Clinical trial NCT02340780
Conditions: Chronic Lymphocytic Leukemia
Sponsor: Canadian Cancer Trials Group
Start date: 2015-04-27; Completion date: 2020-04-28
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out what effects a new drug, buparlisib, has on chronic lymphocytic leukemia.

Detailed description:
Buparlisib has been shown to shrink tumours in animals. It has been studied in some people and seems promising but it is not clear if it can offer better results than standard treatment.

The standard or usual treatment for this disease is chemotherapy, targeted therapy or radiation, either alone or in combination.

Arms: arm 1: 100mg daily orally every 28 days
Interventions: intervention 1: Buparlisib
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_001.pdf: 
 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
HEALTH CANADA SUBMISSION 
 
AMENDMENT #1: 2015-OCT-22 
 
AMENDMENT #2: 2016-JAN-04 
 
 
AMENDMENT #3: 2016-AUG-24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCTG) 
 
A PHASE II STUDY OF BUPARLISIB IN PATIENTS WITH RELAPSED 
AND REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA 
 
CCTG Protocol Number: IND.216 
 
 
 
 
STUDY CHAIR: 
Sarit Assouline 
 
 
SENIOR INVESTIGATOR: 
Annette Hay 
 
 
SENIOR BIOSTATISTICIAN: 
Bingshu Chen 
 
 
STUDY COORDINATOR: 
Linda Hagerman 
 
 
REGULATORY SPONSOR: 
CCTG  
 
 
SUPPORTED BY: 
Novartis 
 
 
(For contact information of study personnel see Final Page.) 
 
 


 
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TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE ............................................................................................... 1 
 
TREATMENT SCHEMA ..................................................................................................................................... 2 
 
1.0 
OBJECTIVES ......................................................................................................................................... 5 
1.1 
Primary Objective ................................................................................................................................... 5 
1.2 
Secondary Objectives .............................................................................................................................. 5 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ...................................................................... 6 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION............................................................................ 8 
3.1 
Name and Chemical Information ............................................................................................................ 8 
3.2 
Chemical Structure .................................................................................................................................. 8 
3.3 
Mechanism of Action .............................................................................................................................. 8 
3.4 
Experimental Antitumour Activity .......................................................................................................... 8 
3.5 
Animal Toxicology ................................................................................................................................. 8 
3.6 
Phase I Trials ........................................................................................................................................... 9 
3.7 
Phase II Trials ......................................................................................................................................... 9 
3.8 
Pharmacokinetic Studies ......................................................................................................................... 9 
3.9 
Pharmaceutical Data .............................................................................................................................. 10 
 
4.0 
TRIAL DESIGN ................................................................................................................................... 11 
 
5.0 
STUDY POPULATION ....................................................................................................................... 12 
5.1 
Eligibility Criteria ................................................................................................................................. 12 
5.2 
Ineligibility Criteria ............................................................................................................................... 14 
 
6.0 
PRE-TREATMENT EVALUATION ................................................................................................... 16 
 
7.0 
ENTRY/registration PROCEDURES ................................................................................................... 17 
7.1 
Entry Procedures ................................................................................................................................... 17 
7.2 
Registration ........................................................................................................................................... 17 
 
8.0 
TREATMENT PLAN ........................................................................................................................... 18 
8.1 
Chemotherapy Treatment Plan .............................................................................................................. 18 
8.2 
Patient Self Rating Mood Questionnaires ............................................................................................. 19 
8.3 
Toxicity Grading ................................................................................................................................... 19 
8.4 
Dose Adjustments ................................................................................................................................. 20 
8.5 
Duration of Therapy .............................................................................................................................. 26 
8.6 
Concomitant Therapy ............................................................................................................................ 26 
 
9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT .............................................. 27 
9.1 
Evaluation During Protocol Treatment ................................................................................................. 27 
9.2 
Overview of Efficacy Evaluations ........................................................................................................ 28 
9.3 
Evaluation After Protocol Treatment .................................................................................................... 29 


 
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10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ......................................................... 30 
10.1 
Definitions ............................................................................................................................................. 30 
10.2 
Documenting Enlarged Lymph Nodes .................................................................................................. 30 
10.3 
Documenting Organomegaly ................................................................................................................ 30 
10.4 
Response ............................................................................................................................................... 30 
10.5 
Response Duration ................................................................................................................................ 32 
10.6 
Stable Disease Duration ........................................................................................................................ 32 
10.7 
Progression-Free Survival ..................................................................................................................... 33 
10.8 
Methods of Measurement for CT-Scan Evaluation ............................................................................... 33 
 
11.0 
SERIOUS ADVERSE EVENT REPORTING ..................................................................................... 34 
11.1 
Definition of a Reportable Serious Adverse Event ............................................................................... 34 
11.2 
Serious Adverse Event Reporting Instructions ..................................................................................... 34 
11.3 
Other Protocol Reportable Events – Pregnancy/Exposure Reporting ................................................... 35 
11.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada .................................. 37 
11.5 
CCTG Responsibility for Reporting Serious Adverse Events to Novartis ............................................ 37 
11.6 
Novartis Reporting Responsibilities ...................................................................................................... 37 
11.7 
Reporting Safety Reports to Investigators ............................................................................................. 37 
 
12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ............ 38 
12.1 
Criteria for Discontinuing Protocol Treatment ..................................................................................... 38 
12.2 
Duration of Protocol Treatment ............................................................................................................ 38 
12.3 
Therapy After Protocol Treatment is Stopped ...................................................................................... 38 
12.4 
Follow-up Off Protocol Treatment ........................................................................................................ 38 
 
13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION ............................................... 39 
13.1 
Central Radiology Review .................................................................................................................... 39 
13.2 
Central Pathology Review ..................................................................................................................... 39 
 
14.0 
STATISTICAL CONSIDERATIONS .................................................................................................. 40 
14.1 
Objectives and Design ........................................................................................................................... 40 
14.2 
Sample Size and Duration of Study ...................................................................................................... 40 
14.3 
Safety .................................................................................................................................................... 40 
14.4 
Correlative Studies ................................................................................................................................ 41 
14.5 
Prospective Validation of Survival Scale .............................................................................................. 41 
 
15.0 
PUBLICATION POLICY ..................................................................................................................... 42 
15.1 
Authorship of Papers, Meeting Abstracts, Etc ...................................................................................... 42 
15.2 
Responsibility for Publication ............................................................................................................... 42 
15.3 
Submission of Material for Presentation or Publication ........................................................................ 42 
 
16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES ...................................................... 43 
16.1 
Regulatory Considerations .................................................................................................................... 43 
16.2 
Inclusivity in Research .......................................................................................................................... 43 
16.3 
Obtaining Informed Consent ................................................................................................................. 44 
16.4 
Discontinuation of the Trial .................................................................................................................. 45 
16.5 
Retention of Patient Records and Study Files ....................................................................................... 45 
16.6 
Centre Performance Monitoring ............................................................................................................ 45 
16.7 
On-Site Monitoring/Auditing ................................................................................................................ 45 
16.8 
Case Report Forms ................................................................................................................................ 46 
 


 
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AMEND #1: 2015-OCT-22 
17.0 
CORRELATIVE BLOOD WORK ....................................................................................................... 47 
17.1 
Objectives .............................................................................................................................................. 47 
17.2 
PIK3CA Gene Amplification Analysis ................................................................................................. 48 
 
18.0 
REFERENCES ...................................................................................................................................... 49 
 
APPENDIX I -  
PATIENT EVALUATION FLOW SHEET ..................................................................... 51 
APPENDIX II -  
PERFORMANCE STATUS SCORES ............................................................................. 53 
APPENDIX III - 
 DRUG DISTRIBUTION, SUPPLY AND CONTROL ................................................... 54 
APPENDIX IV -  
DOCUMENTATION FOR STUDY ................................................................................ 55 
APPENDIX V -  
NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS .................. 57 
APPENDIX VI -  
CLL DIAGNOSTIC CRITERIA AND INDICATIONS FOR TREATMENT ................ 58 
APPENDIX VII -  
CYP3A INHIBITORS/INDUCERS AND CYP450 SUBSTRATES ............................... 59 
APPENDIX VIII -  QT PROLONGING DRUGS............................................................................................ 61 
 
 
LIST OF CONTACTS ........................................................................................................................... Final Page 
 


 
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AMEND #3: 2016-AUG-24 
STUDY ACKNOWLEDGMENT/DISCLOSURE 
 
I understand that this protocol contains information that is confidential and proprietary to Novartis. 
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, and according to Good Clinical Practice and any 
applicable local regulations. I will make a reasonable effort to complete the study within the time 
designated. I confirm that I and study personnel participating under my supervision have adequate resource 
to fulfill their responsibilities as outlined in this protocol. I will maintain documentation of any investigator 
responsibilities assigned to participating study personnel. I confirm that all data will be submitted in a timely 
manner and will be accurate, complete and supported by source documents. I will complete any protocol 
specific training required by the sponsor and that I understand the requirement to inform additional site 
personnel with delegated duties of this information. 
 
I will provide copies of the protocol and access to all information furnished by CCTG and Novartis to study 
personnel under my supervision. I will discuss this material with them to ensure that they are fully informed 
about the investigational product and the study. 
 
I understand that this trial will be registered on a public trial registry and that my contact information and 
site name will be included in the registry listing. 
 
I will provide protocol information to my Research Ethics Board (REB), Institutional Review Board(s) 
[IRB(s)] or Independent Ethics Committee(s) [IEC(s)], subject to the following condition: The contents of 
this protocol may not be used in any other clinical trial and may not be disclosed to any other person or 
entity without the prior written permission of Novartis and CCTG. The foregoing shall not apply to 
disclosure required by governmental regulations or laws; however, I will give prompt notice to Novartis 
and CCTG of any such disclosure. 
 
I understand that I may terminate or suspend enrolment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to CCTG. The study may 
be terminated at any time by CCTG or Novartis with or without cause. 
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
Novartis and CCTG and must be kept in confidence in the same manner as the contents of this protocol. 
Publication will proceed per policy and as per protocol. Novartis require a review period of fifteen (15) 
working days for presentation materials and abstracts and forty-five (45) working days for manuscripts. 
 
Please note: Novartis has not provided a contractual indemnification to investigators or study sites for any 
claims arising out of or in connection with the administration or use of the drugs being studied through the 
study (“study drugs”) during the course of this study. 
 
___________________________________________________ 
_________________________ 
Qualified Investigator 
Date 
(printed name and signature) 
 
___________________________________________________ 
_________________________ 
Institutional Representative 
Date 
(printed name and signature) 
 
Protocol Number: CCTG IND.216 
 
CENTRE: ___________________________________________ 


 
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TREATMENT SCHEMA 
 
A phase II study of buparlisib in patients with relapsed and refractory chronic lymphocytic leukemia. 
 
Eligibility Criteria 
• 
Previously documented CLL as defined by the 2008 International Workshop on Chronic Lymphocytic 
Leukemia (IWCLL) Guidelines that is recurrent or relapsed after previous therapy and that requires 
treatment (see Appendix VI); 
• 
Measurable disease with at least one of lymphocyte count > 10 x 109/L OR at least one pathologically 
enlarged lymph node (> 2 x 2 cm) by CT scan; 
• 
ECOG performance status of 0, 1 or 2; 
• 
At least one prior systemic treatment regimen (single agent or combination therapy, may include 
autologous or allogeneic stem cell transplantation) and have recovered from all reversible toxicity 
related to prior systemic therapy and have adequate washout period (See Section 5.1.6); 
• 
Age > 18 years; 
• 
Life expectancy of at least 12 weeks; 
• 
Neutrophils > 1.0 x 109/L; 
• 
Platelets > 50 x 109/L and more than 5 days since last transfusion; 
• 
Creatinine clearance > 50 mL/min; 
• 
Bilirubin < 1.5 x upper normal limit (UNL) (direct if known Gilbert’s); 
• 
AST and ALT < 1.5 x UNL (< 3 x UNL if hepatic involvement with CLL); 
• 
Potassium and calcium (within normal limits for laboratory (supplementation permitted)); 
• 
Fasting glucose < 7.8 mm/L (AND HbA1c < 8% if diabetic). 
 
Ineligibility Criteria 
• 
Prior treatment with buparlisib (BKM120); 
• 
Progression to high grade lymphoma or myelodysplasia; 
• 
History of other malignancies, except those which have been curatively treated and require no ongoing 
therapy; 
• 
Known hypersensitivity to study drug or its components; 
• 
Serious illness or medical condition; 
• 
Uncontrolled or significant cardiovascular disease including left ventricular ejection fraction < 50%; 
• 
Mood disorders (see Section 5.2.6); 
• 
Impairment of gastrointestinal function or GI disease that may significantly alter the absorption of 
buparlisib; 
• 
Patients unable to swallow capsules; 
• 
Patients on strong CYP3A inhibitors/inducers or therapeutic doses of warfarin-like anticoagulants; 
• 
Patients on drugs with a known risk to induce Torsades de Pointes (see Appendix VIII) 
• 
Patients receiving high dose steroid therapy or another immunosuppressive agent; 
• 
Patients with known HIV positivity; 
• 
Patients with known CLL involvement of the central nervous system. 


 
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AMEND #1: 2015-OCT-22 
Pre-Treatment Evaluations 
• 
History, physical exam, vital signs, ECOG performance status, toxicity/baseline symptoms, 12-lead 
ECG (within 7 days prior to registration); 
• 
Hematology, biochemistry and coagulation (within 7 days prior to registration); 
• 
Mood Questionnaires (within 7 days prior to registration); 
• 
MUGA/LVEF (only if clinically indicated) (within 28 days prior to registration); 
• 
Pregnancy test (within 7 days prior to registration) (if applicable); 
• 
Direct anti-globulin test (DAGT) (within 7 days prior to registration); 
• 
CT scan of neck, chest, abdomen and pelvis (within 21 days prior to registration); 
• 
Bone marrow aspirate and biopsy for routine local pathology to assess CLL (within 28 days prior to 
registration); 
• 
Hepatitis B surface antigen (HBsAg) (within 28 days prior to registration); 
• 
Hepatitis C serology (within 28 days prior to registration); 
• 
Fluorescence in situ hybridization (FISH) for 17p and 11q deletion (within 28 days prior to 
registration); 
• 
Immunoglobulin variable region (IgVH) mutation status (any time prior to registration); 
• 
Peripheral blood for correlatives (within 28 days prior to registration). 
 
Treatment 
• 
Buparlisib will be given orally daily starting day 1 cycle 1. A cycle is defined as 28 days of treatment. 
 
On Treatment Evaluations 
• 
Physical exam, ECOG, vital signs (Day 1 each cycle); 
• 
Hematology and Biochemistry (Days 1 and 14 cycle 1 and 2, then Day 1 each cycle thereafter; more 
frequently if clinically indicated); 
• 
CT scan of neck, chest, abdomen and pelvis. (To be repeated 8, 16, and 24 weeks from registration and 
thereafter every 12 weeks. Patients who have no evidence of disease on CT at baseline can omit follow 
up scans unless palpable disease arises or there is clinical suspicion of disease progression.); 
• 
Bone marrow aspirate and biopsy (at time other criteria for CR first met and 8 weeks later to confirm 
sustained CR; or if cytopenia of uncertain cause) (see Section 9); 
• 
Assessment for minimal residual disease (MRD) (Optional – if CR criteria otherwise met) (see Section 
9); 
• 
Mood Questionnaires (Day 1 and 14 in cycles 1 and 2, then Day 1 each cycle and End of Treatment 
visit); 
• 
Correlative blood work (At time of disease progression-if applicable) (See Section 17 and Laboratory 
Manual); 
• 
Adverse events -patients to be evaluated continuously for adverse events. 
 
Correlative Blood Work 
• 
See Section 17 and Laboratory Manual. 


 
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Duration of Treatment 
Patients may stop protocol treatment in the following instances: 
• 
Intercurrent illness which would, in the judgment of the investigator, affect assessments of clinical 
status to a significant degree, and require discontinuation of protocol therapy. 
• 
Unacceptable toxicity as defined in Section 8.0; 
• 
Tumour progression or disease recurrence as defined in Section 10.0; 
• 
Request by the patient; 
• 
Completion of therapy as outlined in Section 8.0. Efforts should be made to maintain the investigations 
schedule and continue follow-up, even if patients discontinue protocol treatment prematurely and/or no 
longer attend the participating institution.  


 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To determine the overall response rate (complete + partial response) to oral buparlisib in patients 
with relapsed and refractory chronic lymphocytic leukemia. 
 
1.2 
Secondary Objectives 
 
1.2.1 
To evaluate the safety and tolerability of buparlisib administered at 100 mg per day on a 28 day 
cycle, in patients with previously treated chronic lymphocytic leukemia. 
 
1.2.2 
To evaluate additional measures of efficacy including: 
• 
duration of response rate 
• 
progression free survival 
 
1.2.3 
To explore potential molecular factors which may be prognostic or predictive of response or of 
relapse including: 
• 
correlation between clinical response to buparlisib and MTT assay (cell viability assay) in 
B-CLL exposed ex-vivo to buparlisib 
• 
correlation between response to buparlisib and western blot and flow cytometry analysis of key 
proteins involved in the PI3K pathway 
• 
identification of mechanisms of resistance among patients who relapse after therapy with 
buparlisib 
 
1.2.4 
To prospectively validate a survival prediction scale. 


 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of malignant B 
lymphocytes expressing the surface antigens CD19, CD20, CD23 and CD5 [Klein 2001]. These B-
CLL cells display altered apoptosis that is caused by both primary tumour features and co-
dependent stromal elements [Burger 2000]. Current treatments for this disease include alkylating 
agents (chlorambucil, cyclophosphamide, bendamustine), purine analogs such as fludarabine, and 
immunotherapeutic agents (rituximab, alemtuzumab), either given as single agents or in 
combination. The current gold standard for CLL treatment is fludarabine, cyclophosphamide and 
rituximab (FCR). However, none of these standard treatments result in cure, supporting the need 
for investigation of new therapeutic targets and drug development in CLL as well as markers that 
can predict clinical response to therapy [Gribben 2011]. 
 
The phosphatidylinositol 3-kinase (PI3K) cascade is a critical component of survival signaling 
including PI3K-activated Akt (phosphorylated Akt) which inhibits cell death pathways by 
inactivating pro-apoptotic proteins such as Bad, procaspase-9 and members of the Forkhead 
transcription factor family. Overexpression of PI3K appears to play a critical role in B-CLL cell 
survival. Recently, the PI3Kδ inhibitor idelalisib showed preclinical activity in CLL lymphocytes 
and is now in clinical trials in combination with chemotherapeutic and immunotherapeutic agents 
in patients with relapsed B-cell malignancy including CLL [Herman 2010, Lannutti 2011, Furman 2014]. 
The pan class I PI3K inhibitor buparlisib (BKM120, Novartis Pharma AG, Basel, Switzerland) is 
currently under investigation in phase I, II and III clinical trials in patients with advanced solid 
tumours [Bendell 2012], clinicaltrials.gov). 
 
In view of the critical role of PI3K in CLL homeostasis [Liu 2009], in vitro cytotoxic effect of 
buparlisib was assessed in 3 B-CLL cell lines and in primary B-lymphocytes isolated from 65 B-
CLL patient samples utilizing the MTT assay. The IC50 (drug concentration resulting in 50% cell 
death) obtained in the B-CLL cell lines JVM2, EHEB and MEC2 were 0.9±0.1, 0.7±0.1 and 0.7±0.1 
µM respectively. Buparlisib was cytotoxic (IC50 below the maximum concentration (20µM) of 
buparlisib used in the MTT assay) in 78% of the primary B-CLL lymphocyte samples tested. It is 
known that patients whose CLL bears a 17p (del17) or 11q (del11) deletion have a poorer response 
to standard therapy and a shortened overall survival [Grever 2007]. Buparlisib was demonstrated to 
be cytotoxic in all patient samples harboring these deletions [Amrein 2013]. 
 
In the phase I clinical study, the maximum plasma concentration (Cmax) of buparlisib obtained 
after administration of the maximum tolerated dose of the drug was 5µM [Grever 2007]. Interestingly, 
60% of the B-CLL samples tested by Amrein [Amrein 2013] have an IC50 below this Cmax. 
Furthermore, 5 out of the 6 patient samples with del11 or del17 have a clinically achievable IC50. 
These results indicate that buparlisib may be useful as a single agent in CLL. MTT assay 
demonstrated buparlisib to be 3.6 times more toxic than idelalisib in malignant B-CLL 
lymphocytes in vitro in 20 patient samples. Furthermore buparlisib was cytotoxic (IC50< 20µM) in 
80% of these 20 samples tested while idelalisib was only cytotoxic (IC50< 50µM) in 45% of these 
samples. CLL has a widely variable response to therapy. Positive correlations were observed 
between buparlisib cytotoxicity and the basal expression of Akt (r = 0.592, p = 2.468E-06, n =54), 
rictor (r = 0.418; p = 1.65E-03; n = 54), raptor (r = 0.463; p = 4.5E-03; n = 54), p70S6K (r = 0.584, 
p = 3.561E-06, n = 54) and 4E-BP1 (r = 0.371, p = 5.75E-03, n = 54) but not with PTEN, mTOR, 
IgVH or CD38 expression. Only patients very sensitive to buparlisib (IC50 < 3 µM) expressed low 
basal levels (below the cut off) of mTOR, raptor and p70S6K simultaneously. Thus, simultaneous 
expression of low basal levels of these three proteins may be useful to predict response to 
buparlisib. 


 
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In vitro studies have identified that stromal cells promote cell survival and drug resistance of B-
CLL lymphocytes by cell-cell interaction and secretion of chemokines [Hayden 2012]. Buparlisib 
induced apoptosis in primary B-CLL lymphocytes both in the presence, and in the absence of 
BMS2 stromal cell support, indicating that malignant lymphocytes are not protected against the 
cytotoxic effect of buparlisib by the stromal microenvironment [Amrein 2013]. There is increasing 
evidence that the major cause of resistance to therapy in CLL patients is a consequence of a small 
number of leukemic cells that remain after treatment. This phenomenon, called minimal residual 
disease (MRD), is in part a consequence of protection conferred by the stromal microenvironment 
to the malignant lymphocytes; eradication of MRD by alemtuzumab and other agents improved 
overall and treatment-free survival in CLL patients [Hayden 2012, Moreton 2005].  
 
Although many patients are asymptomatic at diagnosis, CLL is a progressive disease and most 
patients eventually require treatment. Standard chemo-immunotherapy regimens are not curative 
and most patients require retreatment for their disease. Preclinical results demonstrate that the class 
I PI3K inhibitor buparlisib may be useful as a single agent in CLL patients independently of their 
IgVh mutational status, CD38expression or genomic deletions (del11 and del17). Furthermore, 
combination of different biomarkers (expression of mTOR, raptor and p70S6K) may predict the 
response to buparlisib treatment. Also, buparlisib abolishes the protection against apoptosis and 
drug resistance conferred by the microenvironment to the primary B-CLL lymphocytes in vitro. 
For these reasons, this clinical trial will test buparlisib in patients with relapsed and refractory CLL. 
The efficacy of buparlisib will be determined and predictors of response to therapy will be 
validated. Ultimately, the identification of predictive biomarkers can help personalize the use of 
PI3K inhibitors in patients with CLL. 


 
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AMEND #3: 2016-AUG-24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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4.0 
TRIAL DESIGN 
 
This is an open-label, single-arm phase II study of buparlisib, 100 mg orally daily for patients with 
relapsed or refractory chronic lymphocytic leukemia. This trial is being conducted by the Canadian 
Cancer Trials Group, with support in the form of partial funding and study drug provision from 
Novartis. 


 
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5.0 
STUDY POPULATION 
 
This study is designed to include women and minorities as appropriate, but is not designed to 
measure differences in intervention effects. 
 
5.1 
Eligibility Criteria 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of registration. Questions 
about eligibility criteria should be addressed prior to registration. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates for 
this therapy. For the safety of the patients, as well as to ensure that the results of this study can be 
useful for making treatment decisions regarding other patients with similar diseases, it is important 
that no exceptions be made to these criteria for admission to the study. 
 
Patients must fulfill all of the following criteria to be eligible for admission to the study: 
 
5.1.1 
Previously documented CLL as defined by the 2008 International Workshop on Chronic 
Lymphocytic Leukemia (IWCLL) guidelines [Hallek 2008] that is recurrent or relapsed after previous 
therapy and that requires treatment (see Appendix VI). 
 
5.1.2 
Age > 18 years. 
 
5.1.3 
ECOG Performance Status score of 0, 1 or 2 (See Appendix II). 
 
5.1.4 
Patients must have a life expectancy of at least 12 weeks. Those who have previously completed 
curative treatment of a malignancy other than CLL will be eligible. 
 
5.1.5 
Patients must have at least ONE of: 
Lymphocyte count > 10 x 109/L 
OR 
At least one pathologically enlarged lymph node (> 2 x 2 cm) by CT scan 
 
5.1.6 
Previous Therapy 
 
Patients must have received at least 1 prior systemic treatment regimen (single agent or 
combination therapy). There is no upper limit on number of prior regimens. Patients who have 
received prior autologous or allogeneic stem cell transplantation are eligible. 
 
Patients must have recovered (to < grade 2) from all reversible toxicity related to prior systemic 
therapy, and have adequate washout from prior chemotherapy and investigational agents defined 
as the longest of:  
• 
two weeks 
• 
standard cycle length of prior regimen (e.g. 28 days for FCR) 
• 
5 half-lives for investigational drugs 


 
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AMEND #2: 2016-JAN-04; AMEND #3: 2016-AUG-24 
Not permitted:  
• 
prior treatment with buparlisib (BKM120) 
 
Radiation:  
Patients may have had radiation, provided a minimum of 21 days has elapsed prior to enrollment. 
(Exceptions may be made for low dose palliative radiotherapy. Please call CCTG at 613-533-6430 
PRIOR to registration if questions arise about the interpretation of this criterion). Patients must 
have recovered from any acute toxic effects from radiation prior to registration.  
 
Surgery: 
Previous surgery is permitted provided that wound healing has occurred and at least 14 days have 
elapsed if surgery was major. 
 
5.1.7 
Laboratory Requirements 
(must be done within 7 days prior to registration) 
 
Hematology 
Absolute neutrophil counts 
(ANC) 
> 1.0 x 109/L  
Platelets  
> 50 x 109/L and more than 5 days since last 
transfusion 
Chemistry 
Creatinine clearance* 
> 50 mL/min  
Bilirubin** 
< 1.5 x upper normal limit (UNL) 
Alanine aminotransferase 
(AST) and aspartate 
aminotransferase (ALT) 
< 1.5 x UNL 
< 3 x UNL if hepatic involvement with CLL 
Potassium and calcium 
Within normal limits for laboratory 
(supplementation permitted) 
Glucose (fasting) 
< 7.8 mmol/L (AND HbA1c ≤ 8% if diabetic) 
*  Creatinine clearance as calculated by Cockcroft-Gault formula or by 24 hour urine measurement:  
 
Females: 
GFR =  1.04 x (140-age) x weight in kg  
 
 
 
serum creatinine in μmol/L  
 
Males: 
GFR = 1.23 x (140-age) x weight in kg  
 
 
 
serum creatinine in μmol/L  
 
**  Direct if patient known to have Gilbert’s syndrome 


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
CONFIDENTIAL 
14 
CONFIDENTIAL 
 
AMEND #1: 2015-OCT-22; AMEND #3: 2016-AUG-24 
5.1.8 
Patient consent must be obtained according to local Institutional and/or University Human 
Experimentation Committee requirements. It will be the responsibility of the local participating 
investigators to obtain the necessary local clearance, and to indicate in writing to the CCTG Study 
Coordinator that such clearance has been obtained, before the trial can commence in that centre. 
Because of differing requirements, a standard consent form for the trial will not be provided but a 
sample form is provided on the IND.216 webpage. A copy of the initial REB approval and approved 
consent form must be sent to the central office. The patient must sign the consent form prior to 
registration and prior to tests which are considered to be study specific (see Section 6). Please note 
that the consent form for this study must contain a statement which gives permission for the CCTG 
and monitoring agencies to review patient records.  
 
5.1.9 
Patients must be accessible for treatment and follow-up. Patients registered on this trial must be 
treated and followed at the participating centre. This implies there must be reasonable geographical 
limits (for example: 1 ½ hour's driving distance) placed on patients being considered for this trial. 
(Please call CCTG at 613-533-6430 if questions arise regarding the interpretation of this criterion.) 
Investigators must assure themselves that patients registered on this trial will be available for 
complete documentation of the treatment, adverse events, and follow-up. 
 
5.1.10 In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
registration.  
 
5.2 
Ineligibility Criteria 
 
Patients who fulfill any of the following criteria are not eligible for admission to the study: 
 
5.2.1 
Progression to high grade lymphoma (Richter’s transformation) or myelodysplasia. 
 
5.2.2 
Patients with a history of other malignancies, except those which have been curatively treated and 
require no ongoing therapy. 
 
5.2.3 
Patients with known hypersensitivity to the study drug or its excipients. 
 
5.2.4 
The following are exclusions for enrolment on the study: 
• 
Pregnant or lactating women. (N.B. All women of childbearing potential must have a negative 
serum or urine pregnancy test within 7 days prior to registration). 
• 
Men and women of childbearing potential who do not agree to use adequate contraception 
(barrier method of birth control or abstinence, see Section 11.3.1) 
• 
prior to study entry 
• 
while taking buparlisib 
• 
and after completion of study therapy for 12 weeks in men and 4 weeks in women. 
(Should a woman become pregnant or suspect she is pregnant, or should a man father a child, 
while participating in this study, she/he should inform the treating physician immediately).  
 
5.2.5 
Serious illness or medical condition which would not permit the patient to be managed according 
to the protocol, including, but not limited to: 
a) active uncontrolled or serious infection (viral, bacterial or fungal); 
b) pulmonary disease requiring oxygen; 
c) known HIV infection or other immune deficiency disorders (except for CLL); 


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
CONFIDENTIAL 
15 
CONFIDENTIAL 
 
AMEND #1: 2015-OCT-22; AMEND #2: 2016-JAN-04 
d) uncontrolled auto-immune hemolytic anemia (AIHA) or auto-immune thrombocytopenia (ITP) 
e) acute or chronic pancreatitis 
 
5.2.6 
Uncontrolled or significant cardiovascular disease including: 
• 
Myocardial infarction within 12 months 
• 
Uncontrolled angina within 6 months 
• 
Clinically significant congestive heart failure (eligible if controlled and LVEF > 50%) 
• 
Stroke, TIA or other ischemic event within 12 months 
• 
Severe cardiac valve dysfunction 
• 
Left ventricular ejection fraction < 50% (only required if symptoms suggestive or history of 
cardiovascular disease) 
• 
Uncontrolled hypertension 
 
5.2.7 
Patient has any of the following mood disorders: 
• 
Medically documented history of or active major depressive episode, bipolar disorder (I or II), 
obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or 
homicidal ideation (e.g. risk of doing harm to self or others) 
• 
Score of > 12 on the PHQ-9 questionnaire (posted on IND 216 website) 
• 
Score of > 15 on the GAD-7 mood scale (posted on IND 216 website) 
• 
> CTCAE Version 4.0 grade 3 anxiety 
• 
Patient selects a positive response of ‘1,2,3’ to question 9 (suicidal ideation) in the PHQ-9 
questionnaire  
 
5.2.8 
Patients who have received prior buparlisib (BKM120. 
 
5.2.9 
Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter 
the absorption of buparlisib (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, or small bowel resection). 
 
5.2.10 Patients who are unable to swallow capsules. 
 
5.2.11 Patients on strong CYP3A inhibitors/inducers or therapeutic doses of warfarin-like anticoagulants 
(must have discontinued > 7 days prior to day 1). Patients may receive low molecular weight 
heparin if indicated. See Appendix VII for a list of prohibited medications. 
 
5.2.12 Patients on drugs with a known risk to induce Torsades de Pointes (see Appendix VIII). 
 
5.2.13 Patients receiving high dose steroid therapy 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 who are on stable moderate dose corticosteroid 
treatment for treatment of conditions other than CLL (< dexamethasone 4 mg/day, prednisone 25 
mg/day) for at least 14 days before start of study treatment are eligible. 
 
5.2.14 Patients with known HIV positivity. 
 
5.2.15 Patients with known CLL involvement of the central nervous system. 


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
CONFIDENTIAL 
16 
CONFIDENTIAL 
 
AMEND #1: 2015-OCT-22; AMEND #3: 2016-AUG-24 
6.0 
PRE-TREATMENT EVALUATION 
(See Appendix I) 
 
Investigations 
Timing 
History and 
Physical Exam 
including: 
• 
history 
• 
height/weight  
• 
ECOG performance status 
• 
vital signs: blood pressure & pulse 
• 
clinical tumour / organomegaly measurements (if applicable) 
Within 7 days prior to 
registration 
Hematology 
CBC, differential (including lymphocytes) 
Coagulation 
PT, PTT 
Biochemistry 
• 
creatinine  
• 
potassium  
• 
bilirubin (fractionated if 
known Gilbert’s) 
• 
AST, ALT  
• 
alkaline phosphatase 
• 
calcium 
• 
albumin 
• 
glucose (fasting)  
• 
LDH 
• 
Β2 microglobulin  
• 
HbA1c (if diabetic) 
Radiology1 
• 
CT scan of neck, chest, abdomen and pelvis 
Within 21 days2 prior to 
registration 
Mood 
Questionnaires3 
• 
Patient self-rating mood scales for depression (PHQ-9) and 
anxiety (GAD-7)* 
Within 7 days prior to 
registration 
Cardiac 
Investigations 
• 
12-lead ECG 
Within 7 days prior to 
registration 
• 
MUGA/LVEF (only if symptoms suggestive or history of 
cardiovascular disease) 
Within 28 days prior to 
registration 
Bone Marrow 
Studies 
• 
Bone marrow aspirate and biopsy for routine local pathology to 
assess CLL 
Within 28 days prior to 
registration 
Other 
Investigations 
• 
Direct anti-globulin test (DAGT) 
Within 7 days prior to 
registration 
• 
Serum or Urine Pregnancy test* (for women of childbearing 
potential) 
• 
Fluorescence in situ hybridization (FISH) for 17p and 11q 
deletion. Can be tested in bone marrow aspirate sample OR 
peripheral blood. Patient can be enrolled on trial before results 
are known.  
Within 28 days prior to 
registration 
• 
Hepatitis B surface antigen (HBsAg) 
• 
Hepatitis C serology 
• 
Immunoglobulin variable region (IgVH) mutation status. Can be 
tested on blood or bone marrow. Patient can be enrolled on trial 
before results are known. 
Any time prior to registration 
Correlative blood 
work 
• 
Peripheral blood processed as per Section 17 and Laboratory 
Manual* 
Within 28 days prior to 
registration 
Adverse Event4 
• 
Baseline adverse event evaluation (to document residual adverse 
event from previous therapy and baseline symptoms) 
Within 7 days prior to 
registration 
1 To ensure comparability, baseline and subsequent CT scans to assess response must be performed using identical techniques 
(i.e. scans performed immediately following bolus contrast administration using a standard volume of contrast, the identical 
contrast agent, and preferably the same scanner). 
2 Twenty-eight days if negative. 
3 Patient self-rating mood questionnaires (PHQ-9 and GAD-7) are posted on the IND 216 website. 
4 Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) (Appendix V) with the exception of hematological and psychiatric toxicity which should be graded according to 
IW CLL guidelines (see Section 8.3). 
* These tests are considered study-specific and must be performed AFTER the informed consent form has been signed. 


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
CONFIDENTIAL 
17 
CONFIDENTIAL 
 
AMEND #3: 2016-AUG-24 
7.0 
ENTRY/REGISTRATION PROCEDURES 
 
7.1 
Entry Procedures 
 
All registrations will be done through the CCTG web-based, password-operated Electronic Data 
Capture (EDC) system. Complete details regarding obtaining a password, accessing the system and 
registering patients will be provided at the time of study activation and will also be included in the 
“EDC Data Management Guidebook”, posted on the IND. 216 trial specific web-site. If sites 
experience difficulties accessing the system and/or registering patients, please contact the help desk 
(link in EDC) or the IND.216 Study Coordinator. 
 
All eligible patients enrolled on the study by the participating treatment centre will be assigned a 
serial number which must be used on all documentation and correspondence with CCTG. 
 
The following information will be required: 
• 
trial code (CCTG IND.216) 
• 
patient's initials (may be coded)  
• 
informed consent version date, date signed by patient, name of person conducting consent 
discussion and date signed 
• 
confirmation of the requirements listed in Section 5.0, including dates of essential tests and 
actual laboratory values 
• 
height and weight  
 
7.2 
Registration 
 
Registration will be provided electronically. 
 
Note: All eligible patients admitted to the trial will be followed by the coordinating centre. It is the 
responsibility of the physician in charge to satisfy himself or herself that the patient is indeed 
eligible before requesting registration. 
 


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
CONFIDENTIAL 
18 
CONFIDENTIAL 
 
AMEND #3: 2016-AUG-24 
8.0 
TREATMENT PLAN 
 
Although the Canadian Cancer Trials Group acts as the coordinating agency for the trial, the 
responsibility for treatment of patients rests with the individual investigator. 
 
In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
registration. 
 
8.1 
Chemotherapy Treatment Plan 
 
8.1.1 
Drug Administration 
 
Agent 
Route 
Starting Dose 
Frequency 
Schedule 
Buparlisib (BKM120) 
oral 
100 mg 
Daily 
Every 28 days 
Safety will be reviewed after the first 3 patients are enrolled. If excess toxicity observed, starting dose will be 
reduced to 80 mg daily for subsequent patients. CCTG will advise. 
 
A complete treatment cycle of buparlisib is defined as 28 days of once daily continuous treatment 
with a flat-fixed dose, i.e. not based on body weight or body surface area. There will be no breaks 
between dosing cycles. 
 
The following general guidelines should be followed for buparlisib administration: 
• 
Patients should be instructed to take the dose of buparlisib once daily in the morning, at 
approximately the same time each day.  
• 
Buparlisib can be taken with or without food. 
• 
Buparlisib should be taken with a glass of water. Patients should swallow the capsules whole 
and not chew them. 
• 
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed before 
the next scheduled dose. The occurrence and frequency of any vomiting during a treatment 
cycle must be noted in the adverse events section of the eCRF. 
• 
If the patient forgets and does not take their dose before 6:00 pm, then the dose should be 
withheld that day and buparlisib should be restarted the following day. 
• 
Patients must avoid consumption of Seville orange (and juice), grapefruit or grapefruit juice, 
grapefruit hybrids, pummelos, starfruits and cranberry juice from 7 days prior to the first dose 
of study drug and during the entire study treatment period due to potential CYP3A interaction. 
Regular orange (Citrus X sinensis) juice is allowed. 


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
CONFIDENTIAL 
19 
CONFIDENTIAL 
8.1.2 
Premedication 
 
Routine anti-emetic premedication is not required but may be administered at the physician’s 
discretion. Nausea and vomiting should be managed symptomatically if they arise. Non-steroid 
therapies are preferred since steroids may confuse the interpretation of response. Strong CYP3A 
inhibitors / inducers are prohibited and other CYP450 substrates should be used with caution (see 
Appendix VII). 
 
Tumour lysis syndrome is uncommon in patients treated with buparlisib or idelalisib, an alternative 
PI3 kinase inhibitor. Investigators should follow standard local procedures for prophylaxis (e.g. 
hydration and allopurinol for those with high disease burden). 
 
Buparlisib may cause lymphopenia thus prophylaxis with appropriate anti-microbial agents could 
be considered for patients at particular risk for serious viral infection or pneumocystis at the 
discretion of the investigator according to local protocols. Strong CYP3A inhibitors / inducers are 
prohibited and other CYP450 substrates should be used with caution (see Appendix VII). 
 
Details of any premedication given must be properly recorded on the electronic CRFs.  
 
8.2 
Patient Self Rating Mood Questionnaires 
 
The patient must complete two different mood questionnaires (PHQ-9 and GAD-7) on day 1 and 
day 14 in cycles 1 and 2, then day 1 each cycle, as well as the End of Treatment visit (Questionnaires 
are posted on the IND.216 website).  
 
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. 
 
8.3 
Toxicity Grading 
 
Adverse events will be graded using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) (see Appendix V) with the exception of hematological and mood questionnaires toxicity 
which should be graded according to IW CLL guidelines below. Guidance is also provided for 
interpretation of mood questionnaire scores. 
 
Toxicity grading based on mood questionnaire scores: 
 
PHQ-9 (Depression Score) 
GAD-7 (Anxiety Score) 
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 
Investigator assessment for suicidal ideation is required for any patient who does not answer Question #9 or the whole 
PHQ-9 questionnaire. 
The grading guidance above may be overruled at the discretion of the provider performing a psychiatric consult. 
 


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
CONFIDENTIAL 
20 
CONFIDENTIAL 
Hematology toxicity grading based on IW CLL guidelines: 
 
Grade* 
Decrease in platelets** 
(nadir) from pre-
treatment value 
Decrease in Hb*** 
(nadir) from pre-
treatment value 
Absolute neutrophil**** 
count/µL (nadir) 
0 
No change to 10% 
No change to 10% 
≥ 2000 
1 
11 – 24% 
11 – 24% 
≥ 1500 and < 2000 
2 
25 – 49% 
25 – 49% 
≥ 1000 and < 1500 
3 
50 – 74% 
50 – 74% 
≥ 500 and < 1000 
4 
≥ 75% OR  
platelets < 20 at any time 
≥ 75% 
< 500 
* 
Grades: 1 mild, 2 moderate, 3 severe, 4 life-threatening, 5 fatal. Death occurring as a result of toxicity at any level of 
decrease from pre-treatment will be recorded as grade 5. 
**  
Platelet counts must be below normal levels for grades 1 to 4. If at any level of decrease, the platelet count is < 20 x 
109/L, this will be considered grade 4 toxicity. 
*** 
Hb levels must be below normal levels for grades 1 to 4. Baseline and subsequent Hb determinations must be 
performed before any given transfusions. In the event of red cell transfusion within 14 days prior to the baseline 
value, patient will be inevaluable for Hb toxicity. The use of erythropoietin is irrelevant for the grading of toxicity 
but should be documented. 
**** If the absolute neutrophil count (ANC) reaches < 1 x 109/L, it should be judged to be grade 3 toxicity. Other 
decreases in the white blood cell count, or in circulating neutrophils, are not to be considered because a decrease in 
the white blood cell count is a desired therapeutic endpoint. A gradual decrease in granulocytes is not a reliable 
index in CLL for stepwise grading of toxicity. The use of growth factors such as G-CSF is not relevant to the 
grading of toxicity, but should be documented.  
Grading scale for hematologic toxicity in CLL studies [Hallek 2008] 
 
8.4 
Dose Adjustments 
 
Dose Level 
Daily dosing of buparlisib in 28 day cycle 
-1 
Reduce by 20 mg daily 
-2 
Reduce by 20 mg daily 
-3 
If required patients must discontinue protocol therapy 
 
Doses will be reduced for hematologic and other adverse events considered related to buparlisib. 
Dose adjustments are to be made according to the system showing the greatest degree of toxicity.  
 
The most frequently observed toxicities with buparlisib include transaminitis, skin toxicity, 
hyperglycemia, GI effects (diarrhea, anorexia, constipation, nausea, vomiting, mucositis), fatigue, 
abdominal pain and mood alterations. 
 
The guidelines which follow outline buparlisib dose adjustments for several of these toxic effects. 
If a patient experiences several toxicities and there are conflicting recommendations, please use the 
recommended dose adjustment that reduces the dose to the lowest level. 
 
Doses of buparlisib reduced for toxicity may not be re-escalated. For each patient, a maximum of 
2 dose reductions will be allowed. Patients requiring an additional dose reduction will stop 
buparlisib and come off study. 
 
Patients requiring a buparlisib dose delay of > 28 days must permanently discontinue buparlisib 
and come off study.  


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
CONFIDENTIAL 
21 
CONFIDENTIAL 
8.4.1 
Hematologic Toxicity 
 
Worst Hematologic Toxicity* 
Management 
Grade 1 or 2 
Maintain dose level 
Grade 3 or 4 neutropenia 
Grade 3 thrombocytopenia 
Omit dose until resolved to < grade 1 (or baseline) then: 
If resolved in < 7 days, then maintain dose level 
If resolved in > 7 days, then decrease one dose level *** 
Grade 4 thrombocytopenia 
Omit dose until resolved to < grade 1 (or baseline) then decrease one 
dose level *** 
Febrile neutropenia** 
Omit dose until resolved to < grade 1 then decrease one dose level 
*  
As defined according to IW CLL guidance in Section 8.3. 
** ANC < 1 x 109/L with a single temperature of ≥ 38.3oC or a sustained temperature of ≥ 38oC for more than one 
hour. 
*** After treatment is resumed at a lower dose, if the same toxicity recurs with the same severity, then the next 
treatment should be resumed at a lower dose regardless of duration. If the same toxicity occurs with a worse 
severity, then the patient must discontinue treatment with buparlisib. 
If a third dose reduction is required, patients must discontinue protocol therapy. 
If therapy is delayed by > 28 days, patients must discontinue protocol therapy. 
 
8.4.2 
Renal Toxicity 
 
Worst Toxicity 
Serum creatinine 
Management 
Grade 1  
Maintain dose level 
Grade 2  
(> 1.5-3 x baseline or ULN) 
Omit dose until resolved to < grade 1 (or baseline) then: 
If resolved in < 7 days, then maintain dose level 
If resolved in > 7 days, then decrease one dose level* 
Grade 3 or 4  
(> 3 x baseline or ULN) 
Permanently discontinue buparlisib 
* After treatment is resumed at a lower dose, if the same toxicity recurs with the same severity, then the next 
treatment should be resumed at a lower dose regardless of duration. If the same toxicity occurs with a worse 
severity, then the patient must discontinue treatment with buparlisib. 
If a third dose reduction is required, patients must discontinue protocol therapy. 
If therapy is delayed by > 28 days, patients must discontinue protocol therapy. 
 


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
CONFIDENTIAL 
22 
CONFIDENTIAL 
 
AMEND #1: 2015-OCT-22 
8.4.3 
Hepatic Toxicity 
 
In event of hepatotoxicity, consider alternate causes (cholestasis, viral, malignant, concomitant 
medication, etc.) and refer to hepatologist as clinically indicated. 
 
Bilirubin* 
Dose of buparlisib**** 
Follow-up 
Grade 1  
No change 
See Section 9 
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, maintain 
dose level 
If resolved in > 7 days, decrease 
one dose level** 
LFTs weekly or more frequently if 
clinically indicated until resolved 
to < grade 1. 
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, decrease 
one dose level**  
If resolved in > 7 days, discontinue 
buparlisib 
LFTs weekly or more frequently if 
clinically indicated until resolved 
to < grade 1, then every other week 
until off treatment and recovered to 
< grade 1 
Grade 4 (>10 x ULN) 
Discontinue buparlisib 
LFTs weekly or more frequently if 
clinically indicated until resolved 
to < grade 1 (or stable) 
AST or ALT 
 
 
Same grade as baseline:  
No change 
See Section 9 
Increase from baseline: 
 < 1.5 ULN at baseline, 
increases to 1.5 to 
< 3 x ULN  
 Grade 1 to grade 2 
Continue with a one dose level 
reduction 
LFTs weekly or more frequently if 
clinically indicated until resolved 
to < grade 1 
Increase of two grades from 
baseline: 
 Grade 0 to Grade 2***  
 Grade 1 to Grade 3*** 
Omit dose until resolved to ≤ grade 
1 then reduce 1 dose level**.  
If no recovery < 28 days, 
permanently discontinue buparlisib. 
LFTs weekly or more frequently if 
clinically indicated until resolved 
to < grade 1, then every other week 
until off treatment and recovered to 
< grade 1 
Grade 4 (> 20.0 x ULN)  
Discontinue buparlisib 
LFTs weekly or more frequently if 
clinically indicated until resolved 
to < grade 1 (or stable) 
AST/ALT and bilirubin* 
 
 
AST or ALT > 3 x ULN 
(grade 2) and total bilirubin 
> 2 x ULN 
Discontinue buparlisib 
LFTs weekly or more frequently if 
clinically indicated until resolved 
to < grade 1 (or stable) 
*  
If known Gilbert’s, use direct bilirubin to grade 
** 
After treatment is resumed at a lower dose, if the same toxicity recurs with the same severity, then the next 
treatment should be resumed at a lower dose regardless of duration. If the same toxicity occurs with a worse 
severity, then the patient must discontinue treatment with buparlisib. 
*** If grade 2 or 3 and bilirubin > 2 x ULN, meets criteria below to discontinue buparlisib. In case of recurring 
Grade 3 or higher toxicity after re-challenge, buparlisib should be permanently discontinued. 
**** If a third dose reduction is required or therapy is delayed by > 28 days, patients must discontinue protocol 
therapy. 


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
CONFIDENTIAL 
23 
CONFIDENTIAL 
 
AMEND #1: 2015-OCT-22; AMEND #3: 2016-AUG-24 
8.4.4 
Mood Disorders (e.g. Anxiety, Depression, Agitation) 
 
Worst Toxicity* 
Management 
Grade 1 or grade 2 without increase in 
GAD7/PHQ9 scores from baseline 
Maintain dose level. Consider psychiatric consultation at the 
investigator’s discretion and introduce optimal management. 
Grade 2 with increase in GAD7/PHQ9 
scores from baseline 
Omit dose until resolved to < Grade 1 or baseline status. 
Consider psychiatric consultation at the investigator’s 
discretion and introduce optimal management**. 
First event: if the condition resolves to Grade < 1 or to baseline 
status, continue to co-medicate and then maintain the dose 
level. 
Second and further events: if the condition resolves to Grade < 
1 or to baseline status, continue to co-medicate and then 
decrease 1 dose level. 
Grade 3 
Omit dose until resolved to < Grade 1 or baseline status, then 
decrease one dose level***. Co-medicate** 
Psychiatric referral recommended. 
Grade 4  
Discontinue buparlisib 
Urgent psychiatric referral 
Suicidal ideation regardless of grade 
Interrupt buparlisib. 
Refer for psychiatric consultation for optimal management and 
to confirm if study drug should be interrupted or permanently 
discontinued. In this specific case, the psychiatric advice can 
overrule the patient’s PHQ-9 self-assessment. 
*  
See Section 8.3. 
** Under the guidance of the psychiatrist if needed. Possible first line management for anxiety might include 
lorazepam (e.g. 0.5 mg po tid), clonazepam (e.g. 1 mg po bid) or haloperidol (0.5-1 mg po bid). Options for first 
line treatment of depression might include citalopram (e.g. starting doses 10-20mg, usual treatment dose 20-60 
mg/d). In the event of agitation interrupting sleep, consider trazodone (e.g. 25 to 50 mg at night).  
*** After treatment is resumed at a lower dose, if the same toxicity recurs with the same severity, then the next 
treatment should be resumed at a lower dose regardless of duration. If the same toxicity occurs with a worse 
severity, then the patient must discontinue treatment with buparlisib. 
If a third dose reduction is required, patients must discontinue protocol therapy. 
If therapy is delayed by > 28 days, patients must discontinue protocol therapy. 


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
CONFIDENTIAL 
24 
CONFIDENTIAL 
8.4.5 
Hyperglycemia 
 
Fasting plasma 
glucose (FPG) 
Management * 
Grade 1 
Maintain dose level 
Check FPG at least weekly for 8 weeks, then at least every 2 weeks 
Grade 2 
If signs or symptoms of hyperglycemia (e.g. mental status changes, excessive thirst, 
polyuria) manage as per grade 3 below 
If asymptomatic, maintain dose and recheck FPG in 24 hours. If grade worsens or 
improves follow specific grade recommendations. If remains at grade 2: 
• 
Maintain dose level and monitor FPG at least weekly until resolves to ≤ grade 1 
• 
Initiate or intensify appropriate anti-diabetic treatment** such as metformin; 
consider adding a second oral agent if no improvement after several days 
• 
If FPG does not resolve to ≤ grade 1 within 14 days after institution of anti-
diabetic treatment, reduce buparlisib by one 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 
Omit buparlisib, initiate or intensify medication with anti-diabetic therapy, recheck 
FPG within 24 hours. If grade worsens or improves follow specific grade 
recommendations. If remains at grade 3: 
• 
Continue to omit buparlisib 
• 
Monitor FPG at least twice weekly until resolves to < grade 1  
• 
If FPG resolves to < grade 1 in 7 days or less then restart buparlisib and decrease 
one dose level *** 
• 
If FPG remains greater than grade 1 severity for more than 7 days, then 
discontinue buparlisib  
• 
Continue oral anti-hyperglycemic therapy** such as metformin as appropriate 
• 
Check FPG weekly for 8 weeks, then every 2 weeks 
Grade 4 
Omit buparlisib, initiate or intensify medication with appropriate anti-diabetic 
treatment, re-check within 24 hours. If grade improves then follow specific grade 
recommendations. If FPG is confirmed at Grade 4: 
• 
discontinue buparlisib  
• 
check FPG at least weekly for 8 weeks, then at least every 2 weeks until resolved 
*  
At any grade give appropriate dietary advice 
** Some oral anti-diabetic drugs are CYP2C9 substrates (glipizide, glimepiride, gliclazide, glibenclamide, 
nateglinide, rosiglitazone) and should be used with caution. See Appendix VII. 
*** If a third dose reduction is required, patients must discontinue protocol therapy. 
If therapy is delayed by > 28 days, patients must discontinue protocol therapy. 


 
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8.4.6 
Interstitial Pneumonitis 
 
Symptoms suggestive of pneumonitis require evaluation and investigation with CT imaging and 
bronchoscopy as clinically appropriate.  
 
Worst Toxicity 
Management* 
Grade 1 
Maintain dose level 
Grade 2 
Reduce by one dose level** and continue therapy OR 
Omit buparlisib if symptoms are troublesome. If resolved to ≤ grade 1 within 28 
days, may restart at a reduced dose level. 
Grade 3 
Omit dose until resolved to ≤ grade 1. May restart buparlisib within 28 days at a 
reduced dose level**, if evidence of clinical benefit. 
Grade 4 
Discontinue buparlisib 
*  
Consider corticosteroids if symptoms troublesome and infective origin excluded (patients requiring high dose 
steroids may become inevaluable for response assessment) 
** After treatment is resumed at a lower dose, if the same toxicity recurs with the same severity, then the next 
treatment should be resumed at a lower dose regardless of duration. If the same toxicity occurs with a worse 
severity, then the patient must discontinue treatment with buparlisib. 
If a third dose reduction is required, patients must discontinue protocol therapy. 
If therapy is delayed by > 28 days, patients must discontinue protocol therapy. 
 
8.4.7 
Skin Reactions 
 
Worst Toxicity 
Management* 
Grade 1 
Maintain dose level 
Grade 2  
Tolerable maculopapular rash: 
 Initiate/intensify appropriate skin toxicity therapy, e.g. with topical steroids 
BID and oral antihistamines. 
 Maintain dose level. 
Intolerable maculopapular rash: 
 Omit dose and initiate/intensify appropriate skin toxicity therapy, e.g. with 
topical steroids BID, oral antihistamines and oral steroids if required*. 
First occurrence: 
 If resolved to grade < 1 in < 2 weeks, maintain dose level. 
 If resolved grade < 1 in more than 2 weeks, reduce 1 dose level. 
 Consider continuing skin toxicity therapy up to 2 weeks after re-
introduction of buparlisib.  In case of flare after cessation of skin toxicity 
therapy, consider prompt reimplementation. 
Second occurrence: omit dose and follow treatment guidance above. 
 Once resolved to grade < 1, reduce 1 dose level**. 
Grade 3 
Omit dose until resolved to ≤ grade 1 then decrease one dose level** 
Grade 4 
Discontinue buparlisib 
*  
Co-medicate as appropriate with antihistamines, topical or oral steroids (patients requiring high dose steroids 
may become inevaluable for response assessment), moisturizers, sunscreen. In addition for acneiform rash 
consider topical or oral antibiotics and bacterial swab if infection suspected. 
**  After treatment is resumed at a lower dose, if the same toxicity recurs with the same severity, then the next 
treatment should be resumed at a lower dose regardless of duration. If the same toxicity occurs with a worse 
severity, then the patient must discontinue treatment with buparlisib. 
If a third dose reduction is required, patients must discontinue protocol therapy. 
If therapy is delayed by > 28 days, patients must discontinue protocol therapy. 


 
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8.4.8 
Other Non-Hematological Adverse Events, Including Diarrhea 
 
Worst Toxicity 
Management 
Grade 1 
Maintain dose level 
Grade 2 
Symptomatic management*; continue dosing with no change. 
For persistent grade 2 effects, investigator may decrease by one dose level 
Grade 3 ** 
Omit dose*** until resolved to ≤ grade 1 then decrease one dose level**** 
Grade 4 
Permanently discontinue buparlisib 
*  
For buparlisib induced diarrhea, standard treatment including prompt commencement of loperamide is 
recommended alongside rehydration (can refer to Recommended Guidelines for the Treatment of Cancer 
Treatment-Induced Diarrhea, [Benson 2004]). 
**  
Omit for grade 3 nausea or vomiting only if it cannot be controlled with optimal anti-emetics. 
 
Omit for fatigue only if significant worsening from baseline (investigator discretion).  
*** Patients requiring treatment hold for >28 days will discontinue protocol therapy. 
**** After treatment is resumed at a lower dose, if the same toxicity recurs with the same severity, then the next 
treatment should be resumed at a lower dose regardless of duration. If the same toxicity occurs with a worse 
severity, then the patient must discontinue treatment with buparlisib. 
 
8.5 
Duration of Therapy 
 
Treatment will continue until the criteria for removal from protocol treatment have been met (see 
section 12.0). 
 
8.6 
Concomitant Therapy 
 
Permitted: 
• 
Other supportive and palliative care (e.g. pain control) as required throughout the study. 
• 
Anti-emetics or anti-diarrheal agents as required. 
• 
Growth factors may be used according to centre policy. 
• 
Low molecular weight heparin if indicated.  
 
Permitted with caution: 
• 
CYP450 substrates other than strong CYP3A4 inhibitors and inducers (see Appendix VII). 
• 
Drugs with possible or conditional risk of inducing Torsades de Pointes  (see Appendix VIII). 
 
Not permitted: 
• 
Strong CYP3A4 inhibitors and inducers (see Appendix VII).  
• 
Drugs with known risk to induce Torsades de Pointes (see Appendix VIII). 
• 
Warfarin. 
• 
Other anti-cancer therapy or investigational therapy. 
 
Details of any concomitant medications given should be recorded on the appropriate Electronic 
Case Report Form. 
 
Infections including Pneumocystis Jiroveci pneumonia (PJP) and cytomegalovirus (CMV) 
reactivation have been observed in patients with CLL treated with alternate PI3 kinase inhibitors. 
Opportunistic infections have not been associated with buparlisib therapy to date. Physicians 
should remain vigilant and investigate as clinically appropriate in event of fever or respiratory 
symptoms. Prophylaxis can be considered in those at high risk at investigator discretion. 


 
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AMEND #3: 2016-AUG-24 
9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT 
 
All patients entered on study must be evaluated according to the schedule outlined in Appendix I 
with documentation submitted according to the schedule in Appendix IV. 
 
9.1 
Evaluation During Protocol Treatment 
 
Investigations 
Timing 
History and 
Physical Exam 
including: 
• 
History 
• 
Weight 
• 
ECOG Performance status 
• 
Blood pressure and pulse 
• 
Clinical tumour / organomegaly 
measurements (if applicable) 
Day 1 each cycle 
Hematology1 
CBC, differential (including lymphocytes) 
Days 1 and 14 cycle 1 and 22 
Day 1 each cycle thereafter2 
 
Tumour lysis monitoring on days 1, 2, and 3  
of cycle 1 required only in first 4 patients treated,  
see below6 
Biochemistry1 
• 
creatinine 
• 
potassium 
• 
bilirubin 
(fractionated if 
known Gilberts) 
• 
LDH 
• 
AST, ALT 
• 
calcium 
• 
albumin 
• 
glucose 
(fasting)5 
• 
phosphate6 
• 
uric acid6 
• 
lipase 
Radiology3 
• 
CT scan of neck, chest, abdomen and pelvis  
• 
To be repeated 8, 16, and 24 weeks from registration 
and thereafter every 12 weeks7. 
• 
At time PR or CR criteria are otherwise met and 8 
weeks after PR or CR to confirm.  
Assessment for 
Minimal 
Residual 
Disease (MRD) 
(Optional) 
MRD assessment either by:  
• 
4-color Flow Cytometry (MRD Flow) 
or  
• 
Allele Specific Oligonucleotide PCR on 
peripheral blood  
or 
• 
Flow cytometry or immunohistochemistry 
on bone marrow 
Desirable if CR criteria otherwise met, but optional. 
Bone Marrow  
• 
Bone marrow aspirate and biopsy  
At time other criteria for CR first met and 8 weeks later 
to confirm sustained CR or if cytopenia of uncertain 
cause. 
Correlative 
blood work 
• 
Whole blood processed as per Section 17 
and Laboratory Manual 
At time of disease progression (if applicable) 
Mood 
Questionnaire 
• 
Patient self-rating mood scales for 
depression (PHQ-9) and anxiety (GAD-7) 
Days 1 and 14 cycle 1 and 2, Day 1 of each cycle 
thereafter and end of treatment visit 
Adverse Events4 
Patients must be evaluated each cycle for adverse events 
 
footnotes on next page … 
 
 


 
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1 
Bloodwork Timing: Pre-treatment blood draws may be done the day prior to treatment if necessary, and when treatment is to begin on a 
Monday, may be done on the previous Friday (maximum 72 hours prior to treatment). In order to ensure that nadir counts are not 
missed, every effort should be made to do interim blood draws within 24 hours of the day specified in the protocol. 
2 
See Section 8 for additional monitoring of AST/ALT and bilirubin with hepatic toxicity. 
3  
To ensure comparability, the baseline CT scans and subsequent CT scans to assess response must be performed using identical 
techniques (i.e. scans performed immediately following bolus contrast administration using a standard volume of contrast, the identical 
contrast agent, and preferably the same scanner). Patients with an unconfirmed PR or CR should have scans repeated after 8 weeks to 
confirm response. 
4 
Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
(Appendix V) with the exception of mood questionnaires and hematological toxicity which should be graded according to IW CLL 
guidelines (see Section 8.3). Patients whose treatment is interrupted due to an adverse event or clinically significant laboratory value 
must be followed up at least once a week for 4 weeks and subsequently at approximately 4 week intervals until resolved to < grade 2. 
5 
More frequently in event of hyperglycemia, see Section 8.4.5. 
6 
The first 4 patients treated on study will require monitoring for tumour lysis on days 1, 2 and 3 of cycle 1 only: calcium, creatinine, 
potassium, phosphate, uric acid. CCTG will notify centres if this applies at the time of registration. 
7 
Patients who have no evidence of disease on CT at baseline can omit follow up scans unless palpable disease arises or there is clinical 
suspicion of disease progression. 
 
9.2 
Overview of Efficacy Evaluations 
 
 
 
 
 
 
 
Baseline 
CT scan 
Bone marrow aspirate and trephine 
FISH analysis 
Correlative blood work 
On Treatment 
CT scan* every 8 weeks for 6 months 
then every 12 weeks until progression 
Partial Response 
Repeat CT scan in 8 weeks to 
confirm 
Complete Response 
Bone marrow aspirate and trephine 
Repeat bone marrow and CT in  
8 weeks to confirm 
Assess for MRD (optional) 
Progression 
Correlative blood work 
*  Patients who have no evidence of disease on CT at baseline can omit follow-up scans unless 
palpable disease arises or there is clinical suspicion of disease progression.  
 
Always consult Tables in Section 6 and 9 for details of all investigations required. 


 
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9.3 
Evaluation After Protocol Treatment 
 
All patients will be seen 4 weeks after the end of the last cycle (4 Week Post Treatment Report).  
 
Patients whose treatment is permanently discontinued due to an adverse event or non-hepatic 
clinically significant laboratory value, should be followed as clinically indicated until resolved to 
< grade 2. See Section 8.4.3 for more detailed guidance on patients who discontinue study treatment 
due to hepatic toxicity. 
 
Follow-up beyond the 4 week treatment report is not required for patients who go off protocol 
treatment with progressive disease, except to document ongoing toxicities (until resolved to 
< grade 2), late toxicities (including second malignancies) and death if within 30 days of last dose.  
 
For patients who go off protocol treatment with objective CR, PR or SD ongoing, follow up 
including response assessment will be required every three months until relapse/progression 
(Follow-Up Report). If the patient starts new anticancer therapy, contact the study coordinator to 
discuss whether further follow-up is required.  
 
For patients who go off protocol therapy with suspected PR or CR, an 8 week confirmatory 
response assessment including CT scanning will be required as per Sections 9.1 and 10.4, if not 
already performed.  
 
A Death Report is only required if death occurs within 30 days of last dose or if patient dies before 
progression/relapse; due within 2 weeks of knowledge of death (see Appendix IV –Documentation 
for Study).  


 
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10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
10.1 
Definitions 
 
10.1.1 Evaluable for Response 
 
All patients who have received at least one cycle of therapy and have their disease re-evaluated will 
be considered evaluable for response (exceptions will be those who exhibit objective disease 
progression prior to the end of cycle 1 who will also be considered evaluable). Patients on therapy 
for at least this period and who meet the other listed criteria will have their response classified 
according to the definitions set out below, as recommended by Revised International Workshop on 
Chronic Lymphocytic Leukemia 2008 [Hallek 2008] and incorporating updated recommendations for 
refinement of clinical trial endpoints when using novel targeted agents [Cheson 2012].  
 
10.2 
Documenting Enlarged Lymph Nodes 
 
A maximum of the 6 largest nodes or nodal masses (minimum size > 1.5 x 1.5 cm) will be followed 
for response if enlarged at baseline. Wherever possible, enlarged nodes should be documented in 
the nodal disease case report form and followed by CT scan.  
 
Notes:  
If a patient does not have baseline lymphocytosis of at least 10 x 109/L, he or she must have at least 
one node > 2 x 2 cm on CT scan to be eligible. 
 
For additional enlarged lymph nodes/nodal masses beyond the maximum of 6 recorded, record 
them as “multiple enlarged nodes” as a single entry on the nodal disease case report form. Do not 
list each individual non-target node or node group as separate lesions.  
 
10.3 
Documenting Organomegaly 
 
If hepatomegaly is documented on the baseline CT scan, record as extra nodal lesion (“Liver”) on 
the baseline extra nodal case report form. Splenomegaly or splenic lesions on the baseline CT scan 
are considered nodal disease and should be recorded on the nodal case report form. At the time of 
follow-up CT examination, record “present” (if still enlarged or continuing enlargement seen) or 
“absent” (if normal size). Record “increased” ONLY if unequivocal progression of substantial 
magnitude is seen (estimated 50% increase) and is believed sufficient to consider overall that the 
patient has progressed.  
 
10.4 
Response 
 
All patients will have their BEST RESPONSE from the start of study treatment until the end of 
treatment classified as outlined below. In patients with limited disease at study entry, response will 
be assessed using only parameters that were abnormal at baseline.  
 
Complete Response (CR): CR requires all of the following criteria, maintained for a period of at 
least 8 weeks. 
 
Peripheral blood lymphocytes (evaluated by blood and differential count) < 4 x 109/L; 
 
Absence of significant lymphadenopathy > 1.5cm in diameter on physical examination and CT 
scan 


 
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 
No hepatomegaly or splenomegaly by CT scan 
 
Absence of constitutional symptoms attributable to disease 
 
Normal blood counts above the following values: 
- 
Neutrophils more than 1.5 x 109/L without need for exogenous growth factors 
- 
Platelets more than 100 x 109/L without need for exogenous growth factors 
- 
Hemoglobin more than 110 g/L without red blood cell transfusion or need for exogenous 
erythropoietin.  
 
A marrow aspirate and biopsy should be performed to demonstrate that a CR has been achieved 
at the time other criteria for CR are met. 
- 
To define a CR, the marrow sample must be at least normocellular for age, with < 30% of 
nucleated cells being lymphocytes. Lymphoid nodules should be absent. If lymphoid 
nodules are found, they will often reflect residual disease. These nodules should be 
recorded as “nodular PR”. Immunohistochemistry should be performed to define whether 
these nodules are composed primarily of T cells or lymphocytes other than CLL cells.  
- 
If the marrow is hypocellular, a repeat determination should be performed after 4 weeks, 
or when peripheral blood counts have recovered. However, this time interval should not 
exceed 6 months after the last treatment. A marrow biopsy should be compared with that 
of pretreatment marrow. 
- 
Optional: The quality of the CR may be assessed for minimal residual disease by flow 
cytometry or by immunohistochemistry (IHC). 
 
Patients who fulfill all the criteria for a CR (including the marrow examinations described 
above) but who have a persistent anemia or thrombocytopenia or neutropenia apparently 
unrelated to CLL but related to drug toxicity will be considered as CR with incomplete marrow 
recovery (CRi). A repeat bone marrow should ideally be done in these patients when counts 
recover fully. If the bone marrow at this time reveals no CLL, these patients will be considered 
as having CR at that time.  
 
Partial Response (PR): To define a PR, at least 1 of the criteria of Group A plus 1 of the criteria of 
Group B must be met and persist for ≥ 8 weeks, in the absence of any criteria definitive of 
progressive disease. 
 
Group A:  
 
A 50% or more decrease in peripheral blood lymphocytes from the value before therapy. 
 
A 50% or more reduction in lymphadenopathy (by CT scan) either in the sum products of up 
to 6 measurable lymph nodes, or in the largest diameter of the enlarged lymph node(s) detected 
prior to therapy. 
 
A 50% or more reduction in the noted pretreatment enlargement of the spleen or liver, as 
estimated by CT scan.  
 
Group B:  
 
The blood count should show one of the following results: 
- 
Neutrophils more than 1.5 x 109/L without need for exogenous growth factors or 50% 
improvement over baseline without need for exogenous growth factors. 
- 
Platelet counts greater than 100 x 109/L or 50% improvement over baseline without need 
for exogenous growth factors.  


 
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- 
Hemoglobin greater than 110 g/L or 50% improvement over baseline without requiring red 
blood cell transfusions or exogenous erythropoietin. 
 
Progressive Disease (PD): Progressive disease during or after therapy is characterized by at least 
one of the following: 
 
Progression of lymphadenopathy  
- 
Appearance of any new lesion, such as new enlarged lymph nodes (> 1.5 x 1.5 cm), 
splenomegaly, hepatomegaly, or other organ infiltrates.  
- 
An increase by 50% or more in greatest determined diameter (= greater than 65% increase 
in bidimensional product) of any previously recorded measurable node.  
 
An unequivocal increase in the previously noted enlargement of the liver or spleen by an 
estimated 50% or more or the de novo appearance of hepatomegaly or splenomegaly. 
 
Transformation to a more aggressive histology (e.g. Richter syndrome). 
- 
Whenever possible, this diagnosis should be established by lymph node biopsy.  
 
Occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL. 
- 
During therapy: 
· During therapy, cytopenias cannot be used to define disease progression.  
- 
After treatment:  
· The progression of any cytopenia (unrelated to autoimmune cytopenia), as documented 
by a decrease of Hb levels by more than 20 g/L (2 g/dL) or to less than 100 g/L, or by 
a decrease of platelet counts by more than 50% or to less than 100 x 109/L, which 
occurs at least 3 months after treatment, defines disease progression, if the marrow 
biopsy demonstrates an infiltrate of clonal CLL cells. 
 
Note:  
B cell receptor targeted drugs can mobilize CLL cells from tissues into the peripheral blood, 
interfering with their homing. This characteristic pharmacologic action can be prominent early in 
therapy, but can also persist over time. This occurrence should not be confused with PD unless the 
treated patient develops other CLL-related signs or symptoms of PD. In the absence of other 
objective evidence of PD, lymphocytosis alone should not be considered an indicator of PD 
[Cheson 2012]. 
 
Stable Disease (SD): Patients who have not achieved a CR or a PR, and who have not exhibited 
progressive disease, will be considered to have stable disease (which is equivalent to a 
nonresponse). 
 
10.5 
Response Duration 
 
Response duration will be measured from the time measurement criteria for CR/PR (whichever is 
first recorded) are first met until the first date that recurrent or progressive disease is objectively 
documented, taking as reference the smallest measurements recorded on study (including baseline). 
 
10.6 
Stable Disease Duration 
 
Stable disease duration will be measured from the time of start of treatment until the criteria for 
progression are met, taking as reference the smallest sum on study (including baseline). 


 
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10.7 
Progression-Free Survival 
 
Progression-free survival (PFS) is defined as the time from study entry until disease progression or 
death.  
 
10.8 
Methods of Measurement for CT-Scan Evaluation 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up as indicated in Section 9. While on 
study, all lesions recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g. 2 mm). If it is the opinion of the radiologist that 
the lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned. For lesions which fragment/split add together the longest diameters of the fragmented 
portions; for lesions which coalesce, measure the maximal longest diameter for the “merged 
lesion”. 
 
10.8.1 Clinical Lesions. Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm as assessed using callipers (e.g. skin nodules). For the case of skin lesions, documentation 
by colour photography including a ruler to estimate the size of the lesion is recommended. If 
feasible, imaging is preferred. Lymph nodes should be measured by CT scan as described in section 
10.2 if followed. 
 
10.8.2 Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT is advised. 


 
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AMEND #3: 2016-AUG-24 
11.0 
SERIOUS ADVERSE EVENT REPORTING 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for Adverse Event (AE) reporting (version can be found in 
Appendix V). All appropriate treatment areas should have access to a copy of the CTCAE. A copy 
of the CTCAE can be downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse 
events must be recorded on case report forms. In addition, all “reportable” serious adverse events 
are subject to expedited reporting using the CCTG SAE form. The term ‘reportable SAE’ is used 
in the definitions which follow to describe those SAEs which are subject to expedited reporting to 
CCTG.  
 
11.1 
Definition of a Reportable Serious Adverse Event 
 
• 
All serious adverse events, regardless of whether they are unexpected or related to protocol 
treatment, occurring during the treatment period and within 30 days after the last protocol 
treatment administration, must be reported in an expedited manner. Any late serious adverse 
event occurring after this 30-day period which is unexpected and related to protocol treatment 
must also be reported in an expedited manner (see Section 11.2 for reporting instructions). 
• 
A serious adverse event (SAE) is any adverse event that at any dose: 
− 
results in death 
− 
is life-threatening 
− 
requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care) 
− 
results in persistent or significant disability or incapacity 
− 
is a congenital anomaly/birth defect 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the events listed above. 
 
Note: Adverse events which are unequivocally only related to the underlying malignancy or disease 
progression are NOT reportable Serious Adverse Events. These include such adverse events as 
admission for pain control, palliative care or paracentesis of malignant effusions. 
 
11.2 
Serious Adverse Event Reporting Instructions 
 
All reportable serious adverse events must be reported using a web-based Electronic Data Capture 
(EDC) system being used for this trial. For details about accessing the EDC system and completing 
the on-line SAE report form, please refer to the CCTG Generic Data Management Guidebook for 
EDC Studies posted on the IND. 216 section of the CCTG website (www.ctg.queensu.ca). 


 
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AMEND #3: 2016-AUG-24 
Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to CCTG 
via EDC system. 
 
Within 7 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to CCTG via EDC system. 
 
EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website. 
 
FAX paper SAE Report to: 
 
Linda Hagerman, Study Coordinator 
Canadian Cancer Trials Group 
Fax No.: 613-533-2411 
 
Please use the same timelines for submission as for direct EDC reporting. 
 
Once internet connectivity is restored, the information that was FAXED to CCTG on the paper 
SAE Report must also be entered by the site into the EDC SAE web application.  
 
Local internet interruption: 
If you are unable to access the EDC SAE system, and cannot access a paper copy of the SAE Report 
from the trial website, please phone the IND 216 trial team (613-533-6430) to obtain a copy of the 
SAE Report by FAX. Once completed, the report must be FAXED back to CCTG as indicated 
above. Once internet connectivity is restored, the information that was FAXED to CCTG on the 
paper SAE Report must also be entered by the site into the EDC SAE web application.  
 
In cases of prolonged internet interruptions, please contact the CCTG Safety Desk for further 
instructions (613-533-6430).  
 
11.3 
Other Protocol Reportable Events – Pregnancy/Exposure Reporting 
 
In accordance with CCTG’s inclusivity in research policy, women of childbearing potential 
(WOCBP) may be enrolled in this clinical trial. WOCBP are defined as women who have had a 
menstrual period during the last year and have not had a hysterectomy. Precautions are required to 
be taken to prevent pregnancy during the clinical trial when the research population includes 
WOCBP. This includes pregnancy testing, use of effective methods of birth control, and pregnancy 
as an exclusion factor. The trial sample informed consent form includes the potential for 
unidentified risks to the embryo/fetus. It also includes general information on pregnancy prevention 
and the required minimum period during which birth control must be utilized.  
 
11.3.1 Pregnancy Prevention 
 
WOCBP and males who are enrolled in the trial must be informed of the requirement to use 
appropriate contraception. Investigators are advised to inform the female partners of male 
participants when appropriate and compliant with local policy.  


 
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AMEND #1: 2015-OCT-22; AMEND #3: 2016-AUG-24 
Sexually active males should use a condom during intercourse while taking drug and for 12 weeks 
after the final dose of study treatment. A condom is required to be used also by vasectomized men 
in order to prevent delivery of the drug via seminal fluid. 
 
WOCBP must use highly effective contraception while taking drug and for at least 4 weeks after 
the final dose of study treatment. Highly effective contraception is defined as 
i. 
total abstinence 
ii. male partner sterilization  
iii. use of a combination of both:  
a. placement of an intrauterine device (IUD) or intrauterine system (IUS) AND 
b. barrier methods of contraception: condom or occlusive cap (diaphragm or cervical /vault 
camps) with spermicidal foam/gel/film/cream/vaginal suppository 
 
Note hormonal contraception methods (oral, injected and implanted) are not allowed as buparlisib 
decreases the effectiveness of hormonal contraceptives. 
 
11.3.2 Pregnancy Reporting  
 
The investigator is required to report to CCTG any pregnancy occurring in female participants, and 
female partners of male participants. Pregnancies occurring up to 6 months after the completion of 
study treatment must also be reported.  
 
The investigator should report the pregnancy in a timely manner, within 24 hours of learning of the 
pregnancy using the CCTG Pregnancy Reporting Form available from the trial webpage.  
 
Once informed consent has been obtained, the form should be updated to provide further pregnancy 
information and to reflect the outcome of the pregnancy. All follow-up reports must be submitted 
to CCTG in a timely manner. For pregnant partner of trial participant (and pregnant participants, if 
required by local policy), a copy of the signed signature page of the pregnancy follow-up consent 
must be submitted to CCTG. 
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812 / safety-desk@ctg.queensu.ca).  
 
If the pregnancy results in death; is life-threatening; requires inpatient hospitalization or 
prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is 
a congenital anomaly/birth defect, then an SAE report must be additionally submitted as described 
above. Please note, hospitalization for labour/delivery alone does not constitute an ‘inpatient 
hospitalization’ for the purposes of pregnancy reporting. 
 
11.3.3 Exposure Reporting (Non-study Participants) 
 
The investigator is required to report to CCTG any incidence of exposure to study agent(s). 
Exposure is defined as significant, direct, contact/inhalation/consumption of agent(s) by non- study 
participant (an individual who is not otherwise participating in this clinical trial). An example of 
an exposure includes a non-study participant swallowing study medication. The investigator is 
responsible for determining significance, based on the agent to which the individual is exposed.  
 
The investigator should report the exposure in a timely manner, within 24 hours of learning of the 
exposure, using the CCTG Exposure Reporting Form available from the trial webpage.  


 
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Once informed consent has been obtained, the form should be updated to provide further exposure 
information and to reflect the outcome of the exposure as the information becomes available upon 
appropriate follow-up of the exposed individual. All follow-up reports must be submitted to CCTG 
in a timely manner. A copy of the signed exposure follow-up consent signature page must also be 
submitted to CCTG.  
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812 / safety-desk@ctg.queensu.ca).  
 
If the exposure results in death; is life-threatening; requires inpatient hospitalization or prolongation 
of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital 
anomaly/birth defect, then an SAE report must be additionally submitted as described above. 
 
11.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada 
 
The CCTG will provide expedited reports of SAEs to Health Canada (Office of Clinical Trials) for 
those events which meet regulatory requirements for expedited reporting, i.e. events which are 
BOTH serious AND unexpected, AND which are thought to be related to protocol treatment (or 
for which a causal relationship with protocol treatment cannot be ruled out). 
 
11.5 
CCTG Responsibility for Reporting Serious Adverse Events to Novartis 
 
Novartis will be notified of all reportable serious adverse events (SAE) and pregnancies reported 
as SAEs, within 15 calendar days of receipt. 
 
11.6 
Novartis Reporting Responsibilities 
 
Novartis will send all regulatory reportable serious unexpected suspected adverse reactions 
(SUSARs) from non-CCTG trials (Safety Updates) for buparlisib to CCTG. Novartis will report 
these events to Health Canada. 
 
11.7 
Reporting Safety Reports to Investigators 
 
CCTG will notify Investigators of all Safety Reports (Serious Adverse Events (SAEs) from this 
trial and Safety Updates (SUs) from other clinical trials) that are reportable to regulatory authorities 
in Canada as reported to the CCTG. This includes all serious events that are unexpected and related 
(i.e. possibly, probably, or definitely) to protocol treatment. The reports will be posted to the CCTG 
trial IND 216 web-based safety monitoring utility. 
 
Investigators must notify their Research Ethics Boards (REBs) of events which involve corrective 
action(s) to be taken as a result of the event(s) such as protocol and/or informed consent changes. 
The date of REB Submission for these SAEs and SUs will need to be entered into the CCTG trial 
IND 216 web based safety monitoring utility and documentation of REB submission must be 
retained in the study binder on site. The REB submission template provided by CCTG can be used 
to assist with tracking, submission, filing and monitoring. 
 
The submission of events to your ethics board should be done as soon as possible (we suggest 
within 30 days). REB submissions greater than 90 days from the date of notification will be 
regarded as delinquent and a major deficiency will be assigned. These safety reports are to be filed 
in the trial files on site. 


 
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12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
12.1 
Criteria for Discontinuing Protocol Treatment 
 
Patients may stop protocol treatment in the following instances: 
• 
Intercurrent illness which would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy. 
• 
Unacceptable toxicity as defined in Section 8.0. 
• 
Progression or disease recurrence as defined in Section 10.0. 
• 
Request by the patient. 
• 
Completion of therapy as outlined in Section 8.0. Efforts should be made to maintain the 
investigations schedule and continue follow-up, even if patients discontinue protocol treatment 
prematurely and/or no longer attend the participating institution. 
 
12.2 
Duration of Protocol Treatment 
(see Section 10.0 for response definition) 
• 
For patients who achieve a complete or partial response, therapy will continue until objective 
disease progression or unacceptable toxicity, whichever occurs first.  
• 
For stable patients, therapy will continue for a maximum of 6 cycles (24 weeks). Patients who 
have no evidence of tumour shrinkage at this point should go off therapy and receive other 
treatment at the investigator's discretion. 
• 
Patients who progress (treatment failure) will go off study at the time progression is 
documented clinically and/or radiographically. 
 
12.3 
Therapy After Protocol Treatment is Stopped 
 
At the discretion of the investigator. 
 
12.4 
Follow-up Off Protocol Treatment 
 
See Section 9.3.  


 
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13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION 
 
13.1 
Central Radiology Review 
 
There will be no central radiology review for this study. 
 
13.2 
Central Pathology Review 
 
There will be no central pathology review for this study. 
 


 
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AMEND #1: 2015-OCT-22; AMEND #2: 2016-JAN-04 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Objectives and Design 
 
This is a single arm, open label, phase II study designed to assess the efficacy and toxicity of 
buparlisib in patients with relapsed and refractory chronic lymphocytic leukemia. The primary 
endpoint is objective response rate. Secondary end points include duration of response and 
progression-free survival. 
 
14.2 
Sample Size and Duration of Study 
 
PI3K Inhibitor Naïve Cohort 
The null hypothesis at which buparlisib will be considered of no value in this disease is an overall 
response rate of < 5%. The alternative hypothesis at which the drug will be considered worthy of 
further study is > 30%. Enrolment of 12 evaluable patients is required to test this hypothesis with 
a one-sided α of 0.1 and 80% power.  
 
According to the Simon 2 stage design, 5 patients will be enrolled in the first stage. If at least one 
PR or CR is observed, then a total of 12 patients will be enrolled. When 2 or more patients among 
12 evaluable patients achieve CR or PR, the null hypothesis will be rejected.  
 
Exploratory Cohort  
Outcomes of individuals previously treated with alternative PI3 kinase inhibitors will be presented 
descriptively. It is anticipated these numbers will be small, in which case any observed CR or PR 
will be of interest and considered worthy of further study. If for example 8 patients are enrolled, 
this would enable detection of a 5% versus 20% overall response rate with 53% power at a one 
sided α of 0.1. A maximum of 17 individuals will be enrolled on this exploratory cohort.  
 
Overall 
Accrual of up to 29 patients overall is anticipated to take place over 24 months. Follow-up of 6 
months will be required after the last patient is enrolled. Thus, total duration of study is expected 
to be 30 months.  
 
14.3 
Safety 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported annually at investigators’ meetings. Adverse events will be categorized using the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) or other protocol specified criteria 
for hematological and psychiatric toxicity (see Appendix V). The worst event for each patient in 
each category or subcategory will be described. Both events related and unrelated to treatment will 
be captured. 
 
Clinical and laboratory data will be tabulated and compared to normal ranges for the institution. 


 
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14.4 
Correlative Studies 
 
Secondary objectives related to correlative studies are exploratory in nature. Peripheral blood will 
be assayed to investigate the correlation, if any, between response and potential biomarkers. Chi-
square (categorical results) or regression models (continuous results) will be used to explore the 
relationship between laboratory findings and response or early progression. 
 
14.5 
Prospective Validation of Survival Scale 
 
We have previously designed and validated a scale which can predict 90 day mortality among 
patients with hematological malignancies enrolled in Phase I and II clinical trials [Jamal 2012]. This 
scale uses 5 easy to measure, objective clinical variables, including albumin, LDH, diagnosis (AML 
vs non AML), platelet count and alkaline phosphatase. Each is attributed one point. A patient 
having 3 or more points has up to a 40% chance of mortality within 3 months of treatment on a 
clinical trial. The initial validation did not include patients with CLL. We therefore intend to 
validate this scale in CLL in the context of this trial.  
 
The scale will be applied to each individual patient and mortality risk calculated. A Kaplan Meier 
survival curve will be generated and hazard ratio for death estimated comparing low and high risk 
patients within this study, in order to determine the ability of the scale to distinguish mortality risk 
between these two groups. 
 


 
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AMEND #3: 2016-AUG-24 
15.0 
PUBLICATION POLICY 
 
15.1 
Authorship of Papers, Meeting Abstracts, Etc 
 
15.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether to 
publish the trial under a group title, or with naming of individual authors. If the latter approach is 
taken, the following rules will apply: 
• 
The first author will generally be the chair of the study. 
• 
A limited number of the members of the Canadian Cancer Trials Group and Novartis, may be 
credited as authors depending upon their level of involvement in the study. 
• 
Additional authors, up to a maximum of 15, will be those who have made the most significant 
contribution to the overall success of the study. This contribution will be assessed, in part but 
not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the 
study chair. 
 
15.1.2 In an appropriate footnote, or at the end of the article, the following statement will be made: 
 
"A study coordinated by the Canadian Cancer Trials Group. Participating 
investigators included: (a list of the individuals who have contributed 
patients and their institutions)." 
 
15.2 
Responsibility for Publication 
 
It will be the responsibility of the Study Chair to write up the results of the study within a reasonable 
time of its completion. If after a period of six months following study closure the manuscript has 
not been submitted, the central office reserves the right to make other arrangements to ensure timely 
publication. 
 
Dissemination of Trial Results 
CCTG will inform participating investigators of the primary publication of this trial. The complete 
journal reference and, if where publicly available, the direct link to the article will be posted on the 
Clinical Trial Results public site of the CCTG web site (http://www.ctg.queensu.ca). 
 
15.3 
Submission of Material for Presentation or Publication 
 
Material may not be submitted for presentation or publication without prior review by Novartis, 
the CCTG Senior Investigator, Senior Biostatistician, Study Coordinator, and approval of the Study 
Chair. Individual participating centres may not present outcome results from their own centres 
separately. Supporting groups and agencies will be acknowledged. 
 


 
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16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 
 
16.1 
Regulatory Considerations 
 
All institutions in Canada must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines. 
 
This trial is being conducted under a Clinical Trial Application (CTA) with Health Canada. As a 
result, the conduct of this trial must comply with Division 5 of the Canadian Regulations 
Respecting Food and Drugs (Food and Drugs Act). 
 
16.2 
Inclusivity in Research 
 
CCTG does not exclude individuals from participation in clinical trials on the basis of attributes 
such as culture, religion, race, national or ethnic origin, colour, mental or physical disability (except 
incapacity), sexual orientation, sex/gender, occupation, ethnicity, income, or criminal record, 
unless there is a valid reason (i.e. safety) for the exclusion.  
 
In accordance with the Declaration of Helsinki and the Tri-Council Policy Statement (TCPS), it is 
the policy of CCTG that vulnerable persons or groups will not be automatically excluded from a 
clinical trial (except for incompetent persons) if participation in the trial may benefit the patient or 
a group to which the person belongs.  
 
However, extra protections may be necessary for vulnerable persons or groups. It is the 
responsibility of the local investigator and research ethics board (REB) to ensure that appropriate 
mechanisms are in place to protect vulnerable persons/groups. In accordance with TCPS, 
researchers and REBs should provide special protections for those who are vulnerable to abuse, 
exploitation or discrimination. As vulnerable populations may be susceptible to coercion or undue 
influence, it is especially important that informed consent be obtained appropriately.  
 
Centres are expected to ensure compliance with local REB or institutional policy regarding 
participation of vulnerable persons/groups. For example, if a vulnerable person/group would be 
eligible for participation in a CCTG clinical trial under this policy but excluded by local policy, it 
is expected that they would not be enrolled in the trial. It is the centre’s responsibility to ensure 
compliance with all local SOPs.  
 
It is CCTG’s policy that persons who cannot give informed consent (i.e. mentally incompetent 
persons, or those physically incapacitated such as comatose persons) are not to be recruited into 
CCTG studies. It is the responsibility of the local investigator to determine the subject’s 
competency, in accordance with applicable local policies and in conjunction with the local REB (if 
applicable).  
 
Subjects who were competent at the time of enrolment in the clinical trial but become incompetent 
during their participation do not automatically have to be removed from the study. When re-consent 
of the patient is required, investigators must follow applicable local policies when determining if it 
is acceptable for a substitute decision maker to be used. CCTG will accept re-consent from a 
substitute decision maker. If this patient subsequently regains capacity, the patient should be re-
consented as a condition of continuing participation.  


 
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16.3 
Obtaining Informed Consent 
 
It is expected that consent will be appropriately obtained for each participant/potential participant 
in an CCTG trial, in accordance with ICH-GCP section 4.8. The centre is responsible for ensuring 
that all local policies are followed. 
 
Additionally, in accordance with GCP 4.8.2, CCTG may require that participants/potential 
participants be informed of any new information may impact a participant’s/potential participant’s 
willingness to participate in the study.  
 
Based upon applicable guidelines and regulations (Declaration of Helsinki, ICH-GCP), a 
participating investigator (as defined on the participants list) is ultimately responsible, in terms of 
liability and compliance, for ensuring informed consent has been appropriately obtained. CCTG 
recognizes that in many centres other personnel (as designated on the participants list) also play an 
important role in this process. In accordance with GCP 4.8.5, it is acceptable for the Qualified 
Investigator to delegate the responsibility for conducting the consent discussion. 
 
CCTG requires that each participant sign a consent form prior to their enrollment in the study to 
document his/her willingness to take part. CCTG may also require, as indicated above, that 
participants/potential participants be informed of new information if it becomes available during 
the course of the study. In conjunction with GCP 4.8.2, the communication of this information 
should be documented. 
 
CCTG allows the use of translators in obtaining informed consent. Provision of translators is the 
responsibility of the local centre. Centres should follow applicable local policies when procuring 
or using a translator for the purpose of obtaining informed consent to participate in a clinical trial.  
 
In accordance with ICH-GCP 4.8.9, if a subject is unable to read then informed consent may be 
obtained by having the consent form read and explained to the subject.  
 
16.3.1 Obtaining Consent for Pregnancy/Exposure Reporting 
 
Information from and/or about the subject (i.e. the pregnant female, the newborn infant, male 
partner, exposed individual) should not be collected about or from them unless or until they are a 
willing participant in the research. The rights and protections offered to participants in research 
apply and consent must be obtained prior to collecting any information about or from them.  
 
Trial-specific consent forms for “Pregnancy Follow-up” and “Exposure Follow-up” can be found 
on the trial webpage. The appropriate consent form must be used to obtain consent from any non-
trial participant (such as the pregnant partner or exposed individual). 
 
Participants will not be withdrawn from the main trial as a result of refusing or withdrawing 
permission to provide information related to the pregnancy/exposure. Similarly, male participants 
will not be withdrawn from the main study should their partner refuse/withdraw permission. 
 
Obtaining Consent for Research on Children 
 
In the case of collecting information about a child (i.e. the child resulting from a pregnant 
participant/partner or an exposed child), consent must be obtained from the parent/legal guardian. 


 
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AMEND #3: 2016-AUG-24 
For reporting an exposure, the parent/guardian is required to sign an “exposure follow-up” consent 
form (even if they are a participant in the main study) prior to collecting information about the 
child.  
 
16.4 
Discontinuation of the Trial 
 
If this trial is discontinued for any reason by the CCTG all centres will be notified in writing of the 
discontinuance and the reason(s) why. If the reason(s) for discontinuance involve any potential 
risks to the health of patients participating on the trial or other persons, the CCTG will provide this 
information to centres as well. 
 
If this trial is discontinued at any time by the centre (prior to closure of the trial by the CCTG), it 
is the responsibility of the qualified investigator to notify the CCTG of the discontinuation and the 
reason(s) why.  
 
Whether the trial is discontinued by the CCTG or locally by the centre, it is the responsibility of 
the qualified investigator to notify the local Research Ethics Board and all clinical trials subjects of 
the discontinuance and any potential risks to the subjects or other persons. 
 
16.5 
Retention of Patient Records and Study Files 
 
All essential documents must be maintained as per C.05.012 and in accordance with ICH-GCP.  
 
The Qualified Investigator must ensure compliance with the Regulations and the GCP Guideline 
from every person involved in the conduct of the clinical trial at the site.  
 
Essential documents must be retained for 25 years following the completion of the trial at the centre 
(25 years post final analysis, last data collected, or closure notification to REB, whichever is later), 
or until notified by CCTG that documents no longer need to be retained.  
 
In accordance with GCP 4.9.7, upon request by the monitor, auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct access.  
 
CCTG will inform the investigator/institution as to when the essential documents no longer need 
to be retained.  
 
16.6 
Centre Performance Monitoring 
 
This study is eligible for inclusion in the Centre Performance Index (CPI).  
 
Forms are to be submitted according to the schedule in the protocol. There are minimum standards 
for performance. 
 
16.7 
On-Site Monitoring/Auditing 
 
CCTG site monitoring/auditing will be conducted at participating centres in the course of the study 
as part of the overall quality assurance program. The monitors/auditors will require access to patient 
medical records to verify the data, as well as essential documents, standard operating procedures 
(including electronic information), ethics and pharmacy documentation (if applicable). 


 
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AMEND #3: 2016-AUG-24 
As this trial is conducted under a CTA with Health Canada, your site may be subject to an 
inspection by the Health Canada Inspectorate. 
 
Novartis has reserved the right to audit participating centres. Audits may only be conducted after 
consultation with CCTG. 
 
16.8 
Case Report Forms 
 
A list of forms to be submitted, as well as expectation dates, are to be found in Appendix IV. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection. For 
details of accessing the EDC system and completing the on-line Case Report Forms please refer to 
the “Registration and Data Management Guidebook” posted on the IND. 216 area of the CCTG 
web-site (www.ctg.queensu.ca). 


 
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17.0 
CORRELATIVE BLOOD WORK 
 
Collection of Lymphocytes From the Peripheral Blood (Mandatory) 
 
The collection of malignant lymphocytes is an important part of this trial. This is mandatory for 
participation in the study. 
 
See Lab Manual posted on the IND 216 webpage for complete details. 
 
17.1 
Objectives 
 
Samples will be used to determine: 
 
1) In vitro sensitivity to buparlisib using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide) assay, correlated with clinical response.  
 
2) Level of biomarkers predictive of sensitivity to buparlisib by protein isolation and flow 
cytometry. The candidate proteins include raptor and p70S6K which are involved in the PI3K 
signaling pathway. 
 
3) In relapsing patients after treatment with buparlisib, protein, RNA and DNA will be isolated in 
order to identify mechanisms of resistance to buparlisib and potentially to other PI3K 
inhibitors. 
 
17.1.1 Rationale for Correlative Blood Work 
 
PI3K inhibitors are effective therapies for CLL. However not all patients respond and many relapse 
as evidenced by the recent publication of data on idelalisib [Furman 2014]. The correlative blood 
work proposed here aims to identify by MTT assay and by the identification and validation of 
biomarkers, those patients likely to respond to therapy. Recent translational studies demonstrated 
that simultaneous low raptor and p70S6K protein expression may be predictive of sensitivity to 
buparlisib in-vitro [Amrein 2013].This clinical trial aims to confirm if these two proteins involved in 
the PI3K signaling pathway, can be used as biomarkers to predict clinical response of patients with 
CLL to buparlisib therapy. This will allow for better selection of patients for PI3K inhibitor therapy 
in the future. In addition, mechanisms of resistance to PI3K inhibitors is unknown; the research to 
be conducted using patient samples will allow exploration of resistance mechanisms.  
 


 
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AMEND #1: 2015-OCT-22 
17.2 
PIK3CA Gene Amplification Analysis 
 
PI3K mutations are well described in solid tumours (particularly in PIK3CA-the gene which 
encodes p110α), however activating PI3K mutations are noticeably absent in B cell malignancies 
such as CLL [Marincevic 2009; Ortiz-Maldonado 2015; Thorpe 2015]. A recent study of 188 patients with 
CLL showed no point mutations in p110α, -δ or -β isoforms, despite PI3K pathway constitutive 
activation [Brown 2012]; however, the same study demonstrated that amplifications of the PIK3CA 
locus were present in 6% of CLL patients (with 80% of the CLL cohort investigated being treatment 
naïve). Thus, gene amplification will be studied as a mechanism for PI3K pathway activation in 
this relapsed/refractory CLL population, by investigation of the copy number status of the genes 
PIK3CD and PIK3CA, which encode the p110δ and p110α isoforms respectively. Gene 
amplification will be measured using digital PCR, a highly sensitive and accurate methodology, in 
all patients treated on the IND 216 trial, both prior to therapy and after disease progression 
correlating with development of drug resistance. 
 
Univariate analysis will be attempted to investigate for any association of copy number variation 
with known clinical characteristics and prognostic factors (age, gender, number of prior lines of 
therapy, cytogenetics, unmutated IgHV status and response and duration of response to buparlisib).  


 
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18.0 
REFERENCES 
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Benson AB, Ajani JA, Catalano RB, et al. Recommended Guidelines for the Treatment of Cancer Treatment-
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Brown, J.R., Hanna, M., Tesar, B., Werner, L., Pochet, N., Asara, J.M., Wang, Y.E., Dal Cin, P., Fernandes, 
S.M., Thompson, C., et al. (2012). Integrative genomic analysis implicates gain of PIK3CA at 3q26 and MYC 
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Burger JA, Tsukada N, Burger M, Zvaifler NJ, Dell'Aquila M, Kipps TJ. Bloodderived nurse-like cells protect 
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Cheson BD et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic 
leukemia. JCO 2012; 30(23): 2820-2822. 
Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed 
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Grever MR, Lucas DM, Dewald GW, Neuberg DS, Reed JC, Kitada S, et al. Comprehensive assessment of 
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Gribben JG, O'Brien S. Update on therapy of chronic lymphocytic leukemia. J Clin Oncol 2011 Feb 10; 29(5): 
544-550. 
Hallek M, Cheson BD, Catovsky D, et al. Blood 2008: 111:5446-5456. 
Hayden RE, Pratt G, Roberts C, Drayson MT, Bunce CM. Treatment of chronic lymphocytic leukemia requires 
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Herman SE, Gordon AL, Wagner AJ, Heerema NA, Zhao W, Flynn JM, et al. Phosphatidylinositol 3-kinase-
delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing 
intrinsic and extrinsic cellular survival signals. Blood 2010 Sep 23; 116(12): 2078-2088. 
Jamal R, Chen BE, Hristova G, Seymour L, Assouline SE. Predictive model for survival and toxicity in early 
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Klein U, Tu Y, Stolovitzky GA, Mattioli M, Cattoretti G, Husson H, et al. Gene expression profiling of B cell 
chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 2001 
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Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, et al. CAL-101, a p110delta 
selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K 
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Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug 
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Marincevic, M., Tobin, G., and Rosenquist, R. (2009). Infrequent occurrence of PIK3CA mutations in chronic 
lymphocytic leukemia. Leukemia & lymphoma 50, 829-830. 


 
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AMEND #1: 2015-OCT-22 
Mayer IA, Abramson VG, Balko JM, Isakoff SJ, Kuba MG, Sanders M, Forero-Torres A, Yap JT, Van Den 
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study of pan-PI3K inhibitor BKM120 with letrozole in ER+/HER2- metastatic breast cancer (MBC) 
[abstract]. In ASCO Annual Meeting Proceedings: June 1-5 2012; Chicago, IL. Alexandria, VA: American 
Society of Clinical Oncology; 2012. Abstract 510 
Moreton P, Kennedy B, Lucas G, Leach M, Rassam SM, Haynes A, et al. Eradication of minimal residual disease 
in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin 
Oncol 2005 May 1; 23(13): 2971-2979. 
Ortiz-Maldonado, V., Garcia-Morillo, M., and Delgado, J. (2015). The biology behind PI3K inhibition in 
chronic lymphocytic leukaemia. Therapeutic advances in hematology 6, 25-36. 
Thorpe, L.M., Yuzugullu, H., and Zhao, J.J. (2015). PI3K in cancer: divergent roles of isoforms, modes of 
activation and therapeutic targeting. Nature reviews Cancer 15, 7-24. 


 
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APPENDIX I - PATIENT EVALUATION FLOW SHEET 
 
Required Investigations 
Prestudy 
(within 7 days 
prior to 
registration 
unless otherwise 
indicated) 
Days 1 & 14  
cycle 1 and 2; 
thereafter day 1 
each cycle (and as 
clinically indicated) 
Day 1 
each 
cycle 
At 8, 16 and 24 
weeks from 
registration, and 
thereafter every 
12 weeks 
4 weeks after Off 
Protocol Therapy 
History and Physical 
 
 
 
 
 
Physical Exam 
(including height, weight) 
X 
 
X 
 
X 
ECOG Performance Status 
 
 
Pulse, blood pressure 
 
 
Clinical tumour / organomegaly 
measurements (if applicable) 
 
X 
To confirm PR or CR and as 
clinically indicated1 
Hematology 
 
 
 
 
 
CBC, differential (including lymphocytes) 
X 
X 
 
 
X 
(and at 8 weeks if 
required to confirm 
PR or CR) 
 
 
PT, PTT 
X 
As clinically indicated 
Biochemistry1 
 
 
 
 
 
creatinine, potassium, bilirubin, AST, ALT, 
alkaline phosphatase, LDH, albumin, calcium, 
glucose (fasting), phosphate2, uric acid2 
X 
X 
 
 
X 
lipase 
 
X 
 
 
 
HbA1c (if diabetic), Beta 2 microglobulin 
X 
 
 
 
 
Radiology 
 
 
 
 
 
Neck/chest/abdominal/pelvic CT 
X3 
 
 
X4 
X4 
Assessment for MRD (optional) 
 
X (at CR only) 
X (at CR only) 
Cardiac Investigations 
 
 
 
 
 
12-lead ECG  
X 
As clinically indicated  
MUGA/LVEF  
X5 
As clinically indicated 
Other Investigations 
 
 
 
 
 
Pregnancy test (serum or urine for women of 
childbearing potential only) 
X 
 
 
 
 
Fluorescence in situ hybridization 
X5 
 
 
 
 
Direct antiglobulin test (DAGT) 
X 
 
 
 
 
Bone Marrow Aspirate and Biopsy 
X6 
 
 
X7 
X7 
Immunoglobulin variable region (IgVH) 
mutation status 
X8 
 
 
 
 
Mood Questionnaires9 
X 
X 
 
 
X10 
Hepatitis B surface antigen (HBsAg) 
X11 
 
 
 
 
Hepatitis C serology 
X11 
 
 
 
 
Correlative Blood Work 
 
 
 
 
 
Peripheral Blood (See Section 17 and 
Laboratory Manual for details) 
X11 
 
 
X (at progression)  
(if applicable) 
 
Adverse Events 
 
 
 
 
 
CTCAE v 4.0 
X 
continuously 
 
footnotes on next page … 


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
CONFIDENTIAL 
52 
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AMEND #1: 2015-OCT-22; AMEND #3: 2016-AUG-24 
 
1. See section 8 for additional monitoring of AST/ALT and bilirubin with hepatic toxicity. 
2. The first 4 patients treated on study will require monitoring for tumour lysis on days 1, 2 and 3 of cycle 1 only: calcium, creatinine, potassium, 
phosphate and uric acid. CCTG will notify centres if this applies at the time of registration. 
3. Within 21 days prior to registration (within 28 days if negative). 
4. Patients with an unconfirmed PR or CR should have scans repeated after 8 weeks to confirm response. Scans should also be repeated at 8, 16 
and 24 weeks from study registration and thereafter every 12 weeks. 
5. Within 28 days prior to registration (only if symptoms suggestive or history of cardiovascular disease). 
6. Within 28 days prior to registration for routine local pathology to assess CLL 
7. At time CR criteria first met, 8 weeks later to confirm sustained CR, or if cytopenia of uncertain cause. 
8. Can be done any time prior to registration on peripheral blood or bone marrow. 
9. Patient self-rating mood questionnaires (PHQ-9 and GAD-7) are posted on the I216 website. 
10. Mood questionnaires also required to be completed by patient at the End of Treatment visit. 
11. Within 28 days prior to registration. 


 
PROTOCOL DATE: 2014-DEC-03 
 
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53 
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APPENDIX II - PERFORMANCE STATUS SCORES 
 
ECOG (Zubrod) 
Score 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
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. 
2 
Ambulatory and capable of all self care but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self care; confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self care. Totally confined to bed or chair. 
 


 
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AMEND #3: 2016-AUG-24 
APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL 
 
Drug Distribution 
Buparlisib will be sent by Novartis to participating centres.  
 
Drug Labelling 
Drug supplies for this study will be labelled in accordance with Health Canada regulations. The labels 
contain all information required under the drug labelling regulations. 
 
Initial Drug Supply 
Once a centre is locally activated (following receipt and review of all required documentation), the CCTG 
will authorize a start-up supply of buparlisib to be shipped directly to the centre. The drug will be shipped 
to the centre within 5 working days of local activation. Drug accountability and drug re-order forms will be 
included 
with 
the 
drug 
shipment 
and 
are 
also 
available 
on 
the 
trial 
website: 
(www.ctg.queensu.ca/trials/ind/216/216.html). 
 
Drug Ordering (Re-supply) 
Fax a copy of the buparlisib drug re-order form (available at www.ctg.queensu.ca/trials/ind/216/216.html) 
to Novartis. 
 
Please allow sufficient time for shipment of drug. 
 
Drug Accountability 
The investigational products are to be prescribed only by the investigator and co-investigators on the 
participants list. Under no circumstances will the investigator allow the drug to be used other than as 
directed by the protocol. Accurate records must be maintained accounting for the receipt of the 
investigational product and for the disposition of the product (Drug Accountability Log). 
 
Drug Destruction or Return: 
Details to be supplied at the time of study closure. 
 
 
**PLEASE NOTE ** 
 
DRUG FROM THIS SUPPLY IS TO BE USED ONLY 
 
FOR PATIENTS REGISTERED ON THIS STUDY 
 
 
Study drug shipped to participating centres may be transferred from the main hospital pharmacy to a satellite 
pharmacy, provided separate drug accountability records are maintained in each pharmacy. Investigational 
agent may NOT however, be transferred to pharmacies or physicians outside the participating centre. 


 
PROTOCOL DATE: 2014-DEC-03 
 
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55 
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AMEND #3: 2016-AUG-24 
APPENDIX IV - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of registration and will apply to all eligible and ineligible 
patients. This trial will use a web-based Electronic Data Capture (EDC) system for all data collection including 
SAE reporting (see section 11.0 for details regarding SAE reporting). For details about accessing the EDC system 
and completing the on-line Case Report Forms, please refer to the Data Management Guidebook posted on the 
IND 216 area of the CCTG website (www.ctg.queensu.ca). 
 
Form 
To be Completed/Submitted Electronically: 
Supporting Documentation  
to be sent using Supporting  
Document Upload Tool 
PATIENT 
ENROLLMENT 
FOLDER 
Must be completed at time of registration to confirm 
eligibility. 
 
BASELINE 
REPORT 
Due within 2 weeks of patient registration.  
Copies of the signed signature page(s) 
of the consent form; relevant 
pathology and radiology reports; 
mood questionnaires; ECG reports; 
MUGA/LVEF report (if applicable) 
TREATMENT 
REPORT 
To be completed every 28 days (i.e. after each 
cycle). Due within 2 weeks of end of cycle. This 
form documents treatment, adverse events, 
investigations and response assessment for each 
cycle. 
Relevant radiology reports. 
Patient diary. 
Mood questionnaires. 
CORRELATIVE 
BLOOD WORK 
See Section 17 and Laboratory Manual for details. 
 
END OF 
TREATMENT 
REPORT 
To be completed when patient permanently 
discontinues protocol treatment. Due within 2 weeks 
of end of protocol treatment. 
Mood questionnaires. 
4 WEEK POST 
TREATMENT 
REPORT 
To be completed once on all patients, 4 weeks after 
the end of the last cycle. Due within 2 weeks after 
contact with patient. 
Relevant radiology reports. 
FOLLOW-UP 
REPORT 
Continued follow-up is not required for patients who 
go off protocol treatment with progressive disease, 
except to document ongoing toxicities (until resolved 
to < grade 2) and late toxicities (including second 
malignancies). For patients who go off protocol 
therapy with suspected PR or CR, an 8 week 
confirmatory response assessment including CT 
scanning will be required as per sections 9.1 and 
10.4, if not already performed. For patients who go 
off protocol treatment with objective CR, PR or SD 
ongoing, a follow-up report will be required every 
3 months until relapse/progression. Due within 
2 weeks after contact with patient. 
Relevant radiology reports. 
RELAPSE/ 
PROGRESSION 
REPORT 
To be completed at the time of disease relapse or 
progression. Due within 2 weeks after contact with 
patient. 
Relevant radiology reports. 
 
 
continued on next page … 
 
 


 
PROTOCOL DATE: 2014-DEC-03 
 
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AMEND #3: 2016-AUG-24 
 
Form 
To be Completed/Submitted Electronically: 
Supporting Documentation  
to be sent using Supporting  
Document Upload Tool 
DEATH REPORT 
Required only on patients who die during protocol 
therapy, within 30 days after last dose, or within the 
protocol defined follow-up period for patients with 
response or stable disease ongoing.* Due within 
2 weeks of knowledge of death. 
Autopsy report, if done. 
SERIOUS 
ADVERSE EVENT 
REPORT FORM 
All reportable serious adverse events must be 
reported as described in Section 11.0. All reportable 
serious adverse events must be reported as described 
in Section 11.0. Preliminary CCTG Serious Adverse 
Event Report due within 24 hours. Updated CCTG 
Serious Adverse Event Report due within 7 days. 
 
* 
NB It is the investigator's responsibility to investigate and report the date/cause of death of any patient who dies during this period. 
Any death that occurs during this period and that is thought to be treatment related must also be reported as a Serious Adverse 
Event as described in Section 11. 
 


 
PROTOCOL DATE: 2014-DEC-03 
 
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APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for Adverse Event (AE) reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
Please note: 
HEMATOLOGICAL AND PSYCHIATRIC TOXICITY SHOULD BE GRADED ACCORDING TO 
CRITERIA DESCRIBED IN SECTION 8.3. 


 
PROTOCOL DATE: 2014-DEC-03 
 
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APPENDIX VI - CLL DIAGNOSTIC CRITERIA AND INDICATIONS FOR TREATMENT 
(Abbreviated from the 2008 International Workshop on Chronic Lymphocytic Leukemia Guidelines) 
 
Diagnosis 
a. Presence of at least 5 x 109 B lymphocytes /L (5000/μL) in the peripheral blood, of which 
prolymphocytes comprise no more than 55%. 
b. Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing at 
least one B-cell marker (CD19, CD20, or CD23) and CD5. 
 
Indications for treatment 
a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia 
or thrombocytopenia. 
b. Massive (i.e. at least 6 cm below the left costal margin), progressive, or symptomatic splenomegaly. 
c. Massive nodes (i.e. At least 10 cm in longest diameter), progressive, or symptomatic lymphadenopathy. 
d. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or 
lymphocyte doubling time (LDT) of less than 6 months (which may be extrapolated). Lymphocyte 
doubling time can be obtained by linear regression extrapolation of absolute lymphocyte counts 
obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial 
blood lymphocyte counts of less than 30 x 109/L (30,000/μL), LDT should not be used as a single 
parameter to define indication for treatment. 
e. Constitutional symptoms, defined as 1 or more of the following disease-related symptoms or signs:  
• 
Unintentional weight loss of 10% or more within the previous 6 months prior to screening 
• 
Significant fatigue (inability to work or perform usual activities) 
• 
Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without evidence of infection or  
• 
Night sweats for more than 1 month without evidence of infection.  


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
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APPENDIX VII - CYP3A INHIBITORS/INDUCERS AND CYP450 SUBSTRATES 
 
Table 1. List of prohibited CYP3A inhibitors and inducers 
 
Strong CYP3A inhibitors 
Strong CYP3A inducers 
boceprevir 
avasimibe 
clarithromycin* 
carbamazepine * 
conivaptan 
fosphenytoin * 
elvitegravir 
phenobarbital * 
indinavir 
phenytoin * 
itraconazole 
primidone * 
ketoconazole 
rifabutin 
lopinavir* 
rifampin 
mibefradil 
St. John's Wort 
nefazodone 
 
nelfinavir 
 
posaconazole 
 
ritonavir* 
 
saquinavir* 
 
telaprevir 
 
telithromycin 
 
tipranavir 
 
troleandomycin 
 
voriconazole 
 
* 
These drugs are Enzyme Inducing Anti-Epileptic drugs 
This database of CYP inhibitors and inducers was compiled from the Indiana University 
School of Medicine’s “Clinically Relevant” Table, from the University of Washington’s Drug 
Interaction Database based on in vitro studies and from the FDA’s “Guidance for Industry, 
Drug Interaction Studies;” from the Indiana University School of Medicine’s “Clinically 
Relevant” Table. 
 
 


 
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Table 2. List of CYP450 substrates to be used with caution 
 
CYP2C8 
CYP2C9 
CYP2C19 
CYP3A* 
amodiaquine 
celecoxib 
amitriptyline 
adinazolam 
felodipine1 
cerivastatin 
diclofenac 
citalopram 
alfentanil1,2 
fentanyl2 
pioglitazone 
flurbiprofen 
clobazam 
alpha-
dihydroergocryptine1 
flunitrazepam 
repaglinide 
fluvastatin 
clomipramine 
alprazolam 
fluticasone1 
rosiglitazone 
glibenclamide 
(glyburide) 
clopidogrel  
amlodipine 
lovastatin1 
torasemide 
gliclazide 
diazepam 
aripiprazole 
maraviroc1 
troglitazone 
glimepiride 
fluoxetine 
atorvastatin 
midazolam1 
 
glipizide 
imipramine 
brecanavir 
nifedipine 
indomethacin 
lansoprazole 
brotizolam1 
nisoldipine 
irbesartan 
mephobarbital 
budesonide1 
nitrendipine 
ketobemidone 
moclobemide 
buspirone1 
perospirone1 
lornoxicam 
omeprazole 
capravirine 
quinine 
losartan 
pantoprazole 
cerivastatin 
sildenafil1 
meloxicam 
progesterone 
chlorpheniramine 
simvastatin1 
naproxen 
quazepam 
cyclosporine2 
sirolimus1,2 
nateglinide 
rabeprazole 
darifenacin1 
tolvaptan 
piroxicam 
sertraline 
diazepam 
trazodone 
rosiglitazone 
S-mephenytoin 
diergotamine2 
triazolam1 
S-ibuprofen 
 
ebastine1 
 
sulfamethoxazole 
eletriptan1 
tenoxicam 
eplerenone1 
tolbutamide 
ergotamine2 
torasemide 
estazolam 
valdecoxib 
everolimus1 
*  
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 strong 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 strong inhibitors may lead to serious safety concerns (e.g., Torsades de 
Pointes). 
 


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
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AMEND #1: 2015-OCT-22 
APPENDIX VIII - QT PROLONGING DRUGS  
 
Updates to this list will be published on the trial website. 
 
List of prohibited QT prolonging drugs with known risk of Torsades de Pointes 
 
Drug 
QT risk(*) 
Comment 
Amiodarone 
Known risk for TdP 
Females>Males, TdP risk regarded as low 
Arsenic trioxide 
Known risk for TdP 
 
Astemizole 
Known risk for TdP 
No Longer available in U.S. 
Bepridil 
Known risk for TdP 
Females>Males 
Chloroquine 
Known risk for TdP 
 
Chlorpromazine 
Known risk for TdP 
 
Cisapride 
Known risk for TdP 
Restricted availability; Females>Males. 
Disopyramide 
Known risk for TdP 
Females>Males 
Dofetilide 
Known risk for TdP 
 
Domperidone 
Known risk for TdP 
Not available in the U.S. 
Droperidol 
Known risk for TdP 
 
Halofantrine 
Known risk for TdP 
Females>Males 
Haloperidol 
Known risk for TdP 
When given intravenously or at higher-than- recommended doses, risk 
of sudden death, QT prolongation and torsades increases. 
Ibutilide 
Known risk for TdP 
Females>Males 
Levomethadyl 
Known risk for TdP 
 
Mesoridazine 
Known risk for TdP 
 
Methadone 
Known risk for TdP 
Females>Males 
Pentamidine 
Known risk for TdP 
Females>Males 
Pimozide 
Known risk for TdP 
Females>Males 
Probucol 
Known risk for TdP 
No longer available in U.S. 
Procainamide 
Known risk for TdP 
 
Quetiapine 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate 
Quinidine 
Known risk for TdP 
Females>Males 
Sotalol 
Known risk for TdP 
Females>Males 
Sparfloxacin 
Known risk for TdP 
 
Tacrolimus 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate with narrow TI 
Terfenadine 
Known risk for TdP 
No longer available in U.S. 
Thioridazine 
Known risk for TdP 
 
Vardenafil 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate 
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-administered 
with a potent inhibitor of the respective enzyme. 
 
Note: drugs with a known risk for TdP that are also strong inhibitors of CYP3A are not repeated here and only mentioned in 
Table 1. 


 
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List of QT prolonging drugs to be used with caution 
 
Updates to this list will be published on the trial website. 
 
Drug 
QT risk (*) 
Alfuzosin 
Possible risk for TdP 
Amantadine 
Possible risk for TdP 
Amitriptyline 
Conditional risk for TdP 
Azithromycin 
Possible risk for TdP 
Chloral hydrate 
Possible risk for TdP 
Citalopram 
Conditional risk for TdP 
Clomipramine 
Conditional risk for TdP 
Clozapine 
Possible risk for TdP 
Desipramine 
Conditional risk for TdP 
Diphenhydramine 
Conditional risk for TdP 
Dolasetron 
Possible risk for TdP 
Doxepin 
Conditional risk for TdP 
Dronedarone 
Possible risk for TdP 
Escitalopram 
Possible risk for TdP 
Flecainide 
Possible risk for TdP 
Fluoxetine 
Conditional risk for TdP 
Foscarnet 
Possible risk for TdP 
Galantamine 
Conditional risk for TdP 
Gatifloxacin 
Possible risk for TdP 
Gemifloxacin 
Possible risk for TdP 
Granisetron 
Possible risk for TdP 
Imipramine 
Conditional risk for TdP 
Indapamide 
Possible risk for TdP 
Isradipine 
Possible risk for TdP 
Levofloxacin 
Possible risk for TdP 
Lithium 
Possible risk for TdP 
Mexiletine 
Conditional risk for TdP 
Moexipril/HCTZ 
Possible risk for TdP 
Moxifloxacin 
Possible risk for TdP 
Nicardipine 
Possible risk for TdP 
Nortriptyline 
Conditional risk for TdP 
Octreotide 
Possible risk for TdP 
Ofloxacin 
Possible risk for TdP 
Ondansetron 
Possible risk for TdP 
Oxytocin 
Possible risk for TdP 
Paliperidone 
Possible risk for TdP 
Paroxetine 
Conditional risk for TdP 
(*) Classification according to the QTdrugs.org Advisory Board of the Arizona CERT 
table continued on next page … 
 
 


 
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Drug 
QT risk (*) 
Perflutren lipid microspheres 
Possible risk for TdP 
Protriptyline 
Conditional risk for TdP 
Ranolazine 
Possible risk for TdP 
Risperidone 
Possible risk for TdP 
Roxithromycin* 
Possible risk for TdP 
Sertindole 
Possible risk for TdP 
Sertraline 
Conditional risk for TdP 
Solifenacin 
Conditional risk for TdP 
Tizanidine 
Possible risk for TdP 
Trazodone 
Conditional risk for TdP 
Trimethoprim-Sulfa 
Conditional risk for TdP 
Trimipramine 
Conditional risk for TdP 
Venlafaxine 
Possible risk for TdP 
Ziprasidone 
Possible risk for TdP 
(*) Classification according to the QTdrugs.org Advisory Board of the Arizona CERT 
 
 


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.216 
 
 
CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
 
AMEND #3: 2016-AUG-24 
LIST OF CONTACTS 
 
PATIENT REGISTRATION 
All patients must be registered via the web-based, password-operated electronic data system at the CCTG web page 
before any treatment is given. 
 
 
Contact 
Tel. # 
Fax # 
STUDY SUPPLIES 
Data Management Guidebook, 
Protocol, Safety Information, 
Electronic Case Report Forms. 
Available on CCTG Website: 
http://www.ctg.queensu.ca  
under: Clinical Trials 
 
 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Linda Hagerman 
Study Coordinator 
CCTG 
Email:  
lhagerman@ctg.queensu.ca  
or: 
Dr. Annette Hay 
Senior Investigator, CCTG 
Investigational New Drug Program 
Email:  
ahay@ctg.queensu.ca  
613-533-6430 
613-533-2411 
STUDY CHAIR 
Dr. Sarit Assouline 
Study Chair 
Email:  
sarit.assouline@mcgill.ca 
514-340-8207 
514-340-8281 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 11.0 for details 
of reportable events. 
Dr. Annette Hay 
Senior Investigator 
CCTG 
or 
Linda Hagerman 
Study Coordinator 
CCTG 
613-533-6430 
613-533-2411 
DRUG ORDERING 
See Appendix III and trial website: 
(www.ctg.queensu.ca/trials/ind/216/216.html) for details 
 
 

SAP_000.pdf: 
 
1
Statistical analysis plan for I216 
 
June 28, 2017 
 
By Bingshu E. Chen 
 
 
The analysis will be descriptive with continuous variable measured by mean and SD or median 
and range and categorical variable measured by percentage.  
 
Table 1 to table 12 are the same as the meeting book table and no additional program is 
needed.  
 
Table 13: Duration of response. Median (Min, Max) of the duration of the response will be 
reported for patients with CR/CRu and PR.  
 
Response duration will be measured from the time measurement criteria for CR/PR (whichever 
is first recorded) are first met until the first date that recurrent or progressive disease is 
objectively documented, taking as reference the smallest measurements recorded on study 
(including baseline). 
 
 
Figure 1. Waterfall plot for tumour shrinkage 
 
Figure 2. KM plot for PFS