Conditions: Chronic Lymphocytic Leukemia Small-Cell Lymphoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 229
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the efficacy of ibrutinib in combination with obinutuzumab compared to chlorambucil in combination with obinutuzumab based on the Independent Review Committee (IRC) assessment of progression free survival (PFS). Efficacy will be evaluated according to 2008 International Workshop for Chronic Lymphocytic Leukemia (IWCLL) criteria with the modification for treatment-related lymphocytosis, in subjects with treatment-naive CLL or SLL.

Detailed description:

Arms:
arm 1: Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity. arm 2: Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity.

Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.

Interventions: intervention 1: Ibrutinib intervention 2: Obinutuzumab intervention 3: Chlorambucil
Intervention descriptions: intervention 1: Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) administration. intervention 2: Obinutuzumab will be supplied as 1000 mg/40 mL solution in a single-use vial for intravenous (IV) administration intervention 3: Chlorambucil will be supplied as 2 mg film-coated tablets for oral (PO) administration

Protocol document:
Prot_000.pdf: 



























































































































































































































































SAP_001.pdf: 
PCYC-1130-CA (NCT02264574)  
 
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Redacted Statistical Analysis Plan for Journal Use 
 
A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton’s Tyrosine 
Kinase Inhibitor Ibrutinib in Combination with Obinutuzumab versus Chlorambucil in 
Combination with Obinutuzumab in Subjects with Treatment-naive Chronic 
Lymphocytic Leukemia or Small Lymphocytic Lymphoma 
 
Protocol PCYC-1130-CA 
 
 
 
 
Version:   1.0  
Version Date:  February 28, 2018 
 
 
 
 
Confidentiality Statement 
This document contains confidential information of Pharmacyclics, LLC. that must not be disclosed to 
anyone other than the recipient study staff and members of the institutional review board/ethics 
committee. This information cannot be used for any other purpose other than the evaluation or conduct of 
the clinical study without the prior written consent of Pharmacyclics, LLC. 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATION ..................................................................................................... 3 
1. 
INTRODUCTION .............................................................................................................. 5 
1.1. Study Design ............................................................................................................. 5 
1.2. Endpoints .................................................................................................................. 6 
1.2.1. Primary Endpoint .......................................................................................... 6 
1.2.2. Secondary Endpoints ..................................................................................... 6 
1.2.3. Safety Assessments ....................................................................................... 6 
1.3. Statistical Hypotheses ................................................................................................ 6 
1.4. Sample Size Determination ........................................................................................ 7 
1.5. Planned Analysis ....................................................................................................... 7 
1.5.1. Interim Analysis ............................................................................................ 7 
1.5.2. Primary Analysis........................................................................................... 7 
1.5.3. Final Analysis ............................................................................................... 8 
1.6. Testing Procedure and Level of Significance ............................................................. 8 
1.7. Blinding and Randomization Methods ....................................................................... 8 
1.7.1. Blinding Method ........................................................................................... 8 
1.7.2. Randomization Method ................................................................................. 8 
2. 
GENERAL ANALYSIS CONSIDERATION ................................................................... 9 
2.1. Analysis Sets ............................................................................................................. 9 
2.2. Definition of Subgroups ............................................................................................. 9 
3. 
SUBJECT INFORMATION............................................................................................ 10 
3.1. Subject Disposition .................................................................................................. 10 
3.2. Demographics and Baseline Characteristics ............................................................. 10 
3.3. Prior and Concomitant Medications ......................................................................... 10 
3.4. Extent of Exposure to Study Treatment .................................................................... 10 
3.5. Subsequent Antineoplastic Therapies ....................................................................... 10 
4. 
ANALYSIS FOR ENDPOINTS....................................................................................... 11 
5. 
SAFETY ASSESSMENTS ............................................................................................... 13 
6. 
REFERENCES ................................................................................................................. 15 
 


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LIST OF ABBREVIATION 
Abbreviation 
Definition 
AE 
adverse event 
ALC 
absolute lymphocyte counts 
ANC 
Absolute neutrophil counts 
ATC 
Anatomical Therapeutic Chemical 
BOR 
best overall response  
CBC 
complete blood count 
CLL 
chronic lymphocytic leukemia 
CMH 
Cochran-Mantel-Haenszel 
CR 
complete response 
CRF 
case report form 
CRi 
complete response with an incomplete marrow recovery 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOL 
duration of lymphocytosis 
DOR 
duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event-free survival 
EQ-5D 
EuroQoL Five-Dimension. 
FISH 
fluorescence in situ hybridization 
DMC 
data monitoring committee 
IGHV 
immunoglobulin heavy-chain variable region 
IRC 
independent review committee 
IRR 
infusion related reaction 
ITT 
intent-to treat 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia Criteria 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRU 
medical resource utilization 
NCI 
National Cancer Institute 
NE 
not evaluable 
NED 
no evidence of disease 
nPR 
nodular partial response  
ORR 
overall response rate 
OS 
overall survival 
 


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Abbreviation 
Definition 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
Pharmacokinetic  
PR 
partial response  
PRO 
patient reported outcome. 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SLL 
small lymphocytic lymphoma 
SOC 
system organ class 
TEAE 
treatment-emergent adverse events 
WBC 
white blood cell count 
WHO 
World Health Organization 
 
 
 
 
 
 
 


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1. INTRODUCTION 
This statistical analysis plan (SAP) lays out key elements including definitions and statistical 
methods for analysis of data in evaluation of efficacy and safety for the PCYC-1130-CA study.  
Analyses of pharmacokinetics (PK) data and exploratory analyses for clonal evolution, disease-
related mechanisms of resistance and the secreted protein analysis for obinutuzumab-related 
infusion reactions will be addressed in separate documents.  
Throughout this SAP, “study treatment” and “study drug” are used interchangeably. 
1.1. 
Study Design 
This is a randomized, multicenter, open-label, Phase 3 study designed to evaluate the safety and 
efficacy of ibrutinib in combination with obinutuzumab, when compared to chlorambucil in 
combination with obinutuzumab, in subjects diagnosed with CLL or SLL, who are treatment-naive 
but now require therapy. 
Subject participation includes a Screening Phase, a Pre- Progressive Disease (Pre-PD) Phase, and a 
Follow-up Phase. 
The Screening Phase is up to 30 days prior to randomization. The Pre-PD Phase extends from 
randomization until disease progression (PD), death, loss to follow up, or consent withdrawal, 
whichever occurs first. During this phase, subjects receive the study treatment once randomized and 
the response evaluations are scheduled every 4 cycles from the initial dose of study drug until Cycle 
33, and then every 6 cycles until disease progression regardless of whether subject is on study 
treatment or has discontinued study treatment due to a reason other than PD. The Follow-up Phase 
begins once a subject has progressive disease and continues until death, loss to follow up, consent 
withdrawal, or study end, whichever occurs first. 
The response and progression evaluations are performed in accordance with the IWCLL guidelines 
including recent clarifications (Hallek 2008, Hallek 2012, Hallek 2013, Cheson 2012, and IWCLL 
2017). An independent review committee (IRC) was established to conduct progression and 
response assessment centrally. Criteria for response categories, as well as the process and 
convention of the IRC were prospectively detailed in the IRC charter. 
An independent Data Monitoring Committee (DMC) is formed and constituted according to 
regulatory agency guidelines. Detailed information regarding the composition of the DMC and 
detailed DMC procedures are provided in a separate charter. The DMC reviews the safety data 
periodically and provides recommendations according to the charter. 
Study Dosage and Administration 
Treatment Arm A: Ibrutinib PO and Obinutuzumab IV 
Ibrutinib will be given orally at a dose of 420 mg daily (3 capsules) until disease progression or 
unacceptable toxicity.  


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Obinutuzumab will be administered intravenous at a fixed dose of 1000 mg over 6 cycles: given on 
Days 1+2 (100 mg on Day 1 and 900 mg on Day 2), Day 8 (1000 mg) and Day 15 (1000 mg) of 
Cycle 1 and on Day 1 (1000 mg) only of subsequent cycles, for up to 6 cycles.  
Treatment Arm B: Chlorambucil PO and Obinutuzumab IV for Six 28-day Cycles 
Chlorambucil will be administered orally at a dose of 0.5 mg/kg body weight, on Days 1 and 15 of 
each cycle, for up to 6 cycles. 
Obinutuzumab will be administered the same as in arm A. 
Upon IRC-confirmed progression, subjects in Arm B have the opportunity to receive ibrutinib 
monotherapy orally at a dose of 420 mg daily (3 capsules) continuously until determined otherwise 
by the investigator. 
1.2. 
Endpoints 
1.2.1. Primary Endpoint 
• Progression free survival (PFS) by IRC 
1.2.2. Secondary Endpoints 
• PFS by IRC in high risk analysis set 
• Rate of sustained hemoglobin improvement  
• Rate of MRD-negative response 
• ORR by IRC 
• OS  
• Rate of infusion related reactions 
• Rate of sustained platelet improvement 
• Rate of clinically meaningful improvement in EQ-5D-5L utility score 
1.2.3. Safety Assessments 
• Safety and tolerability of ibrutinib in combination with obinutuzumab compared 
with chlorambucil in combination with obinutuzumab  
 
1.3. 
Statistical Hypotheses  
The primary hypothesis of this study is that the experimental treatment ibrutinib + obinutuzumab 
compared with chlorambucil + obinutuzumab will significantly improve PFS in subjects diagnosed 
with CLL or SLL who are treatment-naive but now require active therapy. 
The statistical hypotheses are as follows:  


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H0: The PFS distributions of experimental treatment group, SI(t), and the control group, SC(t), are 
equal at all time points t: 
SI(t) = SC(t), for all t > 0 
versus 
H1: The PFS distributions of experimental treatment group, SI(t), are different from the control 
group, SC(t), at at least one time point t: 
SI(t) ≠ SC(t), for some t > 0 
These hypotheses will be tested using a 2-sided stratified log-rank test at α level of 0.05. 
1.4. 
Sample Size Determination 
This study was powered for testing the primary hypothesis of this study.  
The sample size is calculated based on the assumptions: 
• 
Randomization ratio of 1:1  
• 
Median PFS of 27 months for Arm B (chlorambucil in combination with obinutuzumab)  
• 
Target hazard ratio of 0.55, which corresponds to median PFS of 49.1 months for Arm A 
(ibrutinib combined with obinutuzumab). 
On this basis, 94 PFS events provide 80% power to achieve a statistical significance level of 5% (2-
sided) under exponential distribution. With an estimated accrual rate of 18 subjects per month, 
approximately 212 eligible subjects were to be enrolled to observe 94 PFS events in about 36 
months from the first subject randomized.  
The sample size and power calculations were calculated using the software package, East (Cytel 
Software Corp, Cambridge, MA) version 6.3. 
1.5. 
Planned Analysis  
1.5.1. Interim Analysis 
No interim analysis is performed in this study.  
1.5.2. Primary Analysis 
The primary analysis of PFS will be performed after approximately 94 confirmed progression/death 
events have occurred. The analysis of the secondary endpoints including OS will be performed at 
the time of PFS primary analysis.  


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1.5.3. Final Analysis  
After the primary analysis of PFS, the Sponsor will continue to follow the subjects for 
approximately 4 years after the first subject was enrolled. When the study closed, a final analysis 
will be performed, and a CSR addendum will be drafted.  
1.6. 
Testing Procedure and Level of Significance  
To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints will be 
tested based on a serial gatekeeping testing procedure at the two-sided significance level of 0.05 
according to the hierarchical order as listed in 1.2.2.  
1.7. 
Blinding and Randomization Methods 
1.7.1. 
Blinding Method 
In this open-label study, neither the subjects nor the investigators are blinded to treatment. 
However, access to efficacy data is controlled so that the Sponsor’s staff overseeing the conduct of 
the study or analyzing/summarizing data do not have an aggregated efficacy summary by treatment 
arm prior to database lock. Details are described in the Minimizing Bias Document. 
Assessment for progression and response assessment is performed centrally by the IRC. Members 
of the IRC are blinded to the study treatment. The IRC data flow and workflow are detailed in the 
IRC charter.  
1.7.2. 
Randomization Method 
Central randomization will be implemented in this study. Two randomization schemes will be 
generated: one for each geographic region (North America versus Rest of World). Under each 
scheme, subjects will be randomized based on the following stratification factors: 
• 
ECOG 0-1 vs 2 
• 
Cytogenetics - will be stratified into one of three categories 
1. del 17p  
2. del 11q without del 17p 
3. others (neither del 17p nor del 11q) 
Subjects will be randomized in a 1:1 ratio to either Treatment Arm A or Treatment Arm B within 
each randomization stratum. This randomization scheme will be implemented within the Interactive 
Web Response System (IWRS).  


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2. GENERAL ANALYSIS CONSIDERATION 
2.1. 
Analysis Sets 
Intent-To-Treat (ITT) population: defined as all subjects who were randomized. Subjects will be 
grouped according to the treatment assigned at randomization. This population will be the primary 
population for the analyses of efficacy endpoints, disposition, demographics and baseline 
characteristics, baseline disease characteristics, subsequent anticancer therapy and patient-reported 
outcome data. 
Safety population: defined as all subjects who received at least 1 dose of any one of the three 
study drugs (ibrutinib, chlorambucil, or obinutuzumab). Safety data will be analyzed as treated. The 
Safety Population will be used to summarize the safety (including dosing and concomitant 
medications) data. 
High risk analysis set: defined as randomized subjects with del17p or TP53 mutation or del 11q at 
baseline per central lab results. 
2.2. 
Definition of Subgroups 
Subgroup analyses will be performed for the selected variables to assess the internal consistency of 
the treatment benefit.  
 
 


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3. SUBJECT INFORMATION 
Subject information will be summarized descriptively. No inferential test will be performed. 
3.1. 
Subject Disposition 
Subject randomization will be summarized by region, country, site and by stratification factors. 
Subject disposition for each study treatment and for study participation will be tabulated. The 
overall duration of receiving any study treatment and time on study will be summarized 
correspondingly.  
  
Time on study is defined in the same way as overall survival with reversed censoring, i.e., subjects 
who died will be censored at death date. The Kaplan-Meier method will be used to estimate the 
median time on study. 
3.2. 
Demographics and Baseline Characteristics 
Demographic information and baseline characteristics including but not limit to age, gender, race, 
histology type, time from initial diagnosis, staging, and potential prognostic factors will be 
summarized with descriptive statistics for ITT population by treatment arm and, in addition, by 
subgroups.  
3.3. 
Prior and Concomitant Medications 
Medications will be coded to preferred term and Anatomical Therapeutic Chemical (ATC) class 
according to World Health Organization (WHO) Drug dictionary. 
Prior medications are defined as medications that started prior to the first dose date of study drug. 
Concomitant medications are defined as medications that were taken at any time on treatment (i.e. 
from the date of the first dose of study drug through the date of the last dose of study drug).  
Concomitant medications will be summarized by therapeutic class and preferred term in the safety 
population. The following concomitant medications of special interest will be summarized 
separately: growth factors, blood supportive products and immunoglobulin, CYP3A 
inhibitors/inducers, anticoagulants and/or antiplatelet.   
3.4. 
Extent of Exposure to Study Treatment 
Exposure to ibrutinib, chlorambucil, obinutuzumab will be summarized separately for treatment 
duration and dosing information (e.g. total cumulative dose administered, relative dose intensity, 
ibrutinib or chlorambucil dose reduction due to adverse events). 
3.5. 
Subsequent Antineoplastic Therapies 
Subsequent CLL/SLL antineoplastic agents will be summarized by type of therapies.  


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4. ANALYSIS FOR ENDPOINTS 
Analysis of endpoints will be conducted on the ITT population, unless otherwise specified. Table 1 
summarizes the efficacy endpoints and analysis methods to be performed.  
The following two randomization stratification factors will be used for the stratified analysis/test: 
ECOG performance status (0, 1 versus 2) and Cytogenetics (del 17p, del 11q without del 17p, 
others). To reflect the randomization process and maintain the integrity of randomization, all 
stratified tests will be based on randomization stratification factors as recorded in the IWRS. 
For subgroup and exploratory analysis, only the analysis that provide meaningful information will 
be presented. 
 
 


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Table 1: Definitions and Analyses for Endpoints 
Endpoint 
Definition 
Analysis Method 
Primary Endpoint 
PFS assessed 
by IRC 
Time from the date of randomization to 
the date of IRC-assessed disease 
progression or date of death from any 
cause, whichever occurred first, 
regardless of the use of subsequent 
antineoplastic therapy prior to 
documented PD or death. 
 
Primary  
Treatment effect of ibrutinib plus obinutuzumab 
compared to chlorambucil plus obinutuzumab was 
tested with a log-rank test.  The hazard ratio and its 
95% CI based on a Cox regression model are 
calculated. PFS distribution is estimated by Kaplan-
Meier method: median PFS and landmark estimates 
with 2-sided 95% CIs are to be provided for each 
treatment arm.  
 
Sensitivity 
Analyzing PFS assessed by investigator using the 
same method as PFS assessed by IRC. 
 
Subgroup  
Hazard ratio and its 95% CI based on unstratified Cox 
regression model for each subgroup. 
Secondary Endpoints 
PFS assessed 
by IRC in high 
risk analysis 
set  
 
Defined the same as the primary 
endpoint. 
Analyzed the same as primary endpoint in high risk 
analysis set 
ORR assessed 
by IRC 
The proportion of subjects achieving a 
best overall response of CR, CRi, nPR, 
or PR per IRC assessment at or prior to 
initiation of subsequent antineoplastic 
therapy. 
Chi-square test. 
Overall 
survival (OS) 
Time from the date of randomization to 
the date of death from any cause. All 
deaths observed at the time of the 
analysis will be considered as events. 
For subjects who were not known to 
have died at the time of the analysis, 
OS data will be censored at date last 
known alive. 
Analyzed the same as PFS primary analysis. 
  
Rate of MRD-
negative 
response 
Proportion of subjects who achieved 
MRD-negative response defined as < 1 
CLL cell per 10,000 leukocytes as 
assessed by flow cytometry of a bone 
marrow aspirate or peripheral blood 
sample per central laboratory. 
Chi-square test for MRD-negative response rate by 
bone marrow 
  
• Rate of infusion related reactions will be analyzed using a Chi-square method. 
• Rate of sustained platelet improvement will be analyzed using a Chi-square method 
• Rate of clinically meaningful improvement in EQ-5D-5L utility score will be analyzed 
using a Chi-square method 
 


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5. SAFETY ASSESSMENTS 
Safety data will be summarized for the safety population. Table 2 summarizes the safety analyses 
to be performed. 
Adverse events will be coded in accordance with the MedDRA. Severity of AEs will be graded by 
the investigator according to the NCI-CTCAE v4.03 for non-hematological AEs and IWCLL 2008 
guidelines for hematologic toxicity.  
Treatment-emergent period is defined as the period from the date of the first dose of study treatment 
up to 30 days after the date of the last dose of study treatment or the day before initiation of 
subsequent antineoplastic therapy (including the cross-over ibrutinib monotherapy for arm B 
subjects), whichever comes first. 
The treatment-emergent adverse events (TEAE) are those events that occur or worsen during the 
treatment-emergent period or that are related to the study treatment. Unless otherwise specified, 
only TEAEs will be included in the adverse event summaries.   
All laboratory values will be converted to and reported as international standard (SI) units. In 
general, only data from the central laboratory will be summarized and analyzed. Hematologic 
parameters including platelet counts, hemoglobin, and neutrophils will be assessed by the grading 
scale for hematologic toxicity in CLL studies in the IWCLL 2008 guidelines. All other gradable 
laboratory parameters will be graded using the NCI CTCAE v4.03. Unless otherwise specified, only 
baseline and post-baseline values collected during the treatment-emergent period will be included in 
the safety analysis. 
 
 


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Table 2: Summary of Safety Assessments 
Assessment Type 
Definition   
Analysis Methods 
 
AE 
TEAEs, SAEs, Grade 3 or worse TEAEs, 
related TEAEs, TEAEs leading to treatment 
discontinuation, TEAEs leading to dose 
reduction, TEAEs leading to death, protocol- 
defined events of special interest and other 
safety observations. TEAEs within the first 9 
months of study treatment and TEAEs in the 
crossover period 
Descriptive summary 
statistics and/or listings 
Lab 
Worst post-baseline toxicity grade for 
selected CTCAE gradable hematology and 
chemistry.  Abnormalities in creatinine 
clearance, uric acid, and liver function  
Descriptive summary 
statistics and/or listings 
Vital Signs and other 
Observations Related to 
Safety 
Blood pressure, heart rate, new or worsened 
eye-related symptoms 
Descriptive summary 
statistics and/or listings 
TEAE= treatment-emergent adverse event; SAE= serious adverse event; CTCAE= Common Terminology Criteria for 
Adverse Events.  
 
 


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6. REFERENCES 
Bhattacharya S, Fyfe G, Robert J, and Daniel J. Sargent. Role of sensitivity analyses in assessing 
progression-free survival in late-stage oncology trials. J Clin Oncol. 2009;27: 5958-5964  
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in 
chronic lymphocytic leukemia. J Clin Oncol 2012; 23:2820-22.  
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic 
leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the 
National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111:5446-5456. 
Hallek M, Cheson BD, Catovsky D, et al.  Response assessment in chronic lymphocytic leukemia treated with 
novel agents causing an increase of peripheral blood lymphocytes. Blood 2012 (letter; published 4 June 
2012). http://bloodjournal.hematologylibrary.org/content/111/12/5446/reply#bloodjournal_el_6920. Accessed 
23 August 2012. 
Hallek M, Cheson BD, Catovsky D, et al. E-Letter regarding "Guidelines for the diagnosis and treatment 
of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic 
Leukemia updating the National Cancer Institute–Working Group 1996 guidelines": Clarification of 
iwCLL criteria for a partial response to therapy. Blood Nov 13 2013.  
Hallek M. “Presentation and discussion of revised iwCLL guidelines for the approach to a CLL 
patient. ” XVII International Workshop on Chronic Lymphocytic Leukemia; 2017 May 12–15; 
New York, USA. 
Stone AM, Bushnell W, Denne J, et al. Research outcomes and recommendations for the 
assessment of progression in cancer clinical trials form a PhRMA working group. European Journal 
of Cancer 2011; 47, 1763-1711 
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials, Biometrics 1979; 35:549-
556. 
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in health-
related quality-of-life scores. J Clin Oncol. 1998; 16:139-14