A Phase Ib Study of BKM120 With Weekly Cisplatin and Radiotherapy in High Risk Locally Advanced Squamous Cell Cancer of the Head and Neck
Phase: PHASE1
Conditions: Carcinoma, Squamous Cell of Head and Neck, HPV Positive Oropharyngeal Squamous Cell Carcinoma, Hypopharyngeal Cancer, Early Invasive Cervical Squamous Cell Carcinoma, Carcinoma of Larynx, Cancer of Nasopharynx
Sponsor: Dana-Farber Cancer Institute



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SCHEMA
> 2
Start at 
dose level 1
 
 
Treat cohort 
(3 participants)
 
 
0
DLT
1
 
*Next Dose 
Level
Yes
MTD Expansion 
Cohort
(10 participants)
MTD
established
Recruit 3 more 
participants
*Next Dose 
Level
No
Further 
DLTs?
MTD
established
* If this is the highest dose, then recruit 10 participants to MTD expansion cohort

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TABLE OF CONTENTS
SCHEMA .....................................................................................................................................................................2
1.OBJECTIVES............................................................................................................................................................5
1.1
Study Design.......................................................................................................................................5
1.2
Primary Objectives .............................................................................................................................5
1.3
Secondary Objectives .........................................................................................................................5
2.BACKGROUND......................................................................................................................................................5
2.1
Study Disease......................................................................................................................................5
2.2
Study Drug BKM120..........................................................................................................................6
2.3
Rationale...........................................................................................................................................19
3.PARTICIPANT SELECTION ...............................................................................................................................20
3.1
Eligibility Criteria.............................................................................................................................20
3.2
Inclusion Criteria ................................................................................................................19
3.3
Exclusion Criteria.............................................................................................................................20
3.4
Inclusion of Women and Minorities.................................................................................................23
3.5
Screening ...........................................................................................................................................23
4.REGISTRATION PROCEDURES.........................................................................................................................23
4.1
General Guidelines for DF/HCC and DF/PCC Institutions..............................................................23
4.2
Registration Process for DF/HCC and DF/PCC Institutions............................................................23
4.3
General Guidelines for Other Investigative Sites.............................................................................24
4.4
Registration Process for Other Investigative Sites ...........................................................................24
5.TREATMENT PLAN ............................................................................................................................................25
5.1
Treatment Regimen ..........................................................................................................................25
5.2
Treatment Assignment......................................................................................................................25
5.3
Dose Escalation and Stopping Rules.................................................................................................25
5.4
Interruption or discontinuation of treatment......................................................................................27
5.5
Dose-Limiting Toxicity.....................................................................................................................27
5.6
Follow-up for dose-limiting toxicities...............................................................................................28
5.7
Monitoring of BKM120 suspected toxicities.....................................................................................31
5.8
Agent Administration........................................................................................................................31
5.9
Radiation. ..........................................................................................................................................32
5.10
General Concomitant Medication and Supportive Care Guidelines................................................35
5.11
Duration of Therapy..........................................................................................................................35
5.12
Visit Schedule and Assessments.......................................................................................................35
5.13
Duration of Follow Up......................................................................................................................40
5.14
Criteria for Removal from Study......................................................................................................40
6.DOSING DELAYS/DOSE MODIFICATIONS...................................................................................................41
7.ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS...............................................................50
7.1
Expected Toxicities ..........................................................................................................................50
7.2
Adverse Event Characteristics..........................................................................................................55
7.3
Expedited Adverse Event Reporting ................................................................................................56

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7.4
Expedited Reporting to the Food and Drug Administration (FDA) .................................................56
7.5
Expedited Reporting to Hospital Risk Management ........................................................................56
7.6
Routine Adverse Event Reporting....................................................................................................56
8.PHARMACEUTICAL INFORMATION..............................................................................................................56
8.1
BKM120 ...........................................................................................................................................56
9.BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES............................................................................57
9.1
Laboratory Correlative Studies...........................................................................................................57
9.2
ImmunoProfile…………………………………………………………………………………….58
10.STUDY CALENDAR..........................................................................................................................................58
11.MEASUREMENT OF EFFECT..........................................................................................................................60
12.DATA REPORTING / REGULATORY REQUIREMENTS............................................................................60
12.1
Data Reporting..................................................................................................................................60
12.2
Data Safety Monitoring ....................................................................................................................61
13.STATISTICAL CONSIDERATIONS................................................................................................................61
14.PUBLICATION PLAN.......................................................................................................................................62
15.REFERENCES.....................................................................................................................................................62
16.APPENDICES ................................................................................................................................................64
A: PERFORMANCE STATUS CRITERIA.............................................................................................................64
B: DRUGS THAT ARE PROHIBITED..............................................................................................................65
C: RTOG/EORTC LATE RADIATION MORBIDITY SCORING SCHEMA..........................................................72
D: DFCI MEDICAL ONCOLOGY GRANT PROPOSAL......................................................................................1-48
E: QUESTIONNAIRE GAD-7......................................................................................................................................1
F: QUESTIONNAIRE PHQ-9....................................................................................................................................1-2

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1.
OBJECTIVES
1.1
Study Design
This phase Ib study is combining standard chemoradiotherapy with weekly cisplatin and BKM120 to 
assess tolerability of this combination in high risk patients with locally advanced Squamous Cell 
Carcinoma of the Head and Neck (SCCHN). We will also obtain preliminary information about the 
efficacy of this treatment.
The design of this study follows a classical 3+3 design with a planned expansion cohort of 10 patients 
when after determination of MTD.
BKM120 will start 2 weeks prior to first dose of cisplatin and radiation start. Radiotherapy will be 
standard of care.
Patients will be assessed weekly for adverse events for the duration of the treatment (2 weeks of 
BKM120 and 7 weeks of CRT = 9 weeks) and every 2 weeks after conclusion of CRT during the first 
month, then monthly for 3 months, then every 3 months, until first progression , death, or 2 years from 
study entry whichever occurs first.
Fresh biopsies will be obtained prior to BKM120 and after 7-10d of treatment but prior to start of 
radiation treatment. Biopsies will be snap frozen and used for correlative studies. Biopsies are optional 
but encouraged in patients with accessible tumors.
1.2
Primary Objectives
Determine Maximum Tolerated Dose (MTD) of BKM120/cisplatin in combination with radiation 
therapy in patients with locally advanced squamous cell cancer of the head and neck.
1.3
Secondary Objectives
Assess:

Overall response rate

Time to progression

Survival

Mood alteration from BKM120

Activity of BKM120 as single agent in sequential biopsies
2.
BACKGROUND
2.1
Study Disease
There are >50 000 new cases of squamous cell cancer of the head and neck in the US annually and it is 
the fifth leading cause of death among cancer patients (Jemal, et al 2010)

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The majority of patients present with potentially curable, locally advanced disease. For most patients, 
treatment consists of concurrent chemotherapy plus radiation (chemoradiotherapy, CRT). The standard 
chemotherapy agent used in conjunction over the 7 week radiotherapy course (70 Gy, 35 fractions) is 
cisplatin which can be given either as a bolus infusion every 3 weeks or weekly. Many oncologists 
prefer weekly cisplatin because of better tolerability compared to bolus cisplatin and similar efficacy.
The cure rate of locally advanced stage III or IV disease is only around 50% historically and recurrence 
rates have remained high (Forastiere 2000). The primary risk is loco-regional failure, often within the 
field of prior radiotherapy. Maximizing efficacy of radiotherapy is therefore critical to improve 
prognosis.
In recent years, HPV positive squamous cell cancer has been recognized as a clinical entity that is 
characterized by good response to treatment and excellent prognosis. These patients are typically 
younger and do not have a history of smoking (Gillison 2010). Trials are under way that target this 
patient population with the goal of reducing the intensity of treatment and thus the severity of acute and 
long term side effects. However, these patients represent a minority among the head and neck cancer 
population. If a significant smoking history (>10 pack years) is present, the prognosis is poor, even in 
those patients who have HPV positive disease (Ang, et al 2010). Recurrences present primarily as loco- 
regional failures within the radiation field suggesting resistance to radiation.
Resistance to radiotherapy is complex and poorly understood. Recent data suggest however, that PI3 
Kinase/AKT activity is closely connected with three major radioresistance mechanisms: intrinsic 
radioresistance; tumor-cell proliferation; and hypoxia. Conversely, PI3K inhibition is associated with 
radiosensitization (Hosoi, et al 1998; Bussink 2008; Nakamura, et al 2005). Furthermore, activation of 
the PI3K pathway is frequent in head and neck cancer, either through mutations of PI3Kor other 
components of the PI3K pathway such as mTOR, AKT or PTEN which are present in almost one third 
of all head and neck squamous cell cancers, but may also occur in response to radiotherapy in cases 
without mutations along the PI3K pathway (Stransky et al 2011, Lui at a 2013, Toulany et al 2005). 
HPV positive oropharyngeal cancer, which accounts for a large portion of newly diagnosed patients 
with locally advanced SCCHN is also frequently associated with activating PI3K mutations. 
Furthermore, our own data suggest that presence of genetic mutations of the NFE2L2/KEAP1/CUL3 
pathway which is present in one-third of patients with HNSCCs may play a particularly significant role 
and radioresistance could be restored with BKM120 (Abazeed, et al 2013). As a pan-PI3K inhibitor, 
BKM120 should thus act as an effective radiosensitizer and could help to target a key pathway in 
SCCHN, thus improving outcomes.
2.2
Study Drug: BKM120
NVP-BKM120 (BKM120) is a potent and highly specific oral pan-class I PI3K inhibitor that is a 2,6- 
dimorpholino pyrimidine derivatives. This compound has been studied extensively in non-clinical 
models and is currently being evaluated in clinical trials.
2.2.1
PI3K Pathway and mechanism of action
The phosphatidylinositol-3-kinase (PI3K) signaling regulates diverse cellular functions, including cell 
proliferation, survival, translational regulation of protein synthesis, glucose metabolism, cell migration, 
and angiogenesis (Katso, et al 2001). PI3K signaling also serves a central role in the pathogenesis of

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numerous forms of neoplasia. At the structural level, the enzyme PI3K is composed of a 110-kDa 
catalytic subunit and an 85-kDa adaptor subunit. The PI3K signaling is modulated by multiple 
regulators, including growth factors (such as EGF, IGF-1, and FGF), hormones (such as estrogen and 
thyroid hormone), integrins, intracellular calcium levels, and RAS signaling. PI3K signaling is 
negatively regulated at the level of PIP3 clearance by phospholipid phosphatases, such as the 
phosphatase and tensin homologue (PTEN) protein and the inositol 5-phosphatase-2 (SHIP2) protein. 
Constitutive activation of PI3K signaling is known to be a critical step in mediating the transforming 
potential of oncogenes and tumor suppressors and in many tumor types (Liu 2009). Resistance to a 
variety of therapeutic interventions, including chemotherapy, hormonal therapy and anti-HER2 
therapies, can also be linked to constitutive activation of the PI3K pathway (McCubrey 2006). 
Moreover, preliminary data suggest that activation of the PI3K pathway may be a predictor of poor 
prognostic outcome in many cancers. Molecular changes leading to constitutive activation of the PI3K 
pathway are diverse and include, but are not limited to,
a.
Gain-of-function mutations of PI3K subunits (PIK3CA encoding the PI3K catalytic subunit p110α; 
genes encoding the p85 regulatory subunit) or oncogenes encoding positive regulators of PI3K (e.g.,
HER2, EGFR, RAS, Src-family proteins) or
b. Loss-of-function mutations or epigenetic alterations affecting negative regulators of PI3K signaling 
(e.g., loss of PTEN expression or function) (Chow 2006, Cully 2006)
Together these observations suggest that PI3K pathway could be a critical therapeutic target for the 
treatment of patients with advanced solid malignancies who often have limited therapeutic options 
beyond institutional standard of care. Hence, the pan-PI3K inhibitor BKM120 treatment potentially 
addresses an unmet medical need in such patients.

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Figure 1: Schematic representation of the PI3K pathway
2.2.2
Clinical studies
BKM120 activity against class I PI3K (p110α, -β, -δ and -γ), Class III (Vps34), the class IV mTOR related 
PI3K or PI4Kβ, was assessed using either using 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 Table 1.

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Table 1:        Inhibitory activities (IC50) of BKM120 against other PI3K or related kinases
BKM120 significantly inhibits p110α and the most common p110α mutations (H1047R, E454K, E542K), 
p110β, p110δ and p110γ but not the related proteins Vps34, mTOR or PI4Kβ. Hence BKM120 is classified 
as a pure pan-class I PI3K inhibitor. Enzymatic characterization of the inhibitory properties of the compound 
revealed that BKM120 is a mixed inhibitor of PI3Kα with a strong competitive component (largest on 
Vmax). The cocrystal X-ray structure of BKM120 with PI3Kγ confirmed that BKM120 interacts with PI3K 
into 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 the BKM120 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 the PI3K upstream input 
(Kwiatkowski 2003). When exposed to TSC1 null MEFS, BKM120 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 mechanism of action (BCR-Abl inhibitor STI571, mTORC1 
allosteric inhibitor RAD001), BKM120 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.
2.2.3
Preclinical Safety
Please refer to the Investigator’s Brochure for additional information on the preclinical testing of BKM120.
2.2.4
Pharmacodynamics
BKM120 inhibits wild-type PI3K (IC50: 35 nM), with at least 50-fold selectivity towards this target 
compared to other protein kinases as well as against somatic PI3K activating mutants (H1047R-, E542K-
, and E545K-p110), the other three PI3K paralogs as well as the direct downstream effector AKT. 
BKM120 does not inhibit the related kinases mTOR or Vps34, nor does it inhibit other receptors and ion 
channels profiled (IC50 >10 M). BKM120 reduces the phosphorylation of the direct downstream effector 
Akt in relevant tumor cell lines (e.g., IC50 93 nM for S473P-Akt in Rat1-p110cells). This biological activity 
correlates with inhibition of various other downstream signaling components and with antiproliferative 
activity in a variety of tumor cell lines. BKM120 demonstrates significant tumor growth inhibition in 
relevant tumor xenografts in mice and rats when administered orally, including models of renal cell cancer 
(RENCA, 786-0, Caki-1), glioblastoma multiforme (U87MG), prostate cancer (PC3M), lung cancer (A549, 
NCI-H1975), ovarian cancer (A2780), colorectal cancer (HCT116, HCT-15) and melanoma (A2058, A375).

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In vivo PK/PD analyses of tumor tissues shows a good correlation between exposure, PI3K pathway 
blockade (S473P-Akt levels), and anti-tumor activity.
2.2.5
Nonclinical pharmacokinetics and metabolism
BKM120 showed favorable pharmacokinetic properties in all animal species tested. The absorption of [14C]- 
BKM120-related radioactivity was >84% in the rat. Oral bioavailability was high in rats (73%), was 
complete in dogs, and was moderate in monkeys (42%). The estimated steady state plasma volume of 
distribution (Vss) was high (3.0-3.5 L/kg) in all species tested, suggesting a wide tissue distribution. 
BKM120 was found to cross the blood brain barrier in rats with a tissue-to-plasma ratio of approximately 2 
(Novartis internal data). BKM120 is moderately bound to plasma protein in all species examined (about 
80%). In vitro metabolism studies using human liver microsomes showed that oxidative phase I metabolism 
of BKM120 was predominantly mediated by CYP3A4 (estimated fm > 0.9). Formation of a BKM120 N- 
glucuronide conjugate (Phase II metabolism) via the UDP-glucuronosyltransferase-1 family, polypeptide 
A4 (UGT1A4) was also observed in human liver microsomes supplemented with uridine 5'-diphospho- 
glucuronic acid (UDPGA). BKM120 and metabolites have a low potential for covalent binding to protein. 
BKM120 was determined to be a weak reversible inhibitor of CYP3A4 (IC50 = 8 µM, Ki = 13.4 µM 
unbound) at concentrations reached in the clinic. BKM120 very weakly inhibited the CYP2C family (2C8, 
2C9 and 2C19) with IC50 values ranging from 35-65 μM (34-59 μM unbound). BKM120 did not show 
time-dependent inhibition of CYP450 enzymes. In GLP toxicology studies, BKM120 exposure in terms of 
AUC0-24h and Cmax increased in a dose proportional manner in rat and dog. Results from the rat ADME 
study showed that radioactivity was mainly excreted into the feces. Renal excretion was minor. There was 
no noticeable drug accumulation in dog or male rats after 13 weeks of daily dosing. There was a slight 
accumulation in female rat (< 2 fold). Further information concerning the pharmacokinetic and 
pharmacodynamics properties of BKM120 may be found in the Investigator Brochure.
2.2.6
Safety pharmacology and toxicology
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. 
No relevant electrophysiological effect was seen in dogs. The only effect considered relevant was a trend 
towards an increase in systolic and diastolic blood pressure, which was observed in two dog telemetry 
studies. In rats and dogs, clinical pathology and histopathology findings showed quantitative reductions of 
lymphoid and erythroid counts and lymphoid tissue hypoplasia. The pancreas was seen to be affected by 
treatment with BKM120, particularly in dogs, where acinar cell toxicity was seen in the exocrine part of this 
organ. At higher doses in the 2-week dose-range-finding study in rats, there were histopathological findings 
in both the endocrine as well as the exocrine pancreas. Male sexual 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 (highest dose), although 
a clear trend towards recovery was seen. In individual female rats, minimal to slight cyst formation occurred 
in the Graafian follicles. In dogs, there was no effect on female sexual organs. Glucose homeostasis was 
affected in various species (mice, rats, dogs), as expected from the mode of action of BKM120. However, 
these effects were minimal in both rats and dogs at the doses used in the 4-week studies.
Other safety considerations include:

After up to 2 weeks of treatment with up to 2.5 mg/kg/day of BKM120, alterations in the levels of 
multiple brain neurotransmitters were seen in rats.

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
No evidence for a direct DNA interaction was found in an Ames test and two chromosome aberration 
tests in vitro with BKM120. However, evidence of a genotoxic potential with BKM120 has been 
seen in vitro and in vivo and is likely due to an aneugenic effect.

No phototoxic potential or any effect on wound healing has been identified with BKM120 in pre- 
clinical studies.
In conclusion, the majority of the observed effects were related to the pharmacological activity of BKM120 
as an inhibitor of PI3K, such as a potential influence on glucose homeostasis and the risk of increased blood 
pressure.
Please refer to the Investigator’s Brochure for additional information on the preclinical testing of BKM120.
2.2.7
Pharmacodynamic biomarkers
The preclinical in vivo studies with xenografted tumors in mice indicate that detectable inhibition of AKT 
phosphorylation, which is an accurate readout of PI3K activity, as well as further suppression of downstream 
signaling (e.g., phosphorylation of S6) was obtained soon after BKM120 administration. PI3K is known to 
serve a pivotal role in the regulation of glucose homeostasis, and preclinical studies in which oral glucose 
and intraperitoneal insulin tolerance tests were performed suggesting post-treatment induction of insulin 
insensitivity/resistance. Therefore, throughout the trial the circulating levels of several markers for glucose 
metabolism (e.g., glucose, insulin, C-peptide) will be assessed as an additional measure of PI3K signaling 
modulation.
2.2.8
Clinical experience
2.2.8.1
Clinical experience with BKM120
As of September 2012, over 600 patients were enrolled into clinical studies with BKM120 (as 
single agent or combinations). The Novartis sponsored clinical studies were:

Phase I single agent studies [CBKM120X2101], [CBKM120X1101], and [CBKM120Z2102]

Phase II single agent studies [CBKM120C2201] and [CBKM120D2201]

Phase I combination studies [CBKM120B2101], [CBKM120X2107], [BKM120E2101], 
[CBEZ235A2118], [LDE225X2114], [CSTI571X2101], and [CMEK162X2101].

Phase II combination studies [CBKM120F2202]

Phase III combination study [CBKM120F2302]
For the interest of the current protocol, results presented below will focus on phase I single agent studies 
([CBKM120X2101], [CBKM120X1101]), and phase I combinations in breast cancer patients 
([CBKM120X2107], [CBEZ235A2118]). Please refer to the current version of the IB for more detailed 
information.
2.2.8.2
Human safety and tolerability data
Study recruitment in study [CBKM120X2101] has been completed with forty (40) patients included in the 
dose escalation phase at 6 dose levels (all once daily) (12.5 mg (1 patient); 25 mg (2), 50 mg (5), 80 mg

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(11), 100 mg (17), 150 mg (4)) . Dose limiting toxicities were hyperglycemia, skin rash, epigastric pain, 
mood disorder, joint pain. The MTD for BKM120 given as single agent, once daily was established at 100 
mg/day (Bendell 2012). Forty-three additional patients were treated in the expansion cohort at 100 mg/day. 
At the cut-off date of 4th July 2011 (Graña 2011), patient characteristics of 82 patients analyzed were as 
follows: median age 55 years (range 30–78); ECOG performance status 0/1/2 for 35/46/1 patients, 
respectively. The safety experience for this single agent trial of BKM120 is described in Table 2.
Table 2:        Most frequent AEs (> 15%) related to study drug in study CBKM120X2101 (n=81)
Event
All grades
Grade 3/4
Fatigue/asthenia
31(38.3%)
3 (3.7%)
Decreased appetite
24 (29.6%)
-
Diarrhea
24 (29.6%)
3 (3.7%)
Hyperglycemia
24 (29.6%)
4 (4.9%)
Nausea
24 (29.6%)
-
Rash
22 (27.2%)
4 (4.9%)
Mood
altered/emotional 
disorder/affective 
disorder
17 (21.0%)
4 (4.9%)
Transaminases increased
16 (19.8%)
9 (11.1%)
Anxiety
14 (17.3%)
1 (1.2%)
Depression
14 (17.3%)
1 (1.2%)
A second single agent trial, [CBKM120X1101] was a phase I dose escalation study in Japanese patients 
with advanced solid tumors with dose levels ranging from 25 to 100mg/day (Doi 2011). Enrolment of 15 
patients has been completed, including 9 patients at 100 mg/day. One DLT (G4 hepatic function abnormal) 
was observed in the 100 mg/day group. The most common G3 or G4 adverse events occurring in at least 2 
patients were hepatic function abnormal in 6 patients including transaminase increase in 2 patients, G3 
anemia in 2 patients, hypokalemia in 2 patients. The recommended phase 2 dose (RP2D) for Japanese has 
been determined at 100 mg/day, as in the western population.
The safety and efficacy of BKM120 combined with trastuzumab in patients with relapsing HER2- 
overexpressing BC who have previously failed trastuzumab are being explored in a phase Ib/II, multi-center 
study [CBKM120X2107]. The combination of BKM120 and trastuzumab was shown to be tolerable, and 
with one dose-limiting toxicity (G3 asthenia), the MTD for BKM120 was declared at 100 mg/day (Saura 
2011). Among the 18 patients evaluated in the Phase Ib part, the following G3/G4 AEs were observed: 
asthenia, ALT elevation, hyperglycemia, mood alteration, affective disorder, hypersensitivity, 
photosensitivity reaction, and rash. These AEs were all short-lived and reversible with either dose 
interruption or modifications as needed. In the phase II portion of the study, as of June 2012, 53 patients 
have been enrolled and received BKM120 at the recommended phase 2 dose (RP2D) of 100 mg/day in 
combination with trastuzumab (Pistilli ESMO 2012). Overall the treatment was well tolerated. Most 
common AEs (>15%) included gastro-intestinal toxicity (e.g. diarrhea, nausea, stomatitis), rash, fatigue, 
transaminase increase, hyperglycemia, depression and anorexia. No G4 AEs have been reported. Most 
common G3 treatment related AEs included transaminase increase (~10%), rash (9%) and fatigue (6%), and 
were consistent with phase Ib findings with as well as single agent BKM120.

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Details on liver toxicity, mood alterations, pneumonitis, hyperglycemia, skin rash and hypersensitivity as 
side effects of BKM120 are presented below.
2.2.8.3
Liver Toxicity
Liver toxicity has been analyzed based on a search of multiple MedDRA event terms and is presented in 
Table 3. Liver function test (LFT) alterations observed during ongoing and completed studies have been 
mostly transaminase enzyme increases (ALT and/or AST). Data suggest a higher rate of grade 3/4 liver 
enzyme elevations in Japanese patients (44.4%) in [CBKM120X1101] study, however, the number of 
patients (9 patients) treated at 100mg in this study was limited.
Although transaminase increases are relatively common, only a few of the patients with LFT alterations had 
other simultaneous observations related to impaired liver function (e.g. bilirubin increase or clinical 
symptoms). Based on these findings, conservative inclusion criteria and guidelines to monitor and to follow 
patients with LFT alterations (including dose and schedule modifications) are currently implemented in 
study protocols investigating BKM120. Please refer to the respective inclusion/exclusion criteria.
2.2.8.4
Mood disorders
Recently, a number of publications demonstrated that the modulation of AKT/GSK3 signaling pathway by 
neurotransmitters is important for the regulation of behavior (Beaulieu 2009). Preclinical studies conducted 
in rats to investigate the effect of BKM120 on different neurotransmitters have shown that repeated 
administration of BKM120 resulted in an enhanced decrease in glutamate, dopamine, serotonin and 
epinephrine as well as in an enhanced increase in GABA and HIAA.
Psychiatric side effects events have been reported in patients treated with BKM120 and are currently under 
investigation. The current data does not allow the identification of any sign or symptom which could predict

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patient susceptibility to BKM120 induced psychiatric disorders. A broad range of AEs including (but not 
limited to) depression, anxiety, mood alteration, confusion, affective disorders, insomnia, hallucination, 
panic disorders, irritability or difficulties to concentrate have been reported.
Considering the initial symptoms reported during the first-in-man [CBKM120X2101] study, mood 
disorders have been analyzed based on HLGT 'Mood disorders and disturbances NEC' or HLGT 'Personality 
disorders disturbances in behavior' or HLGT “Psychiatric and behavioral symptoms NEC” or HLGT 
“suicidal and behaviors NEC”. The frequency of mood disorders thus defined, regardless of study drug 
relationship, ranged from 6.3% in [CBKM120B2101] study to 50.0% in dose escalation part of 
[CBKM120X2107] study, however, the majority of events were of grade 1 or 2 severity (Table 4).
Therefore, patients must be regularly and closely monitored for signs and symptoms of neuropsychiatric 
disorders with particular attention to changes in mood and personality. To support the identification and the 
assessment of psychiatric disorders, two self-assessment questionnaires, the Patient Health Questionnaire-
9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7), are part of the protocol. Any AEs 
(symptom/diagnosis) should be accurately reported using CTCAE toxicity/grading. A consultation with a 
psychiatrist is strongly recommended for any psychiatric adverse event grade ≥ 1. Protocol guidelines 
further disqualify patients with an active and/or history of major psychiatric disorder. Please refer to the 
respective inclusion/exclusion criteria.
2.2.8.5
Lung Toxicity/ Pneumonitis
Lung changes compatible with pneumonitis have not been observed in the preclinical setting. Among the 
current studies, pneumonitis was reported in five cases and interstitial lung disease in one further case. One 
case of pneumonitis had a fatal outcome in a complex clinical context, combining progression of lung 
metastases and possible infection with pneumocystis carinii or cytomegalovirus. Apart from this fatal case, 
the conditions were resolved or improving at the latest report (except one non-suspected SAE which was

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unchanged).
The currently available data still do not enable a clear assessment about the causal relationship of 
pneumonitis with BKM120 treatment. Newly appearing or significant changes in pulmonary symptoms 
(which cannot be explained by the underlying disease), should be carefully followed with appropriate 
management as per institutional guidelines and the guidelines provided in the protocol. Please refer to Table 
15 for more detailed guideline on the diagnosis and management of Pneumonitis.
2.2.8.6
Hyperglycemia events
The PI3K/AKT pathway plays a significant role in regulating glucose metabolism, particularly by regulating 
glucose transport into adipocytes and muscle tissue. Therefore, hyperglycemia is considered as an “on 
target” effect of BKM120. Regular monitoring of FPG, HbA1c, and insulin C-peptide is implemented in 
BKM120 protocols to evaluate this pharmacodynamics effect. Transient increases of plasma glucose levels 
have been reported commonly in patients treated with BKM120. Hyperglycemia observed at 100 mg/day, 
regardless of study drug relationship, in ongoing BKM120 studies are summarized in Table 5.
The highest rate of hyperglycemia (57.1%) was reported in [CBKM120C2201], a Phase II study conducted 
in patients with advanced endometrial carcinoma, as this was the only study among those listed allowing 
the enrollment of patients with controlled diabetes mellitus.
However, so far, there were only two patients that experienced a grade 4 hyperglycemia, and they both were 
treated at the highest dose level (150mg/day) in [CBKM120X2101] study. In order to mitigate the potential 
risk of developing uncontrolled hyperglycemia, only patients with normal glycaemia defined as fasting 
plasma glucose (FPG) ≤ 120 mg/dL are eligible for study entry. Patients who have a poorly controlled 
diabetes mellitus defined as (HbA1c >8%) are excluded. In addition, detailed guidelines to monitor patients 
are recommended including: regular monitoring of FPG to early identify hyperglycemia and prevent

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acute/sub-acute complications, caution warranted for patients with history of DM, or taking corticosteroids, 
or with other severe medical conditions (e.g. infections). Hyperglycemia management guidance also 
includes: dietetic measures and appropriate anti-diabetic medications as per investigator’s decision and/or 
local guidelines, consider oral anti-diabetics such as metformin as first-line treatment for sustained and more 
severe hyperglycemia (other drugs as appropriate), if sulfonylurea or insulin are initiated, patients should 
be instructed on how to recognize (and treat) hypoglycemia, for patients with history of DM, management 
should be based on prior anti-DM treatment. Detailed guidelines to monitor and manage patients who 
develop hyperglycemia are provided in Table 5.
2.2.8.7
Skin rash and hypersensitivity
Skin rash is commonly observed in patients treated with BKM120. The rate of skin rash and other related 
event terms ranged from 18.4% to 41.4% in single agent studies with a representative number of patients 
treated with 100mg of BKM120. In one study with nine evaluable patients, seven patients (77.8%) reported 
such events Table 6.
Studies of BKM120 in combination with other agents tended to report slightly higher frequencies (e.g. 
combination with MEK inhibitor). The skin rashes seen have no typical location or distribution pattern, are 
mainly papulo-macular (only a minority acneiform) and are frequently associated with pruritus. Events have 
been reversible after treatment interruption and/ or dose reduction. Effective medications have included 
antihistamines, topical corticosteroids and/or low-dose systemic corticosteroids (the latter should be used 
with caution due to the increased risk of hyperglycemia). There have been few cases reported of allergic 
reactions and DRESS (drug rash with eosinophilia and system symptoms), but these have not been of acute 
onset or of a severe nature. Complementary information collected suggests that sun exposure may 
exacerbate the condition and should be avoided; however, genuine photosensitivity reaction has not been 
confirmed and no phototoxic potential seen pre-clinically. Patients are advised (e.g. in the written patient 
information) to avoid sun exposure, or take measures to protect themselves from intense sunlight, during 
study treatment.

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2.2.8.8
Human pharmacokinetic and metabolism data
Preliminary clinical pharmacokinetic data of BKM120 after single and multiple daily dosing is available 
from the first-in-human trial [CBKM120X2101]. BKM120 was administered as a capsule (doses ranging 
between 12.5 and 150 mg) and full pharmacokinetic profiles were collected on Day 1, Day 8 and Day 28 of 
Cycle 1. BKM120 was rapidly absorbed, with the median time to reach the peak plasma concentration 
(Tmax) ranging from 1.0 to 1.75 hours following administration. Tmax was independent of dose and was 
not altered after multiple oral doses. Variability in systemic drug exposure was moderate at all dose levels. 
At 100 mg the variability in systemic drug exposure and Cmax (CV %) at steady-state was moderate, about 
36% and 25%, respectively. During once daily dosing, plasma BKM120 concentrations were found to 
accumulate in reaching steady-state. After one week of oral daily dosing (day 8), both Cmax and AUC0- 
24h were approximately 3-fold higher than after a single dose (day 1). The mean accumulation ratio (Racc) 
of BKM120 at 100 mg was 2.7 and 3.3 on days 8 and 28, respectively, indicating the absence of significant 
drug accumulation after day 8.
The decay in BKM120 plasma concentration over time was bi-exponential, with an apparent long terminal 
half-life. The mean T1/2,acc (effective half-life, obtained from drug accumulation) calculated from 
exposure data at day 28 ranged between 38 and 49 hours across all dose levels. T1/2,acc was found to be 
independent of dose. Based on the effective half-life, steady state BKM120 plasma levels can be expected 
to be reached after 1 week of daily dosing. Furthermore the preliminary PK data within the Japanese 
population [CBKM120X1101] show no significant differences in Cmax or AUC0-24h with the Caucasian 
population [CBKM120X2101]. A preliminary population PK analysis, including data from studies 
[CBKM120X2101] and [CBKM120X1101] confirmed those findings (Novartis internal data).
In study [CBKM120B2101], BKM120 was administered with GSK1120212 (a MEK inhibitor). Single dose 
pharmacokinetics of BKM120 appeared to be unaffected by concomitant administration of GSK1120212. 
Concurrent chronic daily administration of both drugs, however, consistently resulted in a dose- and time-

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dependent decrease in BKM120 systemic drug exposure. After 28 days of once daily combination treatment 
of BKM120 with GSK1120212 (1.5-2.0 mg), exposure of BKM120 at system steady-state was decreased 
by approximately 45-50%, when compared to the mean value determined from [CBKM120X2101]. 
Decrease in exposure was less pronounced at lower doses of GSK1120212 (0.5- 1 mg) (approximately 25%). 
The overall drug clearance of BKM120 increased up to 2-fold in the presence GSK1120212. This dose and 
time dependent effect of GSK1120212 on BKM120 oral clearance is most likely explained by induction of 
CYP3A4, a property of GSK1120212, which has been demonstrated in vitro. These findings are also 
consistent with a high dependence of BKM120 clearance on CYP3A4 activity. Similar changes in the 
pharmacokinetics of BKM120 could be expected to occur when other inducers of CYP3A4 are combined with 
BKM120 treatment (see concomitant medication ). The pharmacokinetics of GSK1120212 was not altered 
by BKM120.
In study [CBKM120X2107] a daily dosing regimen of BKM120 was tested in combination with weekly 
infusions of trastuzumab in patients with relapsed HER2-overexpressing breast cancer. Preliminary 
pharmacokinetic data indicated that the systemic drug exposure (Cmax and AUC) of oral BKM120 in 
combination with trastuzumab was similar to the single agent data. Trastuzumab trough levels were 
consistent with those previously reported to be therapeutic (i.e., generally greater than 20 μg/ml).
2.2.9
Clinical efficacy data
Sixty six patients were evaluable for response in study [CBKM120X2101] where all patients in the 
expansion cohort were required to have mutated and/or amplified PIK3CA and/or mutated PTEN or null/low 
PTEN protein expression: partial tumor responses (PR) were observed in 3 patients, one of which was a 
RECIST v1.0 confirmed PR in a patient with triple negative breast cancer and the other 2 not confirmed (1 
patient with metastatic breast cancer and 1 patient with parotid carcinoma) (Graña 2011). The first patient 
was a 61 year-old female with poorly differentiated ductal metastatic breast cancer assessed as triple 
negative (ER-, PgR-, HER2-), PI3KCA wild type, PTEN IHC positive. Since 2006 she received many 
previous anticancer agents (cyclophosphamide, doxorubicin, gemcitabine, docetaxel, paclitaxel, 
vinorelbine, capecitabine, etoposide, anastrazole). As progressive disease developed (bulky lymph node 
involvement and local breast relapse), she was enrolled (April 2009) in the Phase I study of BKM120 in the 
100 mg/day cohort. A metabolic response (61% decrease in SUV) was observed after 2 cycles, followed by 
a RECIST partial response (66% tumor shrinkage) after 4 cycles. This patient continues to receive treatment 
beyond 32 cycles. The second patient was a 52 year-old female with moderately differentiated ductal 
metastatic breast cancer, assessed as ER positive, HER2 negative, PI3KCA mutated (E545K & H1047Y), 
PTEN IHC positive. She had been previously treated with several antineoplastic agents. When she received 
BKM120 at 100 mg/day (January 2010), she had measurable metastases in the brain, lung and liver. At the 
second radiological assessment after receiving 4 cycles of BKM120 treatment, a 45% reduction of the sum 
of the lesions was recorded. The TTP for this patient was 24 weeks. The third patient was a 45 year-old man 
with grade 4 parotid gland ductal carcinoma, PI3KCA wild type, PTEN IHC positive. He had been 
previously treated with doxorubicin and adriamycin. After disease progression was observed on this regimen 
he was enrolled in the 100mg/day cohort (July 2010) in the [CBKM120X2101] study. At the first 
radiological assessment after receiving 2 cycles of BKM120 treatment, a 33% reduction of the sum of the 
lesions was recorded. The TTP for this patient was 16 weeks.
As of the data cut-off 04July2011, preliminary analysis shows forty-five percent of patients (30 of 66 
evaluable) had stable disease as best response, with 20 patients (30%) with a disease stabilization of 3 
months or longer. A trend towards better activity (long-term stabilizations) has been observed at the higher 
dose cohorts, also expressed in metabolic FDG-PET response. However, considering the impact of a PI3K

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inhibitor on glucose metabolism, further data needs to be acquired to understand whether the current FDG- 
PET assessment data can be used as a predictive factor for efficacy.
With regards to pharmacodynamic markers observed in study [CBKM120X2101], down regulation of pS6 
in skin by 30-80% was demonstrated in 28 out of the 38 evaluable patients at 100 and 150 mg/d and more 
than 25% FDG-PET signal decrease in patients at doses greater than the MTD.
With regards to the PI3K pathway activation, two of the three responders described above, one had a tumor 
with the PIK3CA mutation. Moreover, 18 patients had a stable disease lasting for 16 weeks or longer, 
including 8 patients who had tumors with an activated PI3K pathway. These data are promising and 
continued exploration of the activity of BKM120 in patients with activated PI3K pathway is warranted.
More specifically, in [CBKM120X2101], 25.3% (21/83) of patients had metastatic breast cancer. At the cut- 
off date of 4th July 2011, twenty breast cancer patients were evaluable for objective tumor response by 
RECIST 1.0. Two breast cancer patients (11%), described above exhibited partial responses. For these 2 
patients, the treatment duration was 27+ (ongoing) and 5 months, respectively. An additional 8 breast cancer 
patients (40%) had stable disease. Median progression-free survival was 60 days and the 6-month PFS rate 
was 33% (Rodon 2011).
Please refer to the Investigator’s Brochure for additional information on the available clinical experience 
with BKM120.
2.3
Rationale
Because of the connection with radioresistance and the high rate of mutations along the PI3K pathway in 
HNSCC, PI3Kinase inhibition should be an excellent strategy to overcome radioresistance and ultimately 
improve outcomes in LAHNC patients at high risk for loco-regional recurrence who undergo concurrent 
chemoradiotherapy with curative intent.
We propose a phase Ib study using the combination of BKM120 in combination with standard weekly 
cisplatin and radiotherapy in patients who are treated for locally advanced disease with curative intent.
We believe that weekly cisplatin dosing at 30mg/m2 is a reasonable standard as a starting dose since over 
the course of a 7 week chemoradiotherapy regimen, patients receive a total cumulative dose of 210mg/m2, 
similar to the two standard doses of bolus cisplatin 100mg/m2 each.
A retrospective study comparing chemoradiotherapy with bolus cisplatin (100mg/m2) versus weekly 
cisplatin (20mg/m2 weekly) failed to demonstrate significant differences in outcome (Kose et al 2011).
A prospective study similarly concluded that weekly cisplatin versus bolus cisplatin (100mg/m2 d 1, 22) 
was equally effective. The starting dose of 40mg/m2 had to be modified in many cases and the cut-off for 
successful treatment with cisplatin was a cumulative dose of 200mg/m2 or more (Homma et al 2011).
Even under the unlikely assumption that BKM120 is not active, the starting dose of cisplatin should provide 
sufficient radiosensitization compared to the standard of care.

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3.
PARTICIPANT SELECTION
Depending on toxicities encountered during the trial. Up to 46 patients are anticipated to be treated on this 
protocol.
3.1
Eligibility Criteria
Patients must have baseline evaluations performed prior to the first dose of study drug and must meet all 
inclusion and exclusion criteria. Results of all baseline evaluations, which assure that all inclusion and 
exclusion criteria have been satisfied, must be reviewed by the Principal Investigator or his/her designee 
prior to enrollment of that patient. In addition, the patient must be thoroughly informed about all aspects of 
the study, including the study visit schedule and required evaluations and all regulatory requirements for 
informed consent. The written informed consent must be obtained from the patient prior to enrollment. 
Patients eligible for enrollment in the treatment phase of this study must meet all of the following criteria:
3.2
Inclusion Criteria
1. Patients with stage III/IV per tumor/nodes/metastasis (TNM) guidelines for head and neck sites 
(American Joint Committee on Cancer [AJCC] 7th Edition), locally advanced, biopsy proven squamous 
cell cancer of the head and neck that undergo chemoradiation as their primary treatment with curative 
intent. Patients with oropharynx (HPV positive and HPV negative), hypopharynx, larynx primaries, 
nasopharynx as well as those with documented SCC of the cervical lymph nodes, with unknown 
primaries, are eligible.
2. >10 pack years of tobacco use or more
3. Age ≥ 18 years
4. ECOG performance status  2 (Appendix A)
5. Patients must have at least one site of measurable disease [if applicable] (per RECIST 1.1 for solid 
tumors or the appropriate disease classification/criteria for the target population)
6. Adequate bone marrow function as shown by: ANC > 1.5 x 109/L, Platelets > 100 x 109/L, Hb >9 
g/dL
7. Total calcium (corrected for serum albumin) within normal limits (biphosphonate use for malignant 
hypercalcemia control is not allowed)
8. Magnesium ≥ the lower limit of normal
9. Potassium within normal limits for the institution.
10. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range
11. 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)
12. Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min
13. Serum amylase ≤ ULN
14. Serum lipase ≤ ULN
15. Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L)
16. Signed informed consent

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17. INR ≤ 2
3.3
Exclusion criteria
Patients eligible for enrollment into the treatment phase of this study must not meet any of the following 
criteria:
1. Presence of distant metastatic disease
2. Less than or equal to 10 pack years of tobacco history
3. Patients who have received prior chemotherapy
4. Patients who have received prior radiation to the head and neck or adjacent anatomical site (e.g., upper 
lobe lung, brain)
5. Patients who have received prior treatment with a P13K inhibitor.
6. Patients with a known hypersensitivity to BKM120 or to its excipients
7. Patients with acute or chronic liver, renal disease or pancreatitis
8. Patients with the following mood disorders as judged by the Investigator or a psychiatrist, or as a 
result of patient’s mood assessment questionnaire:

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) or patients with active severe 
personality disorders (defined according to DSM- IV) are not eligible. Note: for patients with 
psychotropic treatments ongoing at baseline, the dose and the schedule should not be 
modified within the previous 6 weeks prior to start of study drug.

≥ CTCAE grade 3 anxiety

Meets the cut-off score of ≥ 12 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7 mood scale, 
respectively, or selects a positive response of “1, 2, or 3” to question number 9 regarding 
potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9)
9. Patients with diarrhea ≥ CTCAE grade 2
10. Patient has active cardiac disease including any of the following:

Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Grated acquisition 
(MUGA) scan or echocardiogram (ECHO)

QTc > 480 msec on screening ECG (using the QTcF formula)

Angina pectoris that requires the use of anti-anginal medication

Ventricular arrhythmias except for benign premature ventricular contractions

Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with 
medication

Conduction abnormality requiring a pacemaker

Valvular disease with document compromise in cardiac function

Symptomatic pericarditis
11. Patient has a history of cardiac dysfunction including any of the following:

Myocardial infarction within the last 6 months, documented by persistent elevated cardiac 
enzymes or persistent regional wall abnormalities on assessment of LVEF function

History of documented congestive heart failure (New York Heart Association functional 
classification III-IV)

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
Documented cardiomyopathy
12. Patient has poorly controlled diabetes mellitus or steroid-induced diabetes mellitus
13. 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

Significant symptomatic deterioration of lung function. If clinically indicated, pulmonary 
function tests including measures of predicted lung volumes, DLco, O2 saturation at rest on 
room air should be considered to exclude pneumonitis or pulmonary infiltrates.
14. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of 
BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, 
or small bowel resection). Patients with unresolved diarrhea will be excluded as previously indicated
15. Patients who are currently receiving treatment with medication with a known risk 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. Please refer to Table 18 for a list of prohibited QT 
prolonging drugs with risk of Torsades de Pointes.
16. Patients receiving chronic treatment with steroids or another immunosuppressive agent.

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 corticosteriods treatment (e,g dexamethasone 2 
mg/day, prednisolone 10 mg/day) for at least 14 days before start of study treatment are 
eligible.
17. 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.
18. 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 B for a list of prohibited inhibitors and inducers 
of CYP3A (Please note that co-treatment with weak inhibitors of CYP3A is allowed).
19. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not 
recovered from side effects of such therapy.
20. Patients who are currently taking therapeutic doses of warfarin sodium or any other coumadin- 
derivative anticoagulant.
21. Women who are pregnant or breast feeding or adults of reproductive potential not employing an 
effective method of birth control. 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 of child-bearing 
potential, defined as sexually mature women who have not undergone a hysterectomy or who have not 
been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time 
in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 72 hours prior 
to initiating treatment.

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

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appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with 
serum FSH levels > 40 mIU/mL [for US only: 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 treatment and for 4 weeks after 
stopping treatment.

The highly effective contraception is defined as either:
1. 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.
2. 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.
3. Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate). For female subjects on the study, the vasectomised male partner should be 
the sole partner for that patient.
4. Use of a combination of any two of the following (a+b):
a) Placement of an intrauterine device (IUD) or intrauterine system (IUS)
b) Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/vaginal suppository

Oral contraception, injected or implanted hormonal methods are not allowed as BKM120 
potentially decreases the effectiveness of hormonal contraceptives.

Fertile males, defined as all males physiologically capable of conceiving offspring must use 
condom during treatment, for 4 weeks after stopping treatment and for additional 12 weeks (16 
weeks in total after study drug discontinuation) and should not father a child in this period.

Female partner of male study subject should use highly effective contraception during dosing 
of any study agent and for 16 weeks after final dose of study therapy.
22. Known diagnosis of human immunodeficiency virus (HIV) infection
23. History of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised 
carcinoma in situ of the cervix
24. Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator
3.4
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.

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3.5
Screening
After consent, patients will undergo screening/baseline testing outlined in table 17. Details of the procedures 
can be found in section 5.12.
4.
REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC and DF/PCC Institutions
Eligible participants will be registered with the DF/HCC Quality Assurance Office for Clinical Trials 
(QACT) central registration system. Registrations must occur prior to the initiation of therapy. Any 
participant not registered to the protocol before treatment begins will be considered ineligible and 
registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the QACT 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol treatment. Issues that would cause treatment delays 
should be discussed with the Overall Principal Investigator (PI). If a participant does not receive protocol 
therapy following registration, the participant’s registration on the study may be canceled. Notify the QACT 
Registrar of registration cancellations as soon as possible.
4.2
Registration Process for DF/HCC and DF/PCC Institutions
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM Eastern 
Standard Time. In emergency situations when a participant must begin treatment during off-hours or 
holidays, call the QACT registration line at 617-632-3761 and follow the instructions for registering 
participants after hours.
The registration procedures are as follows:

Obtain written informed consent from the participant prior to the performance of any protocol 
specific procedures or assessments.

Complete the QACT protocol-specific eligibility checklist using the eligibility assessment 
documented in the participant’s medical record and/or research chart. To be eligible for registration 
to the protocol, the participant must meet all inclusion and exclusion criterion as described in 
the protocol and reflected on the eligibility checklist.

Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 617-632-2295. 
For Phase I protocols, attach participant dose level assignment confirmation from the sponsor.

The QACT Registrar will (a) review the eligibility checklist, (b) register the participant on the 
protocol, and (c) randomize the participant when applicable.

An email confirmation of the registration and/or randomization will be sent to the Overall PI, study

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coordinator and treating investigator and registering person immediately following the registration 
and/or randomization.
4.3
General Guidelines for Other Investigative Sites
N/A
4.4
Registration Process for Other Investigative Sites
N/A
5.
TREATMENT PLAN
5.1
Treatment Regimen
The investigational therapy used in the course of this study is BKM120. Treatment with BKM120 starts 2 
weeks prior to cisplatin and radiotherapy and continues until the end of radiotherapy.
Study medication will be self-administered by the patients continuously throughout radiation. In order to 
assure compliance with protocol procedures drug administration will be thoroughly explained to the 
patients. During the study, BKM120 will be administered orally. It is given every day including weekend 
days. Administration of BKM120 stops with the end of radiotherapy. If radiation is held due to toxicity, 
BKM120 and cisplatin will be held as well. If cisplatin is held due to toxicity, BKM120 and radiation will 
continue. If BKM120 is held due to toxicity, cisplatin and radiation will continue. Medication labels will 
comply with US legal requirements and be printed in English. The storage conditions for study drug will be 
described on the medication label.
BKM120 will be provided by Novartis Pharmaceuticals free of charge. BKM120 is formulated as capsules 
for oral administration of 10mg and 50mg strength. Capsules are packaged in bottles. BKM120 capsule 
cannot be crushed and has to be swallowed. It cannot be given via enteral feeding tube.
If vomiting occurs, no attempt should be made to replace the vomited dose.
5.2
Treatment Assignment
This is a non-randomized study, no treatment assignment is necessary. Patients will be enrolled in cohorts 
of 3- 6 per dose level. Once the MTD is reached, an additional 10 patients will be treated at that dose level 
and an amendment will be submitted to OHRS to declare the dose.
5.3
Dose Escalation and Stopping Rules
The dose-limiting toxicity (DLT), as defined in Section 5.5, will be the basis for determining the maximum 
tolerated dose (MTD). Any subject who receives at least one dose of the study drug (BKM120) will be 
included in analysis for DLT. Treatment cohorts will be dosed in escalating order, as outlined in Table 8, 
only after the safety of the previous dose level has been established, or until an MTD has been determined.
Subsequent dose levels will be opened for treatment as follows:

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1)
Escalation to the subsequent dose level will occur only after all subjects in the previous cohort 
have completed the full 7-week course of BKM120-CRT and have been evaluated for safety and toxicity. 
Safety will be evaluated based on the incidence of adverse events (AEs), physical exam findings, and clinical 
laboratory test results. A review of the safety data for each cohort will be conducted when all of the above 
data are available. In the event that an MTD is not reached after dose level 5, the study will be considered 
to have reached a biologically acceptable dose appropriate for Phase II study. Any further dose escalations 
or de-escalations will require a protocol amendment.
2)
Three patients will initially be enrolled at dose level 1. The following rules apply for the 
advancement to the next dose level and to determine the MTD (see also Table 7). Enrollment may proceed 
at the higher dose according to the rules after three patients have been treated for the 2 weeks of BKM120 
followed by 7 weeks of BKM120+CRT at a given dose level and safety data have been reviewed. The dose 
will be increased until a DLT is observed in one subject. Dose limiting toxicity is graded according to the 
National Cancer Institute’s CTCAE v4.0 (http://ctep.cancer.gov/forms/CTCAEv4.pdf).
Once a DLT occurs, additional subjects will be added to the cohort until either a second subject experiences 
a DLT or six subjects are treated at that dose level. If no additional subject experiences a DLT at the trigger 
dose-level, further dose escalation as outlined in Table 8 will be explored in cohorts of three subjects.
If two or more subjects experience a DLT at a given dose, then three additional subjects will be treated at 
the next lower dose, unless six subjects have already been treated at that dose.
The maximum tolerated dose is the highest dose studied for which the incidence of DLT is less than 33%. 
The final cohort of three to six subjects may be expanded to 10 subjects to provide additional safety and 
pharmacokinetic data.
The decision to enroll subjects in the next higher dose level will be made at the discretion of the principal 
investigator.
Table 7:        Dose Escalation Criteria
Number of Subjects per Cohort 
with DLT During Treatment 
Period
Dose Escalation Decision
0 out of 3
Enter 3 subjects at the next dose 
level.
1 out of 3
Enter 3 more subjects at this dose 
level.
If no additional DLT, proceed to 
the next dose level.
If an additional DLT occurs (i.e. 
2
DLTs/6
subjects),
dose

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escalation is stopped and the 
previous dose level is declared the 
MTD.
 2
The previous dose level is declared 
MTD. There is no advancement to 
higher dose levels.
Table 8:
Dose Escalation
Dose level
BKM120
(mg,
daily)
Cisplatin (mg/m2, 
weekly)
-1
20
30
1
40
30
2
40
35
3
40
40
4
60
40
5
80
40
6
100
40
BKM120 will start 2 weeks prior to first dose of cisplatin and radiation start.
Patients will be assessed weekly for adverse events for the duration of the treatment (2 weeks of BKM120 
and 7 weeks of BKM120+CRT = 9 weeks) and every 2 weeks after conclusion of CRT during the first 
month, then monthly for 3 months, then every 3 months until first progression, death, or 2 years post study 
entry whichever occurs first.
After establishment of MTD, 10 additional patients will be enrolled at the MTD dose level to gain additional 
experience with this regimen and dose. If the MTD is not reached, because  1 DLT is encountered at dose 
level 6, ten additional patients will be enrolled at this dose level. If there are greater than 2 DLTs at dose 
level 1, enrollment will continue at dose level –1 with no advancement beyond dose level -1.
5.4
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 BKM120 must be interrupted 
because of unacceptable toxicity, drug dosing will be interrupted or modified according to rules described 
in Table 9. Toxicity will be assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, 
version 4.0.
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
5.5
Dose-Limiting Toxicity
Toxicity will be assessed using the NCI Common Toxicity Criteria for Adverse Events, version 4.0 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
unless

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otherwise specified (e.g., hyperglycemia). A dose-limiting toxicity (DLT) is defined as an adverse event or 
abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or 
concomitant medications, and occurs < 28 days following the last dose of BKM120, and meets any of the 
criteria listed in Table 9.
Whenever a patient experiences toxicity that fulfills the criteria for a DLT (or a potential DLT), treatment 
with BKM120 will be interrupted (if not otherwise specified) and the toxicity will be followed up as 
described in section 5.3. Exceptions are CTCAE grade 2 hyperglycemia and CTCAE grade 2 mood 
alteration, where BKM120 treatment will be continued under appropriate co-medication. The criteria for 
dose-limiting toxicities are outlined in Table 9.
Table 9:
Criteria for Defining Dose-Limiting Toxicities
TOXICITY
ANY OF THE FOLLOWING CRITERIA
≥ CTCAE grade 3 neutropenia for > 7 consecutive days
CTCAE grade 3 thrombocytopenia for > 7 consecutive days
CTCAE grade 4 thrombocytopenia
Hematologic a
Febrile neutropenia (ANC < 1.0 x 109/L, fever ≥ 38.5°C)
Serum creatinine ≥ 2.0 x ULN to ≤ 3.0 x ULN for > 7 consecutive days
Renal
> CTCAE grade 3 serum creatinine
Total bilirubin ≥ 2xULN to ≤ 3.0 x ULN for > 7 consecutive days
> CTCAE grade 3 total bilirubin
CTCAE grade 3 AST or ALT for > 7 consecutive days
Hepatic b
CTCAE grade 4 AST or ALT
Grade 2 hyperglycemia (confirmed with a repeat FPG within 24 hours) 
that does
not resolve to grade 0 within 14 consecutive days (after initiation of
glimepiride,
metformin or glibenclamide)
Endocrine
≥ Grade 3 hyperglycemia (confirmed with a repeat FPG within 24 
hours)
CTCAE grade 3 asymptomatic amylase and/or lipase, not reversible to
≤ CTCAE
grade 2 for > 7 consecutive days
Metabolic/Laborat 
ory
CTCAE grade 4 asymptomatic amylase and/or lipase
Pancreatitis
≥ CTCAE grade 2
Cardiac toxicity ≥ CTCAE grade 3 or cardiac event that is symptomatic 
or
requires medical intervention
Clinical signs of cardiac disease, such as unstable angina or 
myocardial
Cardiac
infarction, or Troponin ≥ CTCAE grade 3
Neurotoxicity
≥ 1 CTCAE grade level increase
CTCAE grade 2 mood alteration that does not resolve to ≤ grade 1 
within 14
days despite medical treatment (for Anxiety only, if worsened from
baseline)
Mood alteration
≥ CTCAE grade 3 mood alteration
Any phototoxicity ≥ CTCAE grade 2, or skin toxicity (rash) resulting in
Dermatologic
interruption of BKM120 for > 21 consecutive days
Other adverse 
events
≥ CTCAE grade 3 adverse events (excluding ≥ CTCAE grade 3 
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alkaline phosphatase)
≥ CTCAE grade 3 vomiting or CTCAE grade 3 nausea despite the use 
of
standard anti-emetics
≥ CTCAE grade 3 diarrhea despite the use of optimal anti-diarrhea 
treatments
CTCAE grade 3 fatigue (asthenia) for > 7 consecutive days
CTCAE grade 4 fatigue (asthenia)
a ≥ CTCAE grade 3 anemia will not be considered DLT unless judged to be a hemolytic process
secondary to
study drug. ≥ CTCAE grade 3 lymphopenia will not be considered DLT unless clinically significant.
b For any grade 3 or 4 hepatic toxicity that does not resolve within 7 days to ≤ grade 1 (or ≤ grade 2 if
liver
infiltration with tumor present), an abdominal CT scan has to be performed to assess if it is related to 
disease
progression.
A single patient is assumed not to tolerate the dose if he/she experiences at least one DLT.
If a lower grade AE leads to a dose interruption of more than 7 doses of BKM120, this AE will be 
considered as
DLT.
If the 2nd occurrence of an initially non-dose limiting toxicity (e.g., grade 3 AST that resolved to ≤ grade
1 within 7
days at 1st occurrence) leads to a dose reduction ( Section 6) within 28 days of the first dose of
BKM120, this
will be considered a 
DLT.
The investigator must notify the sponsor immediately of any unexpected ≥ CTCAE grade 3 adverse events 
or laboratory abnormalities. Prior to enrolling patients into a higher dose level, ≥ CTCAE grade 2 adverse 
events will be reviewed for all patients at the current dose level.
5.6
Follow-up for dose-limiting toxicities
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 10, 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 > 14 days from the intended day of the next scheduled dose, then the patient 
should be discontinued from the treatment but will only come off study if dead or due to refusal to continue 
on the study. All patients must be followed for adverse events and serious adverse events for 28 days 
following the last dose of BKM120.

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Table 10:
Follow-up for dose-limiting toxicities
TOXICITY
FOLLOW-UP EVALUATION
If ≥ CTCAE grade 3 neutropenia or ≥ CTCAE grade 3 thrombocytopenia have
been demonstrated, these parameters must be repeated at least twice a week
until resolution to ≤ CTCAE grade 1 neutropenia or ≤ CTCAE grade 1
thrombocytopenia to allow for initiation of re-treatment, and then at least weekly
Hematology
until either resolution or until stabilization.
If serum creatinine ≥ 2 x ULN has been demonstrated, this parameter must be
repeated at least twice a week until resolution to ≤ CTCAE grade 1 to allow for
initiation of re-treatment, and then at least weekly until either resolution or until
stabilization.
If [+3] proteinuria, hematuria ≥ CTCAE grade 2 or serum creatinine ≥ 2.0 x ULN
has been demonstrated, a 24-hour urine collection for total protein and total
creatinine must be repeated at least weekly until either resolution to baseline
value or until stabilization. Whenever a measured CrCl is obtained, a serum
Renal
creatinine should be obtained within ≤ 72 hours of the urine collection.
If total bilirubin ≥ 2 x ULN or ≥ CTCAE grade 3 AST/ALT has been
demonstrated, these parameters must be repeated at least twice a week until
resolution to ≤ CTCAE grade 1 (or ≤ grade 2 for AST or ALT, if liver metastasis
are present) to allow for initiation of re-treatment, and then at least weekly until
either resolution or until stabilization.
Patients with total bilirubin > ULN (any duration) should have fractionation of
bilirubin into total/direct or indirect/direct components and any additional work-up
as clinically indicated by these results. Follow-up of hyperbilirubinemia should
Hepatic
proceed as per the guidelines above, irrespective of the results of fractionation.
If amylase and/or lipase ≥ CTCAE grade 3 (> 2 x ULN) has been demonstrated,
these parameters must be assessed once at 2 to 4 days and once again at 7
days (± 1 day) and be repeated twice a week until resolution to ≤ CTCAE grade
2 to allow for initiation of re-treatment, and then at least weekly until either
resolution to ≤ CTCAE grade 1 or until stabilization.
A CT scan or other imaging study to assess the pancreas, liver, and gallbladder
must be performed within 1 week of the first occurrence of any ≥ CTCAE grade 3
of amylase or lipase.
In patients with serum triglycerides ≥ 500 mg/dL, urine amylase needs to be
Metabolic/Laboratory
tested in addition.
Endocrine (no CTCAE
grading; refer to Table 15 for
definition of grades)
For details of the follow-up and treatment of ≥ grade 2 hyperglycemia refer to 
Table 15.

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TOXICITY
FOLLOW-UP EVALUATION
Patient who experience QTc prolongation should be followed as 
per Table 11.
In addition, patients who experience ECG abnormalities indicative
of an ischemic cardiac event, ECGs should be repeated at least 
twice a week until normalization or stabilization of ECG findings.
Cardiac
If troponin ≥ CTCAE grade 3 has been demonstrated, this 
parameter must be repeated twice a week until resolution to
≤ CTCAE grade 1 to allow for initiation of re-treatment, and then 
at least weekly until either resolution or until stabilization.
Neurotoxicity
Patients who experience neurotoxicity should be followed as per 
Table 11.
Mood alteration
For patient who experience ≥ grade 2 mood alteration a 
psychiatrist must be consulted for diagnosis and determination of 
most appropriate medical treatment. Patients must be followed 
twice weekly by patient self-rating mood scale and be seen 
weekly by the psychiatrist until resolved ≤ grade 1 or baseline 
(for anxiety).
≥ grade 2
Continue to test weekly by mood scale until resolution to baseline 
or stabilization
Note: For grade 2 Anxiety
only, if worsened from
baseline
Refer to Table 12 for more details.
Non-Laboratory
Patients who experience non-laboratory DLTs must be evaluated 
at least once a week following demonstration of the toxicity until 
resolution of the toxicity to allow for re-treatment, stabilization of 
the toxicity, or study treatment completion
.
Rash
Whenever a rash is diagnosed, the following should be obtained:

A paired skin biopsy from both an affected and an 
unaffected skin area for local histopathology assessment

A plasma sample to assess the concentration of 
BKM120
For the follow up of skin rash, refer to Table 6

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5.7
Monitoring of BKM120 suspected toxicities
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 10, 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 > 14 days from the intended day of the next scheduled dose, then the 
patient should be discontinued from study treatment. If the patient requires more than 2 dose reductions, 
the patient should be discontinued from study treatment. All patients must be followed for adverse events 
and serious adverse events for 28 days following the last dose of BKM120. All SAEs must be reported to 
Novartis as detailed in section 5.12.11 and 5.12.12.
5.8
Agent Administration
5.8.1
BKM120 Administration
The study drug BKM120 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. BKM120 will be 
administered on a continuous once daily dosing schedule. Patients should be instructed to take the dose of 
BKM120 daily in the morning, one hour after a light breakfast (morning meal) at approximately the same 
time each day. BKM120 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 them. Do not crush capsule. 
Patients should continue to fast for 2 hours after the administration of each BKM120 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 must be noted as an 
adverse event. In addition, on the days of full pharmacokinetic sampling, the exact time of any episodes 
of vomiting within the first 4 hours post-dosing on that day and within the first 4 hours following the 
previous day’s dosing must be noted whenever possible.
If the patient forgets to take her/his dose AFTER 6:00 PM, then the dose should be withheld that day and 
BKM120 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 BKM120 dose delay of >14days from the previous dose, the patient must 
be discontinued from treatment but will only come off study if dead or due to refusal to continue on the 
study. Patients will only require a 28 day follow up visit after the last dose of BKM120.
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.
5.8.2
Cisplatin Treatment

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Commercially available supplies of cisplatin will be used for this study. Preparation instructions can be 
found in the FDA approved package insert. Cisplatin will be administered per institutional guidelines.
Cisplatin injection is a sterile, aqueous solution, available in 50ml, 100ml, and 200ml, multiple dose vials, 
each ml containing 1mg of Cisplatin and 9mg sodium chloride in water for injection. HCI and/or sodium 
hydroxide added to adjust pH to 3.5 to 4.5.  It will be given intra-venously (IV) on days: (1, 8, 15, 22, 29,
36 and 43).
If radiation is held, BKM120 and cisplatin will be held as well. Additional weekly chemotherapy 
treatments may be added to the treatment course if chemo/XRT was held during the course of treatment. 
Cisplatin should be given only if at least 3 more days of radiotherapy treatment remain. Days of 
chemotherapy may be changed (+/-) 2 days if unforeseen circumstances require the timing of treatment. 
Treatment doses are based on body surface area (BSA). The actual body weight will be used for dose 
calculations as long as the BSA is below 2. For a BSA above 2, the BSA will be capped at 2.
Cisplatin is nephrotoxic and the patients will receive pre-and post treatment hydration according to 
institutional standards.
Institutional guidelines for highly emetogenic regimens will be followed. Patients will receive a 5HT 
antagonist for primary prevention of nausea and vomiting and will also receive 8 mg of dexamethasone 
IV according to institutional standards. The patients may receive a 5HT antagonist and decadron per IV 
on day 2 and 3 after chemotherapy for delayed nausea at the discretion of the investigator. The concomitant 
use of aprepitant and BKM120 is not allowed.

Possible side effects of cisplatin are
o
Hematologic: Neutropenia, anemia, thrombocytopenia
o
Gastrointestinal: Nausea, vomiting
o
Dermatologic: Alopecia
o
Renal: Elevation of blood urea nitrogen (BUN) and Creatinine, hypomagnesemia, 
hypokalemia, hypocalcemia
o
Neurologic: Peripheral neuropathy, restlessness
o
Allergic reactions
o
Ototoxicity
Cisplatin is a commercially available product that is provided as part of standard of care.
5.9
Radiation
All patients will receive daily radiotherapy with intensity-modulated radiotherapy (IMRT) delivered at 
DFCI. The prescribed dose will be 70 Gy (gray, SI unit of absorbed radiation) to the primary and nodal 
gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions. Other target volumes will be 
treated to 63 Gy and 56 Gy using differential dosing, as described below. There will be no planned cone 
downs or field changes. Treatment will be given 5 days per week for 7 weeks; treatment will not be 
planned to be delivered on Saturday, Sunday or major holidays, as per standard practice. Radiotherapy 
will be administered according to the general guidelines below.

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
Volume Definitions-Volumes for all structures must be contoured on each relevant CT slice.
Gross tumor volume (GTV) consists of tumor at the primary site and gross nodal disease. The volumes 
will be defined based on imaging studies (CT and/or PET), in conjunction with information from clinical 
examination.
High risk clinical target volume (CTV1) includes volumes of potential tumor extension (adjacent to the 
primary or nodal GTV) and clinically/radiographically uninvolved nodal volumes at highest risk for 
microscopic involvement. The required anatomic margin around the GTV and gross nodal disease will 
be determined on a case-by-case basis by the treating radiation oncologist, limited by appropriate anatomic 
constraints. For gross nodal disease, CTV1 will include the nodal station where that node is located. In 
addition, the high risk clinical target volume may also include the complete anatomic nodal levels 
immediately adjacent to nodal regions that have gross disease.
Low risk clinical target volume (CTV2) includes lymph node regions at lesser risk for nodal 
involvement.
Planning target volume (PTV) incorporates a margin that accounts for daily set up variation. The 
planning target volume will be a 0.5 cm expansion of the gross and clinical target volumes. Modification 
of PTV is allowed at the discretion of the treating radiation oncologist for sparing of normal tissues, or if 
it is needed to facilitate the planning process, e.g. if the PTV overlaps a critical structure that must be 
spared. Each CTV will have an individual PTV designed for set-up uncertainty.

Avoidance Structures–The following normal tissue structures will be defined and delineated on 
all appropriate CT slices:
(a) Spinal cord, brainstem
(b) Expanded Spinal Cord (7 mm expansion around spinal cord)
(c) Right and left parotid glands
(d) Larynx
(e) Oral cavity

Avoidance Structures–For cases in which the nasopharynx or base of skull is the primary target, 
the following avoidance structures will be added:
(a) Inner ear
(b) Optic nerves
(c) Optic chiasm
(d) Expanded optic nerve and chiasm (2 mm expansion around these structures)
(e) Eyes
(f) Brain

Target Dose Prescriptions. The three target volumes are described in Section 5.8. All will be 
treated daily over the course of 35 fractions. The prescription point is at isocenter. To accommodate for 
tissue heterogeneity, density corrections are required, and will be applied to all plans, unless 
contraindicated, for example, by significant amounts of scatter on the planning CT scan. Doses will be 
planned as follows:

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(a) GTV will be treated to a total dose of 70 Gy in 2.0 Gy fractions.
(b) CTV1 will be treated to a total dose of 63 Gy in 1.8 Gy fractions.
(c) CTV2 will be treated to a total dose of 56 Gy in 1.6 Gy fractions.

PTV coverage: No more than 20% of the PTV may receive > 110 % of the prescription dose. No 
more than 3% of the PTV may receive < 95% of the prescription dose. No more than 1cc of tissue outside 
the PTV may receive > 110% of the prescription dose.

Normal Tissue Doses–The following normal tissue limits are recommended:
(a) Parotid Glands: Mean dose of 26 Gy or less.
(b) Larynx: Dose to the larynx should be limited to 50 Gy or less. For tumors in sites adjacent to the 
larynx, priority is given to tumor coverage. In those cases, at a minimum, an attempt will be made to 
minimize hot spots in the larynx.
(c) Oral Cavity: Volume receiving more than 50 Gy will be limited; constraints are similar to those noted 
above for larynx.
(d) Spinal Cord: No segment of the spinal cord should receive more than 46 Gy. The expanded spinal 
cord should be limited to 56 Gy for small volume.
(e) Mandible: Dose to any point should be less than 70 Gy.
(f) Inner Ear: Mean dose should be less than 34 Gy, and the maximum dose less than 47 Gy.
Note: In cases with a conflict/overlap between target and normal tissue, target dose considerations should 
take priority, at the discretion of the treating physician. An exception to this is the spinal cord dose 
limitations, which takes priority.

Treatment Breaks: There are no planned treatment breaks on this study; any breaks in planned 
radiotherapy are strongly discouraged. The Radiation Oncology Study Chair, Roy Tishler, will be 
contacted at 617-632-3591 for interruptions greater than three treatment days. Radiotherapy interruptions 
will be permitted for unavoidable mechanical malfunction or serious illness requiring hospitalization, such 
as sepsis, delirium, severe respiratory compromise or hemodynamic instability, at the discretion of the 
treating physician and Radiation Oncology Chair. Treatment breaks should be as short as possible. The 
reason for any interruption in treatment must be documented in the treatment chart.

Simulation: At the time of radiation simulation all patients will have a thermoplastic mask fitted 
for immobilization. This mask will extend from the top of the skull to below the mid clavicle. Bite blocks, 
dental rolls and other set-up techniques may be used at the discretion of the treating radiation oncologist.

Quality Assurance:
Prior to the first radiation treatment, the standard quality assurance procedures will be followed. The 
monitor units required to deliver the prescribed dose shall be calculated. The monitor units generated by 
the IMRT planning system must be independently checked prior to the patient’s first treatment. 
Measurements in a quality assurance phantom will be done for each patient that will be treated. In addition, 
film measurements will be taken during the QA period.
On the first day of treatment each patient will have electronic portal images taken, which will be approved 
by a radiation oncologist prior to delivery of the first treatment, per standard practice.
Weekly Verification portal images will be taken at least once per week and approved by a radiation

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oncologist prior to continuation of treatment per standard practice.

Isodose Distribution: All plans will have complete documentation in the patient’s chart, 
including representative CT slices with treatment isodoses. A DVH with all relevant PTV and CTV 
structures and all normal tissue structures will be generated for each patient and documented in the 
patient’s radiotherapy chart.

Treatment Equipment and Delivery: Treatment will be delivered on the Dana-Farber Varian 
Clinac 2100EX or Varian TX. 6 MV energy and dynamic multi-leaf collimators will be used to deliver all 
treatment.
5.10
General Concomitant Medication and Supportive Care Guidelines
All medications (excluding prior chemotherapy and biologic, immunologic or radiation therapy) taken 
within 4 weeks prior to the administration of BKM120 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 BKM120 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 exceptions described in Appendix B.
5.11
Duration of Therapy
BKM120 will start 2 weeks prior to first dose of cisplatin and radiation. BMK120+CRT will then last for 
7 weeks. Radiotherapy will be standard of care.
5.12
Visit schedule and assessments (see section 10 for schedule and study calendar)
5.12.1
Laboratory evaluations
5.12.1.1
Pregnancy Test
A serum pregnancy test (β-HCG) is required for all women of child-bearing potential at screening, within 
72 hours prior to the first dose of BKM120. Note: Postmenopausal women must have been amenorrheic 
for ≥ 12 months in order to be considered “of non-childbearing potential”. This should be documented 
appropriately in the patient’s medical history. Additional pregnancy tests should be performed as clinically 
indicated.
5.12.1.2
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.

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5.12.1.3
Coagulation Profile
The coagulation profile includes prothrombin time or INR, and activated partial thromboplastin time.
5.12.1.4
Serum chemistry
Biochemistry includes the following parameters: K+, Na+, Ca++, Mg++, LDH,ALT, AST, total bilirubin 
(direct and indirect), creatinine, amylase, GGT, lipase, alkaline phosphatase (fractionated if alkaline 
phosphatase is grade 2 or higher), bicarbonate, phosphorus, uric acid, total cholesterol, HDL, LDL, 
triglycerides, glucose, urea or BUN, albumin, and total protein are required at baseline and at end of 
treatment. Subsequent assessments always include K+, Na+, Ca++, ALT, AST, total bilirubin (direct and 
indirect), creatinine, alkaline phosphatase, bicarbonate, phosphorus, glucose, urea or BUN, albumin, and 
total protein BUT, lipase, total cholesterol, HDL, LDL, triglycerides should be obtained.
Because accurate serum glucose and lipid measurements are required, patients should be fasting at the 
time of the blood sampling.
5.12.1.5
Urinalysis
Urinalysis includes macroscopic (protein, glucose, ketones, blood, and specific gravity) and will be 
performed at screening visit and EOT visit. 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.
5.12.2
Vital signs
Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, temperature 
and weight. Blood pressure, pulse and respiration rate should be measured on patients after at least 3 
minutes in the sitting position as per the visit schedule.
5.12.3
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).
Significant findings made after the start of study drug which meet the definition of an Adverse Event must 
be recorded.
5.12.4
Neuropsychiatric assessments
Patient self-rating mood questionnaires for anxiety and depression (PHQ-9, GAD-7).
Additional assessments may be done according to the clinical judgment of the Investigator. Symptomatic 
patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis while active on the 
treatment portion of the study. Instructions on how to instruct the patient to complete the questionnaires 
as well as how to determine the scores will be provided together with each instrument.

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5.12.5
ECG/ECHO
A standard 12 lead ECG is to be performed at screening and as clinically indicated. 
An echocardiogram (ECHO) or MUGA will be performed to assess eligibility.
5.12.6
Dental Evaluation
All subjects must undergo dental evaluation prior to beginning BKM120 CRT. Any dental extractions 
must be performed to allow for enough time for healing of the extraction sockets, which is typically 7-10 
days.
5.12.7
Performance status
ECOG performance status (Appendix A).
5.12.8
Efficacy assessments
Time to progression is measured from date of study entry to first progression, otherwise patients are 
censored at date last know progression-free.
Overall survival is measured from date of study entry to death. Otherwise patients are censored at date 
last known alive.
http://ctep.cancer.gov/protocolDevelopment/docs/Recist_Guideline.pdf
5.12.9
Safety assessments
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 CTC
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03 2010-06-14 QuickReference 8.5x11.pdf
5.12.10
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.
5.12.11
Adverse events
Tolerability will be assess using the NCI Common Toxicity Criteria for Adverse Events, version 4.0 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
Information about all adverse events, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be collected 
and recorded and followed as appropriate.

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39
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(s) (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.
5.12.12
Serious adverse events
An adverse event is considered serious if it results in ANY of the following outcomes:
1) Death
2) A life-threatening adverse event
3) An adverse event results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions
5) A congenital anomaly/birth defect.
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one
5.12.13
Novartis instructions for rapid notification of serious adverse events
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB and 
Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E).

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All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A 
(MedWatch Form).
All events must be reported, by FAX (877-778-9739), to Novartis Pharmaceuticals DS&E 
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 started the treatment to 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.
5.12.14
Pregnancies
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to Novartis 
within 24 hours of learning of its occurrence. The pregnancy should be followed up for 3 months after the 
termination of the pregnancy 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.
Pregnancy outcomes must be collected for the female partners of any males who took study treatment in 
this study. Consent to report information regarding these pregnancy outcomes should be obtained from 
the mother.
Information for female partners of male study participants
Your male partner is offered to participate in a clinical research study. As a prerequisite to participate in 
this study your partner must agree to use a condom during intercourse. This is important because test 
results of the study treatment in pregnant animals indicated that the medicine can harm an unborn baby 
through the sperm. At the same time it is also important that you do not become pregnant while your 
partner is taking the medication. Therefore, you should use a highly effective method of birth control 
(contraception) during the time your male partner receives the study treatment and thereafter for another 
3 months. Highly effective methods of contraception are those methods of birth control that have less than 
1% of unwanted pregnancy during one year, if used appropriately according to the instructions of the 
manufacturer.
Those methods are the following (a+b):
a) Placement of an intrauterine device (IUD) or intrauterine system (IUS)

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b) Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/vaginal suppository

Oral contraception, injected or implanted hormonal methods are not allowed as BKM120 
potentially decreases the effectiveness of hormonal contraceptives.

Fertile males, defined as all males physiologically capable of conceiving offspring must 
use condom during treatment, for 4 weeks (5 T1/2) after stopping treatment and for additional 12 
weeks (16 weeks in total after study drug discontinuation) and should not father a child in this period.

Female partner of male study subject should use highly effective contraception during dosing 
of any study agent and for 16 weeks after final dose of study therapy.
For details on the most appropriate contraception you may talk to your regular doctor or if your male 
partner agrees with the study doctor.
If you get pregnant despite taking the birth control precautions, please ask your partner to inform the study 
doctor as soon as possible. The study doctor will ask your permission to collect information about you, 
your pregnancy and your child.
5.13
Duration of Follow Up
Follow up (FU) for adverse events will take place every 2 weeks after conclusion of BKM120+CRT (EOT) 
during the first month, then monthly for 3 months, then every 3 months, until first progression, death, or 
2 years from study whichever occurs first. See Study Calendar for full details.
5.14
Criteria for Removal from Study Treatment and/or Study Itself
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 BKM120 must be 
interrupted because of unacceptable toxicity, drug dosing will be interrupted or modified according 
to rules described in Table 11. Toxicity will be assessed using the NIH-NCI Common Terminology 
Criteria for Adverse Events, version 4.0.
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
The reason for study treatment discontinuation and/or study removal and the date the participant was 
removed must be documented in the case report form (CRF). Alternative care options will be discussed 
with the participant.
Reasons that a patient may discontinue study treatment and/or discontinue participation in a clinical study 
are considered to constitute one of the following:
1. adverse event(s)
2. abnormal laboratory value(s)
3. abnormal test procedure result(s)

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4. disease progression
5. protocol violation
6. subject withdrew consent
7. lost to follow-up
8. administrative problems
9. death
A QACT Treatment Ended/Off Study Form should be filled out when a participant completes study 
treatment and again when the participant comes off study. This form can be found on the QACT website 
or obtained from the QACT registration staff.
In the event of unusual or life-threatening complications, investigators must immediately notify the 
Overall PI, Glenn Hanna, MD at 617.632.3090 or page at 617.632.3352.
6.
DOSING DELAYS/DOSE MODIFICATIONS
Table 11:
BKM120 dose level modification guidelines: Criteria for interruption and 
re-initiation of BKM120 treatment
Recommended Dose Modifications for BKM120
Worst toxicity (CTCAE Grade)**
Recommended Dose Modifications
No toxicity
Maintain dose level
HEMATOLOGICAL
Neutropenia (ANC)
Grade 1 (ANC < LLN – 1.5 x 109/L) 
Grade 2 (ANC < 1.5 – 1.0 x 109/L)
Maintain dose level
Grade 3 (ANC < 1.0 – 0.5 x 109/L) 
Grade 4 (ANC < 0.5 x 109/L)
Omit dose until resolved to ≤ Grade 1, then:

If resolved in ≤ 7 days, then maintain dose level

If resolved in > 7 days, then  1 dose level
Febrile neutropenia
(ANC < 1.0 x 109/L, fever ≥ 38.5°C)
Omit dose until resolved, then  1 dose level
Thrombocytopenia
Grade 1 (PLT < LLN – 75 x 109/L) 
Grade 2 (PLT < 75 – 50 x 109/L)
Maintain dose level
Grade 3 (PLT < 50-25 x 109/L)
Omit dose until resolved to ≤ Grade 1, then:

If resolved in ≤ 7 days, then maintain dose level

If resolved in > 7 days, then  1 dose level
Grade 4 (PLT < 25 x 109/L)
Omit dose until resolved to ≤ Grade 1, then  1 dose level

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Recommended Dose Modifications for BKM120
Worst toxicity (CTCAE Grade)**
Recommended Dose Modifications
HEPATIC
Bilirubin
(*for patients with Gilbert Syndrome 
these dose modifications apply to 
changes in direct bilirubin only)
Will be fractionated if elevated
Grade 1 (> ULN – 1.5 x ULN)
Maintain dose level with LFTs* monitored as per protocol
Grade 2 (> 1.5 – 3.0 x ULN) with ALT or 
AST ≤ 3.0 x ULN
Omit dose until resolved to ≤ Grade 1, then:

If resolved in ≤ 7 days, then maintain dose level

If resolved in > 7 days, then  1 dose level
Grade 3 (> 3.0 – 10.0 x ULN) with ALT 
or AST ≤ 3.0 x ULN
Omit dose until resolved to ≤ Grade 1, then:

If resolved in ≤ 7 days,  1 dose level

If resolved in  7 days discontinue patient from study 
treatment
Grade 4 (> 10.0 x ULN)
Omit dose and discontinue patient from study treatment
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
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
Grade 4 (> 20.0 x ULN) without bilirubin 
elevation to > 2.0 x ULN
Omit dose until resolved to ≤ Grade 1 , then  1 dose level
AST or ALT and concurrent Bilirubin
AST or ALT > 3.0 x ULN and total 
bilirubin > 2.0 x ULN
Discontinue study treatment permanently.
* 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.
Monitoring (*for patients with Gilbert Syndrome: total and direct bilirubin must be monitored, intensified monitoring applies 
to changes in direct bilirubin only; the monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin 
(fractionated if total bilirubin > 2.0 x ULN), alkaline phosphatase (fractionated if alkaline phosphatase is grade 2 or higher) 
and GGT.
ENDOCRINE/METABOLIC
Fasting Plasma Glucose (FPG)
Grade 1 (> ULN - 160 mg/dL) [> ULN -
8.9 mmol/L]
Maintain dose level, check FPG every week

initiate or intensify medication with appropriate anti-diabetic 
treatment as per investigator’s discretion

instruct patient to follow dietary guidelines according to local 
and/or institutional standards for management of diabetes mellitus 
(such as those provided by the American Diabetes Association) 
during the study

Consider use of oral anti-hyperglycemic therapy such as metformin (or 
intensify existing medications)

check FPG at least weekly for 8 weeks, then continue 
checking at least every 2 weeks

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44
Recommended Dose Modifications for BKM120
Worst toxicity (CTCAE Grade)**
Recommended Dose Modifications
Grade 2 (>160 – 250 mg/dL) [> 8.9 -
13.9 mmol/L]

If signs or symptoms of hyperglycemia (for example, mental status 
changes, excessive thirst, polyuria) manage as for Grade 3 hyperglycemia 
(see below).

If asymptomatic, maintain dose and re-check FPG within 24 hours. If grade 
worsens or improves then follow specific grade recommendations. If FPG 
remains at Grade 2:

maintain dose level and monitor FPG at least weekly until FPG 
resolves to ≤ Grade 1

initiate or intensify medication with appropriate anti-diabetic 
treatment such as metformin; consider adding a second oral agent if 
no improvement after several days

instruct patient to follow dietary guidelines according to local and/or 
institutional standards for management of diabetes mellitus (such as 
those provided by the American Diabetes Association) during the 
study

If FPG does not resolve to ≤ Grade 1 within 14 days after institution 
of appropriate anti-diabetic treatment reduce BKM120 by 1 dose level
Continue with anti-diabetic treatment and check FPG at least weekly for 
8 weeks, then continue checking at least every 2 weeks
Grade 3 (> 250 - 500 mg/dL) [> 13.9 -
27.8 mmol/L]

Omit BKM120, initiate or intensify medication with appropriate anti-diabetic 
treatment, re-check FPG within 24 hours. If grade worsens or improves 
then follow specific grade recommendations. If FPG remains at Grade 3:

administer 
intravenous 
hydration 
and 
intervention 
for 
electrolyte/ketoacidosis/hyperosmolar disturbances as clinically 
appropriate

continue to omit BKM120

monitor FPG at least twice weekly until FPG resolves to ≤ Grade 1

If FPG resolves to ≤ Grade 1 in 7 days or less, then re-start BKM120 
and  1 dose level

If FPG remains greater than Grade 1 severity for more than 7 days, 
then discontinue patient from BKM120

initiate or continue anti-diabetic treatment as appropriate

instruct patient to follow dietary guidelines according to local 
and/or institutional standards for management of diabetes 
mellitus (such as those provided by the American Diabetes 
Association) during the study

consider use of oral anti-hyperglycemic therapy such as 
metformin

check FPG at least weekly for 8 weeks, then continue checking at 
least every 2 weeks
For non-fasting plasma glucose >250-500 mg/dL (> 13.9 - 27.8 mmol/L) 
accompanied by signs/symptoms of hyperglycemia (for example, mental 
status changes, excessive thirst, polyuria), or presence of blood or urine 
ketones, omit BKM120 and following guidance for management of Grade 
3 fasting plasma glucose (FPG)

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45
Recommended Dose Modifications for BKM120
Worst toxicity (CTCAE Grade)**
Recommended Dose Modifications
Grade 4 (> 500 mg/dL) [≥ 27.8 mmol/L]

immediately omit BKM120, initiate or intensify medication with 
appropriate anti-diabetic treatment, re-check within 24 hours. if grade 
improves then follow specific grade recommendations. If FPG is confirmed 
at Grade 4:

administer intravenous hydration and intervention for 
electrolyte/ketoacidosis/hyperosmolar disturbances as clinically 
appropriate

discontinue patient from BKM120

instruct patient to follow dietary guidelines according to local 
and/or institutional standards for management of diabetes 
mellitus (such as those provided by the American Diabetes 
Association) during the study

consider use of oral anti-hyperglycemic therapy such as 
metformin

check FPG at least weekly for 8 weeks, then continue checking 
at least every 2 weeks if clinically indicated
For non-fasting plasma glucose >500 mg/dL (> 27.8 mmol/L) 
accompanied by signs/symptoms of hyperglycemia (for example, mental 
status changes, excessive thirst, polyuria), or presence of blood or urine 
ketones, discontinue BKM120 and following guidance for management 
of Grade 4 fasting plasma glucose (FPG).

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46
Recommended Dose Modifications for BKM120
Worst toxicity (CTCAE Grade)**
Recommended Dose Modifications
CARDIAC
Cardiac – Left Ventricular systolic 
dysfunction
Asymptomatic,
resting ejection fraction 50 – 40%; 
or 10-20% drop from baseline
Maintain dose level
Symptomatic,
responsive to intervention, 
ejection fraction 39 – 20% 
or > 20% drop from baseline
Omit dose until resolved to ≤ Grade 1, then  1 dose level
LVEF measurement to be repeated, if not resolved to ≤ Grade 1 
within 3 weeks, permanently discontinue patient from BKM120
Refractory or poorly controlled, 
ejection fraction < 20%
Omit dose and discontinue patient from BKM120
Cardiac – QTc prolongation
QTcF > 500 ms (≥ Grade 3)
or > 60 ms change from baseline 
on at least two separate ECGs
First Occurrence:

omit BKM120

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, BKM120 may be 
restarted at a one lower dose level
Second Occurrence:

discontinue patient from BKM120
Other Cardiac Events
Grade 1 or 2
Maintain dose level
Grade 3
Omit dose until resolved to ≤ Grade 1, then  1 dose level
Grade 4
Omit dose and discontinue patient from BKM120
OTHER
Mood alteration
* 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
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

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47
Recommended Dose Modifications for BKM120
Worst toxicity (CTCAE Grade)**
Recommended Dose Modifications
Grade 2
(for Anxiety only, if worsened from 
baseline)
Institute appropriate co-medication under the guidance of the 
psychiatrist. Maintain dose level.

If the condition does not resolve to ≤ Grade 1 within 14 days 
despite medical treatment; then  1 dose level (continue to 
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 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
Rash
Grade 1
Maintain dose level. Consider to initiate 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 ≤ 7 days,  1 dose level

If resolved in  7 days (despite appropriate skin toxicity 
therapy), discontinue patient from BKM120
Grade 4
Omit dose and discontinue patient from BKM120
Fatigue (asthenia)
Grade 1 or 2
Maintain dose level
Grade 3
Omit dose until resolved to ≤ Grade 1, then:

If resolved in ≤ 7 days, maintain dose level

If resolved in  7 days,  1 dose level
Grade 4
Omit dose and discontinue patient from BKM120
Other non-hematological adverse events
Grade 1 or 2
Maintain dose level
Grade 3
Omit dose until resolved to ≤ Grade 1, then  1 dose level
Grade 4
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 optimal
antiemetic
Pneumonitis
See Table 15
** Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

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Fasting Plasma Glucose (FPG)
Grade 1 (> ULN - 160 mg/dL) 
[> ULN - 8.9 mmol/L]
Maintain dose level, check FPG every week

initiate or intensify medication with appropriate anti-diabetic treatment as per investigator’s discretion

instruct patient to follow dietary guidelines according to local and/or institutional standards for 
management of diabetes mellitus (such as those provided by the American Diabetes Association) 
during the study

Consider use of oral anti-hyperglycemic therapy such as metformin (or intensify existing medications)

Check FPG at least weekly for 8 weeks, then continue checking at least every 2 weeks
Grade 2 (>160 - 250 mg/dL) [>
8.9 - 13.9 mmol/L]

If signs or symptoms of hyperglycemia (for example, mental status changes, excessive thirst, 
polyuria) manage as for Grade 3 hyperglycemia (see below).

If asymptomatic, maintain dose and re-check FPG within 24 hours. If grade worsens or improves 
then follow specific grade recommendations. If FPG remains at Grade 2:

maintain dose level and monitor FPG at least weekly until FPG resolves to ≤ Grade 1

initiate or intensify medication with appropriate anti-diabetic treatment such as metformin; 
consider adding a second oral agent if no improvement after several days

instruct patient to follow dietary guidelines according to local and/or institutional standards for 
management of diabetes mellitus (such as those provided by the American Diabetes 
Association) during the study

If FPG does not resolve to ≤ Grade 1 within 14 days after institution of appropriate anti-diabetic 
treatment reduce  BKM120 by 1 dose level

Continue with anti-diabetic treatment and check FPG at least weekly for 8 weeks, then continue 
checking at least every 2 weeks
Grade 3 (> 250 - 500 mg/dL) [>
13.9 - 27.8 mmol/L]

Omit BKM120, initiate or intensify medication with appropriate anti-diabetic treatment, re-check FPG 
within 24 hours. If grade worsens or improves then follow specific grade recommendations. If FPG 
remains at Grade 3:

administer intravenous hydration and intervention for electrolyte/ketoacidosis/hyperosmolar 
disturbances as clinically appropriate

continue to omit BKM120

monitor FPG at least twice weekly until FPG resolves to ≤ Grade 1

If FPG resolves to ≤ Grade 1 in 7 days or less, then re-start BKM120 and  1 dose level

If FPG remains greater than Grade 1 severity for more than 7 days, then discontinue patient 
from BKM120

initiate or continue anti-diabetic treatment as appropriate

instruct patient to follow dietary guidelines according to local and/or institutional standards 
for management of diabetes mellitus (such as those provided by the American Diabetes 
Association) during the study

consider use of oral anti-hyperglycemic therapy such as metformin

check FPG at least weekly for 8 weeks, then continue checking at least every 2 weeks 
For non-fasting plasma glucose >250-500 mg/dL (> 13.9 - 27.8 mmol/L) accompanied by
signs/symptoms of hyperglycemia (for example, mental status changes, excessive thirst, polyuria), or
presence of blood or urine ketones, omit BKM120 and following guidance for management of Grade 3 
fasting plasma glucose (FPG)
Grade 4 (> 500 mg/dL) [≥ 27.8 
mmol/L]

immediately omit BKM120, initiate or intensify medication with appropriate anti-diabetic treatment, 
re-check within 24 hours. if grade improves then follow specific grade recommendations. If FPG is 
confirmed at Grade 4:

administer 
intravenous 
hydration 
and 
intervention 
for 
electrolyte/ketoacidosis/hyperosmolar disturbances as clinically appropriate

discontinue patient from BKM120

instruct patient to follow dietary guidelines according to local and/or institutional standards 
for management of diabetes mellitus (such as those provided by the American Diabetes 
Association) during the study

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
consider use of oral anti-hyperglycemic therapy such as metformin

check FPG at least weekly for 8 weeks, then continue checking at least every 2 weeks if 
clinically indicated
For non-fasting plasma glucose >500 mg/dL (> 27.8 mmol/L) accompanied by signs/symptoms of 
hyperglycemia (for example, mental status changes, excessive thirst, polyuria), or presence of blood or 
urine ketones, discontinue BKM120 and following guidance for management of Grade 4 fasting plasma 
glucose (FPG).
If the toxicity is due to BKM120, only BKM120 will be dose reduced by one level according to the 
following schedule below. If toxicity occurs at BKM120 20 mg level, BKM120 will be held.
Dose Level
Dose of BKM120 (mg, daily)
Level E
100
Level D
80
Level C
60
Level B
40
Level A
20
6.1
Cisplatin Dose Adjustments
-
Ototoxicity: If hearing loss occurs, analysis of the risk of additional hearing loss versus the potential 
benefit of continuing cisplatin should be made. An audiogram may be obtained at the investigator’s 
discretion.
-
Nephrotoxicity: If, despite adequate hydration, serum creatinine increases to > grade 1 (≥ 1.5 x ULN), 
creatinine clearance should be recalculated before the next cisplatin dose and subsequent dose reductions 
will be recommended as follows:
Dose Modification of Cisplatin in Kidney Impairment
Creatinine
Clearance (mL/min)*
Cisplatin Dose**
≥ 60
100%
≥ 40 but < 60
50%
< 40
0%
* Creatinine clearance as calculated by Cockgroft-Gault equation.
** Percent dose reduction is calculated from the original dose, not the previous dose. If creatinine 
clearance recovers, the dose of cisplatin should be re-escalated to the patient’s previous dose level as is 
outlined in the Dose Modification of Cisplatin in Kidney Impairment chart above. There is no maximum 
limit.
Serum creatinine will be measured weekly within 24 hours of cisplatin dosing.
Dose Modification of Cisplatin Based on ANC
ANC
(x109/L) within 24
Action to be taken

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hrs of therapy
≥ 1.5
Treat at current dose
≥ 1.0, < 1.5
Treat at 75% of cisplatin dose
< 1.0
Hold treatment, and resume therapy at 75% of 
cisplatin dose at the next weekly therapy planned 
when ANC ≥ 1.0. If neutropenia requiring further 
chemotherapy break occurs, cisplatin will be 
discontinued for the remainder of the therapy, and 
only BKM120 and radiation will be continued
Dose Modification of Cisplatin Based on Platelet Count
Platelet count within 24 
hrs of therapy
Action to be taken
≥100,000
Treat at current dose
< 100,000
Hold treatment, and resume therapy at 75% of 
cisplatin dose at the next weekly therapy planned 
when platelets are at or above 100,000. If 
thrombocytopenia requiring further chemotherapy 
break occurs, cisplatin will be discontinued for the 
remainder of the therapy, and only BKM120 and 
radiation will be continued.
7.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list 
of reported and/or potential AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting in addition to routine reporting.
7.1
Expected Toxicities
7.1.1
Known Undesirable Side Effects of BKM120
7.1.1.1
Neuropsychiatric events
In an ongoing Phase Ia study of BKM120 in patients with solid tumors (CBKM120X2101), 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 BKM120. In this study, three out 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/anxiety 
also developed mood alterations while treated with BKM120 at the 100 mg dose level and thus reflecting 
a potential risk group of patients.
In order to lower the risk of experiencing significant mood alterations within the proposed study, cancer 
patients with an active or history of major depressive episode, bipolar disorder, obsessive-compulsive

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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 such as SSRIs 
(sertaline/fluoxetine) may be prescribed as per investigator’s discretion and following consultation of a 
psychiatrist.
Results of the questionnaire will also be reported in the final manuscript as part of toxicity reporting, using 
descriptive statistics.
7.1.1.2
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. 
The following grading system will be used for this study:
Table 12:
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
At Screening, a patient as judged by the investigator or who meets the cut-off score of ≥ 12 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 suicidal thoughts or ideation 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 or indicate a positive response by selecting ‘1, 2, or 3’ to question number 9 on the PHQ-9 
must see a psychiatrist for advice on the most appropriate medical treatment 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).

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Table 13:
GAD-7 anxiety scale
Table 14:
PHQ-9 depression scale

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7.1.1.3
Hyperglycemia
In preclinical studies, insulin/glucose homeostasis was impacted in various species (mice, rats, dogs), as 
expected from the mode of action of BKM120. 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 BKM120 in patients with solid 
tumors (CBKM120X2101). 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 BKM120 treatment 
investigators are advised to adhere to the protocol guidelines outlined in Table 11.
7.1.1.4
Management of Hyperglycemia
In addition to the dose modification and hyperglycemia treatment guidelines in Table 5.

Under the supervision of an endocrinologist, an insulin regimen should be initiated according to 
institutional standard of care or the Treat-To-Target Algorithm for Lantus® (Riddle, Rosenstock, and 
Gerich 2003).
• For any hyperglycemia ≥ grade 1, the patient should continue to follow dietary guidelines provided by 
the American Diabetes Association (American Diabetes Association 2004).
• For each patient, a maximum of 2 dose reductions will be allowed after which the patient should be 
discontinued from the study. In addition, a patient must discontinue treatment with BKM120, if after 
treatment is resumed at a lower dose, hyperglycemia recurs at a worse severity.
• For each patient, once a dose level reduction has occurred, the dose level may not be re-escalated in that 
patient during future treatment with BKM120.
• Based upon the results of preliminary clinical data and actual laboratory values (e.g., glucose, insulin) 
generated, the treatment recommendations for study drug induced hyperglycemia may be modified as 
needed.
7.1.1.5
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. As a precaution in the first-in man study with BKM120 
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

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cardiac events occurring under BKM120 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.
7.1.1.6
Management of Cardiac events
At the screening visit a 12-lead electrocardiogram (ECG), and an echocardiogram or MUGA 
(ECHO/MUGA) will be performed to assess eligibility. Repeat ECGs will be performed at screening and 
as clinically indicated. An ECHO/MUGA will be repeated at Day 1 of CRT and EOT.
7.1.1.7
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 BKM120 in the single agent setting two cases of Pneumonitis occurred. In 
the study BKM120X2101 one patient experienced Pneumonits grade 2 eight weeks after the first dose of 
BKM120 at 100mg which resolved in 7 days after antibiotic therapy and discontinuation of the study 
treatment due to fatigue. In the Japanese study BKM120X1101 one case of Pneumonitis occurred in a 
patient given 100 mg one month after the start of study medication with BKM120. 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 current IB for more details).
All patients participating in clinical trials administering BKM120 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 15 should be followed. Consultation 
with a pulmonologist is highly recommended for any Pneumonitis case identified during the study.

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Table 15:
Management of pneumonitis
Worst 
Grade 
Pneumonitis
Required Investigations
Management
of 
Pneumonitis
BKM120
Dose Adjustment
Grade 1
CT 
scans 
with 
lung 
windows. Repeat at least 
every 8 weeks until return 
to within normal limits.
No
specific 
therapy
is 
required
Administer
100%
of 
BKM120 dose.
Grade 2
CT 
scan 
with 
lung 
windows.
Consider
pulmonary
function
testing
includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. Repeat at least every
8 weeks until return to 
within 
normal 
limits. 
Consider a bronchoscopy 
with biopsy and / or BAL.
Symptomatic 
only.
Consider 
corticosteroids
if 
symptoms
are 
troublesome.
Reduce BKM120 dose by 1 
dose level (see Table 11) 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.
Grade 3
CT 
scan 
with 
lung 
windows and pulmonary 
function testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. Repeat at least every
6 weeks 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 
BKM120 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, 
if 
possible, 
includes: 
spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat 
at least every 6 weeks 
until return to within 
normal
limits.
Bronchoscopy
with 
biopsy and / or BAL is 
recommended if possible.
Consider 
corticosteroids
if 
infective origin is 
ruled out. Taper as 
medically 
indicated.
Discontinue treatment with 
BKM120.

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Management of Liver Toxicities
Monitoring: every week (if visit schedule allows a more frequent monitoring this should be considered) 
or more frequently if clinically indicated especially for patients with borderline acceptable AST/ ALT/ 
bilirubin* values.
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; hereafter the 
monitoring should be continued every other week or more frequently if clinically indicated until the end 
of treatment with study medication.
Patients who discontinued study treatment should be monitored weekly, including LFTs* or more 
frequently if clinically indicated until resolved to ≤ grade 1 or stabilization (no CTCAE grade change 
over 4 weeks).
7.2
Adverse Event Characteristics

CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
7.3
For expedited reporting purposes only:
-
AEs for the agent that is listed above should be reported only if the adverse event varies in 
nature, intensity or frequency from the expected toxicity information which is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in the next 
section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-Specific Expedited 
Adverse Event Reporting Exclusions.
7.4
Expedited Reporting to the Food and Drug Administration (FDA)
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The Overall 
PI will report to the FDA, regardless of the site of occurrence, any serious adverse event that meets the 
FDA’s criteria for expedited reporting following the reporting requirements and timelines set by the FDA.
7.5
Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant safety reports

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or sentinel events that require reporting according to institutional policy.
7.6
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the toxicity 
case report forms. AEs reported through expedited processes (e.g., reported to the IRB, FDA, etc.) 
must also be reported in routine study data submissions.
8.
PHARMACEUTICAL INFORMATION
8.1
BKM120
BKM120 is being developed as a mono hydrochloride salt due to the favorable physicochemical 
properties such as good stability, high crystallinity and slightly hygroscopic properties. The majority of 
the in vivo PK and pharmacology evaluation was performed using this salt form.
8.1.1
Form
The drug product is a hard gelatin capsule for oral administration (10mg, and 50mg). Both dosage strengths 
have the same qualitative composition, although they are not proportionally scaled. The capsules consist of 
dry powder blends made using standard excipients of pharmacopoeial quality: mannitol, microcrystalline 
cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate. The 10-mg capsule uses a Size 
1 or Size 3 pink opaque capsule shell, the 50 mg capsules uses a Size 1 capsule shell of pink opaque or 
grey opaque color.
8.1.2
Storage and Stability
Based on the available stability data, BKM120 capsules are not to be stored above 25°C.
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.
8.1.3
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the 
environment, should undertake the preparation, handling, and safe disposal of the chemotherapeutic agent 
in a self-contained and protective environment.
8.1.4
Ordering
BKM capsules will be supplied by Novartis Pharmaceuticals.

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8.1.5
Accountability
The investigator, or a responsible party designated by the investigator, should maintain a careful record 
of the inventory and disposition of the agent using the NCI Drug Accountability Record Form (DARF) or 
another comparable drug accountability form. (See the NCI Investigator’s Handbook for Procedures for 
Drug Accountability and Storage.)
8.1.6
Destruction and Return
Unused supplies of the agent will be destroyed according to the DFCI Research Pharmacy policy.
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1
Laboratory Correlative Studies
All patients will have pre-treatment tumor tissue collected (fresh or archival) and NexGen sequencing will 
be performed to assess the mutational landscape in these cases. This will include over 500 cancer relevant 
genes.
Fresh biopsies will be obtained prior to and after 7-10d of treatment BKM120 alone. These are optional 
but encouraged in patients with accessible tumor. Biopsies will be snap frozen. Kinome analysis will be 
carried out in collaboration with the Broad Institute/MIT, Cambridge, MA. In this assay, tyrosine kinases 
will be isolated from fresh tumor tissue and phosphorylation status will be assessed in a panel of 55 cancer 
related kinases. This will provide unique insight into how BKM120 blocks PI3K and its downstream 
effectors. In addition this will also provide information about possible activation of escape mechanisms 
such as the MAP-kinase pathway. This could help to further elucidate biological efficacy or resistance.
We expect approximately 30% of patients to be eligible and amenable to sequential biopsies.
The correlative studies to investigate the influence of the NFE2L2/KEAP1/CUL3 pathway, are outlined 
in the attached research proposal (Appendix D), for which we will receive support through an internal 
DFCI grant mechanism.
9.2
 
ImmunoProfile 
In addition to the correlative laboratory studies explained in the section above, the investigators may 
choose to use an additional tissue testing methodology known as ImmunoProfile.  
ImmunoProfile uses multiplex immunofluorescent staining and imaging. Multiplex technology uses 
multiple colors to identify different cells and proteins at the same time on the same slide. Once multiplex 
staining is complete, the Vectra imager is used to acquire an image of the slide/staining for analysis. Image 
analysis software is then used to determine the number and percentage of cells positive for the selected 
immuno-regulatory proteins. 
The current version of ImmunoProfile tests for 5 different proteins/markers on one slide (i.e., DAPI, a 
tumor marker, PDL1, CD8, PD-1 and FOXP3). These initial proteins have been selected because they are 
targets for existing immunotherapies and there are publications supporting their use as predictors of 
response. 

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This test is performed in a CLIA certified clinical laboratory under CLIA guidelines for clinical testing. 
This is a research test and the study results are not released to patient electronic medical records as of the 
writing of this document. 
Detailed Material and Methods 
Staining is performed overnight for ~9 hours on BOND RX fully automated stainers (Leica Biosystems). 
Tissue sections of 5-μm thick FFPE are baked for 3 hours at 60°C before loading into the BOND RX. 
Slides are deparaffinized (BOND DeWax Solution, Leica Biosystems, Cat. AR9590) and rehydrated with 
series of graded ethanol to deionized water. Antigen retrieval is performed in BOND Epitope Retrieval 
Solution 1 (pH 6) or 2 (pH 9), as shown below (ER1, ER2, Leica Biosystems, Cat. AR9961, AR9640) at 
95°C. Deparaffinization, rehydration and antigen retrieval are all pre-programmed and executed by the 
BOND RX. Next, slides are serially stained with primary antibodies, such as anti-CD8 (clone 4B11; Leica, 
dilution 1:200). Incubation time per primary antibody was 30 minutes. Subsequently, anti-mouse plus 
anti-rabbit Opal Polymer Horseradish Peroxidase (Opal Polymer HRP Ms + Rb, Akoya Biosciences, Cat. 
ARH1001EA) is applied as a secondary label with an incubation time of 10 minutes. Signal for antibody 
complexes is labeled and visualized by their corresponding Opal Fluorophore Reagents (Akoya) by 
incubating the slides for 10 minutes. Slides are incubated in Spectral DAPI solution (Akoya) for 10 
minutes, air dried, and mounted with Prolong Diamond Anti-fade mounting medium (Life Technologies, 
Cat. P36965) and stored in a light-proof box at 4 ̊C prior to imaging. The target antigens, antibody clones, 
dilutions for markers, and antigen retrieval details are listed in Table 16. 
Image acquisition is performed using the Vectra Polaris multispectral imaging platform (Vectra Polaris, 
Akoya Biosciences, Marlborough, MA). Areas with non-tumor or residual normal tissue (i.e. residual 
lymph node) are excluded from the analysis. Representative regions of interest are chosen by the 
pathologist, and 3-5 fields of view (FOVs) are acquired at 20x resolution as multispectral images. Cell 
identification is performed as described previously (Carey et al, Blood 2016). In short, after image capture, 
the FOVs are spectrally unmixed and then analyzed using supervised machine learning algorithms within 
Inform 2.4 (Akoya). This image analysis software assigns phenotypes to all cells in the image, based on a 
combination of immunofluorescence characteristics associated with segmented nuclei (DAPI signal). 
Each cell-phenotype specific algorithm is based upon an iterative training / test process, whereby a small 
number of cells (training phase, typically 15-20 cells) are manually selected as being most representative 
of each phenotype of interest and the algorithm then predicts the phenotype for all remaining cells (testing 
phase). The pathologist can over-rule the decisions made by the software to improve accuracy, until 
phenotyping is optimized. Thresholds for "positive" staining and the accuracy of phenotypic algorithms 
are optimized and confirmed by the pathologist for each case.
Table 16: Target antigens, antibody clones, dilution of markers, and antigen retrieval conditions used for 
ImmunoProfile staining
Antibody
Clone
Company
Catalog #
Antibody Dilution
Fluor
Fluor Dilution
Antigen Retrieval, 
Time (min)
CD8
4B11
Leica
NCL-L-CD8-4B11
1:200
Opal 480
1:150
ER1, 20
PD-L1
E1L3N
Cell Signaling
13684
1:300
Opal 520
1:150
ER1, 20
Foxp3
D608R
Cell Signaling
12653
1:100
Opal 570
1:300
ER2, 40
PD-1
EPR4877(2)
Abcam
Ab137132
1:300
Opal 620
1:300
ER1, 20
Cytokeratin
AE1/AE3
Dako
M351529-2
1:100
Opal 690
1:100
ER1, 20

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10.
STUDY CALENDAR
Baseline evaluations are to be conducted within 3 weeks prior to study entry. Scans and x-rays must be 
done <4 weeks prior to study entry. In the event that the participant’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next treatment. Assessments must 
be performed prior to administration of any study agent. During the treatment phase, study assessments 
and agents should be administered within + 2 days of the protocol-specified date, unless otherwise noted. 
Follow up visits must occur within +/- 14 days of the protocol specified date.

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Table 17: Evaluation and visit schedule
Examination
Screening/ 
Baseline
BKM120
alone 
phase
Chemo (cisplatin) – radiotherapy 
(CRT)
Day of treatment
-21
1
8
1
8
15
22
29
36
43
EOT
FU until first 
progression10
After first 
progression11
Informed consent
X
Medical History
X
Inclusion/exclusion 
criteria
X
Serum Pregnancy 
Test (within 72 
hours of first 
treatment for 
WOCBP)
X
as clinically indicated
Urinalysis
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
examination 
(including skin rash 
assessment)
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance Status 
ECOG
X
X
X
X
X
X
X
X
X
X
X
X
Neuro-psychiatric 
assessment (self 
rating
mood 
questionnaire)1
X
X
X
X
X
X
X
X
X
X
X
X
MUGA/ECHO2
X
X
X
12-lead ECG
X
Dental Evaluation
X
Chest X-Ray3
X
X
X
Radiological tumor
assessment/response 
assessment 4
X
X4
Hematology5
X
X
X
X
X
X
X
X
X
X
X
Serum Chemistry6
X
X
X
Coagulation Profile7
X
X
X
Fasting plasma 
glucose8
X
X
X
X
X
X
X
X
X
X
X
Adverse events9
X
X
X
X
X
X
X
X
X
X
X
Placement of a PEG is highly recommended prior to beginning BKM120 CRT. It is recommended that this procedure 
be performed prior to beginning BKM120 CRT or within the first two weeks of therapy.
1 PHQ-9 and GAD-7 questionnaires will be completed until 1 year post treatment
2 MUGA/ECHO screening, Day 1 of BKM120+CRT and EOT

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3 A Chest X-Ray should be performed for all patients at screening, Day 1 of CRT and EOT
4 Screening radiological assessments should be performed within 4 weeks prior to study entry. Radiological tumor assessments 
should subsequently be performed at 3 months post BKM120+CRT. Follow up imaging after the three month assessment will 
be at the discretion of the treating oncologist and performed when necessary. Imaging modality (PET/ CT or CT) is at the 
discretion of the treating oncologist.
5 Hematology - WBC plus differential (neutrophil including bands, lymphocyte, monocyte, eosinophil, basophil and other 
counts, hemoglobin and platelets. Should be performed on screening, before each BKM120 dose; and EOT
6 Serum chemistry - K+, Na+, Ca++, Mg++, LDH, ALT, AST, total bilirubin (direct and indirect), creatinine, amylase, GGT, 
lipase, alkaline phosphatase (fractionated if alkaline phosphatase is grade 2 or higher), bicarbonate, phosphorus, uric acid, total 
cholesterol, HDL, LDL, triglycerides, glucose, urea or BUN, albumin, and total protein are required at baseline and at end of 
treatment. Subsequent assessments always include K+, Na+, Mg++, Ca++, ALT, AST, total bilirubin (direct and indirect), 
creatinine, alkaline phosphatase, bicarbonate, phosphorus, glucose, urea or BUN, albumin, and total protein BUT, lipase, total 
cholesterol, HDL, LDL, triglycerides should be obtained on Day 1 of CRT and EOT 7 Coagulation - PT or INR, PTT: Day 1 
of CRT and EOT
8 Patients must be fasting overnight for at least 8 hours. Additional measurements may be performed as clinically indicated.
9 Patients will be assessed weekly for adverse events for the duration of the treatment (2 weeks of BKM120 and 7 weeks of 
BKM120+CRT = 9 weeks) and every 2 weeks after conclusion of BKM120+CRT (EOT) during the first month, then monthly 
for 3 months, then every 3 months, until first progression, death, or 2 years post study entry whichever occurs first.
10 Follow up (FU) will take place every 2 weeks after conclusion of BKM120+CRT (EOT) during the first month, then monthly 
for 3 months, then every 3 months, until first progression, death, or 2 years post study entry whichever occurs first. Follow up 
visits must occur within +/- 14 days of the protocol specified date.
11 After first progression, patients will be followed for survival every 3 months until 2 years post study entry.
Biologic Sample Submission:
Sample Type
Screening/Baseline
BKM120 alone phase (7-10 days)
Blood (whole blood with EDTA)
X
Archived tumor
X
Fresh Biopsy*
X
X
*optional, but encouraged in patients with accessible tumors.
11.
MEASUREMENT OF EFFECT
Although response is not the primary endpoint of this trial, participants with measurable disease will be 
assessed by standard criteria (RECIST 1.1) 
http://ctep.cancer.gov/protocolDevelopment/docs/Recist_Guideline.pdf
12.
DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse 
Events: List and Reporting Requirements).
12.1
Data Reporting
The QACT will collect, manage, and perform quality checks on the data for this study.

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12.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and 
accrual data from this study. The committee is composed of clinical specialists with experience in 
oncology and who have no direct relationship with the study. Information that raises any questions about 
participant safety will be addressed with the Overall PI and study team.
The DSMC will review each protocol up to four times a year or more often if required to review toxicity 
and accrual data. Information to be provided to the committee may include: up-to-date participant accrual; 
current dose level information; DLT information; all grade 2 or higher unexpected adverse events that 
have been reported; summary of all deaths occurring with 30 days of intervention for Phase I or II 
protocols; for gene therapy protocols, summary of all deaths while being treated and during active follow- 
up; any response information; audit results, and a summary provided by the study team. Other information 
(e.g. scans, laboratory values) will be provided upon request.
13.
STATISTICAL CONSIDERATIONS
This trial follows a standard 3+3 phase I design. The primary endpoint is to determine the MTD. Patients 
will be started at a given dose and escalated according to the information outlined in section 5.3.
The table below gives the probabilities of the dose escalation scheme outlined in section 5.3.
True Rate of DLT
Probability of Escalation
20%
.71
30%
.49
40%
.31
50%
.17
60%
.08
For example, if the true rate of DLT is 20% at a given dose, there is a 71% probability of escalating to a 
higher dose.
At most, 46 patients are estimated to be accrued. This is based on studying 6 levels of BKM120+Cisplatin 
(section 5.3) with at most 6 patients per level plus an additional 10 at the MTD (these 10 accrued to ensure 
that the adverse event rate at the MTD is acceptable). The estimation of adverse events will be based on 
studying these 10 additional patients. The width of the 90% confidence interval for the estimation of the 
adverse event rate will be no more than 56%. The monthly accrual rate is estimated to be 2 to 3 patients.
For secondary objectives: best overall response rate will be summarized as a proportion with a corresponding 90% 
exact confidence interval, the distributions of progression and survival will be estimated using a Kaplan-Meier 
method with corresponding 90% confidence intervals for the median or time-specific event time, scores from the 
GAD-7 and the PHQ-9 to assess mood will be summarized across the timepoints of assessment. Several correlative 
studies are planned to learn more about how BKM120 blocks PIK. NexGen sequencing of the specimens and studies 
to investigate the influence of the NFE2L2/KEAP1/CUL3 are planned (see sections 9.1 and Appendix D). Given 
the small sample size of this trial, these studies are exploratory.

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14.
PUBLICATION PLAN
The results will be made public within 24 months of the end of data collection. A report is planned to be 
published in a peer-reviewed journal and that initial release may be an abstract that meets the requirements 
of the International Committee of Medical Journal Editors. A full report of the outcomes will be made 
public no later than three years after the end of data collection.
15.
REFERENCES
Abazeed ME, Adams DJ, Hurov KE, et al (2013) Integrative radiogenomic profiling of squamous cell lung cancer. 
Cancer Res.
Ang KK, Harris J, Wheeler R, et al (2010) Human papillomavirus and survival of patients with oropharyngeal 
cancer. N Engl J Med 363:24-35.
Beaulieu JM, Gainetdinov RR, Caron MG (2009) Akt/GSK3 signaling in the action of psychotropic drugs. 
Pharmacology and Toxicology; 49: 327-47.
Bendell JC, Rodon J, Burris HA, et al (2012) Phase I, Dose-Escalation Study of BKM120, an
Oral Pan-Class I PI3K Inhibitor, in Patients With Advanced Solid Tumors. J.Clin.Oncol.; 30 (3):282-290.
Bussink J, van der Kogel AJ, Kaanders JHAM (2008) Activation of the PI3-K/AKT pathway and implications for 
radioresistance mechanisms in head and neck cancer. The Lancet Oncology 9:288-296.
Chow L, Baker S (2006) PTEN function in normal and neoplastic growth. Cancer Lett. 241(2):184-96. Epub 2006 
Jan 18.
Cully M, You H, Levine AJ, et al (2006) Beyond PTEN mutations: the PI3K pathway as an integrator of multiple 
inputs during tumorigenesis. Nat Rev Cancer; 6(3):184-92.
Doi T, Ando Y, Bando H, et al (2011) Phase I dose-escalation study of BKM120, an oral
panclass I PI3K inhibitor, in Japanese patients with advanced solid tumors. Molecular Cancer Therapeutics: Volume 
10, Issue 11 (Supplement 1, Abstract B159).
Forastiere AA (2000) Head and neck cancer: overview of recent developments and future directions. Semin Oncol 
27:1-4.
Grana B, Burris HA, Rodon J, et al (2011) Oral PI3 kinase inhibitor BKM120 monotherapy in
patients (pts) with advanced solid tumors: An update on safety and efficacy. J Clin Oncol 29: (suppl; abstract/poster 
3043).
Gillison M (2010) HPV and its effect on head and neck cancer prognosis. Clin Adv Hematol Oncol 8:680-2.
Homma A, Inamura N, Oridate N, et al (2011) Concomitant weekly cisplatin and radiotherapy for head and neck 
cancer. Jpn J Clin Oncol 41:980-6.

Protocol #: 14-008
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65
Hosoi Y, Miyachi H, Matsumoto Y, et al1 (1998) A phosphatidylinositol 3-kinase inhibitor wortmannin induces 
radioresistant DNA synthesis and sensitizes cells to bleomycin and ionizing radiation. International Journal of 
Cancer 78:642-647.
Jemal A, Siegel R, Xu J, et al: Cancer statistics (2010) CA Cancer J Clin 60:277-300.
Katso R, Okkenhaug K, Ahmadi K, et al (2001) Cellular function of phosphoinositide 3- kinases: implications for 
development, homeostasis, and cancer. Cell Dev Biol; 17:615-75.
Kose F, Besen A, Sumbul T, et al (2011) Weekly cisplatin versus standard three-weekly cisplatin in concurrent 
chemoradiotherapy of head and neck cancer: the Baskent University experience. Asian Pac J Cancer Prev 12:1185- 
8.
Kwiatkowski DJ (2003) Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous 
sclerosis. Cancer Biology & Therapy; 2(5):471-6.
Liu P, Cheng H, Roberts TM, et al. (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev 
Drug Discov. Aug; 8(8):627-44.
Lui VW, Hedberg ML, Li H, et al (2013) Frequent mutation of the PI3K pathway in head and neck cancer defines 
predictive biomarkers. Cancer Discov 3:761-9.
McCubrey JA, Steelman LS, Abrams SL, et al (2006) Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways 
in malignant transformation and drug resistance. Adv Enzyme Regul; 46:249-79.
Nakamura J, Karlsson A, Arvold N, et al (2005) PKB/Akt mediates radiosensitization by the signaling inhibitor 
LY294002 in human malignant gliomas. Journal of Neuro-Oncology 71:215-222.
Pursche S, Schleyer E, von Bonin M, et al (2008). Influence of enzyme-inducing antiepileptic drugs on trough level 
of imatinib in glioblastoma patients. Curr Clin Pharmacol. Sep; 3(3):198-203.
Riddle, Rosenstock, and Gerich (2003) The treat-to-target trial: randomized addition of glargine or human NPH 
insulin to oral therapy of type 2 diabetic patients. Nov; 26(11):3080-6.
Rodon J, Bendell JC, Abdul Razak AR, et al (2011) Safety Profile and Clinical Activity of Single-Agent BKM120, 
a Pan-Class I PI3K Inhibitor, for the Treatment of Patients with Metastatic Breast Carcinoma. SABCS Abstract P3- 
16-01.
Saura C, Bendell J, Jerusalem G, et al (2011) Phase I/II Study of BKM120 in Combination with Trastuzumab in 
Patients with HER2 Overexpressing Metastatic Breast Cancer Resistant to Trastuzumab-Containing Therapy. 
SABCS Abstract PD09-03.
Stransky N, Egloff AM, Tward AD, et al (2011) The mutational landscape of head and neck squamous cell 
carcinoma. Science 333:1157-60.
Toulany M, Dittmann K, Kruger M, et al (2005) Radioresistance of K-Ras mutated human tumor cells is mediated 
through EGFR-dependent activation of PI3K-AKT pathway. Radiother Oncol 76:143-50.
Zhou S-F, Liu J-P, Chowbay B (2009) Polymorphism of human cytochrome P450 enzymes and its clinical impact. 
Drug Metabolism Reviews; 41(2): 89-295.
Carey CD1, Gusenleitner D2, Lipschitz M2, Roemer MGM3, Stack EC4, Gjini E2, Hu X5, Redd R5, Freeman 
GJ6, Neuberg D5, Hodi FS6, Liu XS5, Shipp MA6, Rodig SJ7. Topological analysis reveals a PD-L1 associated 

Protocol #: 14-008
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microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood. 2017 Sep 11. pii: blood-2017-
03-770719.

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16.
APPENDICES
APPENDIX A:
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity. Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, 
but 
ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but is 
able to care for most of his/her needs.
2
In 
bed 
<50% 
of 
the 
time. 
Ambulatory and capable of all self- 
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of
waking hours.
30
Severely
disabled,
hospitalization 
indicated. Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% 
bedridden. 
Completely 
disabled. Cannot carry on any self- 
care. Totally confined to bed or 
chair.
10
Moribund,
fatal
processes 
progressing rapidly.
5
Dead.
0
Dead.

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APPENDIX B:
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, and surgery) other than the study 
treatments must not be given to patients while the patient is 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 BKM120 is predominantly mediated 
by CYP3A4 (fm>0.9), with only minor contributions of CYP1A1. As BKM120 is a sensitive CYP3A4 
substrate, co-administration of BKM120 with strong and moderate CYP3A4 inhibitors and CYP3A4 
inducers is prohibited. See below for a list of prohibited drugs. Please note this list may not be 
comprehensive.

Based on in vitro studies, co-administration of BKM120 with CYP3A4 inducers is predicted to 
decrease the systemic exposure to BKM120, thereby increasing the risk of exposing the patient to 
subtherapeutic drug levels. See below for a list of prohibited CYP3A inducers. Please note that this list 
may not be comprehensive. Therapeutic doses of warfarin sodium (Coumadin®) or any other coumadin- 
derivative anticoagulants are not permitted.

If a patient requires the concomitant use of any medication included in Table 18 below 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.

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), ginko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginsing. 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.
Table 17:
LIST OF PROHIBITED CYP3A INHIBITORS AND INDUCERS
Strong
CYP3A 
inhibitors
Moderate
CYP3A 
inhibitors
Strong
CYP3A 
inducers
Moderate
CYP3A 
inducers
clarithromycin
aprepitant
avasimibe
bosentan
conivaptan
atazanavir
carbamazepine
efavirenz
grapefruit juice
cimetidine
Phenobarbital 
(barbiturates)
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

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Strong
CYP3A 
inhibitors
Moderate
CYP3A 
inhibitors
Strong
CYP3A 
inducers
Moderate
CYP3A 
inducers
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 BKM120 AUC > 5-fold, and moderate 
inhibitors are predicted to increase BKM120 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 18:        LIST OF PROHIBITED QT PROLONGING DRUGS
All QT-prolonging drugs listed in this table are prohibited for all patients from screening through 
permanent discontinuation of study treatment. Table 18 lists drugs with a known risk for Torsades de 
Pointes (TdP) as well as sensitive CYP3A substrates (with narrow TI) with a possible or conditional risk 
for TdP.
Drug
QT risk(*)
Comment
Amiodarone
Known risk for TdP
Females>Males,TdP risk regarded as low
Arsenic trioxide
Known risk for TdP
Astemizole
Known risk for TdP
No Longer available in U.S.
Bepridil
Known risk for TdP
Females>Males
Chloroquine
Known risk for TdP
Chlorpromazine
Known risk for TdP
Cisapride
Known risk for TdP
Restricted availability; Females>Males.
Disopyramide
Known risk for TdP
Females>Males
Dofetilide
Known risk for TdP
Domperidone
Known risk for TdP
Not available in the U.S.
Droperidol
Known risk for TdP
Halofantrine
Known risk for TdP
Females>Males

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Drug
QT risk(*)
Comment
Haloperidol
Known risk for TdP
When given intravenously or at higher-than- 
recommended doses, risk of sudden death, QT 
prolongation and torsades increases.
Ibutilide
Known risk for TdP
Females>Males
Levomethadyl
Known risk for TdP
Mesoridazine
Known risk for TdP
Methadone
Known risk for TdP
Females>Males
Pentamidine
Known risk for TdP
Females>Males
Pimozide
Known risk for TdP
Females>Males
Probucol
Known risk for TdP
No longer available in U.S.
Procainamide
Known risk for TdP
Quetiapine
Possible risk for TdP
Prohibited as this drug is a sensitive 3A4 substrate
Quinidine
Known risk for TdP
Females>Males
Sotalol
Known risk for TdP
Females>Males
Sparfloxacin
Known risk for TdP
Tacrolimus
Possible risk for TdP
Prohibited as this drug is a sensitive 3A4 substrate 
with narrow TI
Terfenadine
Known risk for TdP
No longer available in U.S.
Thioridazine
Known risk for TdP
Vardenafil
Possible risk for TdP
Prohibited as this drug is a sensitive 3A4 substrate
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT
Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher 
when co-administered with a potent inhibitor of the respective enzyme.
Drugs to be used with caution
Preliminary in vitro metabolism studies suggest that BKM120 is a weak, reversible inhibitor 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 
a weak reversible inhibitor of CYP2C8/2C9/2C19 (IC50=34 μM, [I]/IC50=0.15). Note: that with the data 
available, we are not able 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. Please refer to Table 19 for a list of CYP450 substrates 
and carefully consider their co-administration with BKM120.
Particularly, caution is advised when BKM120 is co-administered with:

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
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 guidance. It is recommended that treatment start with metformin.

If a patient, after study enrollment, requires the concomitant use of any QT prolonging medication 
with a possible or conditional risk for torsade de pointes then the investigators, at their discretion, may co- 
administer such medications. Patients receiving such medications must be monitored. Refer to Table 18 
for a list of QT prolonging medications to be used with caution.
Note: please refer also to Table 18 for a list of prohibited QT prolonging medication.

Please refer to Table 19 for a list of CYP450 substrates and carefully consider their co-administration 
with BKM120.

Concomitant treatment with corticosteroids and BKM120 should be avoided, whenever possible, 
during this study. A short duration (< 2 weeks) of systemic corticosteriods is allowed (e.g. for chronic 
obstructive pulmonary disease, or as an anti-emetic). Chronic dosing of corticosteriods is known to induce 
CYP3A enzymes, thereby increasing the risk or reducing BKM120 overall exposure to sub-therapeutic 
levels.
Table 19:        LIST OF CYP450 SUBSTRATES TO BE USED WITH CAUTION
CYP2C8
CYP2C9
CYP2C19
CYP3A**
amodiaquine
celecoxib
amitriptyline
Adinazolam
felodipine1
cerivastatin
diclofenac
citalopram
alfentanil1,2
fentanyl2
pioglitazone
flurbiprofen
clobazam
alpha- 
dihydroergocryptine1
flunitrazepam
repaglinide
fluvastatin
clomipramine
Alprazolam
fluticasone1
rosiglitazone
glibenclamide 
(glyburide)
clopidogrel
Amlodipine
lovastatin1
torasemide
gliclazide
diazepam
Aripiprazole
maraviroc1
troglitazone
glimepiride
fluoxetine
Atorvastatin
midazolam1
glipizide
imipramine
Brecanavir
nifedipine
indomethacin
lansoprazole
brotizolam1
nisoldipine
irbesartan
mephobarbital
budesonide1
nitrendipine
ketobemidone
moclobemide
buspirone1
perospirone1
lornoxicam
omeprazole
Capravirine
quinine
losartan
pantoprazole
Cerivastatin
sildenafil1

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meloxicam
progesterone
Chlorpheniramine
simvastatin1
naproxen
quazepam
cyclosporine2
sirolimus1,2
nateglinide
rabeprazole
darifenacin1
tolvaptan
piroxicam
sertraline
Diazepam
trazodone
rosiglitazone
S-mephenytoin
diergotamine2
triazolam1
S-ibuprofen
ebastine1
sulfamethoxazole
eletriptan1
tenoxicam
eplerenone1
tolbutamide
ergotamine2
torasemide
Estazolam
valdecoxib
everolimus1
* This database of CYP substrates was compiled from the Indiana University School of Medicine’s 
“Clinically Relevant” Table, and from (Zhou 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.
1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or 
higher when co-administered with a potent inhibitor of the respective enzyme.
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that 
increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious 
safety concerns (e.g., Torsades de Pointes).
Table 20:
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

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Drug
QT risk
Comment
Dolasetron
possible risk for Torsades de Pointes
Doxepin
conditional risk for Torsades de Pointes
Dronedarone
possible risk for Torsades de Pointes
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

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Drug
QT risk
Comment
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
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT

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APPENDIX C:
RTOG/EORTC LATE RADIATION MORBIDITY SCORING SCHEMA
ORGAN TISSUE
0
Grade 1
Grade 2
Grade 3
Grade 4
5
SKIN
None
Slight atrophy 
Pigmentation change 
Some hair loss
Patch atrophy; 
Moderate telangiectasia; 
Total hair loss
Marked atrophy; Gross 
telangiectasia
Ulceration
SUBCUTANEOUS 
TISSUE
None
Slight induration 
(fibrosia) and loss of 
subcutaneous fat
Moderate fibrosis but 
asymptomatic
Slight field contracture
<10% linear reduction
Severe induration and 
loss of subcutaneous 
tissue
Field contracture
>10% linear 
measurement
Necrosis
MUCOUS 
MEMBRANE
None
Slight atrophy and 
dryness
Moderate atrophy and 
telangiectasia
Little mucous
Marked atrophy with 
complete dryness 
Severe telangiectasia
Ulceration
SALIVARY 
GLANDS
None
Slight dryness of 
mouth
Good response on 
stimulation
Moderate dryness of 
mouth
Poor response on 
stimulation
Complete dryness of 
mouth
No response on 
stimulation
Fibrosis
SPINAL CORD
None
Mild L'Hermitte's 
syndrome
Severe L'Hermitte's 
syndrome
Objective neurological 
findings at or below 
cord level treated
Mono, para quadraplegia
BRAIN
None
Mild headache 
Slight lethargy
Moderate headache 
Great lethargy
Severe headaches 
Severe CNS 
dysfunction (partial 
loss of power or 
dyskinesia)
Seizures or paralysis 
Coma
EYE
None
Asymptomatic cataract 
Minor corneal 
ulceration or keratitis
Symptomatic cataract 
Moderate corneal 
ulceration
Minor retinopathy or 
glaucoma
Severe keratitis 
Severe retinopathy or 
detachment
Severe glaucoma
Panopthalmitis/ Blindness
LARYNX
None
Hoarseness 
Slight arytenoid 
edema
Moderate arytenoid 
edema
Chondritis
Severe edema 
Severe chondritis
Necrosis
LUNG
None
Asymptomatic or mild 
symptoms (dry cough) 
Slight radiographic 
appearances
Moderate symptomatic 
fibrosis or pneumonitis 
(severe cough)
Low grade fever 
Patchy radiographic 
appearances
Severe symptomatic 
fibrosis or pneumonitis 
Dense radiographic 
changes
Severe respiratory 
insufficiency/ Continuous 
O2/ Assisted ventilation
HEART
None
Asymptomatic or mild 
symptoms
Transient T wave 
inversion & ST 
changes
Sinus tachycardia
>110 (at rest)
Moderate angina on 
effort
Mild pericarditis 
Normal heart size 
Persistent abnormal T 
wave and ST changes 
Low ORS
Severe angina 
Pericardial effusion 
Constrictive pericarditis 
Moderate heart failure 
Cardiac enlargement 
EKG abnormalities
Tamponade/ Severe heart 
failure/ Severe constrictive 
pericarditis
ESOPHAGUS
None
Mild fibrosis 
Slight difficulty in 
swallowing solids
No pain on swallowing
Unable to take solid 
food normally 
Swallowing semi-solid 
food
Dilatation may be 
indicated
Severe fibrosis
Able to swallow only 
liquids
May have pain on 
swallowing 
Dilation required
Necrosis/ Perforation 
Fistula
SMALL/LARGE 
INTESTINE
None
Mild diarrhea 
Mild cramping
Bowel movement 5 
times daily
Slight rectal discharge 
or bleeding
Moderate diarrhea and 
colic
Bowel movement >5 
times daily
Excessive rectal mucus 
or intermittent bleeding
Obstruction or bleeding 
requiring surgery
Necrosis/ Perforation 
Fistula
LIVER
None
Mild lassitude 
Nausea, dyspepsia
Moderate symptoms 
Some abnormal liver
Disabling hepatitic 
insufficiency
Necrosis/ Hepatic coma or 
encephalopathy
D 
E 
A 
T 
H
D 
I 
R 
E 
C 
T 
L 
Y
R 
E 
L 
A 
T 
E 
D
T 
O
R 
A 
D 
I 
A 
T 
I 
O 
N
L 
A 
T 
E

Protocol #: 14-008
Version #/ Version Date: Version 5/ 15 July 2021
76
Slightly abnormal liver 
function
function tests
Serum albumin normal
Liver function tests 
grossly abnormal
Low albumin 
Edema or ascites
KIDNEY
None
Transient albuminuria 
No hypertension
Mild impairment of 
renal function 
Urea 25-35 mg%
Creatinine 1.5-2.0 
mg%
Creatinine clearance
>75%
Persistent moderate 
albuminuria (2+) 
Mild hypertension 
No related anemia
Moderate impairment of 
renal function
Urea>36-60 mg% 
Creatinine clearance 
(50-74%)
Severe albuminuria 
Severe hypertension 
Persistent anemia 
(<10g%)
Severe renal failure 
Urea >60 mg%
Creatinine >4.0 mg% 
Creatinine clearance
<50%
Malignant hypertension 
Uremic coma/Urea >100%
BLADDER
None
Slight epithelial 
atrophy
Minor telangiectasia 
(microscopic 
hematuria)
Moderate frequency 
Generalized 
telangiectasia 
Intermittent 
macroscopic hematuria
Severe frequency and 
dysuria
Severe generalized 
telangiectasia (often 
with petechiae) 
Frequent hematuria 
Reduction in bladder
capacity (<150 cc)
Necrosis/ Contracted 
bladder (capacity <100 
cc)
Severe hemorrhagic 
cystitis
BONE
None
Asymptomatic
No growth retardation 
Reduced bone density
Moderate pain or 
tenderness
Growth retardation 
Irregular bone sclerosis
Severe pain or 
tenderness 
Complete arrest of 
bone growth
Dense bone sclerosis
Necrosis/ Spontaneous 
fracture
JOINT
None
Mild joint stiffness 
Slight limitation of 
movement
Moderate stiffness 
Intermittent or 
moderate joint pain 
Moderate limitation of 
movement
Severe joint stiffness 
Pain with severe 
limitation of movement
Necrosis/ Complete 
fixation
E 
F 
F 
E 
C 
T 
S

Protocol #: 14-008
Version #/ Version Date: Version 5/ 15 July 2021
77
Summary of Changes, Protocol Version 2; dated 8/27/2015
Section
Change
10
Table 17: Evaluation and visit schedule, has been revised.

Follow up imaging after the three month assessment will be at the 
discretion of the treating oncologist and performed when 
necessary.

Imaging modality (PET/ CT or CT) is at the discretion of the 
treating oncologist.

A follow-up visit window of +/- 14 days was added.
Summary of Changes, Protocol Version 3; dated 06 Jan 2016
Section
Change
Appendix
Questionnaires:

GAD-7 anxiety and PHQ-9 depression scales translated into Spanish.
Summary of Changes, Protocol Version 4; dated 24 May 2021
Section
Change
 9.2
ImmunoProfile 

Added tumor testing methodology to further evaluate different proteins and 
markers  
 15 
References 

Added reference to align with the information in the new section 9.2 
ImmunoProfile 

Editorial and administrative updates have made throughout the protocol 

Summary of Changes, Protocol Version 5; dated 31 August 2021
Section
Change
Throughout 
Protocol

Change in PI name and contact information