Open-label Phase 3 BTK Inhibitor Ibrutinib vs Chlorambucil Patients 65 Years or Older With Treatment-naive CLL or SLL

• Sponsor: Pharmacyclics LLC. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01722487
• Collaborator: Janssen Research & Development, LLC (Industry)
• Enrollment: 269
• Locations: 108
• Arms: 2
• Duration (Months): 26
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 versus Chlorambucil in Patients 65 Years or Older with Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma	Drug: Ibrutinib; Drug: Chlorambucil	Phase 3

Detailed Description

Study design: This is a randomized, multicenter, open-label, Phase 3 study designed to compare the safety and efficacy of Ibrutinib versus Chlorambucil in treatment-naive patients 65 years or older who have CLL or SLL.

Eligible patients will be randomized in a 1:1 ratio to Treatment Arm A or B:

• Treatment Arm A: Oral Chlorambucil 0.5 mg/kg on Days 1 and 15 of each 28-day cycle; the dose can be increased, if well tolerated, in increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg; patients receive a minimum of 3 and a maximum of 12 cycles, in the absence of progressive disease or unacceptable toxicity.

• Treatment Arm B: Oral Ibrutinib 420 mg/day Randomization will be stratified on Eastern Cooperative Oncology Group (ECOG) performance status (0,1 versus 2); presence of advanced Rai stage (yes/no), advanced being defined as Stages 3-4; and geographic region: US versus non-US.

Study Design

• Study Type: Interventional
• Actual Enrollment: 269 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib Versus Chlorambucil in Patients 65 Years or Older With Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
• Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ibrutinib Ibrutinib will be supplied as hard gelatin 140-mg capsules for oral (PO) administration. Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily. The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an outpatient basis. Ibrutinib will be dispensed to patients in bottles at each visit.	Drug: Ibrutinib; Ibrutinib will be supplied as hard gelatin 140-mg capsules for oral (PO) administration. Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily. The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an outpatient basis. Ibrutinib will be dispensed to patients in bottles at each visit.
Active Comparator: Chlorambucil Chlorambucil will be supplied as 2-mg tablets for PO administration. Chlorambucil is administered orally on Days 1 and 15 of each 28-day cycle.The starting dosage (Cycle 1) is 0.5 mg/kg. If well tolerated, the Chlorambucil dose can be increased starting at Cycle 2, with increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg.	Drug: Chlorambucil; Chlorambucil will be supplied as 2-mg tablets for PO administration. Chlorambucil is administered orally on Days 1 and 15 of each 28-day cycle. The starting dosage (Cycle 1) is 0.5 mg/kg. If well tolerated, the Chlorambucil dose can be increased starting at Cycle 2, with increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg.

Outcome Measures

Primary Outcome Measures

1. PFS (Progression Free Survival) [Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.]

   The primary objective of this study was to evaluate the efficacy of Ibrutinib compared with Chlorambucil based on the independent review committee (IRC) assessment of PFS Progressive disease according to 2008 IWCLL guidelines was defined as: Group A Lymphadenopathy, increase ≥50% Hepatomegaly, increase ≥50% Splenomegaly, increase ≥50% Blood lymphocytes, increase ≥ 50% over baseline Group B Platelets counts, decrease of ≥ 50% from baseline secondary to CLL Hemoglobin, decrease of > 2 g/dL from baseline secondary to CLL

Secondary Outcome Measures

1. Overall Survival (OS) [Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.]

   OS is calculated for all randomized subjects as the duration of time from the date of randomization to the date of death due to any cause or the date last known alive for subjects who were not known to have died at study closure.

2. ORR (Overall Response Rate) [Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.]

   ORR is defined as the proportion of subjects who achieved complete response (CR), complete response with incomplete marrow recovery (CRi), nodule partial response (nPR) or PR per IRC assessment. Response criteria are as outlined in the International Workshop on CLL (iwCLL) 2008 criteria with the 2012 iwCLL modification stating that treatment-related lymphocytosis in the setting of improvement in other parameters was not considered as PD and the 2013 iwCLL clarification of criteria for a partial response to therapy.

3. Proportion of Sustained Hemoglobin Improvement [Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.]

   The proportion of subjects who achieved Hemoglobin >11 g/dL or increase ≥ 2 g/dL over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.

4. Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia [Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.]

   In randomized subjects with baseline hemoglobin ≤ 11 g/dL, the proportion of subjects who achieved Hemoglobin >11 g/dL or increase ≥ 2 g/dL over baseline persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.

5. Proportion of Sustained Platelet Improvement [Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.]

   The proportion of subjects who achieved platelet >100 x 10^9/L or increase ≥50% over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.

6. Proportion of Sustained Platelet Improvement in Subjects With Baseline Thrombocytopenia [Analysis was conducted when 15 months had elapsed after the last subject was randomized with cutoff date of 4 May 2015. The median follow-up time is 18 month.]

   In randomized subjects with baseline platelet ≤ 100 x 10^9/L, the proportion of subjects who achieved platelet >100 x 10^9/L or increase ≥50% over baseline persisted continuously for ≥56 days (8 wee without blood transfusion or growth factors.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Males or females of 65 years of age or greater. Patients between the ages of 65 and 70 years of age must have 1 or more of the following comorbidities that may preclude the use of frontline chemo-immunotherapy with fludarabine, cyclophosphamide, or rituximab:

• creatinine clearance < 70 mL/min using the Cockcroft-Gault equation

• platelet count < 100,000/μL or hemoglobin < 10 g/dL

• clinically apparent autoimmune cytopenia (autoimmune hemolytic anemia or immune thrombocytopenia)

• ECOG performance score = 1 or 2

1. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria (Hallek 2008)

2. Active disease meeting at least 1 of the following IWCLL criteria (Hallek 2008) for requiring treatment:

• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia Massive, progressive, or symptomatic splenomegaly

• Massive nodes or progressive or symptomatic lymphadenopathy

• Progressive lymphocytosis

• Autoimmune hemolytic anemia and/or immune thrombocytopenia that is poorly responsive to corticosteroids or standard therapy

• Constitutional symptoms

1. Measurable nodal disease by computed tomography (CT)

2. ECOG performance status of 0-2

3. Life expectancy > 4 months from randomization

4. Adequate hematologic function, defined as absolute neutrophil count (ANC) ≥ 1,000/μL (independent of growth factor support for at least 7 days prior to screening) and platelet count ≥ 50,000/μL (independent of transfusion and growth factor support for at least 7 days prior to screening)

5. Adequate hepatic function, defined as serum aspartate transaminase (AST) and alanine transaminase (ALT) < 2.5 x upper limit of normal (ULN), and total bilirubin ≤ 1.5 x ULN

6. Adequate renal function, defined as estimated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation

7. Willingness to receive all outpatient treatment, all laboratory monitoring, and all radiological evaluations at the institution that administers study drug for the entire study

8. Willingness of male patients, if sexually active with a female of childbearing potential, to use an effective barrier method of contraception during the study and for 3 months following the last dose of study drug

9. Ability to provide written informed consent and to understand and comply with the requirements of the study

Exclusion Criteria:

1. Known involvement of the central nervous system by lymphoma or leukemia

2. History or current evidence of Richter's transformation or prolymphocytic leukemia

3. Documentation of deletion of the short arm of chromosome 17: del(17p13.1) in more than 20% of cells examined on any pretreatment fluorescence in situ hybridization (FISH) or cytogenetic evaluation

4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura

5. Any previous treatment (chemotherapy, radiotherapy, and/or monoclonal antibodies) intended specifically to treat CLL/SLL

6. Received any immunotherapy, vaccine, or investigational drug within 4 weeks prior to randomization

7. Corticosteroid use within 1 week prior to first dose of study drug, with the exception of inhaled, topical, or other local administrations. Patients requiring systemic steroids at daily doses > 20 mg prednisone (or corticosteroid equivalent, see Appendix N), or those who are administered steroids for leukemia control or white blood cell (WBC)-count-lowering are excluded.

8. Major surgery within 4 weeks prior to randomization

9. History of prior malignancy, with the exception of the following:

• malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician

• adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma without current evidence of disease

• adequately treated cervical carcinoma in situ without current evidence of disease

1. Currently active, clinically significant cardiovascular disease or a history of myocardial infarction within 6 months prior to randomization

2. Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function

3. Uncontrolled active systemic fungal, bacterial, viral, or other infection or requirement for intravenous (IV) antibiotics

4. Known history of infection with human immunodeficiency virus (HIV)

5. Serologic status reflecting active hepatitis B or C infection

6. History of stroke or intracranial hemorrhage within 6 months prior to enrollment

7. Current life-threatening illness, medical condition, or organ-system dysfunction that could compromise patient safety or put the study at risk

8. Requirement for anticoagulation with warfarin

9. Requirement for treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site Reference ID/Investigator #047	Duarte	California	United States	91010
2	Site Reference ID/Investigator #408	La Jolla	California	United States	92093
3	Site Reference ID/Investigator #720	Santa Rosa	California	United States	95403
4	Site Reference ID/Investigator #038	Stanford	California	United States	94305
5	Site Reference ID/Investigator #125	Atlanta	Georgia	United States	30318
6	Site Reference ID/Investigator #126	Chicago	Illinois	United States	60637
7	Site Reference ID/Investigator #071	Louisville	Kentucky	United States	40207
8	Site Reference ID/Investigator #307	Worcester	Massachusetts	United States	01655
9	Site Reference ID/Investigator #387	Ann Arbor	Michigan	United States	48109
10	Site Reference ID/Investigator #221	Saint Louis	Missouri	United States	63110
11	Site Reference ID/Investigator #712	Las Vegas	Nevada	United States	89169
12	Site Reference ID/Investigator #350	New Hyde Park	New York	United States	11042
13	Site Reference ID/Investigator #127	Rochester	New York	United States	14642
14	Site Reference ID/Investigator #656	Goldsboro	North Carolina	United States	27534
15	Site Reference ID/Investigator #734	Columbus	Ohio	United States	43219
16	Site Reference ID/Investigator #677	Portland	Oregon	United States	97227
17	Site Reference ID/Investigator #050	Pittsburgh	Pennsylvania	United States	15232
18	Site Reference ID/Investigator #032	Houston	Texas	United States	77030
19	Site Reference ID/Investigator #381	Laredo	Texas	United States	78041
20	Site Reference ID/Investigator #653	San Antonio	Texas	United States	78229
21	Site Reference ID/Investigator #404	Seattle	Washington	United States	98109
22	Site Reference ID/Investigator #731	Walla Walla	Washington	United States	99362
23	Site Reference ID/Investigator #654	Kogarah	New South Wales	Australia	2217
24	Site Reference ID/Investigator #503	Woolloongabba	Queensland	Australia	4102
25	Site Reference ID/Investigator #163	Bedford Park	South Australia	Australia	5042
26	Site Reference ID/Investigator #555	Hobart	Tasmania	Australia	7000
27	Site Reference ID/Investigator #193	Box Hill	Victoria	Australia	3128
28	Site Reference ID/Investigator #556	Clayton	Victoria	Australia	3168
29	Site Reference ID/Investigator #501	Fitzroy	Victoria	Australia	3065
30	Site Reference ID/Investigator #715	Frankston	Victoria	Australia	3199
31	Site Reference ID/Investigator #558	Geelong	Victoria	Australia	3220
32	Site Reference ID/Investigator #170	Heidelberg	Victoria	Australia	3084
33	Site Reference ID/Investigator #164	Bruxelles	Brussells	Belgium	1200
34	Site Reference ID/Investigator #727	Yvoir	Namur	Belgium	5530
35	Site Reference ID/Investigator #560	Gent	Oost-Vlaanderen	Belgium	9000
36	Site Reference ID/Investigator #559	Leuven	Vlaams Brabant	Belgium	3000
37	Site Reference ID/Investigator #628	Brugge	West-Vlaanderen	Belgium	8000
38	Site Reference ID/Investigator #561	Antwerpen		Belgium	2060
39	Site Reference ID/Investigator #184	Brussells		Belgium	1000
40	Site Reference ID/Investigator #157	Calgary	Alberta	Canada	T2N 4N2
41	Site Reference ID/Investigator #018	Edmonton	Alberta	Canada	T6G 1Z2
42	Site Reference ID/Investigator #159	Ottawa	Ontario	Canada	K1H 8L6
43	Site Reference ID/Investigator #674	Guangzhou	Guangdong	China	510060
44	Site Reference ID/Investigator #671	Nanjing	Jiangsu	China	210029
45	Site Reference ID/Investigator #675	Hangzhou	Zhejiang	China	31003
46	Site Reference ID/Investigator #670	Beijing		China	100142
47	Site Reference ID/Investigator #673	Beijing		China	100191
48	Site Reference ID/Investigator #564	Hradec Kralove	Kralovehradecky Kraj	Czechia	500 05
49	Site Reference ID/Investigator #562	Brno		Czechia	625 00
50	Site Reference ID/Investigator #566	Plzen-Lochotin		Czechia	304 60
51	Site Reference ID/Investigator #572	Dublin		Ireland	7
52	Site Reference ID/Investigator #570	Dublin		Ireland	8
53	Site Reference ID/Investigator #571	Galway		Ireland	ST4 6QG
54	Site Reference ID/Investigator #573	Haifa		Israel	31048
55	Site Reference ID/Investigator #576	Haifa		Israel	31096
56	Site Reference ID/Investigator #577	Jerusalem		Israel	91031
57	Site Reference ID/Investigator #578	Nahariya		Israel	22100
58	Site Reference ID/Investigator #575	Petaẖ Tiqwa		Israel	49100
59	Site Reference ID/Investigator #574	Ramat Gan		Israel	52621
60	Site Reference ID/Investigator #583	Roma	Lazio	Italy	00161
61	Site Reference ID/Investigator #522	Rozzano	Milano	Italy	20089
62	Site Reference ID/Investigator #582	Novara	Piemonte	Italy	28100
63	Site Reference ID/Investigator #527	Padova	Veneto	Italy	35128
64	Site Reference ID/Investigator #580	Bologna		Italy	40138
65	Site Reference ID/Investigator #584	Milano		Italy	20122
66	Site Reference ID/Investigator #523	Milano		Italy	20132
67	Site Reference ID/Investigator #581	Milano		Italy	20162
68	Site Reference ID/Investigator #524	Modena		Italy	41100
69	Site Reference ID/Investigator #589	Christchurch	Canterbury	New Zealand	8011
70	Site Reference ID/Investigator #586	Hamilton	Waikato	New Zealand	3240
71	Site Reference ID/Investigator #663	Auckland		New Zealand	0622
72	Site Reference ID/Investigator #588	Auckland		New Zealand	1023
73	Site Reference ID/Investigator #587	Wellington		New Zealand	6021
74	Site Reference ID/Investigator #590	Lublin	Lubelskie	Poland	20-081
75	Site Reference ID/Investigator #592	Brzozowie	Podkarpackie	Poland	36.200
76	Site Reference ID/Investigator #591	Chorzow		Poland	40
77	Site Reference ID/Investigator #529	Gdansk		Poland	80-952
78	Site Reference ID/Investigator #531	Lodz		Poland	93-510
79	Site Reference ID/Investigator #707	Ryazan		Russian Federation	390039
80	Site Reference ID/Investigator #304	Yaroslavl		Russian Federation	150062
81	Site Reference ID/Investigator #536	Majadahonda	Madrid	Spain	28222
82	Site Reference ID/Investigator #534	Barcelona		Spain	08035
83	Site Reference ID/Investigator #533	Barcelona		Spain	08036
84	Site Reference ID/Investigator #535	Barcelona		Spain	08041
85	Site Reference ID/Investigator #604	Barcelona		Spain	08908
86	Site Reference ID/Investigator #537	Madrid		Spain	28050
87	Site Reference ID/Investigator #608	Ankara		Turkey	06500
88	Site Reference ID/Investigator #606	Ankara		Turkey	06590
89	Site Reference ID/Investigator #599	Istanbul		Turkey	34390
90	Site Reference ID/Investigator #714	Izmir		Turkey	35040
91	Site Reference ID/Investigator #601	Izmir		Turkey	35340
92	Site Reference ID/Investigator #602	Kayseri		Turkey	38039
93	Site Reference ID/Investigator #597	Cherkasy	Cherkas'ka Oblast	Ukraine	18009
94	Site Reference ID/Investigator #594	Dnipropetrovsk	Dnipropetrovs'ka Oblast'	Ukraine	49102
95	Site Reference ID/Investigator #725	Kharkiv	Kharkivs'ka Oblast	Ukraine	61070
96	Site Reference ID/Investigator #596	Lviv	L'vivs'ka Oblast	Ukraine	79044
97	Site Reference ID/Investigator #598	Simferopol	Respublika Krym	Ukraine	95023
98	Site Reference ID/Investigator #595	Vinnytsia	Vinnyts'ka Oblast	Ukraine	21018
99	Site Reference ID/Investigator #724	Zhytomyr	Zhytomyrs'ka Oblast'	Ukraine	10022
100	Site Reference ID/Investigator #551	Bournemouth	Dorset	United Kingdom	BH7 7DW
101	Site Reference ID/Investigator #544	London	England	United Kingdom	SE5 9RS
102	Site Reference ID/Investigator #668	Oxford	England	United Kingdom	OX3 7LE
103	Site Reference ID/Investigator #549	Colchester	Essex	United Kingdom	CO4 5JL
104	Site Reference ID/Investigator #607	Cardiff	South Glamergon	United Kingdom	CF14 4XW
105	Site Reference ID/Investigator #550	Leeds	Yorkshire	United Kingdom	LS9 7TF
106	Site Reference ID/Investigator #721	Birmingham		United Kingdom	B9 5SS
107	Site Reference ID/Investigator #548	Nottingham		United Kingdom	NG5 1PB
108	Site Reference ID/Investigator #367	Southampton		United Kingdom	SO16 6YD

Sponsors and Collaborators

• Pharmacyclics LLC.
• Janssen Research & Development, LLC

Investigators

• Study Director: Lori Styles, MD, Pharmacyclics LLC.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• www.pharmacyclics.com

Publications

None provided.

• Responsible Party: Pharmacyclics LLC.
• ClinicalTrials.gov Identifier: NCT01722487
• Other Study ID Numbers: PCYC-1115-CA; 2012-003967-23
• First Posted: Nov 6, 2012
• Last Update Posted: Nov 30, 2017
• Last Verified: Oct 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Pharmacyclics LLC.: CLL, SLL
• Additional relevant MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Chlorambucil

Study Results

Participant Flow

Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
Period Title: Overall Study
STARTED	136	133
COMPLETED	134	126
NOT COMPLETED	2	7

Baseline Characteristics

Arm/Group Title	Ibrutinib	Chlorambucil	Total
Arm/Group Description	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles	Total of all reporting groups
Overall Participants	136	133	269
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	136 100%	133 100%	269 100%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	73.1 (5.67)	73.4 (5.95)	73.3 (5.81)
Sex: Female, Male (Count of Participants)
Female	48 35.3%	52 39.1%	100 37.2%
Male	88 64.7%	81 60.9%	169 62.8%

Outcome Measures

1. Primary Outcome

Title	PFS (Progression Free Survival)
Description	The primary objective of this study was to evaluate the efficacy of Ibrutinib compared with Chlorambucil based on the independent review committee (IRC) assessment of PFS Progressive disease according to 2008 IWCLL guidelines was defined as: Group A Lymphadenopathy, increase ≥50% Hepatomegaly, increase ≥50% Splenomegaly, increase ≥50% Blood lymphocytes, increase ≥ 50% over baseline Group B Platelets counts, decrease of ≥ 50% from baseline secondary to CLL Hemoglobin, decrease of > 2 g/dL from baseline secondary to CLL
Time Frame	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.

Outcome Measure Data

Analysis Population Description

Intention to treat

Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles.
Measure Participants	136	133
Median (95% Confidence Interval) [Months]	NA	18.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; 0.09 to 0.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is calculated for all randomized subjects as the duration of time from the date of randomization to the date of death due to any cause or the date last known alive for subjects who were not known to have died at study closure.
Time Frame	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.

Outcome Measure Data

Analysis Population Description

Intention to treat

Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
Measure Participants	136	133
Median (95% Confidence Interval) [Months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; 0.05 to 0.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	ORR (Overall Response Rate)
Description	ORR is defined as the proportion of subjects who achieved complete response (CR), complete response with incomplete marrow recovery (CRi), nodule partial response (nPR) or PR per IRC assessment. Response criteria are as outlined in the International Workshop on CLL (iwCLL) 2008 criteria with the 2012 iwCLL modification stating that treatment-related lymphocytosis in the setting of improvement in other parameters was not considered as PD and the 2013 iwCLL clarification of criteria for a partial response to therapy.
Time Frame	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.

Outcome Measure Data

Analysis Population Description

Intention to treat

Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
Measure Participants	136	133
Number [percentage of participants]	82.4 60.6%	35.3 26.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

4. Secondary Outcome

Title	Proportion of Sustained Hemoglobin Improvement
Description	The proportion of subjects who achieved Hemoglobin >11 g/dL or increase ≥ 2 g/dL over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.
Time Frame	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.

Outcome Measure Data

Analysis Population Description

Intention to treat

Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
Measure Participants	136	133
Number [Percentage of Participants]	45.6 33.5%	20.3 15.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Chi-squared
	Comments

5. Secondary Outcome

Title	Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia
Description	In randomized subjects with baseline hemoglobin ≤ 11 g/dL, the proportion of subjects who achieved Hemoglobin >11 g/dL or increase ≥ 2 g/dL over baseline persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.
Time Frame	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.

Outcome Measure Data

Analysis Population Description

Subjects with Baseline Anemia

Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
Measure Participants	51	55
Number [Percentage of Participants]	84.3 62%	45.5 34.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Chi-squared
	Comments

6. Secondary Outcome

Title	Proportion of Sustained Platelet Improvement
Description	The proportion of subjects who achieved platelet >100 x 10^9/L or increase ≥50% over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.
Time Frame	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.

Outcome Measure Data

Analysis Population Description

Intention to treat

Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
Measure Participants	136	133
Number [Percentage of Participants]	27.2 20%	11.3 8.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0009
	Comments
	Method	Chi-squared
	Comments

7. Secondary Outcome

Title	Proportion of Sustained Platelet Improvement in Subjects With Baseline Thrombocytopenia
Description	In randomized subjects with baseline platelet ≤ 100 x 10^9/L, the proportion of subjects who achieved platelet >100 x 10^9/L or increase ≥50% over baseline persisted continuously for ≥56 days (8 wee without blood transfusion or growth factors.
Time Frame	Analysis was conducted when 15 months had elapsed after the last subject was randomized with cutoff date of 4 May 2015. The median follow-up time is 18 month.

Outcome Measure Data

Analysis Population Description

Subjects With Baseline Thrombocytopenia

Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
Measure Participants	35	28
Number [Percentage of Participants]	77.1 56.7%	42.9 32.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0054
	Comments
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	From first dose of study drug to within 30 days of last dose or starting new anti-cancer therapy, whichever occurs earlier, up to 04May2015 ( data cutoff date for final analysis).
Adverse Event Reporting Description	269 subjects were randomized on the study of which 2 subjects withdrew without treatment and were not included in the number of participants at risk. Investigators assess the occurrence of AEs and SAEs at all patient evaluation time points during the study.
Arm/Group Title	PCI-32765		Chlorambucil
Arm/Group Description	Ibrutinib 420 mg daily.		Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
All Cause Mortality
	PCI-32765		Chlorambucil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	PCI-32765		Chlorambucil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	55/135 (40.7%)		33/132 (25%)
Blood and lymphatic system disorders
Anaemia	2/135 (1.5%)		2/132 (1.5%)
Febrile neutropenia	2/135 (1.5%)		2/132 (1.5%)
Neutropenia	1/135 (0.7%)		2/132 (1.5%)
Autoimmune haemolytic anaemia	0/135 (0%)		1/132 (0.8%)
Haemolytic anaemia	0/135 (0%)		1/132 (0.8%)
Lymphadenopathy	0/135 (0%)		1/132 (0.8%)
Cardiac disorders
Atrial fibrillation	2/135 (1.5%)		1/132 (0.8%)
Atrial flutter	2/135 (1.5%)		0/132 (0%)
Aortic valve disease	1/135 (0.7%)		0/132 (0%)
Cardiac failure	1/135 (0.7%)		0/132 (0%)
Cardiac failure congestive	1/135 (0.7%)		1/132 (0.8%)
Coronary artery disease	1/135 (0.7%)		0/132 (0%)
Acute myocardial infarction	0/135 (0%)		1/132 (0.8%)
Aortic valve disease mixed	0/135 (0%)		1/132 (0.8%)
Myocardial ischaemia	0/135 (0%)		1/132 (0.8%)
Eye disorders
Blindness unilateral	2/135 (1.5%)		0/132 (0%)
Hyphaema	1/135 (0.7%)		0/132 (0%)
Retinal vascular occlusion	1/135 (0.7%)		0/132 (0%)
Retinal vein occlusion	1/135 (0.7%)		0/132 (0%)
Vitreous haemorrhage	1/135 (0.7%)		0/132 (0%)
Gastrointestinal disorders
Abdominal pain upper	1/135 (0.7%)		0/132 (0%)
Constipation	1/135 (0.7%)		0/132 (0%)
Pancreatitis acute	1/135 (0.7%)		0/132 (0%)
Gastrointestinal haemorrhage	0/135 (0%)		1/132 (0.8%)
General disorders
Death	2/135 (1.5%)		0/132 (0%)
Oedema peripheral	1/135 (0.7%)		1/132 (0.8%)
Pyrexia	1/135 (0.7%)		5/132 (3.8%)
Chills	0/135 (0%)		1/132 (0.8%)
Pain	0/135 (0%)		1/132 (0.8%)
Hepatobiliary disorders
Bile duct stone	1/135 (0.7%)		0/132 (0%)
Cholangitis	1/135 (0.7%)		0/132 (0%)
Cholecystitis	0/135 (0%)		1/132 (0.8%)
Hepatitis toxic	0/135 (0%)		1/132 (0.8%)
Immune system disorders
Immunodeficiency	1/135 (0.7%)		0/132 (0%)
Infections and infestations
Pneumonia	5/135 (3.7%)		2/132 (1.5%)
Bronchopneumonia	2/135 (1.5%)		0/132 (0%)
Escherichia sepsis	2/135 (1.5%)		0/132 (0%)
Lower respiratory tract infection	2/135 (1.5%)		1/132 (0.8%)
Urinary tract infection	2/135 (1.5%)		0/132 (0%)
Abscess limb	1/135 (0.7%)		0/132 (0%)
Anal abscess	1/135 (0.7%)		0/132 (0%)
Arthritis bacterial	1/135 (0.7%)		0/132 (0%)
Cellulitis	1/135 (0.7%)		0/132 (0%)
Clostridium difficile infection	1/135 (0.7%)		0/132 (0%)
Escherichia bacteraemia	1/135 (0.7%)		0/132 (0%)
Escherichia infection	1/135 (0.7%)		0/132 (0%)
Gastroenteritis	1/135 (0.7%)		1/132 (0.8%)
Gastroenteritis viral	1/135 (0.7%)		0/132 (0%)
Klebsiella infection	1/135 (0.7%)		0/132 (0%)
Lobar pneumonia	1/135 (0.7%)		0/132 (0%)
Lung infection pseudomonal	1/135 (0.7%)		0/132 (0%)
Neutropenic sepsis	1/135 (0.7%)		1/132 (0.8%)
Pneumonia bacterial	1/135 (0.7%)		1/132 (0.8%)
Pneumonia legionella	1/135 (0.7%)		0/132 (0%)
Pneumonia viral	1/135 (0.7%)		0/132 (0%)
Subcutaneous abscess	1/135 (0.7%)		0/132 (0%)
Upper respiratory tract infection	1/135 (0.7%)		0/132 (0%)
Viral infection	1/135 (0.7%)		0/132 (0%)
Acute hepatitis B	0/135 (0%)		1/132 (0.8%)
Pneumonia fungal	0/135 (0%)		1/132 (0.8%)
Injury, poisoning and procedural complications
Fall	1/135 (0.7%)		0/132 (0%)
Laceration	1/135 (0.7%)		0/132 (0%)
Limb traumatic amputation	1/135 (0.7%)		0/132 (0%)
Lumbar vertebral fracture	1/135 (0.7%)		0/132 (0%)
Muscle strain	1/135 (0.7%)		0/132 (0%)
Post procedural haemorrhage	1/135 (0.7%)		0/132 (0%)
Postoperative wound complication	1/135 (0.7%)		0/132 (0%)
Radius fracture	1/135 (0.7%)		0/132 (0%)
Subdural haematoma	1/135 (0.7%)		0/132 (0%)
Toxicity to various agents	1/135 (0.7%)		0/132 (0%)
Traumatic haematoma	1/135 (0.7%)		0/132 (0%)
Ulna fracture	1/135 (0.7%)		0/132 (0%)
Femur fracture	0/135 (0%)		1/132 (0.8%)
Overdose	0/135 (0%)		1/132 (0.8%)
Upper limb fracture	0/135 (0%)		1/132 (0.8%)
Investigations
Heart rate irregular	1/135 (0.7%)		0/132 (0%)
Fibrin D dimer increased	0/135 (0%)		1/132 (0.8%)
Hepatic enzyme increased	0/135 (0%)		1/132 (0.8%)
Metabolism and nutrition disorders
Hyponatraemia	3/135 (2.2%)		0/132 (0%)
Dehydration	1/135 (0.7%)		1/132 (0.8%)
Musculoskeletal and connective tissue disorders
Back pain	1/135 (0.7%)		0/132 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	5/135 (3.7%)		0/132 (0%)
Prostate cancer	2/135 (1.5%)		0/132 (0%)
Squamous cell carcinoma	2/135 (1.5%)		1/132 (0.8%)
Adenocarcinoma	1/135 (0.7%)		0/132 (0%)
Basosquamous carcinoma of skin	1/135 (0.7%)		0/132 (0%)
Colon adenoma	1/135 (0.7%)		0/132 (0%)
Lung adenocarcinoma	1/135 (0.7%)		0/132 (0%)
Non-small cell lung cancer	1/135 (0.7%)		0/132 (0%)
Squamous cell carcinoma of skin	1/135 (0.7%)		0/132 (0%)
Chronic lymphocytic leukaemia	0/135 (0%)		1/132 (0.8%)
Nervous system disorders
Cauda equina syndrome	1/135 (0.7%)		0/132 (0%)
Cerebral haemorrhage	1/135 (0.7%)		0/132 (0%)
Headache	1/135 (0.7%)		0/132 (0%)
Subarachnoid haemorrhage	1/135 (0.7%)		0/132 (0%)
Transient ischaemic attack	1/135 (0.7%)		1/132 (0.8%)
Cognitive disorder	0/135 (0%)		1/132 (0.8%)
Epilepsy	0/135 (0%)		1/132 (0.8%)
Ischaemic stroke	0/135 (0%)		1/132 (0.8%)
Post herpetic neuralgia	0/135 (0%)		1/132 (0.8%)
Presyncope	0/135 (0%)		1/132 (0.8%)
Syncope	0/135 (0%)		2/132 (1.5%)
Psychiatric disorders
Confusional state	1/135 (0.7%)		0/132 (0%)
Somatoform disorder cardiovascular	0/135 (0%)		1/132 (0.8%)
Renal and urinary disorders
Calculus ureteric	1/135 (0.7%)		0/132 (0%)
Hydronephrosis	1/135 (0.7%)		0/132 (0%)
Renal failure	1/135 (0.7%)		0/132 (0%)
Renal failure acute	1/135 (0.7%)		0/132 (0%)
Renal failure chronic	1/135 (0.7%)		0/132 (0%)
Renal impairment	1/135 (0.7%)		0/132 (0%)
Renal haemorrhage	0/135 (0%)		1/132 (0.8%)
Urinary retention	0/135 (0%)		1/132 (0.8%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/135 (0%)		1/132 (0.8%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	2/135 (1.5%)		2/132 (1.5%)
Acute respiratory failure	1/135 (0.7%)		0/132 (0%)
Cough	1/135 (0.7%)		0/132 (0%)
Hypercapnia	1/135 (0.7%)		0/132 (0%)
Hypoxia	1/135 (0.7%)		0/132 (0%)
Pneumomediastinum	1/135 (0.7%)		0/132 (0%)
Wheezing	1/135 (0.7%)		0/132 (0%)
Lung infiltration	0/135 (0%)		1/132 (0.8%)
Skin and subcutaneous tissue disorders
Dermatitis allergic	1/135 (0.7%)		0/132 (0%)
Rash macular	1/135 (0.7%)		0/132 (0%)
Rash maculo-papular	1/135 (0.7%)		0/132 (0%)
Subcutaneous emphysema	1/135 (0.7%)		0/132 (0%)
Vascular disorders
Hypertension	2/135 (1.5%)		0/132 (0%)
Aortic stenosis	0/135 (0%)		1/132 (0.8%)
Peripheral artery aneurysm	0/135 (0%)		1/132 (0.8%)
Other (Not Including Serious) Adverse Events
	PCI-32765		Chlorambucil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	133/135 (98.5%)		123/132 (93.2%)
Blood and lymphatic system disorders
Anaemia	24/135 (17.8%)		27/132 (20.5%)
Neutropenia	20/135 (14.8%)		29/132 (22%)
Thrombocytopenia	11/135 (8.1%)		17/132 (12.9%)
Increased tendency to bruise	8/135 (5.9%)		4/132 (3%)
Cardiac disorders
Atrial fibrillation	7/135 (5.2%)		0/132 (0%)
Eye disorders
Dry eye	23/135 (17%)		6/132 (4.5%)
Lacrimation increased	18/135 (13.3%)		8/132 (6.1%)
Vision blurred	18/135 (13.3%)		10/132 (7.6%)
Visual acuity reduced	15/135 (11.1%)		3/132 (2.3%)
Eye pain	8/135 (5.9%)		2/132 (1.5%)
Vitreous floaters	8/135 (5.9%)		6/132 (4.5%)
Cataract	7/135 (5.2%)		2/132 (1.5%)
Gastrointestinal disorders
Diarrhoea	57/135 (42.2%)		22/132 (16.7%)
Nausea	30/135 (22.2%)		52/132 (39.4%)
Constipation	20/135 (14.8%)		21/132 (15.9%)
Vomiting	18/135 (13.3%)		27/132 (20.5%)
Abdominal pain	17/135 (12.6%)		14/132 (10.6%)
Dyspepsia	15/135 (11.1%)		3/132 (2.3%)
Stomatitis	11/135 (8.1%)		5/132 (3.8%)
Gastrooesophageal reflux disease	9/135 (6.7%)		1/132 (0.8%)
General disorders
Fatigue	41/135 (30.4%)		50/132 (37.9%)
Oedema peripheral	25/135 (18.5%)		12/132 (9.1%)
Pyrexia	22/135 (16.3%)		17/132 (12.9%)
Asthenia	10/135 (7.4%)		5/132 (3.8%)
Infections and infestations
Upper respiratory tract infection	22/135 (16.3%)		23/132 (17.4%)
Urinary tract infection	13/135 (9.6%)		10/132 (7.6%)
Conjunctivitis	11/135 (8.1%)		3/132 (2.3%)
Nasopharyngitis	10/135 (7.4%)		6/132 (4.5%)
Cellulitis	8/135 (5.9%)		1/132 (0.8%)
Sinusitis	7/135 (5.2%)		1/132 (0.8%)
Skin infection	7/135 (5.2%)		3/132 (2.3%)
Herpes zoster	0/135 (0%)		7/132 (5.3%)
Injury, poisoning and procedural complications
Contusion	11/135 (8.1%)		2/132 (1.5%)
Investigations
Weight decreased	14/135 (10.4%)		16/132 (12.1%)
Platelet count decreased	7/135 (5.2%)		6/132 (4.5%)
Metabolism and nutrition disorders
Decreased appetite	13/135 (9.6%)		19/132 (14.4%)
Hyperuricaemia	8/135 (5.9%)		1/132 (0.8%)
Hypokalaemia	8/135 (5.9%)		2/132 (1.5%)
Hyponatraemia	7/135 (5.2%)		1/132 (0.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	22/135 (16.3%)		9/132 (6.8%)
Back pain	16/135 (11.9%)		9/132 (6.8%)
Muscle spasms	15/135 (11.1%)		7/132 (5.3%)
Pain in extremity	13/135 (9.6%)		7/132 (5.3%)
Musculoskeletal pain	11/135 (8.1%)		3/132 (2.3%)
Myalgia	8/135 (5.9%)		4/132 (3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	7/135 (5.2%)		2/132 (1.5%)
Nervous system disorders
Headache	16/135 (11.9%)		13/132 (9.8%)
Dizziness	15/135 (11.1%)		16/132 (12.1%)
Psychiatric disorders
Insomnia	11/135 (8.1%)		9/132 (6.8%)
Anxiety	7/135 (5.2%)		2/132 (1.5%)
Renal and urinary disorders
Haematuria	8/135 (5.9%)		3/132 (2.3%)
Respiratory, thoracic and mediastinal disorders
Cough	30/135 (22.2%)		20/132 (15.2%)
Dyspnoea	14/135 (10.4%)		13/132 (9.8%)
Pleural effusion	9/135 (6.7%)		1/132 (0.8%)
Epistaxis	8/135 (5.9%)		5/132 (3.8%)
Oropharyngeal pain	8/135 (5.9%)		5/132 (3.8%)
Skin and subcutaneous tissue disorders
Rash erythematous	13/135 (9.6%)		5/132 (3.8%)
Night sweats	9/135 (6.7%)		10/132 (7.6%)
Pruritus	8/135 (5.9%)		7/132 (5.3%)
Rash maculo-papular	8/135 (5.9%)		5/132 (3.8%)
Dry skin	7/135 (5.2%)		3/132 (2.3%)
Vascular disorders
Hypertension	18/135 (13.3%)		0/132 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.