 
 
Table 14: Two-sided 95% binominal confidence intervals 
 
Number of participants with overall response: 
6 
8 
10 
12 
14 
16 
Point estimate of overall response rate:  
29% 
38% 
48% 
57% 
67% 
76% 
 
Two-sided 95% confidence interval 
(exact binominal): 
lower 
11.28% 
18.11% 
25.71% 
34.02% 
43.03%
52.83%
 
upper
52.18%
61.56%
70.22%
78.18% 
85.41%
91.78%
 
 
In the unlikely event a patient is lost to follow-up before assessment of the primary endpoint 
he or she will be considered an event in the analysis of the primary endpoint. 
 
In addition to PFS24w, we will assess progression-free survival at 12 weeks and 48 weeks 
(PFS12w and PFS48w). PFS12w/PFS48w is defined as the percentage of patients that have 
not developed progression of disease or died without progression at 3/12 months from the 
start of treatment. PFS12w and PFS48w rates of patients receiving buparlisib will be 
estimated along with a 95% confidence interval. The PFS12w will be assessed based on the 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 44 of 58
 
 
imaging and/or CSF assessment at day 1 cycle 3. PFS24w will be based on the imaging 
and/or CSF assessment at day 1 cycle 6, and PFS48w on imaging and/or CSF assessment 
at day 1 cycle 12. 
 
Frequencies of toxicities will be summarized based on the Common Toxicity Criteria version 
4.0.  Adverse events that occur will be reported for and described in terms of incidence and 
severity.  Objective response rate (defined as proportion of patients who achieve a complete 
and partial response among all patients) will be estimated along with a 95% confidence 
interval. For patients who respond to treatment (complete or partial response), duration of 
response will be calculated from the date of response to the date of progression of disease. 
Patients still responding at date of last follow-up will be censored.  Overall survival will be 
calculated as the time from the start of treatment to the date of death or last follow-up. 
Overall survival and duration of response will be calculated using Kaplan-Meier methodology. 
 
Pharmacokinetic parameters including half-life, Cmax, AUC, volume of distribution, and 
clearance will be determined using non-compartmental methods via WinNonlin (Pharsight, 
Mountain  View,  CA).  Standard  descriptive  statistics  (mean,  standard deviation,  median, 
range) will be presented on all parameters for both serum and CSF samples. 
 
 
Mutational abnormalities (mutant or not) will be assessed for the following genes: A20, 
CARD11, CD79B, PIK3CA, PIK3CD and MYD88. Additionally, the phosphorylation status of 
the following members of the PI3K pathway will be assess through immunohistochemical 
staining (activated or not activated). Both, mutational abnormalities as well as 
immunohistochemical status will be cross tabulated with patient outcomes such as PFS24w 
and ORR.  Associations will be assessed using Fishers exact test.  For patients who receive 
MR spectroscopy peak values will be described and graphically presented through course of 
treatment. Perfusion data (ADC value categorized as high versus low) will be correlated with 
patient outcome if data permit. 
 
The evaluation of NANO will be measured by the distribution of change from baseline in the 
level of function score for each domain. 
 
It is anticipated that 1-2 patients per month will be accrued to this study and the study will be 
completed within 2 years. Accrual is limited to 10 patients with SCNSL and 11 patients with 
PCNSL. 
 
 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1    Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 45 of 58
 
 
15.2 
Randomization 
 
Not applicable in this study 
 
16.0 
DATA MANAGEMENT ISSUES 
 
A Clinical Research Coordinator/Data Manager will be assigned to the study. The 
responsibility of the Clinical Research Coordinator/Data Manager include project compliance, 
data collection, abstraction and entry, data reporting, regulatory monitoring, problem 
resolution and prioritization, and coordination of the activities of the protocol study team. The 
data collected for this study will be entered into the MSKCC secure database, CRDB. 
 
16.1 
Quality Assurance 
 
This study will utilize the MSKCC’s Clinical Research Management Office, and will adhere to 
all regulatory and data management polices accordingly. Monthly 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 extent and accuracy of evaluations and follow-ups 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 samples 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 trial will utilize the MSKCC’s Data Safety Monitoring Plan. The plan addressed the 
issues set forth by the NCI in the document entitled “Policies of the National Cancer Institute 
for Data and Safety Monitoring in Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. 
 
The MSKCC DSM Plan can be found at: 
 
http://onemsk/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20Monitoring% 
20Plans.pdf 
 
MSKCC DSM Plan has been designed to ensure that all clinical trials implemented at our 
center are monitored, and that reporting techniques fulfill sponsor, institutional, and 
governmental requirements. 
 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
The patient (or insurer) will be charged for all costs associated with this protocol except cost 
of the study drug Buparlisib (BMK120) and exploratory analyses conducted following 
registration. 
 
17.1 
Privacy 
 
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 (IRB/PB). 


Amended:08/25/15 
Page 46 of 58
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
 
 
17.2    Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at  sae@mskcc.org. The report should contain the following 
information: 
 
Fields populated from CRDB: 
 
•   Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
•   Medical record number 
•   Disease/histology (if applicable) 
•   Protocol number and title 
 
Data needing to be entered: 
 
•   The date the adverse event occurred 
•   The adverse event 
•   Relationship of the adverse event to the treatment (drug, device, or intervention) 
•   If the AE was expected 
•   The severity of the AE 
•   The intervention 
•   Detailed text that includes the following 
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. 
 
 
17.2.1 Reporting to Novartis 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has 
stopped study treatment must be reported to Novartis within 24 hours of learning of its 
occurrence. 
Any  SAEs  experienced  after  this  30  days  period  should  only  be  reported  to 
Novartis if the investigator suspects a causal relationship to the study treatment. An 
SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new 
event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event 
Report Form; all applicable sections of the form must be completed in order to 
provide a clinically thorough report. The investigator must assess and record the 
relationship of each SAE to each specific study treatment (if there is more than one 
study treatment), complete the SAE Report Form in English, and send the 
completed, signed form by fax within 24 hours to the oncology Novartis Drug 
Safety and Epidemiology (DS&E) department (fax # 877-778-9739). 
The telephone and telefax number of the contact persons in the local department of 
Drug Safety and Epidemiology (DS&E), specific to the site, are listed in the 
investigator folder provided to each site. The original copy of the SAE Report Form 
and the fax confirmation sheet must be kept with the case report form 
documentation at the study site. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 47 of 58
 
 
 
17.2.1 
Follow-up information is sent to the same contact(s) to whom the original SAE 
Report Form was sent, using a new SAE Report Form stating that this is a follow- 
up to the previously reported SAE and giving the date of the original report. Each 
re-occurrence, complication, or progression of the original event should be reported 
as a follow-up to that event regardless of when it occurs. The follow-up information 
should describe whether the event has resolved or continues, if and how it was 
treated, whether the blind was broken or not, and whether the patient continued or 
withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package 
Insert  (new  occurrence)  and  is  thought  to  be  related  to  the  Novartis  study 
treatment,   an   oncology   Novartis   Drug   Safety   and   Epidemiology   (DS&E) 
department associate may urgently require further information from the investigator 
for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN), to inform all investigators involved in any study with the same drug 
that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities 
and relevant ethics committees in accordance with Directive 2001/20/EC or as per 
national regulatory requirements in participating countries. 
 
 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by 
the investigator to the oncology Novartis Drug Safety and Epidemiology (DS&E) 
department. Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the Novartis study treatment 
of any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who 
took study treatment in this study. Consent to report information regarding these 
pregnancy outcomes should be obtained from the mother. 
 
 
Overdoses 
 
Any overdose, even in the absence of a resulting AE, must be forwarded to Novartis and 
reported to the Principal Investigator. 
 
Warnings and precautions 
 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the Investigators’ 
Brochure.  Additional safety information collected between updates of the Investigators’ 
Brochure will be communicated in the form of Investigator Notifications. This information will 
be included in the patient informed consent and should be discussed with the patient during 
the study as needed. 
 
 
 
18.0    INFORMED CONSENT PROCEDURES 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
28;241(2):184-96. Epub 2006 Jan 18. Review.
Amended:08/25/15 
Page 48 of 58
 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
 
 
 
 
 
 
 
 
 
19.0 
REFERENCES 
 
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse 
large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503-11 
 
Arellano-Rodrigo, E., A. Lopez-Guillermo, et al. (2003). "Salvage treatment with etoposide (VP-16), 
ifosfamide and cytarabine (Ara-C) for patients with recurrent primary central nervous system 
lymphoma." European journal of haematology 70(4): 219-224 
 
Barajas RF Jr, Rubenstein JL, Chang JS, Hwang J, Cha S. Diffusion-weighted MR imaging derived 
apparent diffusion coefficient is predictive of clinical outcome in primary central nervous system 
lymphoma. AJNR Am J Neuroradiol. 2010 Jan;31(1):60-6. 
 
Batchelor, T. T., S. A. Grossman, et al. (2011). "Rituximab monotherapy for patients with recurrent 
primary CNS lymphoma." Neurology 76(10): 929-930 
 
Camilleri-Broet S, Criniere E, Broet P, Delwail V, Mokhtari K, Moreau A, et al. A uniform activated B- 
cell-like immunophenotype might explain the poor prognosis of primary central nervous system 
lymphomas: analysis of 83 cases. Blood. 2006;107(1):190-6. 
 
Chow LM, Baker SJ. PTEN function in normal and neoplastic growth. Cancer Lett. 2006 Sep 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 49 of 58
 
 
 
Cully M, You H, Levine AJ, Mak TW. Beyond PTEN mutations: the PI3K pathway as an integrator of 
multiple inputs during tumorigenesis. Nat Rev Cancer 2006 Mar;6(3):184-92. 
 
Deangelis LM, Iwamoto FM. An update on therapy of primary central nervous system lymphoma. 
Hematology Am Soc Hematol Educ Program. 2006:311-6. Review. 
 
Enting, R. H., A. Demopoulos, et al. (2004). "Salvage therapy for primary CNS lymphoma with a 
combination of rituximab and temozolomide." Neurology 63(5): 901-903 
 
Ferreri, A. J., M. Reni, et al. (2009). "High-dose cytarabine plus high-dose methotrexate versus high- 
dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial." 
Lancet 374(9700): 1512-1520. 
 
Ferreri, A. J. (2011). "How I treat primary CNS lymphoma." Blood 118(3): 510-522. 
 
Fischer, L., E. Thiel, et al. (2006). "Prospective trial on topotecan salvage therapy in primary CNS 
lymphoma." Annals of oncology : official journal of the European Society for Medical Oncology / 
ESMO 17(7): 1141-1145 
 
Fruman DA, Rommel C. PI3Kdelta Inhibitors in Cancer: Rationale and Serendipity Merge in the 
Clinic. Cancer discovery. 2011;1(7):562-72. 
 
Gavrilovic, I. T., A. Hormigo, et al. (2006). "Long-term follow-up of high-dose methotrexate-based 
therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma." 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 24(28): 
4570-4574. 
 
 
Grier J, Batchelor T. Metastatic neurologic complications of non-Hodgkin's lymphoma. Curr Oncol 
Rep. 2005 Jan;7(1):55-60. Review. 
 
Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of 
phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell 
Dev Biol. 2001;17:615-75. 
 
Kloo B, Nagel D, Pfeifer M, Grau M, Duwel M, Vincendeau M, et al. Critical role of PI3K signaling for 
NF-kappaB-dependent survival in a subset of activated B-cell-like diffuse large B-cell lymphoma 
cells. Proc Natl Acad Sci U S A. 2011;108(1):272-7. 
 
Koul D, Shen R, Kim YW, Kondo Y, Lu Y, Bankson J, Ronen SM, Kirkpatrick DL, Powis G, Yung 
WK. Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma. 
Neuro Oncol. 2010 Jun;12(6):559-69 
 
Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. 
Nat Rev Drug Discov. 2009 Aug;8(8):627-44. doi: 10.1038/nrd2926. Review. 
 
Macdonald DR, Cascino TL, Schold SC, Jr., and Cairncross JG. Response criteria for phase II 
studies of supratentorial malignant glioma. J Clin Oncol. 1990;8(7):1277-80. 
 
McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, Navolanic PM, Terrian DM, 
Franklin RA, D'Assoro AB, Salisbury JL, Mazzarino MC, Stivala F, Libra M. Roles of the 
RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. 
Adv Enzyme Regul. 2006;46:249-79. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 50 of 58
 
 
 
Nguyen, P. L., A. Chakravarti, et al. (2005). "Results of whole-brain radiation as salvage of 
methotrexate failure for immunocompetent patients with primary CNS lymphoma." Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 23(7): 1507-1513 
 
Plotkin, S. R., R. A. Betensky, et al. (2004). "Treatment of relapsed central nervous system 
lymphoma with high-dose methotrexate." Clinical cancer research : an official journal of the 
American Association for Cancer Research 10(17): 5643-5646 
 
Reni, M., F. Zaja, et al. (2007). "Temozolomide as salvage treatment in primary brain lymphomas." 
British journal of cancer 96(6): 864-867 
 
Soussain, C., K. Hoang-Xuan, et al. (2008). "Intensive chemotherapy followed by hematopoietic 
stem-cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: Societe 
Francaise de Greffe de Moelle Osseuse-Therapie Cellulaire." Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 26(15): 2512-2518. 
 
Soussain, C., F. Suzan, et al. (2001). "Results of intensive chemotherapy followed by hematopoietic 
stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular 
lymphoma." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
19(3): 742-749 
 
Tyson, R. M., T. Siegal, et al. (2003). "Current status and future of relapsed primary central nervous 
system lymphoma (PCNSL)." Leukemia & lymphoma 44(4): 627-633 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 51 of 58
 
 
20.0 
APPENDICES 
 
Appendix 1:  List of prohibited CYP3A inhibitors and inducers 
 
 
Strong CYP3A 
inhibitors 
 
Moderate CYP3A inhibitors 
Strong CYP3A 
inducers 
Moderate CYP3A 
inducers 
clarithromycin 
amprenavir 
carbamazepine * 
felbamate * 
conivaptan 
aprepitant 
phenobarbital * 
topiramate * (>200 mg/day) 
indinavir 
atazanavir 
phenytoin * 
oxcarbazepin * 
itraconazole 
cimetidine 
fosphenytoin * 
eslicarbazepin * 
ketoconazole 
ciprofloxacin 
primidone * 
rufinamide * 
lopinavir 
darunavir 
avasimibe 
bosentan 
mibefradil 
diltiazem 
rifabutin 
efavirenz 
nefazodone 
elvitegravir 
rifampin 
etravirine 
nelfinavir 
erythromycin 
St. John's Wort 
modafenil 
posaconazole 
fluconazole 
 
nafcillin 
ritonavir 
grapefruit juice 
 
ritonavir 
saquinavir 
schisandra sphenanthera 
 
talviraline 
telithromycin 
tipranavir 
 
tipranavir 
troleandomycin 
tofisopam 
 
 
voriconazole 
verapamil 
 
 
* These drugs are Enzyme Inducing Anti-Epileptic drugs (EIAEDs) 
This database of CYP inhibitors and inducers was compiled from the Indiana University School of Medicine’s 
“Clinically Relevant” Table, from the University of Washington’s Drug Interaction Database based on in vitro 
studies and from the FDA’s “Guidance for Industry, Drug Interaction Studies;” from the Indiana University 
School of Medicine’s “Clinically Relevant” Table; and from (Pursche 2008). 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 52 of 58
 
 
Appendix 2:  List of CYP450 substrates to be used with caution 
 
 
CYP2C8 
CYP2C9 
CYP2C19 
CYP3A** 
amodiaquine 
celecoxib 
amitriptyline 
adinazolam 
felodipine1 
cerivastatin 
diclofenac 
citalopram 
alfentanil1,2 
fentanyl2 
pioglitazone 
flurbiprofen 
clobazam 
alpha- 
dihydroergocryptine1 
flunitrazepam 
repaglinide 
fluvastatin 
clomipramine 
alprazolam 
fluticasone1 
rosiglitazone 
glibenclamide 
(glyburide) 
clopidogrel 
amlodipine 
lovastatin1 
torasemide 
gliclazide 
diazepam 
aripiprazole 
maraviroc1 
troglitazone 
glimepiride 
fluoxetine 
atorvastatin 
midazolam1 
 
glipizide 
imipramine 
brecanavir 
nifedipine 
 
indomethacin 
lansoprazole 
brotizolam1 
nisoldipine 
 
irbesartan 
mephobarbital 
budesonide1 
nitrendipine 
 
ketobemidone 
moclobemide 
buspirone1 
perospirone1 
 
lornoxicam 
omeprazole 
capravirine 
quinine 
 
losartan 
pantoprazole 
cerivastatin 
sildenafil1 
 
meloxicam 
progesterone 
chlorpheniramine 
simvastatin1 
 
naproxen 
quazepam 
cyclosporine2 
sirolimus1,2 
 
nateglinide 
rabeprazole 
darifenacin1 
tolvaptan 
 
piroxicam 
sertraline 
diazepam 
trazodone 
 
rosiglitazone 
S-mephenytoin 
diergotamine2 
triazolam1 
 
S-ibuprofen 
 
ebastine1 
 
 
sulfamethoxazole 
 
eletriptan1 
 
 
tenoxicam 
 
eplerenone1 
 
 
tolbutamide 
 
ergotamine2 
 
 
torasemide 
 
estazolam 
 
 
valdecoxib 
 
everolimus1 
 
* This database of CYP substrates was compiled from the Indiana University School of Medicine’s “Clinically 
Relevant” Table, and from (Zhou 2009) 
** CYP3A substrates were compiled from the Indiana University School of Medicine’s “Clinically Relevant” 
Table; and supplemented by the FDA’s “Guidance for Industry, Drug Interaction Studies” and the University of 
Washington’s Drug Interaction Database. 
(1) Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when 
co-administered with a potent inhibitor of the respective enzyme. 
(2) Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases 
in their exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., 
Torsades de Pointes). 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 53 of 58
 
 
Appendix 3: Prohibited QT prolonging drugs with risk of Torsades de Pointes 
All  QT-prolonging  drugs  listed  are  prohibited  for  all  patients  from  screening  through 
permanent discontinuation of study treatment. 
 
 
List of prohibited QT prolonging drugs 
Drug 
QT risk(*) 
Comment 
Amiodarone 
Known risk for TdP 
Females>Males, TdP risk regarded as low 
Arsenic trioxide 
Known risk for TdP 
Astemizole 
Known risk for TdP 
No Longer available in U.S. 
Bepridil 
Known risk for TdP 
Females>Males 
Chloroquine 
Known risk for TdP 
 
Chlorpromazine 
Known risk for TdP 
Cisapride 
Known risk for TdP 
Restricted availability; Females>Males. 
Disopyramide 
Known risk for TdP 
Females>Males 
Dofetilide 
Known risk for TdP 
Domperidone 
Known risk for TdP 
Not available in the U.S. 
Droperidol 
Known risk for TdP 
Halofantrine 
Known risk for TdP 
Females>Males 
Haloperidol 
Known risk for TdP 
When given intravenously or at higher-than- recommended doses, risk of 
sudden death, QT prolongation and torsades increases. 
Ibutilide 
Known risk for TdP 
Females>Males 
Levomethadyl 
Known risk for TdP 
 
Mesoridazine 
Known risk for TdP 
Methadone 
Known risk for TdP 
Females>Males 
Pentamidine 
Known risk for TdP 
Females>Males 
Pimozide 
Known risk for TdP 
Females>Males 
Probucol 
Known risk for TdP 
No longer available in U.S. 
Procainamide 
Known risk for TdP 
Quetiapine 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate 
Quinidine 
Known risk for TdP 
Females>Males 
Sotalol 
Known risk for TdP 
Females>Males 
Sparfloxacin 
Known risk for TdP 
Tacrolimus 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate with narrow TI 
Terfenadine 
Known risk for TdP 
No longer available in U.S. 
Thioridazine 
Known risk for TdP 
Vardenafil 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate 
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co- 
administered with a potent inhibitor of the respective enzyme. 
 
Note: drugs with a known risk for TdP that are also strong inhibitors of CYP3A are not repeated here and only mentioned in 
Appendix 2. 
 
Please also refer to  http://crediblemeds.org/ for a comprehensive list of agents that prolong the QT interval 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 54 of 58
 
 
Appendix 4: List of QT prolonging drugs to be used with caution 
Patients receiving any study treatment may use the following medications but should be 
monitored closely. 
 
 
Drug 
QT risk (*) 
Alfuzosin 
Possible risk for TdP 
Amantadine 
Possible risk for TdP 
Amitriptyline 
Conditional risk for TdP 
Azithromycin 
Possible risk for TdP 
Chloral hydrate 
Possible risk for TdP 
Citalopram 
Conditional risk for TdP 
Clomipramine 
Conditional risk for TdP 
Clozapine 
Possible risk for TdP 
Desipramine 
Conditional risk for TdP 
Diphenhydramine 
Conditional risk for TdP 
Dolasetron 
Possible risk for TdP 
Doxepin 
Conditional risk for TdP 
Dronedarone 
Possible risk for TdP 
Escitalopram 
Possible risk for TdP 
Flecainide 
Possible risk for TdP 
Fluoxetine 
Conditional risk for TdP 
Foscarnet 
Possible risk for TdP 
Galantamine 
Conditional risk for TdP 
Gatifloxacin 
Possible risk for TdP 
Gemifloxacin 
Possible risk for TdP 
Granisetron 
Possible risk for TdP 
Imipramine 
Conditional risk for TdP 
Indapamide 
Possible risk for TdP 
Isradipine 
Possible risk for TdP 
Levofloxacin 
Possible risk for TdP 
Lithium 
Possible risk for TdP 
Mexiletine 
Conditional risk for TdP 
Moexipril/HCTZ 
Possible risk for TdP 
Moxifloxacin 
Possible risk for TdP 
Nicardipine 
Possible risk for TdP 
Nortriptyline 
Conditional risk for TdP 
Octreotide 
Possible risk for TdP 
Ofloxacin 
Possible risk for TdP 
Ondansetron 
Possible risk for TdP 
Oxytocin 
Possible risk for TdP 
Paliperidone 
Possible risk for TdP 
Paroxetine 
Conditional risk for TdP 
Perflutren lipid microspheres 
Possible risk for TdP 
Protriptyline 
Conditional risk for TdP 
Ranolazine 
Possible risk for TdP 
Risperidone 
Possible risk for TdP 
Roxithromycin* 
Possible risk for TdP 
Sertindole 
Possible risk for TdP 
Sertraline 
Conditional risk for TdP 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 55 of 58
 
 
Drug 
QT risk (*) 
Solifenacin 
Conditional risk for TdP 
Tizanidine 
Possible risk for TdP 
Trazodone 
Conditional risk for TdP 
Trimethoprim-Sulfa 
Conditional risk for TdP 
Trimipramine 
Conditional risk for TdP 
Venlafaxine 
Possible risk for TdP 
Ziprasidone 
Possible risk for TdP 
 
Please also refer to  http://crediblemeds.org/ for a comprehensive list of agents that prolong the QT interval 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 56 of 58
 
 
Appendix 5: Patient Self-Reported Mood Questionnaires 
 
 
Scoring the PHQ-9 and GAD-7 
Calculating the Total Score for the PHQ-9 
Total scores from the PHQ-9 will be calculated to assess depression severity according to 
the  developer’s  guidelines  (Instruction  Manual:  Instructions  for  Patient  Health 
Questionnaire (PHQ) and GAD-7 Measures. Accessed on 2010 Sept 9 from: 
www.phqscreeners.com). This is calculated by assigning scores of 0, 1, 2, and 3, to the 
response categories of “not at all,” “several days,” “more than half the days,” and “nearly 
every day,” respectively. PHQ-9 total score for the nine items ranges from 0 to 27. 
PHQ-9 Scoring Example: 
In the example below, the Total Score for the PHQ-9 depression severity is 8, where the 
score is the sum of four items scored “0” (questions: #3, 7, 8, 9), three items scored “1” 
(questions:  #1,  4,  6),  one  item  scored  “2”  (question:  #2),  and  one  item  scored  “3” 
(question: #5). 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 57 of 58
 
 
 
 
Calculating the Total Score for the GAD-7 
Similar to the PHQ-9, scores for the GAD-7 will calculated to assess anxiety severity 
according to the developer’s guidelines (1). This is calculated by assigning scores of 0, 1, 
2, and 3, to the response categories of “not at all,” “several days,” “more than half the 
days,” and “nearly every day,” respectively. A total score for the GAD-7 can range from 0 
to 21. 
GAD-7 Scoring Example: 
In the example below, the Total Score for the GAD-7 anxiety severity is 9, where the score 
is the sum of two items scored “0” (questions: #6, 7), two items scored “1” (questions: #2, 
3), two items scored “2” (questions: #1, 5), and one item scored “3” (question: #4). 
 
 
 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-177 A(5)
Amended:08/25/15 
Page 58 of 58
 
 
 
 
Appendix 6: Karnofsky Performance Status Scale 
 
 
SCORE 
 
DESCRIPTION 
100 
Normal; no complains; no evidence of disease 
90 
Able to carry on normal acidity; minor signs or symptoms of disease 
80 
Normal activity with effort; some sign or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most personal needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization is indicated, although death not imminent 
20 
Very sick; hospitalization necessary; active support treatment is necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead