Conditions: Metastatic Transitional Cell Carcinoma of the Urothelium
Keywords: KIDNEY URETER URINARY BLADDER Buparlisib 11-060
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 19
Healthy volunteers: no

Brief summary:
The purpose of this study is to learn what effects, good and/or bad, Buparlisib has on advanced urothelial cancer. Buparlisib is a pill that works by shutting down some of the signals in cancer cells that make tumors grow. It is being tested in patients in research studies such as this one. As of 2010, more than 80 patients with various types of cancer have received treatment with Buparlisib in research studies.

This clinical research study is divided into two parts. The goal of the first part of this study is to learn if the study drug Buparlisib can shrink or slow the growth of cancer in patients with urothelial tumors. The goal of the second part of this study is to learn if the study drug Buparlisib can shrink or slow the growth of urothelial tumors in patients known to have certain genetic alterations that cause these types of tumors. The study doctor will inform the patient which part of the study is currently enrolling participants. Participants in both parts of the study will receive the same treatment and tests.

The safety of this drug will also be studied in both parts. The physical state, changes in the size of the tumor, and laboratory findings taken while on-study will help us decide if Buparlisib is safe and effective.

Detailed description:

Arms:
arm 1: This is an open-label phase II study of the pan-class I selective phosphoinositide 3-kinase (PI3K) inhibitor Buparlisib in patients with metastatic urothelial carcinoma which has progressed despite treatment with prior cytotoxic chemotherapy.

Interventions: intervention 1: Buparlisib
Intervention descriptions: intervention 1: Buparlisib will be administered at a dose of 100 mg orally once daily (two 50 mg capsules) continuously. Intra-patient dose reduction may be required depending on the type and severity of the individual toxicity encountered. Re-staging imaging studies will be performed after every two cycles of treatment (one cycle = 4 weeks). Patients may continue on study as long as they are tolerating therapy and are free of disease progression.

Protocol document:
Prot_SAP_000.pdf: 
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Phase II Study of Buparlisib in Metastatic Transitional Cell Carcinoma of the Urothelium 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal 
Investigator/Department: 
Dean F. Bajorin, MD 
Dept. of Medicine/GU 
Co-Principal 
Investigator(s)/Department: 
Gopa Iyer, MD 
Dept. of Medicine/GU 
Investigator(s)/Department: 
Lewis Kampel, MD 
Jason Koutcher, MD 
Michael Morris, MD 
Robert Motzer MD 
Howard Scher, MD 
Susan Slovin, MD PhD 
David Solit, MD 
Ethan Basch, MD 
Dana Rathkopf, MD 
Ana Molina, MD 
Daniel Danila, MD 
Darren Feldman, MD 
James Hsieh, MD PhD 
Martin Voss, MD 
Jonathan Rosenberg, MD 
Vivek Arora, MD, PhD 
Yu Chen, MD, PhD 
Chris Tully, MD 
Andrew Roth, MD 
Azeez Farooki, MD 
Mario Lacouture, MD 
Hikmat Al-Ahmadie, MD 
Scott Gerst, MD 
William Alago, MD 
Irina Ostrovnaya, PhD 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Psychiatry 
Dept. of Medicine/Endocrinology 
Dept. of Medicine/Dermatology 
Dept. of Pathology 
Dept. of Radiology 
Dept. of Radiology 
Dept. of Biostatistics 
Consenting 
Professional(s)/Department: 
Dean F. Bajorin, MD 
Gopa Iyer, MD 
Lewis Kampel, MD 
Jason Koutcher, MD 
Michael Morris, MD 
Robert Motzer MD 
Howard Scher, MD 
Susan Slovin, MD PhD 
David Solit, MD 
Ethan Basch, MD 
Dana Rathkopf, MD 
Ana Molina, MD 
Daniel Danila, MD 
Darren Feldman, MD 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 
Dept. of Medicine/GU 


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James Hsieh, MD PhD 
Dept. of Medicine/GU 
Vivek Arora, MD, PhD 
Dept. of Medicine/GU 
Yu Chen, MD, PhD 
Dept. of Medicine/GU 
Chris Tully, MD 
Dept. of Medicine/GU 
Martin Voss, MD 
Dept. of Medicine/GU 
Jonathan Rosenberg, MD 
Dept. of Medicine/GU 
 
 
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 


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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 5 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 6 
3.1 
Buparlisib ........................................................................................................................ 6 
3.2 
PI3K Pathway and mechanism of action ......................................................................... 6 
3.3 
Preclinical Studies ........................................................................................................... 7 
3.4 
Clinical experience ........................................................................................................ 11 
3.5 
Background and Rationale in Urothelial Carcinoma ....................................................... 16 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .......................................................... 18 
4.1 
Design .......................................................................................................................... 18 
4.2 
Intervention ................................................................................................................... 19 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ......................................................................... 19 
5.1 Investigational Drug Description ......................................................................................... 19 
5.2 Drug Dispensing/Administration ......................................................................................... 19 
5.3 Storage and Stability.......................................................................................................... 20 
5.4 Source of Drug .................................................................................................................. 20 
5.5 Drug Accountability ............................................................................................................ 20 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY.......................................................................... 20 
6.1 
Subject Inclusion Criteria ............................................................................................... 20 
6.2 
Subject Exclusion Criteria ............................................................................................. 22 
7.0 
RECRUITMENT PLAN ..................................................................................................... 24 
8.0 
PRETREATMENT EVALUATION .................................................................................... 24 
9.0 
TREATMENT/INTERVENTION PLAN .............................................................................. 25 
9.1 
Buparlisib Administration ............................................................................................... 26 
9.2 
Interruption or Discontinuation of Treatment .................................................................. 26 
9.3 
Monitoring of Adverse Events ........................................................................................ 27 
9.4 
Treatment compliance ................................................................................................... 33 
9.5 
Concomitant therapy ..................................................................................................... 33 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................. 35 
11.0 
TOXICITIES/SIDE EFFECTS ........................................................................................... 39 
11.1 Toxicity Monitoring ........................................................................................................... 39 
11.2 
Neuropsychiatric events ................................................................................................ 39 
11.3 Hyperglycemia ................................................................................................................. 41 


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11.4 Cardiac events ................................................................................................................. 41 
11.5 Management of Pneumonitis ........................................................................................... 42 
11.6 Management of Liver Toxicities ........................................................................................ 42 
11.7 Reproductive Risks .......................................................................................................... 43 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT...................... 43 
12.1 Definitions ..................................................................................................................... 44 
12.2 Guidelines for Evaluation of Measurable Disease .......................................................... 44 
12.3 Response Criteria ......................................................................................................... 44 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ..................................................................... 46 
14.0 
BIOSTATISTICS .............................................................................................................. 46 
15.0 
RESEARCH PARTICIPANT REGISTRATION ................................................................ 48 
15.1 
Research Participant Registration ................................................................................. 48 
15.2 
Randomization .............................................................................................................. 48 
16.0 
DATA MANAGEMENT ISSUES ....................................................................................... 48 
16.1 
Quality Assurance ......................................................................................................... 48 
16.2 
Data and Safety Monitoring ........................................................................................... 48 
17.0 
PROTECTION OF HUMAN SUBJECTS .......................................................................... 49 
17.1 
Privacy .......................................................................................................................... 50 
17.2 
Serious Adverse Event (SAE) Reporting ....................................................................... 50 
18.0 
INFORMED CONSENT PROCEDURES .......................................................................... 52 
19.0 
REFERENCES ................................................................................................................. 53 
20.0 
APPENDICES .................................................................................................................. 57 
Appendix A .............................................................................................................................. 57 
Table 5.1 List of prohibited CYP3A inhibitors (strong and moderate) and CYP3A inducers ..57 
Table 5.2 List of CYP450 substrates to be used with caution ............................................... 57 
Table 5.3 List of QT prolonging drugs to be used with caution .............................................. 58 
Table 5.4 Prohibited QT prolonging drugs with risk of Torsades de Pointes ......................... 60 
Appendix B ...................................................................................Error! Bookmark not defined. 
Appendix C...................................................................................Error! Bookmark not defined. 
Appendix D...................................................................................Error! Bookmark not defined. 
Appendix E ...................................................................................Error! Bookmark not defined. 


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1.0     PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is an open-label phase II study of the pan-class I selective phosphoinositide 3-kinase (PI3K) 
inhibitor Buparlisib in patients with metastatic urothelial carcinoma which has progressed despite 
treatment with prior cytotoxic chemotherapy. The purpose of the study design is to evaluate the 
efficacy and safety of Buparlisib in advanced, refractory disease using 2 month progression free 
survival as a primary endpoint. Buparlisib will be administered orally once daily. Intra-patient 
dose reduction may be required depending on the type and severity of individual toxicity 
encountered. Re-staging imaging studies will be performed after every two cycles of treatment 
(one cycle=4 weeks). Patients may continue on study as long as they are tolerating therapy and in 
the absence of disease progression. 
 
 
 
Screening 
Cycle 1 * 
Additional 
Cycles 
Post- 
treatment/ 
Withdrawal 
Day 1 
Day 15 
Day 1 
Clinic Visits 
X 
X 
X 
X 
X 
Buparlisib** 
X→ 
→ 
→ 
Radiological tumor 
response assessment 
X 
Every 2 
cycles 
* 1 cycle=28 days 
** Buparlisib is taken continuously 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
Phase II Cohort 
Primary 
• To measure the progression free survival (PFS) at 2 months for the pan-class I selective 
PI3K inhibitor Buparlisib in patients with metastatic urothelial cancer that has progressed 
on prior cytotoxic chemotherapy. 
 
Secondary 
• To determine the response rate as determined by RECIST v1.1 for Buparlisib in patients 
with progressive metastatic urothelial cancer who have received prior cytotoxic 
chemotherapy 
• To determine overall response rate (ORR) in patients with an activated PI3K pathway 
• To evaluate the safety and toxicity of Buparlisib in patients with progressive metastatic 
urothelial cancer who have received prior cytotoxic chemotherapy 
• To assess markers of activated PI3K pathway (PIK3CA mutations, PTEN mutations, or loss 
of PTEN expression by IHC) in all pretreatment specimens and to correlate with outcome. 


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Expansion Cohort 
 
Primary 
 
• To measure the progression free survival (PFS) at 2 months for the pan-class I selective 
PI3K inhibitor Buparlisib in patients with metastatic urothelial cancer that has progressed 
on prior cytotoxic chemotherapy and harbors genetic alterations predicted to upregulate the 
PI3K/AKT/mTOR signaling pathway. 
 
Secondary 
 
• To determine the response rate as determined by RECIST v1.1 for Buparlisib in patients 
with metastatic urothelial cancer that has progressed on prior cytotoxic chemotherapy and 
harbors genetic alterations predicted to upregulate the PI3K/AKT/mTOR signaling 
pathway. 
• To evaluate the safety and toxicity of Buparlisib in patients with metastatic urothelial cancer 
that has progressed on prior cytotoxic chemotherapy. 
 
 
3.0     BACKGROUND AND RATIONALE 
 
3.1 
Buparlisib 
NVP-Buparlisib (Buparlisib) is an oral pan-class I phosphatidylinositide 3-kinase (PI3K) inhibitor 
belonging to the 2, 6-dimorpholino pyrimidine derivative family. The eight members of the PI3K 
family have been classified into three classes and class I PI3Ks are key players in the PI3K-PDK1- 
Akt pathway that regulates cell proliferation, growth, survival and apoptosis. In many tumors the 
PI3K signaling pathway is constitutively activated. This is thought to be acritical step in mediating 
the transforming potential and growth stimulating activity of various oncogenes (ErbB2, EGFR, 
Ras, Src, etc.) contributing to the onset and growth of solid tumors as well as hematological 
tumors. 
 
 
3.2 
PI3K Pathway and mechanism of action 
PI3K signaling is a hallmark of many cancers. Subsets of cancers become dependent on PI3K 
pathway signaling (“pathway addicted”, Weinstein and Joe (2008)) as a result of mutations of the 
PIK3CA gene itself or of regulators of PI3K (e.g. PTEN, HER2). As a consequence, pathway 
mutated tumors are particularly sensitive to PI3K pathway inhibition. 
 
The superfamily of PI3 kinases is characterized by primary sequence homologies within the 
catalytic domain of these enzymes. Currently, 8 members of this family are known, belonging to 
three classes (I-III). At the structural level, the enzyme PI3K is composed of a 110 kDa catalytic 
subunit and an 85 kDa adaptor subunit. PI3K signaling regulates diverse cellular functions, 
including protein synthesis and glucose metabolism, cell survival and growth, proliferation, 
cellular  resilience  and  repair,  cell  migration,  and  angiogenesis  (Katso,  et  al  2001).  PI3K  is 


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negatively regulated at the level of PIP3 by phospholipid phosphatases, such as the phosphatase 
and tensin homologue PTEN and the inositol 5′ phosphatase-2 SHIP2. In addition, signaling 
through the PI3K pathway is modulated by crosstalk with other signals and pathways, including 
hormones (estrogen, thyroid hormones), vitamins, integrins, intracellular calcium and the Ras- 
dependent MAPK pathway. 
 
Constitutive activation of PI3K signaling is deemed to be a critical step in mediating the 
transforming potential of oncogenes and tumor suppressors, and in many tumors the PI3K pathway 
is constitutively activated. Moreover, preliminary data suggest that activation of the PI3K pathway 
may be a predictor of poor prognostic outcome in many cancers. Several lines of evidence suggest 
that inhibition of the PI3K signaling pathway might provide benefit for the treatment of many 
cancers including solid tumors (breast cancer, prostate cancer, glioblastoma multiforme, colon 
cancer, lung cancer etc.) and tumors of the hematopoetic system (Kim 1994, Ram 1996, Ma 2000, 
Fry 2001, Roymans 2001, Bachman 2004, Broderick 2004, Samuels 2004, Ohgaki 2005, Zeng 
2006). 
The molecular changes leading to constitutive activation of the PI3K pathway are diverse and fall 
into four categories: (1): Gain-of-function mutations of oncogenes encoding positive regulators of 
PI3K (HER2, EGFR, ras, c-src), including oncogenes coding for components of PI3K itself 
(PIK3CA, which encodes for the p110α catalytic subunit, or PIK3R1, the gene coding for the p85 
adaptor subunit) (2): Loss-of function mutations or deletions affecting negative regulators of PI3K 
such as PTEN (Chow 2006, Cully 2006) (3): Mutations of genes encoding downstream effectors of 
the PI3K signaling cascade (e.g. PDK1, AKT/PKB, RPS6KB1) (4): Mutation of the tumor 
suppressor p53 (i.e. that regulates PI3K signaling through repression of PIK3CA). 
3.3 
Preclinical Studies 
 
Buparlisib activity against class I PI3K (p110α, -β, -δ and -γ), Class III (Vps34), the class IV 
related PI3K mTOR, or PI4Kβ was assessed using either a luciferase luminescence (class I or III 
PI3Ks and PI4Kβ) or a TR-FRET assay (Class IV mTOR). The IC50 in these assays is outlined 
below in Figure 1-1: 
Figure 1-1      Inhibitory activities (IC50) of Buparlisib against other PI3K or related kinases 
 
 
Buparlisib significantly inhibits p110α and the most common p110α mutations (H1047R, E545K, 
and E542K), p110β, p110δ and p110γ but not the related proteins Vps34, mTOR or PI4Kβ. Hence 
Buparlisib is classified as a pure pan-class I PI3K inhibitor. Enzymatic characterization of the 
inhibitory properties of the compound revealed that Buparlisib is a mixed inhibitor of PI3Kα with 
a strong competitive component (largest on Vmax). The cocrystal X-ray structure of Buparlisib 


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with PI3Kγ confirmed that Buparlisib interacts with PI3K in the ATP catalytic cleft. 
 
The PI3K pathway regulates the activity of the mTORC1 complex, when cells are challenged 
through mitogenic stimuli. In order to assess in cells the potential impact of Buparlisib on the 
mTORC1 complex, the compound was tested in TSC1 null cells. These cells express a 
constitutively activated mTORC1 complex that uncouples the mTOR pathway from PI3K 
upstream input (Kwiatkowski 2003). When exposed to TSC1 null mouse embryonic fibroblasts 
(MEFs), Buparlisib reduced the S235/236P-RPS6 levels with an IC50 of 1785 nM, in agreement 
with the data obtained in the mTOR biochemical assay. In contrast, and as expected, the allosteric 
mTORC1 inhibitor RAD001 displayed sub-nanomolar inhibitory activity in this assay. 
 
In contrast to molecules with distinct mechanisms of action (BCR-Abl inhibitor STI571, mTORC1 
allosteric inhibitor RAD001), Buparlisib is able to decrease the phosphorylation status of various 
either direct (GSK3β, FKHRL1/FOXO3a) or indirect downstream Akt effectors (p70S6K, through 
mTOR) in the PTEN null U87MG cell line as efficiently as prototypical PI3K inhibitors such as 
LY294002 and Wortmannin. 
 
Forkhead transcription factors (such as FKHRL1) are re-located from the nucleus to the cytosol 
upon phosphorylation by Akt. Treatment of U2OS cells stably expressing GFP-FKHRL1 chimera 
with Buparlisib produced a strong nuclear localization of the fluorescence signal, in agreement 
with the reduction of the phosphorylated FKHRL1 levels. Signaling pathways from membrane 
receptors to nuclear transcription factors involve many different players such as kinases or 
molecular adaptors. To test whether Buparlisib does influence other signaling molecules outside of 
the PI3K pathway, induction of various pathways (mitogenic with EGF and PDGF, stress 
pathways with anisomycin, and interleukin pathways with IL-4) were interrogated in the presence 
of the compound. In all cases, Buparlisib showed specific PI3K pathway attenuation as 
demonstrated by specific attenuation of S473P-Akt levels, without affecting the non-PI3K driven 
readouts such as activated receptors (EGFR, PDGFR), MAPK kinases (ERK, JNK and p38) or Jak 
cytosolic tyrosine kinases responsible for Stat transcription factor phosphorylation. 
 
3.3.1 
Preclinical Safety 
Safety pharmacology studies in rats revealed no effects on neuronal (behavior) or respiratory 
functions. Cardiac safety studies, conducted in vitro and in vivo, did not indicate a prominent 
electrophysiological risk. In the isolated rabbit heart, effects pointing towards a shortened 
repolarization were seen only at 10 μM. Buparlisib inhibited hERG channel activity significantly 
at concentrations ≥ 100 μM (IC50: 190 μM). The only effect considered relevant was a trend 
towards an increase in systolic and diastolic blood pressure, observed in two dog telemetry studies, 
in the absence of an electrophysiologic effect. 
 
Repeated dose studies of up to 4 weeks of duration were performed in rats and dogs. In rats, 
clinical pathologic changes as well as histopathologic findings were identified the lymphatic 
system. Findings included decreases in lymphocyte counts in the peripheral blood, decreases in 
germinal center development in different lymph nodes, and lymphocytolysis in the thymus. In 
dogs, similar findings were made. In both species, erythropoiesis was affected, as evidenced by 
reduced erythrocyte counts, accompanied by bone marrow depression observed in rats. The 
pancreas was affected by treatment with Buparlisib, particularly in dogs, where acinar cell toxicity 
was seen in the exocrine pancreas. In addition, in one of the four recovery animals minimal acinar 
cell atrophy was observed after a four week treatment-free period. In rats, in the 4-week study, no 
pancreatic toxicity was observed (however, in the 2-week dose range-finding study, at higher 


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doses, there were histopathologic findings of the endocrine as well as the exocrine pancreas). 
Insulin/glucose homeostasis was impacted in various species (mice, rats, dogs), as expected from 
the mode of action of Buparlisib. However, in both rats and dogs, at the doses used in the 4-week 
studies, these effects were minimal. 
 
In mice treated at high doses (30 or 60 mg/kg/day), a clear induction of insulin 
resistance/insensitivity was observed, without clear influence of the dose or the time point of 
testing. Histopathologically, the pancreas and the liver showed changes which are in concordance 
with this activity. 
 
After up to 2 weeks of treatment with doses of 0.5 or 2.5 mg/kg/day, dose- and time-dependent 
fluctuations of neurotransmitters were observed in brain tissue but not in plasma or cerebrospinal 
fluid. However, in two follow-up studies, where effects of an analogue compound lacking tubulin 
interaction, or the effect fo brain sampling times were investigated, this effect was not confirmed 
under comparable buparlisib treatment conditions. Given the disparate results between studies, the 
effects of buparlisib on glutamate, glutamine, GABA, serotonin, 5HIAA, dopamine, or 
epinephrine in total brain, plasma, or cerebrospinal fluid of female rats is considered to  be 
uncertain at this time and will require further investigation. Both in vitro and in vivo, Buparlisib 
elicited a genotoxic potential. While no evidence for a direct DNA interaction was found in an 
Ames test and two chromosome aberration tests in vitro, a potential for genotoxicity was 
concluded based on the observation of an aneugenic potential, seen in this latter experiment. In 
line with this result, Buparlisib treatment resulted in an elevated frequency of micronucleated 
polychromatic erythrocytes in the bone marrow of rats. 
Male reproductive organs and associated tissues were found to be targets of toxicity in both rats 
and dogs. Changes included minimal to slight germ cell depletion, formation of spermatic giant 
cells and abnormal spermatids, and cellular debris in epididymal tubules. Testicular toxicity did 
not fully reverse after the 4-week treatment-free period in rats although a clear trend towards 
recovery was seen. In individual female rats, minimal to slight cyst formation occurred in the 
Graafian follicles; in addition, an increased incidence of diestrus stage of the estrous cycle was 
seen. In dogs, there was no effect on female reproductive organs. 
 
Data indicate the absence of a relevant potential for phototoxicity with Buparlisib. 
 
In conclusion, the majority of the observed effects were related to the pharmacological activity of 
Buparlisib as an inhibitor of PI3K, such as a potential influence on glucose/insulin homeostasis 
and the risk of increased blood pressure. Main target organs of toxic effects were bone marrow and 
lymphoid tissue, pancreas, and male as well as to a lesser extent, female reproductive organs. 
Furthermore, neurotransmitter fluctuations were seen in the brains of rats, not visible in plasma or 
cerebrospinal fluid. 
 
Please refer to the [Investigator’s Brochure] for additional information on the preclinical testing of 
Buparlisib. 
 
3.3.2 
Pharmacodynamics 
 
Buparlisib inhibits wild-type PI3Kα (IC50: 35 nM), with at least 50-fold selectivity toward protein 
kinases. The compound is equipotent against somatic PI3Kα mutations (H1047R-, E542K- and 
E545K-p110α) and is active against the other three PI3K paralogs (PI3Kβ, -γ, -δ; 108 to 348 nM 


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range). Buparlisib does not significantly inhibit the related kinases mTOR and Vps34, nor does it 
inhibit other receptors and ion channels profiled (IC50 >10 μM). 
 
Buparlisib reduces the phosphorylation of the direct downstream effector Akt in mechanistic and 
relevant tumor cell lines (IC50: 93 nM for S473P-Akt in Rat1-p110α cells). This biological 
activity correlates with inhibition of various Akt downstream signaling pathway components, and 
with its anti-proliferative activity against a variety of tumor cell lines. Our data suggest that 
response to Buparlisib in breast cancer cell lines is associated with HER amplification and/or 
PIK3CA mutation. The role of PTEN loss-of-function as a predictor of response seems to be less 
clear. 
 
Buparlisib demonstrated significant tumor growth inhibition in tumor xenografts of a variety of 
cancer types in mice and rats, including several models of breast cancer. In particular, Buparlisib 
showed high anti-tumor activity and synergism when combined with trastuzumab in the Her2- 
amplified breast cancer model BT474 (as well as in the Her2-amplified gastric model NCI-N87). 
In vivo PK/PD analyses of tumor tissues showed a good correlation between exposure, PI3K 
pathway blockade (S473P-Akt levels) and anti-tumor activity. 
 
 
3.3.3 Preclinical Pharmacology, Pharmacokinetics and Metabolism 
 
Buparlisib was rapidly absorbed with a good oral bioavailability in all animal species tested. 
 
The compound has a moderate plasma CL and Vss. Buparlisib is moderately bound to plasma 
proteins across all species examined and widely distributed to most tissues in the rat. Drug related 
radioactivity enters the brain and testes, and has an affinity to melanin containing tissues. No 
unique, major phase I metabolites were identified in human hepatocytes. Buparlisib and 
metabolites have a low potential for covalent binding to protein. Buparlisib is neither a substrate 
for nor an inhibitor of P-glycoprotein (MDR-1) or Multidrug Resistance Related Protein, MRP2. 
The compound is also not an inhibitor of Breast Cancer Resistance Protein (BCRP). 
 
With respect to potential drug-drug interactions, at 100 mg qd Buparlisib is a weak reversible 
inhibitor of CYP3A4 (Ki 13.6 µM, I/Ki < 1). Buparlisib also weakly inhibited the CYP2C family 
(2C8, 2C9 and 2C19) with IC50 values ranging from 35-65 µM (34-59 µM unbound). Buparlisib 
shows no apparent time-dependent inhibition of CYP1A2, CYP2C9, CYP2D6 or CYP3A4/5. 
Hepatic oxidative metabolism of Buparlisib was found to be predominantly mediated by CYP3A4 
(>80%), with only minor contributions of CYP1A1. Hence, Buparlisib is a sensitive CYP3A4 
substrate and there is potential for drug-drug interactions with co-medications that are inhibitors or 
inducers of CYP3A4. Direct glucuronidation via UGT1A4 is implied as well in buparlisib 
metabolism but until now its contribution was not quantified in vitro. However, direct 
glucuronides (CNP320) were observed in urine in the hADME trial up to 10%. 
 
Based on the anticipated large contribution of CYP3A4 in the metabolism of buparlisib, a drug- 
drug interaction trial was conducted with ritonavir (strong mechanism-based inhibitor) to evaluate 
the impact of ritonavir on a single 30 mg oral dose of buparlisib (CBKM120C2111). The co- 
administration of 100 mg bid ritonavir resulted in a 73% increase on geometric mean values of 
AUCinf and a 19% increase on geometric-mean ratio of the Cmax after a single 30 mg dose of 
buparlisib. There was no significant change in the time to reach maximum concentration. The 
mean elimination half-life of buparlisib increased from 53.3 hours to 71.6 hours and its mean 


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apparent clearance decreased from 5.37 L/h to 3.27 L/h as a consequence of the effect of ritonavir 
on CYP3A4 enzyme. These outcomes showed that ritonavir had a limited effect on the maximum 
concentration and caused only a mild increase in the exposure of buparlisib. When translating the 
results of the study to clinical practice, these data could support a less restrictive approach in the 
concomitant use of moderate CYP3A4 inhibitors with buparlisib. 
 
An additional study was conducted testing the impact of repeat dose of 4 mg daily dexamethasone 
on the pharmacokinetics of buparlisib. The study was conducted to assess the potential induction 
impact of dexamethasone at high dose on CYP3A4 and consequently on buparlisib exposure. 
Overall, buparlisib PK is marginally impacted by repeated dose of 4 mg daily dexamethasone. The 
gMean ratio for Cmax and AUC were respectively 1.09 and 0.90. This observation is very likely 
explained by the limited induction capabilities of a 4 mg dose of dexamethasone on CYP3A4. A 
single 50 mg oral dose of buparlisib (D1 and 8) along with dexamethasone 4 mg daily orally for 11 
days (followed by 4 tapering days) was generally safe and well-tolerated in healthy volunteers. 
 
It is possible that Buparlisib may activate PXR in vivo and induce CYP3A4 at concentrations ≥ 50 
μM; however, the absence of time-dependent changes in pharmacokinetics of buparlisib in the 
relevant therapeutic dose range in humans suggests that this may not be relevant in vivo. Finally, 
experiments show a potential for buparlisib to induce UGT1A1 at concentrations between 0.5 and 
100 uM. The mean maximum free concentration calculated at steady state for the 100 mg qd dose 
in the study [CBKM120X2101] was 0.671 uM (Cmax, tot=4.20 uM). Therefore a potential 
induction of UGT1A1 cannot be formally excluded; however, the clinical relevance of observed 
activation of UGT1A1 activity is unclear. 
 
 
3.4 
Clinical experience 
3.4.1 
Buparlisib Pharmacokinetics and pharmacodynamics 
Pharmacokinetic data observed so far showed that Buparlisib is rapidly absorbed after oral 
administration with mean peak plasma concentrations (Cmax) ranging between 0.5 to 4 h post dose 
(tmax). The median tmax at the MTD dose (100 mg daily) was about 1 hour. After reaching Cmax, 
Buparlisib plasma concentrations decreased in a bi-exponential manner. Apparent total body 
clearance from plasma (CL/F) was low at ~5.0 L/h, indicating that Buparlisib is a low clearance 
drug. Buparlisib accumulated ~3-fold in achieving steady-state, consistent with an effective half- 
life of ~40 h. Steady-state can be expected to be reached after approximately 7-10 days of daily 
dosing in most patients. Approximate dose-proportional increase in Cmax and AUC was found in 
the dose range of 12.5-150 mg. Intersubject variability in Cmax and AUC differed at each dose level 
but was relatively low and generally around 40%. Doses of 50 mg/day and above led to steady- 
state drug exposure (AUC0-24) > 10,000 ng*h/mL, a target efficacious exposure level estimated 
preclinically. 
 
Due to the difficulty of obtaining fresh tumor tissue during treatment, pharmacodynamic 
measurements were limited to surrogate tissues such as skin and blood. The parameters assessed 
have been selected for their relevance to PI3K/mTOR signaling modulation: phosphorylated S6 
ribosomal protein in the skin (S6 is a well-known downstream target of the PI3K/mTOR pathway) 
and C-peptide and glucose levels in the blood (PI3K/mTOR signaling has a critical role in glucose 
metabolism). A formal analysis of these assessments is currently ongoing. Consistent suppression 
of S6 activation in skin was evident at the highest doses tested (100 and 150mg/day) with 30 to 
80% decrease from baseline levels. Occasional increases in C-peptide have been seen at all doses, 
while hyperglycemia was one of the DLTs, suggesting potential impairment of glucose transport 


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and utilization by the tissues (insulin resistance). Hyperglycemia is considered an “on target” 
effect of buparlisib and has been commonly observed in patients treated with buparlisib with an 
incidence ranged between 17.6% and 58.3%. The highest rate of hyperglycemia has been observed in 
trials conducted in patients with controlled diabetes mellitus and in patients with brain metastases. 
More information is provided in the Investigator’s Brochure. 
 
3.4.2 
Clinical experience with Buparlisib 
As of 15 September 2013, approximately 1469 patients and healthy volunteers have been enrolled into 
twenty-two Novartis sponsored clinical studies of buparlisib, including 3 blinded phase II and III 
studies: 
 
Phase I single agent studies [CBKM120X2101], [CBKM120X1101], [CBKM120Z2102], 
[CBKM120C2110], 
[CBKM120C2104], 
[CBKM120C2106], 
[CBKM120C2111], 
and 
[CBKM120C2101]. 
 
Phase II single agent studies [CBKM120C2201] and [CBKM120D2201] 
 
Phase I combination studies [CBKM120B2101], [CBKM120X2107], [CBKM120E2101], 
[CBEZ235A2118], [CLDE225X2114], [CSTI571X2101], [CMEK162X2101], [CINC424A2104], and 
[CBEZ235D2101]. 
 
Phase II combination study [CBKM120F2202] 
 
Phase III combination studies [CBKM120F2302], [CBKM120F2303] 
 
Among these 1469 patients and healthy volunteers, 781 have received at least one dose of buparlisib 
treatment, as single agent in 254 patients and 95 subjects in pharmacology studies and in combination 
in 432 patients. Also, 688 patients are enrolled in ongoing blinded phase III studies. The 5 remaining 
patients were enrolled but did not receive a dose of buparlisib at the time of the cut-off (1 patient in 
[CBKM120E2101] study and 4 patients in [CBKM120X2107] study). 
 
In pharmacology studies, 95 subjects have been enrolled including 77 healthy volunteers who received 
one/two doses buparlisib as single agent or in combination. Forty-six out of 77 healthy volunteers were 
enrolled in three completed studies: four healthy volunteers received one 100 mg dose in 
[CBKM120C2102], 27 healthy volunteers received two single doses of 50 mg in [CBKM120C2106] 
and 15 healthy volunteers received two single doses of 30 mg [CBKM120C2111]. Also, 18 hepatically 
impaired subjects and 13 healthy volunteers received a single 30 mg dose of buparlisib in the 
[CBKM120C2104] study. Eighteen healthy volunteers received three single doses of 50 mg buparlisib 
with three different formulations in [CBKM120C2110] a relative bioavailability study. 
 
As of 15 September 2013, six clinical studies have completed recruitment. 
Single Agent 
In Phase I single agent trials, a total of eleven dose limiting toxicities (DLTs) were observed, nine in 
CBKM120X2101 in Caucasian population study, one in CBKM120X1101 in Japanese population 
study and one in CBKM120Z21101 in Chinese population study. The maximum tolerated dose (MTD) 
was determined to be 100 mg/day buparlisib in Caucasian, Japanese, and Chinese patient population. 
The recommended phase II dose (RP2D) was confirmed at 100 mg daily for Caucasian and for 


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Japanese population and is under evaluation in Chinese population. 
 
Moreover, buparlisib single agent at 100 mg daily has been explored in 2 open-label phase II studies 
conducted in patients with advanced endometrial carcinoma (CBKM120C2201) and squamous cell 
advanced NSCLC (CBKM120D2201). The limited anti-tumor activity observed has been considered as 
insufficient to warrant further investigation as single agent in these two indications. 
 
The pharmacokinetic data reveals that buparlisib single agent is rapidly absorbed after oral 
administration with a median time to reach maximum concentration (Tmax) between 0.5 and 3 hours at 
steady-state. The variability in exposure and maximum plasma concentration (Cmax) at steady-state 
for the maximum tolerated dose (MTD) of 100 mg qd is moderate: 33% and 28% respectively. 
Buparlisib accumulated in a linear fashion (~3-fold) and reached steady-state after 8 days of treatment. 
At steady-state the median accumulation half-life was esteimated between 35.7 hours and 58.5 hours, 
calculated based on an accumulation ratio between 3 and 4-fold. 
 
Combinations 
 
Buparlisib is currently tested in several combinations together with trastuzumab (CBKM120X2107) 
and paclitaxel alone, with paclitaxel and trastuzumab (CBEZ235A2118) with the MEK inhibitor 
GSK1120212 in the CBKM120B2101 trial with temozolomide and radiotherapy (BKM120E2101) 
study, with abiraterone in BEZ235D2101 study, LDE2225 in LDE225X2114 study, with STI571 in 
CSTI571X2101 study, with MEK162 in CMEK162X2101 study, with INC424 in CINC424A2104 
study. 
 
Currently three phase III trials are running in patients with metastatic breast cancer with buparlisib at 
100 mg daily in combination with fulvestrant or paclitaxel. 
 
For both doses, the predicted Cmax remained lower than the ones observed with 100 mg daily. 
 
These observed decreases in exposure are currently under investigation. They are thought to be due to 
a combination of formulation factors and the co-administration of anti-acid treatment which might 
decrease the bioavailability of buparlisib by increasing the gastric pH. This hypothesis will be further 
explored in the CBKM120F2202 trial and a specific CP trial is currently being designed to investigate 
the impact of the proton pump inhibitors. 
 
In Phase I combination trials, one DLT was observed in CBKM120X2107 and the MTD and 
recommended phase II dose (RP2D) was determined as 100 mg/day of buparlisib in combination with 
weekly trastuzumab. 
 
In CBKM120B2101 trial, 22 DLTs were observed in 19 patients (buparlisib combined with 
GSK1120121). The MTD was defined at 70 mg/day in combination with 1.5 mg/day of GSK1120212, 
and the RP2D was defined at 60 mg/day in combination with 1.5 mg/day of GSK1120212. 
 
Eight DLTs were observed in six patients in the dual combination treatment arms in the BEZ235A2118 
study, and the MTD was defined at 100 mg/day in combination with weekly paclitaxel 80 mg/m2 for 
cycles of 28 days. Four DLTs were observed in seven patients in the triple combination 
(paclitaxel/trastuzumab/BKM120) treatment arms in the BEZ235A2118 study, and the MTD has not 
yet been determined. Two DLTs were reported in patients treated with temozolomide (TMZ) and 


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buparlisib and the dose of buparlisib of 80 gm daily has been selected to be administered with TMZ at 
150 mg/m2 and 200 mg/m2 day1-5 every 28 days. In addition, 5 DLTs were reported in patients 
treated with TMZ concomitantly with radiotherapy and buparlisib in CBKM120E2101 study and the 
MTD has not yet been defined. In CBEZ236D2101 study, one DLT has been reported in one patient 
treated with abiraterone and buparlisib at 100 mg. When combined with trastuzumab alone, no change 
in the pharmacokinetics of either entity was observed. 
 
When combined with paclitaxel alone exposures at the MTD appeared to be lower than the ones 
observed in the first in human trial CBKM120X2101 by around 25%. Cmax was decreased as well by 
around 50%. The exposures were partially restored in the triple combination with trastuzumab even 
though the Cmax remained low. 
 
In GSK1120212 trial, the recommended dose for the MTD established at 70 mg and the recommended 
dose at 60 mg with 1.5 mg GSK1120212. The predicted exposure for the 100 mg dose, based on the 60 
mg dose exposure was 29% lower than the ones observed at 100 mg daily in the first in man trial when 
they would be comparable for the 70 mg daily dose. For both doses, the predicted Cmax remained 
lower than the ones observed with 100 mg daily. As of 15-Sep-13, there were eleven cases (twenty-two 
events) with a fatal outcome reported with a suspected relationship with buparlisib. 
 
 
 
In the single agent CBKM120Z2102 study, 1 DLT consisting of grade 3 depression was noted at 80 
mg/day. In CBKM120B210 combination therapy with GSK1120212, 22 DLTs were noted in 18 
patients including grade 3 stomatitis (1) and grade 3 pneumonitis (1). 
 
Study [CBuparlisibX2101] is a phase I first-in-man dose escalation study of single-agent oral 
Buparlisib in patients with advanced solid tumors. This study has been completed. 83 patients had been 
enrolled and treated with at least one dose of Buparlisib. The MTD and RP2D of single-agent oral 
Buparlisib was defined at 100 mg/day. The median age was 56 (30–78) years, the male/female ratio 
was 33/50 patients, and the distribution of ECOG performance status of 0/1/2 at baseline was 36/46/1 
patients, respectively. As of 12 Nov 12, all patients were discontinued from the study treatment. 
Reasons for discontinuation were disease progression (65.1% of total enrolled), adverse event (24.1%), 
withdrawal of consent (4.8%), death (4.8%), and protocol deviation (1.2%). The median duration of 
exposure to study treatment was 7.3 weeks overall. The median duration of exposure to study treatment 
at the MTD/RP2D arm was 7.6 weeks. 
 
All patients experienced at least one AE. The most frequent AEs (≥10%), regardless of grade, causality 
and Buparlisib dose, were nausea (45.8%); decreased appetite (42.2%); asthenia (37.3%); diarrhea 
(36.1%);  hyperglycemia  (33.7%),  rash  (32.5%);  constipation  (30.1%);  fatigue  (28.9%);  vomiting 
(26.5%); stomatitis (25.3%); abdominal pain (22.9%); pruritus (20.5%); anxiety (19.3%); depression or 
pyrexia (16.9% each); dry skin, dyspepsia, or somnolence (15.7% each); mood altered (14.5%); AST 
increased, dizziness, dyspnea, or transaminases increased (13.3% each); back pain, insomnia, or 
performance status decreased (12.0% each); and ALT increased, arthralgia, cough, or edema peripheral 
(10.8% each). 
 
The most common CTCAE grade 3 or 4 AEs (>2%), regardless of causality and Buparlisib dose, were 
asthenia (12.0%); performance status decreased (9.6%); transaminases increased or hyperglycemia 
(8.4% each); rash (7.2%); hyperbilirubinaemia or AST increased (4.8% each); ALT increased, 
abdominal pain, fatigue, pneumonia, or diarrhea (3.6% each); and affective disorder, anxiety, mood 
altered, glucose tolerance test abnormal, arthralgia, dyspnea, pruritus, or intestinal obstruction (2.4% 


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each). CTCAE grade 3 or 4 AEs were experienced by 57 (68.7%) patients, and 33 (39.8%) patients 
experienced at least one CTCAE grade 3 or 4 AE suspected to be study drug related. 
BuparlisibBuparlisibBuparlisibBuparlisibBuparlisibBuparlisibBuparlisib 
Study CBKM120D2201 is a phase II open label two-stage study of orally administered buparlisib in 
patients with non-small cell lung cancer with activated PI3K pathway. As of 15-Sept-2013, 62 patients 
have been enrolled and treated with at least one buparlisib dose. The median age of the 62 patients was 
64.5 years (range: 39-78), the male/female ratio was 40/22 patients, and the distribution of ECOG 
performance status of 0/1/2 at baseline was 18/41/3 patients, respectively. As of 15-Sept-2013, 60 
patients were discontinued from the study and 2 patients were still ongoing. Reasons for 
discontinuation were progressive disease (50% of total enrolled), adverse event (27.4%), 
subject/guardian decision (11.3%), physician decision (3.2%), and death (4.8%). The median duration 
of exposure to study treatment was 6.9 weeks. 
 
All patients experienced at least one AE. The most frequent AEs (>10%), regardless of grade, causality 
and buparlisib dose, were decreased appetite and diarrhea (35.5% each); asthenia and nausea (32.3% 
each); hyperglycemia (30.6%); fatigue (25.8%); rash (24.2%); depression and pruritus (21% each); 
dyspnea (19.4%); alanine aminotransferase increased, anxiety, cough, and weight decreased (17.7% 
each); aspartate aminotransferase increased and vomiting (16.1% each); dry skin (14.5%); anemia, 
constipation, and dysgeusia (12.9% each). 
 
The most common CTCAE grade 3 or 4 AEs (>2%), regardless of causality and buparlisib dose were 
hyperglycemia (16.1%); asthenia (11.3%); dyspnea, aspartate aminotransferase increased, alanine 
aminotransferase increased and fatigue (8.1%); pneumonia (6.5%); hyponatremia, depression, and 
respiratory failure (4.8%); mood altered, anemia, nausea, dehydration, hemoptysis, rash, macular rash, 
lower respiratory tract infection, and sepsis (3.2% each). CTCAE grade 3 or 4 AEs were experienced 
by 45 (72.6%) patients, and 32 (51.6%) patients experienced at least one CTCAE grade 3 or 4 AE 
suspected to be study drug related. 
 
 
 
There is evidence indicating that the modulation of  AKT/GSK3 signaling pathway may play an 
important role in the behavior regulation. Psychiatric side effects events have been reported in patients 
treated with buparlisib and are still under investigation. The current data do not allow the identification 
of any sign or symptom which could predict patient susceptibility to buparlisib induced psychiatric 
disorders. 
 
At least one AE (regardless of study drug relationship) belonging to SOC “psychiatric disorders,” 
which include a broad range of AEs such as depression, anxiety, mood altered, confusional state, 
affective disorders, insomnia, hallucination, panic disorders, has been reported in approximately 17.6% 
to 66.7% of patients treated with buparlisib. Overall the incidence of grade 3 and 4 psychiatric events 
ranged from 0 to 13.2%. 
 
No AE corresponding to mood disorder criteria was reported for 11 patients treated with buparlisib, 
paclitaxel, and trastuzumab in CBEZ23A2118 study. The frequency of mood disorders thus defined, 
regardless of study drug relationship, ranged from 0% to 44.4%. 
 
As of 15 Sep 13, approximately 1465 subjects, alone in Novartis sponsored trials, have been exposed 
to buparlisib, mostly patients with advanced solid tumors, in single-agent and combination studies. The 
majority fo the reported adverse events (regardless of study drug relationship) were mild or moderate 
(Grade 1-2) and reversible. Although no formal pooled analysis of all AEs from all clinical trials has 
been conducted to date, AEs can be described in approximate frequency categories based on review of 
data currently available from completed and ongoing trials.   Most frequent events in single agent 


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studies (occurring in >20% of patients) include, but may not be limited to: nausea, vomiting, diarrhea, 
decreased appetite, hyperglycemia, abdominal pain, constipation, asthenia, fatigue, macular-papular 
rash with or without pruritus, mucosal inflammation including stomatitis, increase in liver 
transaminases, anxiety and depression. Other frequent events (about 10% of patients) include: anemia, 
altered mood, confusion, dizziness, headache, insomnia, dry skin, back pain, arthralgia, cough, 
peripheral edema, dyspepsia, fever, hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, 
eosinophilia, increase in blood alkaline phosphatase, lipase increase, dysgeusia, and dyspnea. Less 
common events (less than 5% of patients) that may nevertheless be medically important include: skin 
infection, hypersensitivity and allergic reactions, eye effects (such as blurred vision, conjunctivitis), 
respiratory tract infections, pneumonitis, drug rash with eosinophilia and systemic symptoms 
(DRESS), renal impairment, leukopenia, sepsis, bleeding including epistaxis,  psychotic  disorders, 
visual hallucinations, seizures, peripheral neuropathy, hyper or hypotension, arrhythmia, cataract, 
photosensitivity reactions, activated PTT prolongation, hepatitis, colitis, and encephalitis. One case of 
suicide was reported in a patient with advanced lung cancer. Three cases of posterior reversible 
encephalopathy syndrome (PRES) were reported in patients taking buparlisib in clinical trials. With 
regards to PRES, patients experiencing severe headache, change in behavior, or reason to believe their 
blood pressure has increased should inform investigators immediately. The written patient information 
contains this information. 
 
As of 15 Sep 13, there were twenty-two events (in eleven cases) with a suspected relationship with 
buparlisib and with a fatal outcome.  See IB for details. 
Please refer to the Investigator’s Brochure for additional information on the available clinical 
experience with Buparlisib. 
 
 
3.5 
Background and Rationale in Urothelial Carcinoma 
 
3.5.1 
Urothelial Carcinoma 
 
Bladder cancer is the fourth most common malignancy in men and the ninth most common in 
women with an estimated 14,000 disease-related deaths in 2009. Early stage disease can be 
managed with local therapies, including cystoscopic resection and intravesical therapy, while 
muscle invasive disease is treated with radical cystectomy and perioperative chemotherapy with 
curative intent.  Most patients with metastatic disease are not cured with current therapies and have 
a median survival of 14 months. Furthermore, no FDA-approved second-line treatment exists after 
first-line platinum-based chemotherapy, with conventional cytotoxic therapy resulting in a median 
progression-free survival of 2-3 months and a median survival of 6-9 months (Gallagher 2008). 
The dismal prognosis observed in patients with advanced or progressive disease in the setting of 
traditional cytotoxic therapies underscores the need for novel agents in the treatment of metastatic 
urothelial cancer. 
 
 
3.5.2 
Rationale for BKM-120 in Urothelial Carcinoma 
 
The PI3K-Akt signal transduction pathway is known to be aberrantly activated in a number of 
solid tumor malignancies, and a wide spectrum of mutations within multiple members of this 
pathway have been observed in bladder cancer (Knowles 2010). In select series, mutations of 
PIK3CA, the gene encoding for the catalytic subunit of PI3K, have been detected in up to 25% of 
urothelial carcinoma samples (Platt 2009). Deletions and mutations of PTEN, a phosphatase 
protein which negatively regulates the activation of PI3K, are also documented to occur in a 
significant number of cases (Platt 2009).  Akt itself can possess activating mutations, leading to 


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upregulation of multiple downstream proteins involved in cell cycle progression and inhibition of 
apoptosis (Askham 2010). Other downstream alterations lead to erroneous pathway stimulation, 
including mutational inactivation of TSC-1, which results in constitutive activation of the mTOR 
pathway (Platt 2009). Furthermore, amplification of pathway stimulating molecules and deletion 
of inhibitory proteins are alternative mechanisms of pathway activation which are also observed. 
Mutations of upstream receptor tyrosine kinases, such as FGFR3, are known to occur in up to 70% 
of superficial bladder cancers and approximately 20% of invasive, high grade disease (Kompier 
2009). The plenitude of aberrations of the PI3K-Akt pathway speaks to the significant role that 
this pathway plays in bladder cancer development and progression as well as to the potential for 
deriving clinical efficacy from inhibition of pathway mediators. At Memorial Sloan-Kettering 
Cancer Center (MSKCC), we have sequenced 137 high-grade bladder cancers for mutations within 
PIK3CA (Iyer 2010). Seventeen (12%) samples were found to possess point mutations. Other 
sequenced genes included TP53, HRAS, and BRAF, none of which contained as high a frequency 
of alterations. Mutations within the tyrosine kinase receptor gene FGFR3 were detected in 16 
(12%) samples with three samples containing both PIK3CA and FGFR3 mutations. These results 
demonstrate that mutations within the PIK3CA gene as well as PI3K pathway stimulating 
molecules such as FGFR3 represent a significant proportion of the alterations in this set of high- 
grade bladder tumors and that inhibitors of this pathway may have a clinical impact in patients 
with urothelial carcinoma. 
3.5.3 
Rationale for the Study Population 
 
The first-line treatment of patients with metastatic urothelial carcinoma varies and may involve a 
cisplatin- or carboplatin-based doublet or triplet, the four drug MVAC regimen, or a sequential 
doublet regimen. Furthermore, many patients with metastatic disease have previously received 
cytotoxic chemotherapy in the perioperative setting. Given this heterogeneity in prior exposure to 
chemotherapy, the definition of “second-line” or “third-line” chemotherapy has not been well 
characterized. As a result, we have designed the eligibility for this protocol based on the number of 
prior chemotherapeutic agents patients have received rather than the number of “lines” of therapy 
that have been administered. Second-line chemotherapy trials have typically included patients who 
have received either 1 or ≥ 1 prior regimen(s). Clinical trials at MSKCC have included a maximum 
of 4 prior drugs because patients are treated with multiple agents in the community before referral. 
There are no available data demonstrating that the response proportion in the relapsed setting is 
linked to the number of prior regimens; for example, sunitinib was identified as an active agent in 
an MSKCC phase II trial of patients with metastatic urothelial cancer who have received a 
maximum of 4 prior drugs (Gallagher 2010). This prior treatment inclusion criterion will serve to 
enhance accrual and likely ultimately provide a more homogenous patient population (e.g., most 
patients will have been exposed to a platinum agent, gemcitabine, and a taxane at some point in 
their treatment history). Furthermore, we do not anticipate the response to this targeted agent to be 
closely linked to the number of prior cytotoxic agents administered. If Buparlisib demonstrates 
activity in this second-line trial, future trials will include an evaluation of the combination of 
Buparlisib with chemotherapy in the first- and second-line settings. 
 
3.5.4 
Rationale for a PFS Endpoint 
 
Pertinent to discovering new drugs active in urothelial cancers is the concept that identifying 
clinical benefit should not be limited to response. Some of the newer "targeted therapy" agents 
approved by the FDA have been approved on the basis of improved progression-free survival 
(PFS) and not response rate (e.g., sorafenib in  renal  cell carcinoma  with  a response rate of 


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approximately 10% but a major impact in PFS and, eventually, an improvement in survival). This 
being said, the median progression-free survival for bladder cancer patients treated with 
chemotherapy is modest at only 2-3 months and response rates are in the 10-20% range. In a 
second-line trial of weekly paclitaxel in 31 patients with progressive urothelial cancer, the median 
time to progression was 2.2 months. In an ECOG trial evaluating the epothilone analog BMS- 
247550 in patients with relapsed urothelial cancer, the median progression-free survival was 2.7 
months (95% CI, 1.8, 4.1) (Vaughn 2002; Dreicer 2007). In a recently reported phase 3 
randomized second-line trial of vinflunine versus best supportive care, the PFS for patients treated 
with vinflunine was 3.0 months (95% CI, 2.1, 4.0) (Bellmunt 2009). Novel therapies are 
desperately needed for these patients and identifying activity in the refractory setting by using PFS 
is considered an acceptable approach with these new targeted agents. 
 
 
3.5.4 
Rationale for Expansion Cohort 
PI3K/Akt/mTOR pathway alterations have been genetically characterized in a panel of 97 high- 
grade urothelial tumors. Thirty percent of samples harbor alterations predicted to upregulate 
pathway activation within PIK3CA, PTEN, AKT1, or TSC1. Additionally, FGFR3 amplifications 
and hotspot activating mutations were found in 15% of samples, the majority of which were 
mutually exclusive from alterations within other members of the pathway. These results indicate 
that PI3K/Akt/mTOR pathway activation is a common event in UC with the mechanism of 
activation including truncation of tumor suppressors such as TSC1 and PTEN as well as 
amplification and/or mutation of oncogenes such as PIK3CA, FGFR3, and AKT1. Preliminary 
genetic analysis of tumor samples from 13 patients treated in the Phase II portion of this trial is 
underway. The tumor from one patient who achieved a prolonged partial response to Buparlisib 
therapy harbors TSC1 loss while a second patient who experienced primary progression of disease 
after 2 months of treatment was found to have a tumor with loss of TP53 and CDKN1A but no 
PI3K/Akt/mTOR pathway alterations. These data strongly suggests that in order to maximize the 
efficacy of Buparlisib, patients whose tumors contain known activating alterations within the 
PI3K/Akt/mTOR signaling pathway should selectively be enrolled onto study. Based upon the 
genetic data from the Phase II cohort, e an expansion cohort has been created which comprises 
selective enrollment of patients with tumors harbor activating PI3K/Akt/mTOR pathway 
alterations. Routine prospective genetic screening of patients with both locally advanced and 
metastatic urothelial carcinoma is currently being performed in all bladder-specific medical 
oncology clinics at MSKCC. Patients are enrolled onto either the GU tissue collection protocol 
(IRB #89-076) or the institutional protocol (IRB# 12-245), which allow for genetic analysis 
through Next Generation sequencing using the standardized MiSeq assay as well as the IMPACT 
assay. Patients can also opt for commercial mutational analysis through Foundation One. Patients 
with progressive, metastatic UC whose tumors possess alterations predicted to upregulate 
PI3K/Akt/mTOR pathway activity will be considered for enrollment onto the expansion cohort. 
 
 
 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is an open-label phase II study of the pan-class I selective PI3K inhibitor Buparlisib in 


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patients with metastatic urothelial carcinoma which has progressed despite treatment with prior 
cytotoxic chemotherapy. The purpose of the study design is to evaluate the efficacy and safety of 
Buparlisib in advanced, refractory disease using 2 month progression free survival as a primary 
endpoint. 
 
In the Phase II study, the planned sample size will be 35 patients. A two stage study design will be 
utilized with a PFS rate at 8 weeks of less than 60% considered not promising while a PFS rate at 8 
weeks of 80% or greater will be considered promising. In stage I of the trial, 13 evaluable patients 
will be accrued to the study. If 8 or more patients demonstrate progression on imaging after 8 
weeks on-study, the study will be terminated early and declared to have a negative result. If 9 or 
more are progression-free at two months, enrollment will be extended to accrue a total of 35 
patients. If 24 or more are progression-free after their two month scan (i.e., after stage 2), the 
treatment will be considered effective and worthy of further testing. 
 
In the Expansion Cohort, the planned sample size will be 21 patients with genetic alterations 
upregulating the PI3K/AKT/mTOR pathway. A one-stage study design will be utilized with a PFS 
rate at 8 weeks of less than 60% considered not promising while a PFS rate at 8 weeks of 85% or 
greater will be considered promising. If 6 or more patients demonstrate progression on imaging 
after 8 weeks on-study, the study will be declared to have a negative result. If 16 or more are 
progression-free at two months, the treatment will be considered effective and worthy of further 
testing. 
 
 
4.3 
Intervention 
 
Buparlisib will be administered at a dose of 100 mg orally once daily (two 50 mg capsules) 
continuously. Intra-patient dose reduction may be required depending on the type and severity of 
the individual toxicity encountered. Re-staging imaging studies will be performed after every two 
cycles of treatment (one cycle = 4 weeks). Patients may continue on study as long as they are 
tolerating therapy and are free of disease progression. 
 
 
5.0     THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Investigational Drug Description 
NVP-Buparlisib (Buparlisib) is an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor 
belonging to the 2, 6-dimorpholino pyrimidine derivative family. 
 
The drug product is a hard gelatin capsule for oral administration (10 mg, and 50 mg). Both dosage 
strengths have the same qualitative composition which consists of dry powder blends made using 
standard excipients of pharmacopeial quality: mannitol, microcrystalline cellulose, crospovidone, 
colloidal silicon dioxide, and magnesium stearate. The 10-mg capsules use a Size 1 or Size 3 pink 
opaque capsule shell. The 50 mg capsules use a Size 1 capsule shell of pink opaque or gray 
opaque color. 
 
5.2 2 Drug Dispensing/Administration 
Administration will be performed on an outpatient basis. Buparlisib will be dispensed as capsules at the 


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beginning of each treatment cycle. In case of dose modification, patients will be asked to return all of 
their previously dispensed medication to the clinic and they will be dispensed new-strength capsules. 
All dosages prescribed and dispensed to the patient and all dose changes during the study must be 
recorded. 
 
Medication labels will comply with US legal requirements and will be printed in English. They will 
supply no information about the patient. The storage conditions for study drug will be described on the 
medication label. 
 
Buparlisib  will  be  provided  by  Novartis  formulated  as  capsules  for  oral  administration,  and  the 
standard 100mg dose will be taken as two 50mg capsules. 
 
5.3 3 Storage and Stability 
Based on the available stability data, Buparlisib capsules are not to be stored above 25⁰C.  The 
capsules are packaged in high density polyethylene (HDPE) bottles with induction seals and child 
resistant caps.  The shelf-life period and storage conditions will be continually assessed based on 
accelerated and long-term stability data. 
 
5.4 Source of Drug 
Novartis, Inc. will supply Buparlisib free of charge. 
 
5.5 5 Drug Accountability 
All study drug supplies must be kept in a locked room with limited access. The study drug must 
not be used outside the context of this protocol. Under no circumstances should the investigator or 
other site personnel supply study drug to other investigators, patients, or clinic, or allow supplies to 
be used other than directed by this protocol without prior authorization from Novartis. 
 
The pharmacist will maintain a complete drug accountability record for each tablet strength with 
lot numbers of each drug received, including the number of bottles dispensed to each patient, the 
dates drug was dispensed, and the daily dose of Buparlisib the patient received. The prescribed 
dose should also be recorded in the patient’s medical records. 
 
At the conclusion of the study, all unused Buparlisib capsules will be returned to Novartis for 
destruction. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
• Age ≥ 18 years 
• Karnofsky Performance Status (KPS) ≥60% 
• Urothelial carcinoma of the bladder, urethra, ureter or renal pelvis, with histologic 
confirmation at MSKCC.  Patients with unresected primary tumors may be enrolled as long 
as evidence of metastatic disease is also present. 
• Patients must have progressive metastatic disease. Progressive disease will be defined as 
new or progressive lesions on cross-sectional imaging (RECIST Version 1.1). 


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• Patients must have been previously treated, as defined by the following: 
o Patients must have received treatment with at least one prior cytotoxic 
chemotherapy agent but not more than four prior cytotoxic chemotherapy agents for 
urothelial carcinoma. Up to four prior chemotherapy agents are allowed, since 
conventional chemotherapy ranges from just one drug (e.g., gemcitabine) to 
regimens that contain four agents (e.g., M-VAC is a four-drug regimen containing 
methotrexate, vinblastine, doxorubicin, and cisplatin). 
o The prior therapy must have consisted of at least one of the following: cisplatin, 
carboplatin, paclitaxel, docetaxel, or gemcitabine. 
o The prior cytotoxic agents may have been administered in the perioperative or 
metastatic setting and may have been administered sequentially (e.g., first-line 
treatment followed by second-line treatment at time of progression) or as part of a 
single regimen. 
• Patients must have at least one site of measurable disease per RECIST 1.1 criteria that has 
not been previously irradiated. If the patient has had previous radiation to the marker 
lesion(s), there must be evidence of progression since the radiation. 
• Patients enrolling in the Phase II study must have pre-treatment tumor tissue available for 
PI3K/Akt pathway marker analysis: One paraffin block, frozen curls, or 10 freshly- 
prepared unstained slides from the most representative single paraffin-embedded tumor 
tissue block should be submitted. Slides from the primary tumor are preferred. If both the 
primary and metastatic tumor blocks are available, 10 slides from each of the sites should 
be submitted. If tissue from the primary tumor is not available, a paraffin block or 
unstained slides from a metastatic site are acceptable. Fine needle aspirates (FNAs) have 
insufficient tumor tissue and are not permitted. 
• Patients enrolling in the Expansion Cohort must have prior mutational testing 
demonstrating alterations within the PI3K/Akt/mTOR pathway predicted to result in 
pathway activation. 
• Life expectancy of ≥ 12 weeks 
• Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, 
Hemoglobin >9 g/dL 
• Total calcium (corrected for serum albumin) within normal limits (bisphosphonate use for 
malignant hypercalcemia control is not allowed) 
Corrected Calcium = (0.8 * (Normal Albumin - Pt's Albumin)) + Serum Ca 
• Potassium and magnesium within normal limits 
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal 
range [or < 3.0 x upper limit of normal (ULN) if liver metastases are present] 
• Serum bilirubin within normal range (or < 1.5 x ULN if liver metastases are present; or 
total bilirubin < 3.0 x ULN with direct bilirubin within normal range in patients with well- 
documented Gilbert syndrome) 
• Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min 
• INR < 2 
• Serum amylase and lipase ≤ ULN 


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• Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L) 
• Ability to swallow oral medication 
 
6.3 
Subject Exclusion Criteria 
 
• Patients who have received prior treatment with a P13K inhibitor. 
• Patients receiving any other investigational therapies. 
• Patients with a known hypersensitivity to Buparlisib or to its excipients 
• Patients with untreated brain metastases are excluded. However, patients may participate in 
this trial if > 4 weeks from completion of therapy (radiation and/or surgery) for CNS 
metastases, are clinically stable at the time of registration and are not receiving 
corticosteroid therapy 
• Patients with acute or chronic hepatic or renal disease or pancreatitis 
• Patients with the following mood disorders as judged by the Investigator or a psychiatrist, 
or as a result of patient’s mood assessment questionnaire: 
o 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 (immediate risk of doing harm to 
others) 
o 
≥ CTCAE grade 3 anxiety 
o Meet the cut-off score of ≥ 10 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7 
mood scale, respectively, or select a positive response of “1”, “2”, or “3” to 
question number 9 regarding the potential for suicidal thoughts in the PHQ-9 
(independent of the total score of the PHQ-9) 
• Patients with diarrhea ≥ CTCAE grade 2 or other impairment of gastrointestinal (GI) 
function or GI disease that may significantly alter the absorption of Buparlisib (e.g., 
ulcerative diseases, uncontrolled, nausea, vomiting, malabsorption syndrome, or small 
bowel resection) 
• Patient has active cardiac disease 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 > 480 msec on screening ECG (using the QTcF formula) 
o Angina pectoris that requires the use of anti-anginal medication 
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 document compromise in cardiac function 
o Symptomatic pericarditis 
• Patients with uncontrolled diabetes mellitus or steroid-induced diabetes mellitus. 
• Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active 
or uncontrolled infection) that could cause unacceptable safety risks or compromise 
compliance with the protocol 
o Significant symptomatic deterioration of lung function. If clinically indicated, 
pulmonary function tests including measures of lung volumes, DLCO, O2 


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saturation at rest on room air should be considered to exclude pneumonitis or 
pulmonary infiltrates 
• Patients who have been treated with any hematopoietic colony-stimulating growth factors 
(e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin or 
darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued 
• Patients who are currently receiving treatment with any medication that has the potential to 
prolong the QT interval or inducing Torsades de Pointes and the treatment cannot either be 
discontinued or switched to a different medication prior to starting study drug.  Refer to 
Appendix A for a list of prohibited QT-prolonging medications. 
• Patients receiving chronic treatment with steroids or another immunosuppressive agent 
o Note: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways 
diseases), eye drops or local injections (e.g. intra-articular) are allowed. Patients 
with previously treated brain metastases who are on stable low dose corticosteroid 
treatment (e.g., dexamethasone 2 mg/day, prednisolone 10 mg/day) for at least 14 
days before start of study treatment are eligible. 
• Patients who have taken herbal medications and certain fruits within 7 days prior to starting 
study drug. 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. Fruits include the CYP3A inhibitors Seville oranges, grapefruit, 
pummelos, or exotic citrus fruits. 
• Patients who are currently treated with drugs known to be moderate and strong inhibitors or 
inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a 
different medication prior to starting study drug. Please refer to Appendix A for a list of 
moderate to strong inhibitors of CYP3A4 (Please note that co-treatment with weak 
inhibitors of CYP3A4 is allowed). 
• Patients who have received chemotherapy or targeted anticancer therapy ≤ 4 weeks (6 
weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug or whose 
side effects from chemotherapy or targeted anticancer therapy have not recovered to a 
grade 1 before starting the trial. 
• Patients who have received any continuous or intermittent small molecule therapeutics 
(excluding monoclonal antibodies) ≤ 5 effective half lives prior to starting study drug or 
who have not recovered from side effects of such therapy 
• Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for 
palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side 
effects of such therapy 
• Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug, patients 
who have not recovered from side effects of any major surgery, or patients who may 
require major surgery during the course of the study 
• Patients who are currently taking therapeutic doses of warfarin sodium or any other 
coumarin-derivative anticoagulant. 
• Women who are pregnant or breast feeding or adults of child-bearing potential not 
employing an effective method of birth control. Women of child-bearing potential, defined 
in Section 11.7 (Reproductive Risks), must have a negative serum pregnancy test ≤ 48 
hours prior to initiating treatment.  Effective methods of birth control are defined in Section 
#11.7. 
• Known diagnosis of human immunodeficiency virus (HIV) infection 


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• History of another malignancy within 3 years, except non-melanoma skin cancer, excised 
carcinoma in situ of the cervix, or adenocarcinoma of the prostate that has been surgically 
treated with a post-treatment PSA that is non-detectable 
• Patients who are unwilling or unable to abide by the study protocol or cooperate fully with 
the investigator 
 
 
7.1 
RECRUITMENT PLAN 
 
Patients will be recruited from the outpatient clinics of the Genitourinary Oncology Service at 
MSKCC. Potential research subjects will be identified by a member of the patient’s treatment 
team, the protocol investigator, or the research team. If the investigator is a member of the 
treatment team, s/he will screen their patients’ medical records for suitable research study 
participants and discuss the study and their potential for enrolling in the research study. Potential 
subjects contacted by their treating physician will be referred to the investigator/research staff of 
the study. The patient’s initial conversation with the investigator/research staff and portions of the 
patient’s MSKCC medical records will be used to confirm that the patient is eligible for study 
participation. 
 
 
8.1 
PRETREATMENT EVALUATION 
 
The following will be completed within 14 days prior to initiation of treatment (unless otherwise 
indicated): 
 
• Vital signs 
Vital sign assessment consists of height, pulse, blood pressure, respiration rate, temperature 
and weight. 
• Physical examination 
Physical examination will be performed which must comprise a total body examination 
(general appearance, skin, neck, including thyroid, eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities and basic nervous system), including a skin rash 
assessment. 
• Performance status 
Performance status will be assessed at screening and per the visit schedule using the 
Karnofsky performance status. 
• Pregnancy Test 
A serum pregnancy test (β-HCG) is required for all women of child-bearing potential 
(WOCBP) at screening, within 48 hours prior to the first dose of Buparlisib. 
• Hematology 
Hematology includes the following parameters: complete blood count (CBC) consisting of 
red blood cell (RBCs), a total white blood cell count (WBC) with differential (total 
neutrophil count including bands, lymphocyte, monocyte, eosinophil, and basophil counts); 
hemoglobin (Hgb); and platelet count. 
• Coagulation Profile 
The coagulation profile includes prothrombin time (PT) or INR, and activated partial 
thromboplastin time (PTT). 
• Serum Chemistry 
Serum Chemistry includes the following parameters: 


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o Comprehensive metabolic panel with conjugated bilirubin (urea or blood urea 
nitrogen (BUN), creatinine, sodium, potassium, calcium, glucose, bicarbonate, 
albumin, total protein, total bilirubin (direct and indirect), alkaline phosphatase 
(fractionated if grade 2 or higher elevation), AST (SGOT), ALT (SGPT)) 
o Lipid  Panel  (total  cholesterol,  high  density  lipoprotein  (HDL),  low  density 
lipoprotein (LDL), and triglycerides) 
o Phosphorus 
o Uric acid 
o Lactic dehydrogenase (LDH) 
Because accurate serum glucose and lipid measurements are required, patients should be 
fasting at the time of the blood sampling. 
• Screening tests 
The additional screening tests include: 
o Magnesium 
o Amylase and lipase 
o Gamma glutamyl transpeptidase (GGT) 
 
• Urinalysis 
Urinalysis includes macroscopic (protein, glucose, ketones, blood, and specific gravity). A 
microscopic (WBC/hpf, RBC/hpf, and any additional findings) exam need only be 
performed if the urinalysis result is abnormal. 
This must be supplemented with laboratory quantification of any potentially relevant 
abnormalities. 
• Neuropsychiatric assessments 
Patient self-rating mood questionnaires for anxiety and depression (PHQ-9, GAD-7) will 
be conducted during screening. Patients must be below the cutoff scores in either of these 
questionnaires to be eligible for the trial (see Exclusion Criteria for further details). Please 
see sections 10.0 and 11.1 for more information regarding neuropsychiatric assessments 
during treatment. 
 
The following will be completed within 30 days prior to initiation of treatment (unless otherwise 
indicated): 
• ECG 
A standard 12 lead ECG is to be performed at screening and significant findings must be 
recorded. 
• ECHO/MUGA 
An echocardiogram or MUGA will be performed at screening to assess eligibility 
• Chest X-ray 
A CT of chest may be performed instead if clinically relevant. 
• Radiological tumor assessment 
Baseline abdominal and pelvic CT scan and/or MRI of the abdomen and pelvis for abdominal 
or pelvic indicator lesions 
• Bone Scan 
In patients with osseous lesions, bone X-rays and/or bone scans should be obtained. 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 


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9.1 
Buparlisib Administration 
The study drug Buparlisib will be self-administered (by the patients themselves). The investigator 
will instruct the patient to take the study drug exactly as specified in the protocol. Buparlisib will 
be administered orally on a continuous once daily dosing schedule of 100 mg (two  50  mg 
capsules) continuously from study day 1 until progression of disease or unacceptable toxicity. 
Patients should be instructed to take the dose of Buparlisib daily in the morning, one hour after a 
light breakfast (morning meal) at approximately the same time each day. Buparlisib should be 
taken with a glass of water and consumed over as short a time as possible. Patients should swallow 
the capsules as a whole and not chew or crush them. Patients should continue to fast for 2 hours 
following the administration of each Buparlisib dose. 
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 as an adverse event. 
If the patient forgets to take her/his dose before 6:00 PM, then the dose should be withheld that 
day and Buparlisib should be restarted the following day. 
Patients must avoid consumption of St. John’s Wort, Seville oranges, grapefruit or grapefruit juice, 
grapefruit hybrids, pummelos and exotic citrus fruits from 7 days prior to the first dose of study 
medication and during the entire study treatment period due to potential CYP3A4 interaction with 
the study medication. Patients must avoid concomitant intake of strong and moderate CYP3A4/5 
inhibitors and inducers. Orange juice is allowed. 
All dosages prescribed and dispensed to the patient and all dose changes during the study must be 
recorded. If a patient requires a Buparlisib dose delay of > 21 days from the previous dose, the 
patient must be discontinued from treatment completely and will only require a 28 day follow up 
visit for study completion. 
Medication labels will comply with US legal requirements and be printed in English. They will 
supply no information about the patient. The storage conditions for study drug will be described on 
the medication label. 
9.2 
Interruption or Discontinuation of Treatment 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted in order to keep the patient on study drug. If administration of Buparlisib must be 
interrupted because of unacceptable toxicity, drug dosing will be interrupted or modified according 
to rules described in Table 2. Drug may also be interrupted per investigator’s discretion  if 
clinically warranted. Toxicity will be assessed using the NIH-NCI Common Terminology Criteria 
for 
Adverse 
Events, 
version 
4.0 
(CTCAEv4.0, 
http://ctep.cancer.gov/protocol 
Development/electronic applications/docs/ctcaev4.pdf). 
 
 
Table 1-0  Buparlisib dose level modification guidelines 
 
Dose level 
Dose and schedule 
-2 
60 mg daily by mouth 
-1 
80 mg daily by mouth 
* 0 
100 mg daily by mouth 
* Starting Dose 


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9.3 
Monitoring of Adverse Events 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory tests,  or  other 
means will be collected, recorded, and followed as appropriate. 
 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related to 
study drug. Medical conditions/diseases present before starting study drug are only considered 
adverse events if they worsen after starting study drug. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
 
The occurrence of adverse events should be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by the 
patient during or between visits or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade (mild, moderate, severe or grade 1-4) 
2. Its relationship to the study drug (suspected/not suspected) 
3. Its duration (start and end dates or if continuing at final exam) 
4. Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization) 
5. Whether it constitutes a serious adverse event (SAE) 
 
All adverse events should be treated appropriately. Such treatment may include changes in study 
drug treatment including possible interruption or discontinuation, starting or stopping concomitant 
treatments, changes in the frequency or nature of assessments, hospitalization, or any other 
medically required intervention. Once an adverse event is detected, it should be followed until its 
resolution, and assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to treat 
it, and the outcome. 
 
Information about common side effects already known about the investigational drug can be found 
in the Investigators’ Brochure. This information should be included in the patient informed consent 
and should be discussed with the patient during the study as needed. 
 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
clinically significant laboratory value, must be followed as outlined in Table 2, at least once a 
week for 4 weeks and subsequently at 4-week intervals until resolution or stabilization of the 
event, whichever comes first. If a patient requires a dose delay of > 21 days from the previous 
dose, then the patient should be discontinued from the study. If the patient requires more than 2 
dose reductions, the patient should be discontinued from the study (i.e., patients cannot be treated 
below dose level -2). All patients must be followed for adverse events and serious adverse events 
for 28 days following the last dose of Buparlisib. All SAEs must be reported to Novartis as 
detailed in section 17.2. 


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Table 2 
Criteria for dose-modification in case of suspected Buparlisib toxicity and re- 
initiation of Buparlisib treatment 
Toxicity 
Actions 
Non-Hematological Toxicity 
Mood Alterations 
* See Table 4 for toxicity grading of mood questionnaires. Questionnaire scores should be considered when 
assigning the AE Grade but psychiatric consult, if required, may determine the grade 
Buparlisib should be omitted for any patient who requires initiation of mood stabilizers for 
control of mood alteration until their mood alteration has resolved to < Grade 1. 
Grade 1 
(or Grade 2 anxiety if present at baseline) 
Maintain dose level 
Note: If question 9 on the PHQ-9 has a positive response, or 
worsens in severity, the patient should be referred for 
psychiatric consult regardless of the total questionnaire 
score 
Grade 2 
(for Anxiety only, if worsened from baseline) 
Institute appropriate co-medication after consultation with 
the psychiatrist. 
• 
If the condition requires > 14 days for resolution to 
<Grade 1 despite medical treatment, Buparlisib dose 
should be reduced by 1 dose level. 
Note: If question 9 on the PHQ-9 has a positive response, or 
worsens in severity, the patient should be referred for 
psychiatric consult regardless of the total questionnaire 
score 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
(co-medicate) 
Note: If question 9 on the PHQ-9 has a positive response, or 
worsens in severity, the patient should be referred for 
psychiatric consult regardless of the total questionnaire 
score 
Grade 4 
Omit dose and discontinue patient from study 
Note: If question 9 on the PHQ-9 has a positive response, or 
worsens in severity, the patient should be referred for 
psychiatric consult regardless of the total questionnaire 
score 
Neurotoxicity 
≥ 1 CTCAE grade level increase 
Interrupt BKM until resolved to ≤ grade 1, then resume Buparlisib at 
one lower dose level 
≥ Grade 3 
Discontinue Buparlisib 
Pneumonitis 
Grade 1 
• 
CT scans with lung windows. Repeat at least every 8 weeks 
until return to within normal limits. 
• 
Maintain dose level 
Grade 2 
• 
CT scan with lung windows. Consider pulmonary function 
testing including: spirometry, DLCO, and room air O2 saturation 
at rest. Repeat at least every three cycles until return to within 
normal limits. Consider a bronchoscopy with biopsy and / or 
BAL. 
• 
Consider corticosteroids if symptoms are troublesome. 
• 
Reduce Buparlisib dose by 1 dose level (see Table 1) 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 3 weeks. 


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Grade 3 
• 
CT scan with lung windows and pulmonary function testing 
including: spirometry, DLCO, and room air O2 saturation at 
rest. Repeat at least every two cycles 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 3 weeks at a reduced dose (by one 
level) if evidence of clinical benefit. 
Grade 4 
• 
CT scan with lung windows and required pulmonary function 
testing including: spirometry, DLCO, and room air O2 
saturation at rest. Repeat at least every two cycles 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. 
• 
Discontinue treatment with Buparlisib. 
Endocrine/Metabolic 
Fasting Plasma Glucose Elevation 
≥ 120 mg/dL - 160 mg/dL 
First Occurrence: 
Maintain dose level 
Second Occurrence: 
Maintain dose level, check Fasting Plasma Glucose (FPG) every 
week 
• 
Initiate or intensify medication with appropriate anti-diabetic 
treatment as per investigator’s discretion 
• 
Instruct patient to follow dietary guidelines provided by the 
American Diabetes Association during the study 
• 
Check FPG weekly for 8 weeks, then continue checking every 
2 weeks 
Grade 2 (>160 – 250 mg/dL) [> 8.9 - 13.9 mmol/L] 
First Occurrence: 
Maintain dose, re-check FPG within 48 hours, and if no worse than 
Grade 2*: 
• 
Maintain dose level 
• 
Initiate or intensify medication with appropriate anti-diabetic 
treatment 
• 
Instruct patient to follow dietary guidelines provided by the 
American Diabetes Association during the study 
If FPG does not resolve to ≤ Grade 1 within 14 days after 
initiation/intensifying anti-diabetic treatment: omit Buparlisib 
• 
monitor FPG at least weekly until FPG resolves to ≤ Grade 1 
• 
then re-start Buparlisib and  by 1 dose level 
• 
continue with anti-diabetic treatment 
• 
check FPG weekly for 8 weeks, then continue checking every 
2 weeks 
* If grade “worsens” then follow specific grade recommendations 
Grade 2 (>160 – 250 mg/dL) [> 8.9 - 13.9 mmol/L] 
Second Occurrence: 
Maintain dose, re-check FPG within 48 hours, and if no worse than 
Grade 2*: 
• 
Omit Buparlisib 
• 
Initiate or intensify medication with appropriate anti-diabetic 
treatment 
• 
Monitor FPG at least twice weekly until FPG resolves to 
≤ Grade 1 
• 
Then re-start Buparlisib and  by 1 dose level 
• 
Continue with anti-diabetic treatment 
• 
Check FPG weekly for 8 weeks, then continue checking every 
2 weeks 
 


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* If grade “worsens” then follow specific grade recommendations 
Grade 3 (> 250 - 500 mg/dL) [> 13.9 - 27.8 mmol/L] 
First Occurrence: 
Immediately omit Buparlisib, initiate or intensify medication with 
appropriate anti-diabetic treatment, re-check FPG within 48 hours, 
and if no worse than Grade 3*: 
• 
Continue to omit Buparlisib 
• 
Monitor FPG at least twice weekly until FPG resolves to 
≤ Grade 1 
• 
Stop or reduce insulin medication 
• 
Then re-start Buparlisib and  by 1 dose level 
• 
Continue with anti-diabetic treatment as appropriate 
• 
Instruct patient to follow dietary guidelines provided by the 
American Diabetes Association during the study 
• 
Check FPG weekly for 8 weeks, then continue checking every 
2 weeks 
Second Occurrence: 
Same process as for first occurance, however at the second re- 
initiation Buparlisib must be dose-reduced a second time. 
* If grade “worsens” then follow specific grade recommendations 
Grade 4 (> 500 mg/dL) [≥ 27.8 mmol/L] 
Immediately omit Buparlisib, initiate or intensify medication with 
appropriate anti-diabetic treatment, re-check within 48 hours, if 
confirmed Grade 4: 
• 
discontinue patient from Buparlisib 
• 
instruct patient to follow dietary guidelines provided by the 
American Diabetes Association during the study 
• 
check FPG weekly for 8 weeks, then continue checking every 
2 weeks 
Asymptomatic Amylase and/or Lipase Elevation 
Grade 3 (> 2.0 – 5.0 x ULN) 
Interrupt until resolved to ≤ grade 2, then: 
• 
If resolution to grade ≤ 1 in ≤ 7 days, resume Buparlisib at the 
current dose level; 
• 
If resolution to grade ≤ 1 in > 7 days, resume Buparlisib at one 
lower dose level 
Grade 4 (> 5.0 x ULN) 
Discontinue Buparlisib 
Renal 
Serum Creatinine 
Grade 2 (> 1.5 – 3 x ULN) 
Interrupt treatment until resolution to ≤ grade 1, then : 
• 
If resolved to ≤ grade 1 in ≤ 7 days, resume Buparlisib at the 
current dose level 
• 
If resolution to ≤ grade 1 takes > 7 days, resume Buparlisib 
decreased by one dose level 
Grade 3 (>3.0 – 6.0 x ULN) 
Discontinue Buparlisib 
Grade 4 ( > 6.0 x ULN) 
Discontinue Buparlisib 
Hepatic 
In case of any occurrence of ALT/ AST/ bilirubin increase ≥ grade 2, the liver function tests must be monitored weekly or more 
frequently if clinically indicated until resolved to ≤ grade 1. Furthermore, for all patients who have experienced ALT/ AST/ bilirubin 
increase ≥ grade 3 during the study treatment, the monitoring should be continued 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. 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. 
Bilirubin 
(For patients with Gilbert syndrome, these 
dose modifications apply to changes in direct 
bilirubin only) 
 


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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 
• 
See above for monitoring parameters 
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 study treatment 
• 
See above for monitoring parameters 
Grade 4 (> 10.0 x ULN) 
Omit dose and discontinue patient from study treatment. See above 
for monitoring parameters. 
AST or ALT 
Grade 1 (> ULN – 3.0 x ULN) 
Maintain dose level with LFTs monitored as per protocol 
Grade 2 (> 3.0 – 5.0 x ULN) without bilirubin elevation to > 2.0 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 
• 
See above for monitoring parameters 
Grade 3 (> 5.0 - 20.0 x ULN) without bilirubin elevation to >2.0 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 
• 
See above for monitoring parameters 
Grade 4 (> 20.0 x ULN) 
Omit dose until resolved to ≤ Grade 1 , then  1 dose level 
See above for monitoring parameters. 
AST or ALT and concurrent bilirubin 
AST or ALT > 3.0 x ULN and total bilirubin > 2.0 x ULN 
Discontinue study treatment permanently 
Monitoring for patients with Gilbert syndrome includes the above LFTs and total and direct bilirubin. Intensified monitoring applies to 
changes in direct bilirubin only for these patients. 
Gastrointestinal 
Diarrhea 
Grade 2 (4-6 stools/day > pretx) 
If diarrhea can be controlled with optimal anti-diarrheal treatment, 
continue Buparlisib. If not, interrupt treatment until resolved to ≤ 
grade 1, then resume Buparlisib at the current dose. If diarrhea 
returns as ≥ grade 2, then interrupt treatment until resolved to ≤ 
grade 1, then resume Buparlisib at one lower dose. 
Grade 3 (7-9 stools/day > pretx) 
If diarrhea can be controlled with optimal anti-diarrheal treatment, 
continue Buparlisib. If not, for diarrhea ≥ grade 3, interrupt 
treatment until resolved to ≤ grade 1, then resume Buparlisib at one 
lower dose level. 
Note: Anti-diarrheal medication is recommended at the first sign of 
abdominal cramping, loose stools or overt diarrhea. 
Grade 4 (≥ 10 stools/day > pretx) 
If diarrhea can be controlled with optimal anti-diarrheal treatment, 
continue Buparlisib. If not, for diarrhea ≥ grade 3, interrupt 
treatment until resolved to ≤ grade 1, then resume Buparlisib at one 
lower dose level. 
Note: Anti-diarrheal medication is recommended at the first sign of 
abdominal cramping, loose stools or overt diarrhea. 
Cardiac 
Cardiac – Left Ventricular Systolic Dysfunction 
Asymptomatic, 
resting ejection fraction 40 – 50%; 
or 10-20% drop from baseline 
Maintain dose level and repeat LVEF measurement at 2 month 
intervals until return to baseline 
Symptomatic, 
responsive to intervention, 
Omit dose until resolved to ≤ Grade 1, then  by 1 dose level 
LVEF measurement to be repeated; if not resolved to ≤ Grade 1 
 


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ejection fraction 20 – 39% 
or > 20% drop from baseline 
within 3 weeks, permanently discontinue Buparlisib 
Refractory or poorly controlled, 
ejection fraction < 20% 
Omit dose and discontinue Buparlisib 
Cardiac – QTc prolongation 
QTcF > 500 ms (≥ Grade 3) 
and/or > 60 ms change from baseline 
on ECG, first occurrence 
QTcF> 500 ms (> Grade 3) 
and/or >60 ms change from 
baseline on ECG, two separate occurrences 
• 
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 
• 
If QTcF remains > 500 ms, repeat ECG as clinically indicated, 
but at least once a day until the QTcF returns to < 480 ms. 
• 
Once QTcF prolongation has resolved, Buparlisib may be 
restarted at a one lower dose level 
• 
Discontinue Buparlisib 
• 
24 hour Holter monitoring for all patients 
Other Cardiac Events 
Grades 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then  by 1 dose level 
Grade 4 
Omit dose and discontinue Buparlisib 
General Adverse Events 
Rash 
Grade 1 
Maintain dose level. Consider initiation of appropriate skin toxicity 
therapy (such as antihistamines, topical corticosteroids) 
Grade 2 
Maintain dose level. Initiate/intensify appropriate skin toxicity 
therapy (such as antihistamines, topical corticosteroids) 
Grade 3 
Omit dose until resolved to CTCAE Grade ≤ 1, then: 
• 
If resolved in ≤ 14 days,  1 dose level 
• 
If resolved in  14 days (despite appropriate skin toxicity 
therapy), discontinue Buparlisib 
Grade 4 
Omit dose and discontinue Buparlisib 
Photosensitivity 
Grade 2 (painful erythema) 
Interrupt Buparlisib until resolution to ≤ grade 1, then : 
• 
If resolution to grade ≤ 1 in ≤ 14 days, resume Buparlisib 
decreased by one dose level; 
• 
If resolution to ≤ grade 1 takes > 14 days, discontinue 
Buparlisib 
Grade 3 (erythema with desquamation) 
Discontinue Buparlisib 
Grade 4 (life threatening; disabling) 
Discontinue Buparlisib 
Fatigue 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then: 
• 
If resolved in ≤ 7 days, maintain dose level 
• 
If resolved in  7 days,  by 1 dose level 
Grade 4 
Omit dose and discontinue Buparlisib 
Any CTCAE Grade 3 Non-Hematological Toxicity not listed above 
Interrupt treatment until resolution to ≤ grade 1, then resume 
Buparlisib at one lower dose level 
Any CTCAE Grade 4 Non-Hematological Toxicity not listed above 
Discontinue Buparlisib 
Other Non-Hematologic Toxicities 
 


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Grade 3 
Omit dose until resolved to ≤ Grade 1, then  by 1 dose level 
Grade 4 
Omit dose and discontinue patient from study 
Note: Omit dose for ≥ Grade 3 vomiting or Grade 3 nausea only if 
the vomiting or nausea cannot be controlled with antiemetics 
Hematological Toxicities 
Neutropenia 
Grade 1 (ANC < LLN – 1.5 x 109/L) 
Grade 2 (ANC < 1.5 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  by 1 dose level 
Febrile neutropenia 
(ANC < 1.0 x 109/L, fever ≥ 38.5°C) 
Omit dose until resolved, then  by 1 dose level 
Thrombocytopenia 
Omit dose until resolved, then  by 1 dose level 
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  by 1 dose level 
Grade 4 (PLT < 25 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then  by 1 dose level 
Treatment Delay ≥ 3 weeks 
Any hematologic or non-hematologic toxicity requiring interruption 
for ≥ 3 weeks 
Discontinue Buparlisib 
 
 
9.4 
Treatment compliance 
Records of study medication used, dosages administered, and intervals between visits will be 
recorded during the study. Drug accountability will be noted and patients will be asked to return all 
unused study medication. All patients will be provided with a pill diary to record daily drug self- 
administration. 
9.5 
Concomitant therapy 
All medications (excluding prior chemotherapy and biologic, immunologic or radiation therapy) 
taken within 4 weeks prior to the administration of Buparlisib and all concomitant therapy 
administration during the study with reasons for therapy should be recorded. All prior 
chemotherapy, biologic, immunologic or radiation therapy, and surgery within 4 weeks prior to the 
administration of study drug will be recorded. 
 
Patients on chronic medications that can be given concomitantly with Buparlisib should be 
maintained on the same dose and dose schedule throughout the study period, as medically feasible. 
The investigator should instruct the patient to notify the study 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 herbal medicines, physical therapy and blood 
transfusions) administered after the patient starts treatment with study drug, and any changes in 
dosing should be recorded. 
 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
patient is permitted with the following exceptions described in section 9.5.1. 


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9.5.1 Drugs that are prohibited 
• Other investigational therapies must not be used while the patient is on the study. 
• Anticancer therapy (chemotherapy, biologic, or radiation therapy) other than the study 
treatment must not be administered to patients while they are on the study. If such agents 
are required for a patient then the patient must be discontinued from the study. 
• In vitro metabolism studies suggest that oxidative metabolism of Buparlisib is 
predominantly mediated by CYP3A4 (fm>0.9), with only minor contributions of CYP1A1. 
As Buparlisib is a sensitive CYP3A4 substrate, co-administration of Buparlisib with strong 
and moderate CYP3A4 inhibitors and CYP3A4 inducers (which are predicted to reduce 
systemic exposure to Buparlisib and thereby increasing the risk of exposing patients to 
subtherapeutic drug levels) is prohibited. 
• Therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative 
anticoagulants are not permitted. 
• Herbal preparations/medications are not allowed throughout the study. 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 7 days prior to first dose of study drug. 
• Hormonal contraceptives may be affected by cytochrome P450 interactions, and are 
therefore not considered effective in this study. 
• If a patient requires the concomitant use of any medication included in Table 5.4 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 Torsades des 
de Pointes), study treatment administration must be interrupted as long as the patient 
requires therapy with the QT prolonging agent. 
9.5.2 Drugs to be used with caution 
Preliminary in vitro metabolism studies suggest that Buparlisib is a weak, reversible inhibitor of 
CYP3A4/5 (Ki=13.6 μM, [I]/Ki= 0.4 where [I] is the average Cmax at steady-state following 100 
mg daily dose) and of CYP2C8/2C9/2C19 (IC50=34 μM, [I]/IC50=0.15). Note that with the data 
available, we are unable 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 carefully monitored for potentiation of toxicity due to any individual 
concomitant medications, and may require dose titration or reduction of the drug substrate. See 
Appendix A for a full list of drugs that are prohibited and drugs that must be used with caution. 
Caution is particularly advised when Buparlisib is co-administered with: 
• Drugs which are substrates for CYP3A4, CYP2C8, CYP2C9 or CYP2C19 and which have a 
narrow therapeutic index. 
• Oral anti-diabetics which are metabolized by CYP2C8 or CYP2C9 can possibly result in 
hypoglycemia. Patients who develop diabetes mellitus during the study should be treated 
according to the American Diabetes Association guidelines. It is recommended that treatment 
start with metformin. 
• Concomitant treatment with corticosteroids and Buparlisib should be avoided, whenever 
possible, during this study.  A short duration (< 2 weeks) of systemic corticosteroids is allowed 


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(e.g. for chronic obstructive pulmonary disease, or as an anti-emetic). Chronic dosing of 
corticosteroids is known to induce CYP3A enzymes, thereby increasing the risk of reducing 
Buparlisib overall exposure to sub-therapeutic levels. 
• If a patient, after study enrollment, requires the concomitant use of any medication which may 
cause QT prolongation and/or Torsades de Pointes (Table 5.3), then the investigators, at their 
discretion, may co-administer such medications. Patients receiving such medications must be 
monitored. 
• Unless otherwise indicated, investigators should use their clinical discretion if any other 
concomitant medications known to be metabolized by CYP2C8, CYP2C9, CYP2C19 and/or 
CYP3A4/5 need to be co-administered with Buparlisib. Patients should be carefully monitored 
for signs of possible toxicity due to any individual concomitant medications. 
• Please refer to a list of known medications that are substrates, inhibitors, and inducers 
(provided in Appendix A) of CYP2C8, CYP2C9, CYP2C19 and/or CYP3A4/5 isoenzymes as 
well as QT prolonging drugs and carefully consider their co-administration with Buparlisib. 
 
 
 
 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 


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Table 3  Evaluation and Visit Schedule 
Procedure 
Screening 
Cycle 1 
Cycle 2 
Additional Cycles 
(Cycle ~28 days) 
Post-treatment/ 
Withdrawal 
Survival/ 
Follow-up 
<30 days prior 
to tx start 
≤14 days prior 
to tx start 
Day 1 
(±2 days) 
Day 15 
(±2 days) 
Day 11 
(±2 days) 
Day 15 
(±2 days) 
Day 11 
(±2 days) 
(4 weeks after last 
treatment) +/-7 days19 
Informed Consent 
X 
Medical History 
X 
Serum Pregnancy Test 
(WOCBP)2 
X Within 48 
hrs 
As clinically indicated 
Vital Signs18 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Karnofsky Performance Status 
X 
X 
X 
X 
Adverse Events3 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Neuro-psychiatric 
questionnaire4 
X 
X 
X 
X 
X 
X 
X 
Patient Pill Diary5 
X 
X 
X 
Hematology6 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry (Fasting)7 
X 
X 
X 
X 
X 
X 
X 
Screening Bloods8 
X 
Coagulation Profile9 
X 
X 
X 
Even Cycles9 
X9 
Urinalysis10 
X 
X 
12-lead ECG11 
X 
X 
X 
X 
X 
ECHO/MUGA17 
X 
X 
Chest X-ray12 
X 
Every 8 weeks from start of treatment 
Radiological tumor response 
assessment 13 
X 
Every 8 weeks from start of treatment 
Buparlisib14 
X14→ 
→ 
→ 
→ 
→ 
Survival Status15 
X 
Tumor tissue Evaluation16 
X 


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1. Cycle = 28 days, Day 28=Day 1of next cycle. 
2. Serum pregnancy test must be performed for all women of childbearing potential within 48 hours of starting study drug.  Additional testing will be performed as clinically 
indicated. 
3. Adverse Events: Patients must be followed for adverse events from the first day of study treatment until at least 28 days after the last on-study treatment administration, or until 
all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable,” whichever is later. Serious adverse events should be monitored and reported 
as described in the protocol. 
4. PHQ-9 and GAD-7 questionnaires will be completed at Screening, C1D1, C1D15, C2D1, C2D15 and on Day 1 of subsequent cycles. The questionnaires should also be completed at 
the end of study treatment visit. Symptomatic patients may require more frequent questionnaires – please see Section 11.2 for more information. 
5. At the start of each cycle, patients will be given a Pill Diary and asked to record the time, date, and side-effects of each dose of Buparlisib taken. Patient diaries are collected at the 
end of each cycle. 
6. Hematology includes the following parameters: complete blood count (CBC) consisting of red blood cell (RBCs), a total white blood cell count (WBC) with differential (total 
neutrophil count including bands, lymphocyte, monocyte, eosinophil, and basophil counts), hemoglobin (Hgb), and platelet count. This should be performed on D1 and D15 of cycle 1 
and cycle 2 and day 1 of all subsequent cycles. 
7. Serum Chemistry: Patients must be fasting overnight for at least 8 hours prior to blood sampling. These tests should be performed on D1 and D15 of cycle 1 and cycle 2, and day 1 
of all subsequent cycles. C1D1 assessments may be performed up to 72 hours prior to the scheduled visit. In patients with serum triglycerides ≥ 500 mg/dL, urine amylase needs to be 
tested as well upon receipt of the chemistry panel results. 
Serum Chemistry includes: 
o Comp with conjugated bilirubin (urea or blood urea nitrogen (BUN), creatinine, sodium, potassium, calcium, glucose, albumin, total protein, total bilirubin (direct and indirect), 
alkaline phosphatase (fractionated if alkaline phosphatase level is grade 2 or higher), AST (SGOT), ALT (SGPT)) 
o Lipid Panel (total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL) and triglycerides) 
o Lactic dehydrogenase (LDH) 
o Phosphorus 
o Uric acid 
8. Screening tests should be performed ≤14 days prior to treatment start. These tests include: 
o 
Magnesium 
o 
Amylase, lipase, and GGT 
9. Coagulation - PT or INR and PTT C1D1 assessments may be performed up to 72 hours prior to the scheduled visit. Additional assessments will be performed on Day 1 of Cycle 2 
and repeated every even cycle (≤ 72 hours prior to the scheduled visit). A repeat coagulation profile panel is required at the time of study treatment discontinuation.  Patients entering 
the study while receiving anticoagulation therapy or those who are initiated on anticoagulation therapy while on study should have their coagulation profile performed at every visit. 
10. Urinalysis includes macroscopic (protein, glucose, ketones, blood, and specific gravity). A microscopic (WBC/HPF, RBC/HPF, and any additional findings) exam need only be 
performed if the urinalysis result is abnormal.  This must be supplemented with laboratory quantification of any potentially relevant abnormalities. 


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11. A standard 12 lead ECG is to be performed at screening and significant findings must be recorded. ECGs will be performed at the beginning of each cycle. However, the C1D1 
ECG is not required if the baseline ECG was performed within 7 days. 
12. A Chest X-Ray should be performed for all patients at screening and every 8 weeks from start of treatment until progression as per RECIST.  Chest CT is an acceptable 
alternative to a screening chest x-ray. 
13. Screening radiological assessments should be performed within 4 weeks of the first dose. Radiological assessments include baseline abdominal and pelvic CT scan and/or MRI of 
the abdomen and pelvis. In patients with osseous lesions, bone X-rays and/or bone scans should be obtained.  Radiological tumor assessment should be performed at baseline within 
30 days before start of treatment and subsequently every 8 weeks (2 cycles), until progression of disease or end of treatment. All radiological assessments should be performed within 
±7 days of the scheduled day of assessment. 
14. Buparlisib: Buparlisib will be orally self-administered, once daily in the morning, at a dose of 100 mg (two 50 mg capsules). Patients will receive a prescription for a 4-week 
supply of drug at the beginning of each cycle. The Buparlisib drug bottles (including any unused capsules) will be returned to the clinic for drug accountability at the end of each 
cycle. 
X14→: Start and continue treatment. → : Continue treatment. 
15. Post-study survival status: Follow-up survival information will be collected for all patients by clinic visit or telephone contact approximately every 6 months from the date of first 
dose of Buparlisib. Patients will be followed until disease progression and/or death. 
16. For all patients enrolling to the Phase II portion, pre-treatment tumor tissue specimens will be analyzed using immunohistochemistry for PTEN expression levels.  Mutation 
testing may also be performed on samples. 
• 
Pretreatment tumor tissue specimens will be analyzed to detect markers of activation of the PI3K-Akt pathway as well as additional alterations that may impact upon 
sensitivity to Buparlisib.  Levels of PTEN expression will be measured utilizing immunohistochemistry. All tumors will be classified based upon level of PTEN expression. 
If normal DNA is required, patients may be asked to provide peripheral blood or a saliva sample during study participation for comparison with the tumor tissue.  DNA 
extracted from samples  may be sequenced to detect multiple alterations in both the PI3K/Akt pathway in additional genes that may condition response to Buparlisib. Other 
sequencing methods may also be used to screen tumor and germline DNA for commonly occurring mutations in genes within the PI3K-Akt pathway, including AKT, 
PIK3CA, and FGFR3.  Extracted DNA will be sequenced to detect potential mechanisms of resistance to Buparlisib. 
Patients enrolling in the Expansion Cohort must have prior mutational testing demonstrating alterations predicted to activate the PI3K/Akt/mTOR pathway.. 
17. A screening echocardiogram (ECHO) or multigated acquisition scan (MUGA) will be performed and repeated every 3 cycle unless a drop in EF occurs as described in Table 2. 
18. Vitals include: heart rate, blood pressure, respiration rate, temperature, weight and height. Height is only required at baseline. 
19. The post-treatment/withdrawal visit can be foregone for patients who are too unwell to attend or for other reasons at the investigators discretion. Patients may be contacted by 
phone to assess resolution of toxicities, and may be contacted for survival follow up. 


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11.0 TOXICITIES/SIDE EFFECTS 
 
Risks are possible side effects of study medication or another medicine, and those related to any of 
the study procedures (e.g. taking blood, biopsy, imaging, etc). 
Based on information from patients already treated with Buparlisib alone or in combination with 
other medicines, the most frequently reported side effects (in more than 20% of patients) include, but 
may not be limited to: decreased appetite, nausea, vomiting, diarrhea, abdominal pain, constipation, 
feeling weak or tired, rash with or without itching, inflammation and pain in the mouth and other 
mucosal areas, mood disorders (such as depression, anxiety or irritability), shortness of breath, cough, 
and changes in blood tests such as increase in blood sugar, alteration in liver tests, decrease in red 
blood cell counts, changes in white blood cells counts, longer time for blood clotting and change in 
levels of some electrolytes (e.g. potassium, sodium). 
Less frequent side effects (in more than  5% of patients) include: indigestion and disturbance of taste, 
weight loss, fever, headache, dizziness, confusion, change in blood pressure, pain in joints and 
extremities, swelling, sleep disturbances, urinary tract infection, changes in blood tests for kidney and 
pancreas function. 
Uncommon events (less than 5% of patients) that may nevertheless be medically important include: 
skin infection, allergic reactions, eye effects (such as blurred vision, conjunctivitis), lung infection/ 
inflammation. A few cases reported visual hallucinations, seizures and alterations in nerve 
functioning (mainly in combination with paclitaxel). One case was reported in a patient with 
advanced lung cancer committing suicide. 
Rare cases of encephalopathy have been described, including PRES (posterior reversible 
encephalopathy syndrome). 
BuparlisibBuparlisibBuparlisib 
11.1 Toxicity Monitoring 
Safety assessments will consist of monitoring and recording all adverse events and serious adverse 
events, the regular monitoring of hematology, blood chemistry and urine values, regular measurement 
of vital signs and the performance of physical examinations. 
 
These assessments should be performed within ±2 days of the scheduled day of assessment except for 
adverse events that will be evaluated continuously through the study. Safety and tolerability will be 
assessed according to the NIH/NCI CTCAE v4.0, 
http://ctep.cancer.gov/protocolDevelopment/ 
electronic_applications/docs/ctcaev4.pdf 
 
11.2 Neuropsychiatric events 
 
In [CBuparlisibX2101], neuro-psychiatric adverse events, including reversible and generally mild to 
moderate mood alterations, described as anxiety, agitation with crying episodes and depression have 
been reported in patients treated with Buparlisib. Three of five patients with moderate to severe 
mood alterations had a history of depression and/or anxiety. All patients with a documented medical 
history of depression and/or anxiety also developed mood alterations when treated with Buparlisib at 
the 100 mg dose level, reflecting a potential risk group of patients. 


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In order to lower the risk of experiencing significant mood alterations within the proposed study, 
cancer patients with a history of or active major depressive episode, bipolar disorder, obsessive- 
compulsive disorder, schizophrenia, a history of suicide attempt or ideation, or homicide/homicidal 
ideation as judged by the investigator and/or based on recent psychiatric assessment will not qualify 
for study participation. Patients with corresponding symptoms CTCAE Grade ≥ 2 should 
immediately be examined by a psychiatrist and closely followed medically. Medical treatment with 
mood stabilizers (2nd generation antipsychotics such as olanzapine and quetiapine) and 
antidepressants may be applied as per the investigator’s discretion and following consultation with a 
psychiatrist. Buparlisib dose will be omitted for any patient with mood alterations requiring mood 
stabilizers until their mood alteration has resolved to < Grade 1. A log will be maintained of all 
patients who are discontinued from this trial based on questionnaire responses during study. 
11.2.1 Management of mood alteration 
 
Patient self-rating mood questionnaires PHQ-9 (depression) and GAD-7 (anxiety) will be used: 
• To support assessment of eligibility at Screening 
• To monitor for newly occurring or worsening mood alterations during the study 
 
Patient self-rating mood questionnaires for anxiety and depression (PHQ-9, GAD-7) will be applied 
at: 
• Screening 
• Days 1 and 15 of Cycle 1 
• Days 1 and 15 of Cycle 2 
• Day 1 of Cycle 3 and subsequent cycles (only for patients who have not shown mood 
alterations during the first cycle; patients who did should continue to fill out the 
questionnaire on an every other week basis). 
• End of Study treatment 
• Additional assessments may be done according to the clinical judgment of the 
Investigator. 
• Patients who experience ≥ grade 2 mood alteration will be followed twice weekly by 
patient self-rating mood scale and will be seen weekly by the psychiatrist until 
resolved ≤ grade 1 or baseline (for anxiety). Questionnaire responses will be checked 
by the psychiatrist at the weekly visits until resolution to Grade 1 or baseline (for 
anxiety). 
 
The PHQ-9 and GAD-7 in the protocol appendix or in the MSKCC Medical Records Forms may be 
used. All questionnaires will be reviewed by a research staff member. The following grading system 
will be used for this study: 
 
Table 4 Toxicity grading based on mood questionnaire scores 
 
PHQ-9 
GAD-7 
Score 
Severity 
CTCAE grading 
Score 
Severity 
CTCAE grading 
0-4 
None 
Normal 
0-4 
None 
Normal 
5-9 
Mild 
Grade 1 
5-9 
Mild 
Grade 1 
10-19 
Moderate 
Grade 2 
10-14 
Moderate 
Grade 2 
20-27 
Severe 
Grade 3 
≥ 15 
Severe 
Grade 3 


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At screening, a patient as judged by the investigator or who meets the cut-off score of ≥ 10 in the 
PHQ-9 or a cut-off of ≥ 15 in the GAD-7 mood scale, respectively, will be excluded from the study. 
 
During the study, patients who meet the cut-off score of ≥ 10 (≥ CTCAE grade 2 mood alteration) in 
either questionnaire must see a psychiatrist for diagnosis and determination of most appropriate 
medical treatment. For anxiety, this applies only if status has worsened from baseline. Patients who 
experience ≥ grade 2 mood alteration will be followed twice weekly by patient self-rating mood scale 
and will be seen weekly by the psychiatrist until resolved ≤ grade 1 or baseline (for anxiety). 
Questionnaire responses will be checked by the psychiatrist at the weekly visits until resolution to 
Grade 1 or baseline (for anxiety). Please see Table 2 for further details on changes in drug dosing in 
response to symptoms. If an investigator feels that a patient requires a dose reduction and/or dose 
delay other than those specified herein, this may be allowed after communication with the Principle 
Investigator, and would not be considered a protocol violation. 
 
11.3 Hyperglycemia 
 
In preclinical studies, insulin/glucose homeostasis was impacted in various species (mice, rats, dogs), 
as expected from the mode of action of Buparlisib. In both rats and dogs, at the doses used in the 4- 
week studies, these effects were minimal. However, in mice treated at high doses (30 or 60 
mg/kg/day) a clear induction of insulin resistance/insensitivity was observed, without clear influence 
of the dose or the time point of testing. Histopathologically, pancreas and liver showed changes 
which are in concordance with this activity. 
 
Grade 4 Hyperglycemia was also observed in an ongoing Phase Ia study of Buparlisib in patients 
with solid tumors (CBuparlisibX2101). Therefore, no patients with uncontrolled diabetes mellitus 
will be enrolled in this study. In all patients, fasting plasma glucose will obtained at screening and 
will be monitored throughout the trial. For the treatment of glucose disturbances occurring under 
Buparlisib treatment investigators are advised to adhere to the protocol guidelines outlined in table2. 
 
11.4 Cardiac events 
Cardiac safety studies, conducted in vitro and in vivo, did not indicate a prominent 
electrophysiological risk. The only effect considered relevant was a trend towards an increase in 
systolic and diastolic blood pressure, observed in two dog telemetry studies. ECG abnormalities and 
QT prolongation have been noted in CBuparlisibX2101 as detailed in section 3.4.2.  As a precaution, 
no patients with a severe or unstable cardiac disease or cardiac disease requiring continuous 
treatment, and no patients with uncontrolled hypertension will be enrolled in early clinical studies. In 
addition, all patients will be assessed for cardiac diseases before start of treatment, while all patients 
enrolled in the trial will undergo regular cardiac monitoring throughout the conduct of the trial. For 
the treatment of acute cardiac events occurring under Buparlisib treatment investigators are advised 
to adhere to the protocol guidelines. Vital signs, including pulse rate and blood pressure, will closely 
be followed during the early clinical studies. 
 
11.4.1 Management of Cardiac events 
 
At screening, a 12-lead electrocardiogram (ECG) and an ECHO/MUGA will be performed at the 
Screening Visit to assess eligibility and at the end of treatment. Repeat ECGs will be performed at the 


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beginning of every cycle and ECHO/MUGA after every third cycle. Please refer to Table 2 for the 
management of specific cardiac toxicities and drug dose adjustments. 
 
 
11.5 Management of Pneumonitis 
Pneumonitis is a known side effect of rapamycin analogues. Based on the literature, the class of PI3K 
inhibitors has not previously been associated with the development of pneumonitis. Clinically 
significant pneumonitis is typically accompanied by non-specific symptoms including dyspnea, 
nonproductive cough, fatigue, and fever. Diagnosis is generally suspected in individuals who develop 
these symptoms or in asymptomatic individuals in whom a routine chest CT scan reveals a new 
ground glass or alveolar infiltrate. 
 
In ongoing clinical trials with Buparlisib in the single agent setting two cases of  Pneumonitis 
occurred. In the study BuparlisibX2101 one patient experienced Pneumonitis grade 2 eight weeks 
after the first dose of Buparlisib at 100mg which resolved in 7 days after antibiotic therapy and 
discontinuation of the study treatment due to fatigue. In the Japanese study BuparlisibX1101 one case 
of Pneumonitis occurred in a patient given 100 mg one month after the start of study medication with 
Buparlisib. The patient experienced Pneumonitis with fatal outcome which was concomitant to 
progression of underlying malignancy including the progression of existing and the appearance of 
new lesions in combination with increasing pleural effusion (please see Investigator’s Brochure for 
more details). 
 
All patients participating in clinical trials administering Buparlisib will be routinely asked about the 
occurrence of adverse events which could include new or changed pulmonary symptoms (consistent 
with lung abnormalities). CT scans and pulmonary function test 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 2 should be 
followed. Consultation with a pulmonologist is highly recommended for any pneumonitis case 
identified during the study. 
 
11.6 Management of Liver Toxicities 
Monitoring of liver function tests will be performed at: 
• Screening 
• Days 1 and 15 of cycles 1 and 2 
• More frequently if clinically indicated and in patients with borderline acceptable AST, ALT, 
and/or bilirubin values at screening 
 
From Cycle 3 onwards, liver function tests will be performed monthly. In case of any occurrence of 
ALT/ AST/ 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/ bilirubin increase ≥ grade 3, the liver function tests must be 
monitored weekly or more frequently if clinically indicated until resolved to ≤ grade 1; thereafter, 
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  or  more  frequently  if 


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clinically indicated until resolved to ≤ grade 1 or stabilization (no CTCAE grade change over 4 
weeks). 
 
11.7 Reproductive Risks 
 
Male and, to a lesser extent, female reproductive organs were found to be targets of toxicity of 
Buparlisib in both rats and dogs.  Double barrier contraceptives must be used through the trial by 
both sexes. Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 
interactions, and are therefore not considered effective for this study. 
• 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 (e.g. 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 or without hysterectomy) at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up 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 the study and for 12 weeks after 
stopping treatment. Highly effective contraception is defined as either: 
o True abstinence: When this is in 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: Have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks ago. In 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 the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). For female subjects on 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 foam/gel/film/cream/vaginal suppository 
o Oral contraception as well as injected or implanted hormonal methods are not allowed 
as Buparlisib potentially decreases the effectiveness of hormonal contraceptives. 
o Fertile males, defined as all males physiologically capable of conceiving offspring 
must use condoms during treatment and for an additional 12 weeks after study drug 
discontinuation and should not father a child during this period. 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Response and progression will be evaluated in this study using the international criteria by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI, 92(3):205-216, 2000; 
EJC, 45(2):228-247, 2009]. Changes in the largest diameter (uni-dimensional measurement) are used 
in the RECIST v1.1 criteria. Note: lesions are either measurable or non-measurable using the criteria 
provided below: 


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12.1 Definitions 
Measurable lesions: lesions that can be accurately measured in at least one dimension with longest 
diameter ≥ 10 mm by clinical exam or with spiral CT scan (irrespective of scanner type) or MRI (no 
less than double the slice thickness and a minimum of 10mm). Malignant lymph nodes must be 15 
mm in the short axis when assessed by spiral CT scan to be considered measurable. Lytic bone 
lesions, with an identifiable soft tissue component, evaluated by CT or MRI, can be considered as 
measurable lesions if the soft tissue component otherwise meets the definition of measurability 
previously described. Blastic bone lesions are unmeasurable. Tumors that are situated in a previously 
irradiated area are measurable only if unequivocal growth can be documented. 
 
Non-measurable lesions: all other lesions (or sites of disease) including small lesions (longest 
diameter < 20 mm with conventional techniques or < 10 mm using spiral CT scan) are considered 
non-measurable disease. Leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses/abdominal organomegaly (not 
followed by CT or MRI) are all non-measurable. 
 
Target lesions: all measurable lesions – up to a maximum of two lesions per organ and 5 lesions in 
total, representative of all involved organs – should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be calculated 
and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor response. 
Non-target lesions: all other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but the presence 
or absence of each should be noted throughout follow-up. 
 
12.2 Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation. The same method of assessment 
and the same technique should be used to characterize each identified and reported lesion at baseline 
and during follow-up. 
12.3 Response Criteria 
 
12.3.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, taking 
as reference the baseline sum LD. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment started 
or the appearance of one or more new lesions. In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute 


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increase of at least 5 mm. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the 
treatment started. 
 
 
12.3.2 Evaluation of Non-Target Lesions 
 
 
Complete Response (CR): 
Disappearance 
of 
all 
non-target lesions 
and 
normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (< 10 
mm short axis). 
Incomplete Response/Stable Disease (SD): 
Persistence of one or more non-target lesion(s) 
or/and maintenance of tumor marker level above the 
normal limits. 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. 
 
 
12.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). In general, the patient's best response assignment will depend on the achievement 
of both measurement and confirmation criteria. 
 
 
Target lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
12.3.4 Confirmation of Response 
There will be no repeat imaging studies done solely for the purpose of confirming response. Patients 


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will have follow-up imaging studies as outlined in the protocol and responses that are confirmed on 
follow-up scans will be noted. 
 
12.3.5 Duration of Overall Response/Progression Free Survival 
The duration of overall response is measured from the time that measurement criteria are met for CR 
or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively 
documented, taking as reference for PD the smallest measurements recorded since the treatment  
started. 
 
Progression Free Survival will be calculated from the start of treatment until progressive disease or 
death. Patients who die before documented progression will be considered failures at their time of 
death. If the patient did not progress or die, the patient will be censored on the date of last follow-up. 
 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the 
following criteria applies: 
 
▪ Disease progression 
▪ Intercurrent illness that prevents further administration of treatment 
▪ Unacceptable adverse events 
▪ Dose delay of > 21 days from the previous dose 
▪ Patient decides to withdraw from the study 
▪ General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
▪ Inability of subject to comply with study requirements 
If at any time the patient is found to be ineligible for the protocol as designated in the inclusion and 
exclusion criteria detailed in Section 6.0 (i.e., a change in diagnosis), the patient will be removed 
from the study. 
 
14.0    BIOSTATISTICS 
The purpose of this study is to assess the efficacy of Buparlisib in patients with progressive urothelial 
cancer who have received prior cytotoxic chemotherapy. Historically, patients in this setting 
experience a median PFS of 2-3 months (Vaughn 2002; Dreicer 2007; Gallagher 2008). Thus, the 
primary endpoint of this study will be the proportion of patients who are progression-free after eight 
weeks on-study.  Kaplan-Meier analysis of PFS will be performed. 
 
Patients will not be considered evaluable for the primary objective (PFS rate at 8 weeks) if they 
receive < one cycle of protocol therapy and are discontinued from protocol treatment for either rapid 
clinical deterioration related to progression of disease, withdrawal of consent, or adverse events 
unrelated to Buparlisib. These patients will be replaced. They will still be evaluable for toxicity 
assessment. 
 
To establish the safety and toxicity of Buparlisib, the frequency of toxicity will be tabulated 
according to the NCI Common Toxicity Criteria, version 4.0. 
 
 
For the Phase II portion of the study: 


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A minimax Simon two stage study design will be utilized with a PFS rate at 8 weeks of <60% 
considered not promising while a PFS rate of 80% or greater is considered promising. In stage I of 
the trial, 13 evaluable patients will be accrued to the study. If 8 or more patients demonstrate either 
progression on imaging or death after two months on-study, the study will be terminated early and 
declared to have a negative result. If 9 or more are progression-free at two months, enrollment will 
be extended to accrue a total of 35 patients. If 26 or more are progression-free after their two month 
scan (i.e., after stage 2), the treatment will be considered effective and worthy of further testing. 
 
 
For the purposes of this study, the Type I (false acceptance of a non-promising therapy) and Type II 
(false rejection of a promising therapy) error rates have been set at 0.05 and 0.20, respectively. This 
statistical design would effectively discriminate between two-month PFS rates of <60% and >80% 
and yields 80% probability of a positive result if the true two-month PFS rate is >80%. It yields 95% 
probability of a negative result if the true two-month PFS rate is <60%. The probability of early 
stopping under the null hypothesis is 65%. 
 
The secondary endpoint of response rate will be estimated as the proportion of patients meeting the 
criteria outlined above for a complete response or partial response. This proportion will be reported 
along with its binomial confidence interval. 
 
An accrual rate of 2-4 patients per month is anticipated with an expected accrual time of 
approximately 10-20 months for this study. 
 
Buparlisib 
Another secondary end-point involves correlating outcome with an activated PI3 kinase pathway. 
Patient samples will be sequenced for mutations in PTEN and PIK3CA as well as for reduced or 
absent PTEN expression. Patients will be categorized on the basis of PTEN expression levels into 
three categories: no expression, low expression, or high expression. PTEN levels and PTEN and 
PIK3CA mutation status (present/absent) will be correlated with PFS using a log rank test, and with 
response to treatment (complete response/partial response versus no response) using Fisher’s exact 
test. 
 
For the Expansion Cohort: 
 
A one-arm study design will be utilized with a PFS rate at 8 weeks of < 60% considered not 
promising while a PFS rate of 85% or greater is considered promising. 21 evaluable patients whose 
tumors harbor genetic alterations predicted to upregulate the PI3K/Akt/mTOR pathway will be 
accrued to this cohort. If 16 or more patients are progression-free at two months, the treatment will be 
considered effective and worthy of further testing. 
The secondary endpoint of response rate will be estimated as the proportion of patients meeting the 
criteria outlined above for a complete response or partial response. This proportion will be reported 
along with its binomial confidence interval. 
 
An accrual rate of 1-2 patients per month is anticipated with an expected accrual time of 
approximately 10-20 months for this study. 


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For the purposes of this cohort, the Type I (false acceptance of a non-promising therapy) error rate 
has been set at .10 and the power (acceptance of a promising therapy) is approximately .92. 
 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION 
 
15.2 
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. 
15.3 
Randomization 
 
Not applicable. 
 
16.1 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordination of the activities of the protocol 
study team. The data collected for this study will be entered into the Clinical Research Database. 
Source documentation will be available to support the computerized patient record. 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action. Random-sample data quality and protocol 
compliance audits will be conducted by the study team at a minimum of two times per year, more 
frequently if indicated. 
 
 
16.3 
Data and Safety Monitoring 


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The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new policies set 
forth by the NCI in the document entitled “Policy of the National Cancer Institute for Data and Safety 
Monitoring 
of 
Clinical 
Trials,” 
which 
can 
be 
found 
at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and Safety 
Monitoring Plans can be found on the MSKCC Intranet at: http://mskweb2.mskcc.org /irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety and 
quality. There are institutional processes in place for quality assurance (e.g., protocol monitoring, 
compliance and data verification audits, therapeutic response, and staff education on clinical research 
QA) and departmental procedures for quality control, plus there are two institutional committees that 
are responsible for monitoring the activities of our clinical trials programs. The committees, Data and 
Safety Monitoring Committee (DSMC) for Phase I and II clinical trials and the Data and Safety 
Monitoring Board (DSMB) for Phase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its level of 
risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and the monitoring 
procedures will be established at the time of protocol activation. 
 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
17.1.1 Risks of treatment and provisions for preventing adverse events 
 
Potential risks to human subjects include drug related toxicity, pain and discomfort associated with 
Buparlisib side effects, phlebotomy, and possible psychological discomfort from the stresses 
associated with obtaining imaging studies (e.g., CT scan). The side effects and potential toxicities of 
Buparlisib are listed in section 11. All efforts will be made to avoid any complication by completely 
reviewing patients’ symptoms, providing appropriate management, and monitoring blood tests. If an 
adverse medical event occurs, the patient will first contact the primary oncologist or the principal 
investigator. At nights and weekends, there is an oncology physician on call at all times. Patients may 
either call or come directly to the urgent care center at Memorial Hospital (or to their local 
emergency room) to be seen. Patients suffering serious adverse reactions must be carefully followed 
and all follow-up information recorded. 
Safety assessments will consist of monitoring and recording all adverse events and serious adverse 
events, the regular monitoring of hematology, blood chemistry and urine values, regular 
measurement of vital signs and the performance of physical examinations. These assessments 
should be performed within ±2 days of the scheduled day of assessment except for adverse events 
that will be evaluated continuously through the study. 
 
 
17.1.2 Alternatives/Options for treatment 
 
Patients can elect to receive conventional chemotherapeutics such as paclitaxel or pemetrexed for their 
metastatic urothelial cancer. However, there is no FDA-approved drug in this setting. Patients can also 
elect to receive best supportive care or to participate in another clinical trial. Participation in a clinical 
trial is voluntary. 


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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). 
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. 
 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 
written at the top of the report. The report will be forwarded to the FDA by the Institutional 
SAE staff through the IND Office. 
 
 
17.2.1 Serious Adverse Event (SAE) Reporting to Novartis 
The principal investigator has the obligation to report all serious adverse events to the IRB, MSKCC 
IND Office, FDA, and Novartis Pharmaceuticals Drug Safety and Epidemiology Department 
(DS&E). 
 
All  events  must  be  reported,  by  FAX  (877-778-9739),  to  Novartis  Pharmaceuticals  DS&E 


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Department within 24 hours of learning of its occurrence. This includes serious, related, labeled 
(expected) and serious, related, unlabeled (unexpected) adverse experiences. All deaths during 
treatment or within 30 days following completion of active protocol therapy must be reported within 
5 working days. 
 
Any serious adverse event occurring after the patient has provided informed consent and until 4 
weeks after the patient has stopped study participation must be reported. This includes the period in 
which the study protocol interferes with the standard medical treatment given to a patient (e.g. 
treatment withdrawal during washout period, change in treatment to a fixed dose of concomitant 
medication). 
 
Serious adverse events occurring more than 4 weeks after study discontinuation need only  be 
reported if a relationship to the Novartis study drug (or therapy) is suspected. 
 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring: 
• After the patient is enrolled and until 4 weeks after the patient has stopped study 
treatment/participation 
• After the patient begins taking study drug and until 4 weeks after the patient has stopped study 
treatment 
• After protocol-specified procedures begin (e.g., placebo run-in, washout period, double-blind 
treatment, etc.) and until 4 weeks 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 4-week period should only be reported to Novartis if the investigator suspects a causal 
relationship to the study drug. Recurrent episodes, complications, or progression of the initial SAE 
must be reported as follow-up to the original episode within 24 hours of the investigator receiving the 
follow-up information. 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. 
 
The investigator must assess and record the relationship of each SAE to Buparlisib, complete the 
MSKCC CRDB SAE Report and send the completed, signed form by fax (888-299-4565) within 24 
hours to the Novartis Drug Safety and Epidemiology Department. 
 
The original copy of the SAE Report and the fax confirmation sheet must be kept within the Trial 
Master File at the study site. 
 
Follow-up information is sent to the same person 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 (if applicable), 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 drug, a Drug Safety and Epidemiology 


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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. 
 
17.2.1.1 
Pregnancies 
Any pregnancy that occurs during study participation should be reported. To ensure patient safety 
each pregnancy must also 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 Study 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. 
 
 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full details 
of the protocol and study procedures as well as the risks involved to participants prior to their 
inclusion in the study. Participants will also be informed that they are free to withdraw from the study 
at any time. All participants must sign an IRB/PB-approved consent form indicating their consent to 
participate. This consent form meets the requirements of the Code of Federal Regulations and the 
Institutional Review Board/Privacy Board of this Center. The consent form will include the 
following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic 
studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to signing 
the IRB Informed Consent, all patients must agree to the Research Authorization component of the 
informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must receive 


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a copy of the signed informed consent form. 
 
 
19.0 
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20.0 
APPENDICES 
 
Appendix A 
 
Table 5.1 List of prohibited CYP3A inhibitors (strong and moderate) and CYP3A inducers 
 
Strong CYP3A 
inhibitors 
Moderate CYP3A 
inhibitors 
Strong CYP3A 
inducers 
Moderate CYP3A 
inducers 
clarithromycin 
aprepitant 
avasimibe 
Bosentan 
conivaptan 
atazanavir 
Phenobarbital 
(barbiturates) 
Efavirenz 
grapefruit juice 
cimetidine 
carbamazepine 
Etravirine 
indinavir 
ciprofloxacin 
phenytoin 
Modafenil 
itraconazole 
darunavir 
rifabutin 
Nafcillin 
ketoconazole 
diltiazem 
rifampin 
Ritonavir 
lopinavir 
erythromycin 
St. John's wort 
Talviraline 
mibefradil 
fluconazole 
Tipranavir 
nefazodone 
tofisopam 
nelfinavir 
verapamil 
posaconazole 
amprenavir 
ritonavir 
fosamprenavir 
saquinavir 
elvitegravir 
telithromycin 
tipranavir 
troleandomycin 
voriconazole 
This database of CYP inhibitors was compiled from the Indiana University School of Medicine’s 
“Clinically Relevant” Table and from the University of Washington’s Drug Interaction Database 
based on in vitro studies. Strong inhibitors are predicted to increase Buparlisib AUC > 5-fold, and 
moderate inhibitors are predicted to increase Buparlisib AUC ≥ 2-fold but < 5-fold. 
This database of CYP inducers was compiled from the FDA’s “Guidance for Industry, Drug 
Interaction Studies;” from the Indiana University School of Medicine’s “Clinically Relevant” Table; 
and from (Pursche et al. 2008). 
 
 
 
Table 5.2 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 
Torsemide 
gliclazide 
diazepam 
aripiprazole 
maraviroc1 
Troglitazone 
glimepiride 
fluoxetine 
atorvastatin 
midazolam1 


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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 
torsemide 
estazolam 
valdecoxib 
everolimus1 
* This database of CYP substrates was compiled from the Indiana University School of Medicine’s 
“Clinically Relevant” Table, and from (Zhou et al. 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. 
1Sensitive 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). 
 
 
Table 5.3 List of QT prolonging drugs to be used with caution 
Drug 
QT risk 
Comment 
Alfuzosin 
possible risk for Torsades de Pointes 
Amantadine 
possible risk for Torsades de Pointes 
Amitriptyline 
conditional risk for Torsades de Pointes 
Azithromycin 
possible risk for Torsades de Pointes 
Chloral hydrate 
possible risk for Torsades de Pointes 
Citalopram 
conditional risk for Torsades de Pointes 
Clomipramine 
conditional risk for Torsades de Pointes 
Clozapine 
possible risk for Torsades de Pointes 
Desipramine 
conditional risk for Torsades de Pointes 
Diphenhydramine 
conditional risk for Torsades de Pointes 
Dolasetron 
possible risk for Torsades de Pointes 
Doxepin 
conditional risk for Torsades de Pointes 
Dronedarone 
possible risk for Torsades de Pointes 


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Drug 
QT risk 
Comment 
Felbamate 
possible risk for Torsades de Pointes 
Flecainide 
possible risk for Torsades de Pointes 
Fluoxetine 
conditional risk for Torsades de Pointes 
Foscarnet 
possible risk for Torsades de Pointes 
Fosphenytoin 
possible risk for Torsades de Pointes 
Galantamine 
conditional risk for Torsades de Pointes 
Gatifloxacin 
possible risk for Torsades de Pointes 
Gemifloxacin 
possible risk for Torsades de Pointes 
Granisetron 
possible risk for Torsades de Pointes 
Imipramine 
conditional risk for Torsades de Pointes 
Indapamide 
possible risk for Torsades de Pointes 
Isradipine 
possible risk for Torsades de Pointes 
Levofloxacin 
possible risk for Torsades de Pointes 
Lithium 
possible risk for Torsades de Pointes 
Mexiletine 
conditional risk for Torsades de Pointes 
Moexipril/HCTZ 
possible risk for Torsades de Pointes 
Moxifloxacin 
possible risk for Torsades de Pointes 
Nicardipine 
possible risk for Torsades de Pointes 
Nortriptyline 
conditional risk for Torsades de Pointes 
Octreotide 
possible risk for Torsades de Pointes 
Ofloxacin 
possible risk for Torsades de Pointes 
Ondansetron 
possible risk for Torsades de Pointes 
Oxytocin 
possible risk for Torsades de Pointes 
Paliperidone 
possible risk for Torsades de Pointes 
Paroxetine 
conditional risk for Torsades de Pointes 
Perflutren lipid 
microspheres 
possible risk for Torsades de Pointes 
Protriptyline 
conditional risk for Torsades de Pointes 
Ranolazine 
possible risk for Torsades de Pointes 
Risperidone 
possible risk for Torsades de Pointes 
Roxithromycin* 
possible risk for Torsades de Pointes 
*not available in the 
United States 
Sertindole 
possible risk for Torsades de Pointes 
Sertraline 
conditional risk for Torsades de Pointes 
Solifenacin 
conditional risk for Torsades de Pointes 
Tizanidine 
possible risk for Torsades de Pointes 
Trazodone 
conditional risk for Torsades de Pointes 
Trimethoprim-Sulfa 
conditional risk for Torsades de Pointes 
Trimipramine 
conditional risk for Torsades de Pointes 
Venlafaxine 
possible risk for Torsades de Pointes 
Ziprasidone 
possible risk for Torsades de Pointes 
 


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Drug 
QT risk 
Comment 
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
 
 
Table 5.4 Prohibited QT prolonging drugs with risk of Torsades de Pointes 
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 US. 
CYP3A4 substrate with narrow therapeutic index. 
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 US. 
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 
Sensitive CYP3A substrate 
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. Sensitive CYP3A substrate with 
narrow therapeutic index 
Probucol 
known risk for TdP 
No longer available in U.S. 
Procainamide 
known risk for TdP 
Quetiapine 
possible risk for TdP 
Prohibited as drug is a sensitive CYP3A substrate 
Quinidine 
known risk for TdP 
Females>Males. Sensitive CYP3A substrate 
Sotalol 
known risk for TdP 
Females>Males 
Sparfloxacin 
known risk for TdP 
Tacrolimus 
possible risk for TdP 
Prohibited as drug is a sensitive CYP3A substrate with 
narrow therapeutic index 
Terfenadine 
Known risk for TdP 
No longer available in U.S. 
Thioridazine 
Known risk for TdP 
Vardenafil 
possible risk for TdP 
Prohibited as drug is a sensitive CYP3A 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. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-060 A(8) 
Amended: 12/17/13 
Page 61 of 61 
 
 
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