A Multi-Center Study of Ibrutinib in Combination With Obinutuzumab Versus Chlorambucil in Combination With Obinutuzumab in Patients With Treatment naïve Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 3 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: IBR + OB 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. |
Drug: Ibrutinib
Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) administration.
Drug: Obinutuzumab
Obinutuzumab will be supplied as 1000 mg/40 mL solution in a single-use vial for intravenous (IV) administration
|
Experimental: CLB + OB 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. |
Drug: Obinutuzumab
Obinutuzumab will be supplied as 1000 mg/40 mL solution in a single-use vial for intravenous (IV) administration
Drug: Chlorambucil
Chlorambucil will be supplied as 2 mg film-coated tablets for oral (PO) administration
|
Outcome Measures
Primary Outcome Measures
- Primary Analysis: Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 30 [Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).]
PFS was defined as time from the date randomization to the date of first IRC-confirmed disease progression (PD) or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. The primary analysis was performed after observing 94 PFS events as pre-specified in the study protocol. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 30 months (that is, the estimated percentage of participants with progression-free survival at Month 30) are presented.
- Final Analysis: PFS Based on Investigator Assessment - Kaplan Meier Landmark Estimates at Month 48 [Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).]
PFS was defined as time from the date randomization to the date of first investigator-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 48 months (that is, the estimated percentage of participants with progression-free survival at Month 48) are presented.
Secondary Outcome Measures
- Primary Analysis: PFS in High-Risk Sub-Population (del17p/TP53 Mutation/Del 11q) Based on IRC Assessment - Kaplan Meier Landmark Estimates at Month 30 [Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).]
PFS was analyzed within the high-risk sub-population of participants with del17p or TP53 mutation or del 11q at baseline per central lab results. PFS was defined as time from the date randomization to the date of first IRC-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the IWCLL 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of PD was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 30 months (that is, the estimated percentage of participants with progression-free survival at Month 30) are presented.
- Primary Analysis: Rate of Sustained Hemoglobin Improvement [Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).]
Percentage of participants with sustained hemoglobin improvement, defined as hemoglobin increase ≥ 2 g/dL over baseline continuously for ≥ 56 days without blood transfusions or growth factors.
- Primary Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response [Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).]
Percentage of participants who achieved MRD-negative response, defined as < 1 CLL cell per 10,000 leukocytes as assessed by flow cytometry of a bone marrow aspirate per central laboratory. MRD samples were collected before initiation of subsequent antineoplastic treatment and MRD status was reported by central lab within 5 days after collection date. Participants with missing MRD data were considered non-responders.
- Primary Analysis: Overall Response Rate (ORR) Based on IRC Assessment [Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).]
ORR, defined as the percentage of participants achieving a best overall response of protocol-specified complete response (CR), CR with incomplete blood count recovery (CRi), nodular partial response (nPR), or partial response (PR) per IRC assessment at or prior to initiation of subsequent antineoplastic therapy. Assessment of response included physical examination, radiographic imaging, and evaluation of blood and marrow (if applicable), evaluated in accordance with the IWCLL 2008 criteria (Halleck et al). CR, CRi, nPR, and PR required confirmation with 2 consecutive assessments that were at least 56 days apart and no use of blood supportive product and/or growth factor during this period. Kaplan-Meier estimate.
- Primary Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 30 [Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).]
OS, defined as the time from the date of randomization to the date of death from any cause. All deaths observed as the time of the analysis were considered as events. For participants who were not known to have died at the time of the analysis, OS data were censored at the date last known alive. As the median OS was not reached in either treatment arm at the time of the analysis, Kaplan Meier landmark estimates of the OS rate (that is, the estimated percentage of participants still surviving at Month 30 [primary analysis]) are presented.
- Primary Analysis: Rate of Grade ≥ 3 or Serious Infusion-Related Reaction (IRR) Adverse Events [Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).]
Percentage of participants experiencing grade ≥ 3 (severe or life threatening) or serious IRR adverse events that started on the day of an obinutuzumab infusion and were assessed as related or possibly related to obinutuzumab. Categories included those events with the Medical Dictionary for Regulatory Activities (MedDRA) dictionary preferred term of IRR and those events which are among the customized standardized MedDRA query (SMQ) for IRR.
- Primary Analysis: Rate of Sustained Platelet Improvement [Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).]
Percentage of participants with platelet counts increase ≥ 50% over baseline continuously for ≥ 56 days without blood transfusion or growth factors.
- Primary Analysis: Rate of Clinically Meaningful Improvement in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EuroQol Five-Dimension (EQ-5D-5L) [Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).]
Percentage of participants with EQ-5D-5L utility score increase ≥ 0.08 points over baseline at or prior to initiation of subsequent antineoplastic therapy. The EQ-5D-5L is a standardized non-disease specific instrument for describing and valuing health-related quality of life, comprising 5 dimensions of health (mobility, self -care, usual activities, pain/discomfort, and anxiety/depression) to describe the participant's current health state. Each dimension comprises 5 levels with corresponding numeric scores, where 1 indicates no problems, and 5 indicates extreme problems. A unique EQ-5D-5L health state is defined by combining the numeric level scores for each of the 5 dimensions and the total score is normalized from -0.594 to 1.000, with higher scores representing a better health state. An increase in the EQ-5D-5L total score indicates improvement. Participants with missing EQ-5D-5L data were considered not achieving clinically meaningful improvement.
- Final Analysis: PFS in High-Risk Population (del17p/TP53 Mutation/Del 11q/Unmutated Immunoglobulin Heavy Chain Variable Region [IGHV]) Based on Investigator Assessment - Kaplan Meier Landmark Estimates at Month 48 [Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).]
PFS was analyzed within the high-risk population of participants with del17p or TP53 mutation or del 11q or IGHV unmutated at baseline per central lab results. PFS was defined as time from the date randomization to the date of first investigator-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the IWCLL 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of PD was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 48 months (that is, the estimated percentage of participants with progression-free survival at Month 48) are presented.
- Final Analysis: Rate of Sustained Hemoglobin Improvement [Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).]
Percentage of participants with sustained hemoglobin improvement, defined as hemoglobin increase ≥ 2 g/dL over baseline continuously for ≥ 56 days without blood transfusions or growth factors.
- Final Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response [Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).]
Percentage of participants who achieved MRD-negative response, defined as < 1 CLL cell per 10,000 leukocytes as assessed by flow cytometry of a bone marrow aspirate per central laboratory. MRD samples were collected before initiation of subsequent antineoplastic treatment and MRD status was reported by central lab within 5 days after collection date. Participants with missing MRD data were considered non-responders.
- Final Analysis: ORR Based on Investigator Assessment [Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).]
ORR, defined as the percentage of participants achieving a best overall response of protocol-specified CR, CRi, nPR or PR per investigator assessment at or prior to initiation of subsequent antineoplastic therapy. Assessment of response included physical examination, radiographic imaging, and evaluation of blood and marrow (if applicable), evaluated in accordance with the IWCLL 2008 criteria (Halleck et al). CR, CRi, nPR, and PR required confirmation with 2 consecutive assessments that were at least 56 days apart and no use of blood supportive product and/or growth factor during this period. Kaplan-Meier estimate.
- Final Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 48 [Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).]
OS, defined as the time from the date of randomization to the date of death from any cause. All deaths observed as the time of the analysis were considered as events. For participants who were not known to have died at the time of the analysis, OS data were censored at the date last known alive. As the median OS was not reached in either treatment arm at the time of the analysis, Kaplan Meier point estimates of the OS rate (that is, the estimated percentage of participants still surviving at Month 48 [final analysis]) are presented.
- Final Analysis: Rate of Sustained Platelet Improvement [Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).]
Percentage of participants with platelet counts increase ≥ 50% over baseline continuously for ≥ 56 days without blood transfusion or growth factors.
Eligibility Criteria
Criteria
Inclusion Criteria:
Disease Related:
-
Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria.
-
Age 65 yrs and older OR if less than 65 years, must have at least one of the following criteria:
-
Cumulative Illness Rating Score (CIRS) >6
-
Creatinine clearance estimated <70 mL/min using Cockcroft-Gault equation.
-
Del 17p by fluorescence in situ hybridization (FISH) or TP53 mutation by polymerase chain reaction (PCR) or Next Generation Sequencing
- Active disease meeting at least 1 of the following IWCLL criteria for requiring treatment:
-
Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and thrombocytopenia
-
Massive, progressive, or symptomatic splenomegaly
-
Massive nodes (at least 10 cm longest diameter), or progressive or symptomatic lymphadenopathy.
-
Progressive lymphocytosis with an increase of more than 50 percent over a 2-month period or a lymphocyte doubling time (LDT) of <6 months. LDT may 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 <30,000/µL, LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded.
-
Autoimmune hemolytic anemia and/or immune thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy.
-
Autoimmune hemolytic anemia is defined by at least one marker of hemolysis (indirect bilirubin above the upper limit of normal (ULN) not due to liver disease, increased lactate dehydrogenase (above ULN) without alternative etiology, or increased absolute reticulocytosis (above ULN) or bone marrow erythropoiesis in the absence of bleeding AND at least one marker direct or indirect autoimmune mechanism (positive direct antiglobulin for immunoglobulin G [IgG] or C3d, cold agglutinins).
-
Immune thrombocytopenia is defined by platelets ≤100,000/µL and increased megakaryocytes on the bone marrow exam.
-
Constitutional symptoms, defined as one or more of the following disease-related symptoms or signs, documented in the patient's record prior to randomization:
-
unintentional weight loss >10 percent within 6 months prior to screening.
-
significant fatigue (inability to work or perform usual activities).
-
fevers >100.5°F or 38.0°C for 2 or more weeks prior to screening without evidence of infection.
-
night sweats for more than 1 month prior to screening without evidence of infection.
- Measurable nodal disease by computed tomography (CT), defined as at least 1 lymph node
1.5 cm in the longest diameter in a site that has not been previously irradiated. An irradiated lesion may be assessed for measurable disease only if there has been documented progression in that lesion since radiotherapy has ended.
Laboratory
-
Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening and randomization.
-
Adequate hepatic and renal function
-
Men and women ≥ 18 years of age.
-
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
Exclusion Criteria:
-
Any prior treatment of CLL or SLL
-
Evidence of central nervous system (CNS) involvement with primary disease of CLL/SLL
-
History of other malignancies, except:
- Malignancy treated with curative intent and with no known active disease present for ≥3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician.
-
Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura
-
Known or suspected history of Richter's transformation.
-
Concurrent administration of >20mg/day of prednisone within 7 days of randomization unless indicated for prophylaxis or management of allergic reactions (eg, contrast)
-
Known hypersensitivity to one or more study drugs
-
Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
-
Any uncontrolled active systemic infection or an infection requiring systemic treatment that was completed ≤ 7 days before randomization.
-
Known bleeding disorders or hemophilia.
-
History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
-
Known history of human immunodeficiency virus (HIV) or active with hepatitis B virus (HBV) or hepatitis C virus (HCV).
-
Major surgery within 4 weeks of randomization.
-
Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk.
-
Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
-
Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
-
Concomitant use of warfarin or other vitamin K antagonists.
-
Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
-
Lactating or pregnant
-
Unwilling or unable to participate in all required study evaluations and procedures.
-
Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Site Reference ID/Investigator# 0241 | La Jolla | California | United States | |
2 | Site Reference ID/Investigator# 0844 | Fort Myers | Florida | United States | |
3 | Site Reference ID/Investigator# 0763 | West Palm Beach | Florida | United States | |
4 | Site Reference ID/Investigator# 071 | Louisville | Kentucky | United States | |
5 | Site Reference ID/Investigator# 0712 | Las Vegas | Nevada | United States | |
6 | Site Reference ID/Investigator# 0845 | Cincinnati | Ohio | United States | |
7 | Site Reference ID/Investigator# 0868 | Chattanooga | Tennessee | United States | |
8 | Site Reference ID/Investigator# 0123 | Nashville | Tennessee | United States | |
9 | Site Reference ID/Investigator #0503 | Woolloongabba | Queensland | Australia | |
10 | Site Reference ID/Investigator# 0650 | Adelaide | South Australia | Australia | |
11 | Site Reference ID/Investigator# 0888 | Ballarat | Victoria | Australia | |
12 | Site Reference ID/Investigator# 0193 | Box Hill | Victoria | Australia | |
13 | Site Reference ID/Investigator# 0633 | Fitzroy | Victoria | Australia | |
14 | Site Reference ID/Investigator# 0170 | Heidelberg | Victoria | Australia | |
15 | Site Reference ID/Investigator# 0352 | Linz | Austria | ||
16 | Site Reference ID/Investigator# 0869 | Salzburg | Austria | ||
17 | Site Reference ID/Investigator# 0559 | Leuven | Belgium | ||
18 | Site Reference ID/Investigator# 0850 | Turnhout | Belgium | ||
19 | Site Reference ID/Investigator# 018 | Edmonton | Alberta | Canada | |
20 | Site Reference ID/Investigator# 0564 | Hradec Kralove | Czechia | ||
21 | Site Reference ID/Investigator# 0854 | Praha 10 | Czechia | ||
22 | Site Reference ID/Investigator# 0769 | Pessac cedex | Gironde | France | |
23 | Site Reference ID/Investigator# 0520 | Nantes cedex 1 | Loire Atlantique | France | |
24 | Site Reference ID/Investigator# 0775 | Vandoeuvre les Nancy | Meurthe Et Moselle | France | |
25 | Site Reference ID/Investigator# 0855 | Bayonne | Pyrenees Atlantiques | France | |
26 | Site Reference ID/Investigator# 0573 | Haifa | Israel | ||
27 | Site Reference ID/Investigator# 0577 | Jerusalem | Israel | ||
28 | Site Reference ID/Investigator# 0579 | Jerusalem | Israel | ||
29 | Site Reference ID/Investigator# 0575 | Petach Tikva | Israel | ||
30 | Site Reference ID/Investigator# 0856 | Tel Aviv | Israel | ||
31 | Site Reference ID/Investigator# 0875 | Zerifin | Israel | ||
32 | Site Reference ID/Investigator# 0860 | Firenze | Italy | ||
33 | Site Reference ID/Investigator# 0523 | Milano | Italy | ||
34 | Site Reference ID/Investigator# 0581 | Milano | Italy | ||
35 | Site Reference ID/Investigator# 0584 | Milano | Italy | ||
36 | Site Reference ID/Investigator# 0524 | Modena | Italy | ||
37 | Site Reference ID/Investigator# 0582 | Novara | Italy | ||
38 | Site Reference ID/Investigator# 0732 | Roma | Italy | ||
39 | Site Reference ID/Investigator# 0859 | Siena | Italy | ||
40 | Site Reference ID/Investigator# 0663 | Auckland | New Zealand | ||
41 | Site Reference ID/Investigator# 662 | Auckland | New Zealand | ||
42 | Site Reference ID/Investigator# 0586 | Hamilton | New Zealand | ||
43 | Site Reference ID/Investigator# 0592 | Brzozow | Poland | ||
44 | Site Reference ID/Investigator# 0531 | Lodz | Poland | ||
45 | Site Reference ID/Investigator# 0708 | Nizhniy Novgorod | Russian Federation | ||
46 | Site Reference ID/Investigator# 0707 | Ryazan | Russian Federation | ||
47 | Site Reference ID/Investigator# 0881 | Saint-Petersburg | Russian Federation | ||
48 | Site Reference ID/Investigator# 710 | St. Petersburg | Russian Federation | ||
49 | Site Reference ID/Investigator# 304 | Yaroslavl | Russian Federation | ||
50 | Site Reference ID/Investigator# 0604 | L'Hospitalet de Llobregat | Madrid | Spain | |
51 | Site Reference ID/Investigator# 0536 | Majadahonda | Madrid | Spain | |
52 | Site Reference ID/Investigator# 0533 | Barcelona | Spain | ||
53 | Site Reference ID/Investigator# 0534 | Barcelona | Spain | ||
54 | Site Reference ID/Investigator# 0535 | Barcelona | Spain | ||
55 | Site Reference ID/Investigator# 0537 | Madrid | Spain | ||
56 | Site Reference ID/Investigator# 0864 | Madrid | Spain | ||
57 | Site Reference ID/Investigator# 0874 | Madrid | Spain | ||
58 | Site Reference ID/Investigator# 0790 | Salamanca | Spain | ||
59 | Site Reference ID/Investigator# 0870 | Borås | Sweden | ||
60 | Site Reference ID/Investigator# 0865 | Luleå | Sweden | ||
61 | Site Reference ID/Investigator# 0631 | Lund | Sweden | ||
62 | Site Reference ID/Investigator# 0632 | Stockholm | Sweden | ||
63 | Site Reference ID/Investigator# 0678 | Istanbul | Nisantasi | Turkey | |
64 | Site Reference ID/Investigator# 0608 | Ankara | Turkey | ||
65 | Site Reference ID/Investigator# 606 | Ankara | Turkey | ||
66 | Site Reference ID/Investigator# 0889 | Denizli | Turkey | ||
67 | Site Reference ID/Investigator# 0601 | Izmir | Turkey | ||
68 | Site Reference ID/Investigator# 0866 | Samsun | Turkey | ||
69 | Site Reference ID/Investigator# 0867 | Harlow | Essex | United Kingdom | |
70 | Site Reference ID/Investigator# 0365 | London | United Kingdom | ||
71 | Site Reference ID/Investigator# 0543 | London | United Kingdom |
Sponsors and Collaborators
- Pharmacyclics LLC.
Investigators
- Study Director: Lori Styles, Pharmacyclics LLC.
Study Documents (Full-Text)
More Information
Publications
None provided.- PCYC-1130-CA
Study Results
Participant Flow
Recruitment Details | This study was conducted in 71 sites: 8 in the US, 36 in the EU, and 27 sites in 6 additional countries (Canada, Australia, New Zealand, Russia, Israel, Turkey). The first participant consented 06 October 2014. The last visit of the last participant was 03 September 2019, with a final database lock of 17 October 2019. |
---|---|
Pre-assignment Detail | Eligible participants were required to have had a diagnosis of active CLL/SLL conformant to IWCLL 2008 criteria. All subjects were required to have measurable nodal disease. Key exclusion criteria included any previous CLL/SLL treatment; known lymphoma or leukemia of the central nervous system, history/current evidence of Richter's transformation. |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Period Title: Overall Study | ||
STARTED | 113 | 116 |
COMPLETED | 84 | 86 |
NOT COMPLETED | 29 | 30 |
Baseline Characteristics
Arm/Group Title | IBR+OB | CLB+OB | Total |
---|---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. | Total of all reporting groups |
Overall Participants | 113 | 116 | 229 |
Age (Count of Participants) | |||
<=18 years |
0
0%
|
0
0%
|
0
0%
|
Between 18 and 65 years |
22
19.5%
|
24
20.7%
|
46
20.1%
|
>=65 years |
91
80.5%
|
92
79.3%
|
183
79.9%
|
Age (years) [Median (Full Range) ] | |||
Median (Full Range) [years] |
70.0
|
72.0
|
71.0
|
Sex: Female, Male (Count of Participants) | |||
Female |
46
40.7%
|
37
31.9%
|
83
36.2%
|
Male |
67
59.3%
|
79
68.1%
|
146
63.8%
|
Ethnicity (NIH/OMB) (Count of Participants) | |||
Hispanic or Latino |
4
3.5%
|
6
5.2%
|
10
4.4%
|
Not Hispanic or Latino |
109
96.5%
|
110
94.8%
|
219
95.6%
|
Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
Race (NIH/OMB) (Count of Participants) | |||
American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
Asian |
1
0.9%
|
2
1.7%
|
3
1.3%
|
Native Hawaiian or Other Pacific Islander |
1
0.9%
|
1
0.9%
|
2
0.9%
|
Black or African American |
2
1.8%
|
2
1.7%
|
4
1.7%
|
White |
109
96.5%
|
111
95.7%
|
220
96.1%
|
More than one race |
0
0%
|
0
0%
|
0
0%
|
Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
Region of Enrollment (participants) [Number] | |||
United States |
13
11.5%
|
11
9.5%
|
24
10.5%
|
Czechia |
8
7.1%
|
6
5.2%
|
14
6.1%
|
United Kingdom |
2
1.8%
|
2
1.7%
|
4
1.7%
|
Spain |
17
15%
|
9
7.8%
|
26
11.4%
|
Russia |
11
9.7%
|
9
7.8%
|
20
8.7%
|
New Zealand |
0
0%
|
9
7.8%
|
9
3.9%
|
Canada |
3
2.7%
|
5
4.3%
|
8
3.5%
|
Austria |
5
4.4%
|
6
5.2%
|
11
4.8%
|
Sweden |
8
7.1%
|
3
2.6%
|
11
4.8%
|
Turkey |
15
13.3%
|
13
11.2%
|
28
12.2%
|
Belgium |
2
1.8%
|
2
1.7%
|
4
1.7%
|
Poland |
2
1.8%
|
2
1.7%
|
4
1.7%
|
Italy |
13
11.5%
|
15
12.9%
|
28
12.2%
|
Israel |
5
4.4%
|
11
9.5%
|
16
7%
|
France |
3
2.7%
|
5
4.3%
|
8
3.5%
|
Australia |
6
5.3%
|
8
6.9%
|
14
6.1%
|
Outcome Measures
Title | Primary Analysis: Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 30 |
---|---|
Description | PFS was defined as time from the date randomization to the date of first IRC-confirmed disease progression (PD) or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. The primary analysis was performed after observing 94 PFS events as pre-specified in the study protocol. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 30 months (that is, the estimated percentage of participants with progression-free survival at Month 30) are presented. |
Time Frame | Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]). |
Outcome Measure Data
Analysis Population Description |
---|
Intent to Treat population: all randomized participants |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 113 | 116 |
Number (95% Confidence Interval) [percentage of participants] |
78.5
69.5%
|
31.1
26.8%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | Log Rank | |
Comments | The treatment effect was tested with an unstratified log rank test. | |
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.231 | |
Confidence Interval |
(2-Sided) 95% 0.145 to 0.367 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The hazard ratio and its 95% confidence interval were estimated using a Cox regression model with treatment as the only covariate. |
Title | Primary Analysis: PFS in High-Risk Sub-Population (del17p/TP53 Mutation/Del 11q) Based on IRC Assessment - Kaplan Meier Landmark Estimates at Month 30 |
---|---|
Description | PFS was analyzed within the high-risk sub-population of participants with del17p or TP53 mutation or del 11q at baseline per central lab results. PFS was defined as time from the date randomization to the date of first IRC-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the IWCLL 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of PD was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 30 months (that is, the estimated percentage of participants with progression-free survival at Month 30) are presented. |
Time Frame | Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]). |
Outcome Measure Data
Analysis Population Description |
---|
High-Risk Sub-Population Analysis Set: participants with del17p or TP53 mutation or del 11q at baseline per central lab results. |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 30 | 45 |
Number (95% Confidence Interval) [percentage of participants] |
82.4
72.9%
|
14.1
12.2%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | < 0.0001 |
Comments | ||
Method | Log Rank | |
Comments | The treatment effect was tested with an unstratified log rank test. | |
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.119 | |
Confidence Interval |
(2-Sided) 95% 0.046 to 0.307 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The hazard ratio and its 95% confidence interval were estimated using a Cox regression model with treatment as the only covariate. |
Title | Primary Analysis: Rate of Sustained Hemoglobin Improvement |
---|---|
Description | Percentage of participants with sustained hemoglobin improvement, defined as hemoglobin increase ≥ 2 g/dL over baseline continuously for ≥ 56 days without blood transfusions or growth factors. |
Time Frame | Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018). |
Outcome Measure Data
Analysis Population Description |
---|
Intent to Treat population: all randomized participants |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 113 | 116 |
Number [percentage of participants] |
39.8
35.2%
|
44.0
37.9%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.5253 |
Comments | ||
Method | Chi-squared | |
Comments |
Title | Primary Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response |
---|---|
Description | Percentage of participants who achieved MRD-negative response, defined as < 1 CLL cell per 10,000 leukocytes as assessed by flow cytometry of a bone marrow aspirate per central laboratory. MRD samples were collected before initiation of subsequent antineoplastic treatment and MRD status was reported by central lab within 5 days after collection date. Participants with missing MRD data were considered non-responders. |
Time Frame | Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018). |
Outcome Measure Data
Analysis Population Description |
---|
Intent to Treat population: all randomized participants |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 113 | 116 |
Number [percentage of participants] |
20.4
18.1%
|
17.2
14.8%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.5465 |
Comments | ||
Method | Chi-squared | |
Comments |
Title | Primary Analysis: Overall Response Rate (ORR) Based on IRC Assessment |
---|---|
Description | ORR, defined as the percentage of participants achieving a best overall response of protocol-specified complete response (CR), CR with incomplete blood count recovery (CRi), nodular partial response (nPR), or partial response (PR) per IRC assessment at or prior to initiation of subsequent antineoplastic therapy. Assessment of response included physical examination, radiographic imaging, and evaluation of blood and marrow (if applicable), evaluated in accordance with the IWCLL 2008 criteria (Halleck et al). CR, CRi, nPR, and PR required confirmation with 2 consecutive assessments that were at least 56 days apart and no use of blood supportive product and/or growth factor during this period. Kaplan-Meier estimate. |
Time Frame | Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018). |
Outcome Measure Data
Analysis Population Description |
---|
Intent to Treat population: all randomized participants |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 113 | 116 |
Number [percentage of participants] |
88.5
78.3%
|
73.3
63.2%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0035 |
Comments | ||
Method | Chi-squared | |
Comments | ||
Method of Estimation | Estimation Parameter | Rate Ratio |
Estimated Value | 1.208 | |
Confidence Interval |
(2-Sided) 95% 1.062 to 1.373 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Primary Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 30 |
---|---|
Description | OS, defined as the time from the date of randomization to the date of death from any cause. All deaths observed as the time of the analysis were considered as events. For participants who were not known to have died at the time of the analysis, OS data were censored at the date last known alive. As the median OS was not reached in either treatment arm at the time of the analysis, Kaplan Meier landmark estimates of the OS rate (that is, the estimated percentage of participants still surviving at Month 30 [primary analysis]) are presented. |
Time Frame | Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]). |
Outcome Measure Data
Analysis Population Description |
---|
Intent to Treat population: all randomized participants |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 113 | 116 |
Number (95% Confidence Interval) [percentage of participants] |
85.5
75.7%
|
84.9
73.2%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.8057 |
Comments | ||
Method | Log Rank | |
Comments | The treatment effect was tested with an unstratified log rank test. | |
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.921 | |
Confidence Interval |
(2-Sided) 95% 0.479 to 1.772 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The hazard ratio and its 95% confidence interval were estimated using a Cox regression model with treatment as the only covariate. |
Title | Primary Analysis: Rate of Grade ≥ 3 or Serious Infusion-Related Reaction (IRR) Adverse Events |
---|---|
Description | Percentage of participants experiencing grade ≥ 3 (severe or life threatening) or serious IRR adverse events that started on the day of an obinutuzumab infusion and were assessed as related or possibly related to obinutuzumab. Categories included those events with the Medical Dictionary for Regulatory Activities (MedDRA) dictionary preferred term of IRR and those events which are among the customized standardized MedDRA query (SMQ) for IRR. |
Time Frame | Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018). |
Outcome Measure Data
Analysis Population Description |
---|
Intent to Treat population: all randomized participants |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 113 | 116 |
IRR (Preferred Term) |
2.7
2.4%
|
8.6
7.4%
|
By Customized SMQ |
4.4
3.9%
|
9.5
8.2%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | IRR Preferred Term To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0835 |
Comments | ||
Method | Fisher Exact | |
Comments |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | IRR By Customized SMQ To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.1944 |
Comments | ||
Method | Fisher Exact | |
Comments |
Title | Primary Analysis: Rate of Sustained Platelet Improvement |
---|---|
Description | Percentage of participants with platelet counts increase ≥ 50% over baseline continuously for ≥ 56 days without blood transfusion or growth factors. |
Time Frame | Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018). |
Outcome Measure Data
Analysis Population Description |
---|
Intent to Treat population: all randomized participants |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 113 | 116 |
Number [percentage of participants] |
29.2
25.8%
|
13.8
11.9%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0045 |
Comments | ||
Method | Chi-squared | |
Comments |
Title | Primary Analysis: Rate of Clinically Meaningful Improvement in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EuroQol Five-Dimension (EQ-5D-5L) |
---|---|
Description | Percentage of participants with EQ-5D-5L utility score increase ≥ 0.08 points over baseline at or prior to initiation of subsequent antineoplastic therapy. The EQ-5D-5L is a standardized non-disease specific instrument for describing and valuing health-related quality of life, comprising 5 dimensions of health (mobility, self -care, usual activities, pain/discomfort, and anxiety/depression) to describe the participant's current health state. Each dimension comprises 5 levels with corresponding numeric scores, where 1 indicates no problems, and 5 indicates extreme problems. A unique EQ-5D-5L health state is defined by combining the numeric level scores for each of the 5 dimensions and the total score is normalized from -0.594 to 1.000, with higher scores representing a better health state. An increase in the EQ-5D-5L total score indicates improvement. Participants with missing EQ-5D-5L data were considered not achieving clinically meaningful improvement. |
Time Frame | Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018). |
Outcome Measure Data
Analysis Population Description |
---|
Intent to Treat population: all randomized participants with a baseline and post-baseline assessment. |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 109 | 107 |
Number [percentage of participants] |
54.9
48.6%
|
56.0
48.3%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints were tested based on serial gatekeeping testing procedure at the two-sided significance level of 0.05 according to the hierarchical order of the primary analysis outcome measures presented in this record. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.8590 |
Comments | ||
Method | Chi-squared | |
Comments |
Title | Final Analysis: PFS in High-Risk Population (del17p/TP53 Mutation/Del 11q/Unmutated Immunoglobulin Heavy Chain Variable Region [IGHV]) Based on Investigator Assessment - Kaplan Meier Landmark Estimates at Month 48 |
---|---|
Description | PFS was analyzed within the high-risk population of participants with del17p or TP53 mutation or del 11q or IGHV unmutated at baseline per central lab results. PFS was defined as time from the date randomization to the date of first investigator-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the IWCLL 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of PD was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 48 months (that is, the estimated percentage of participants with progression-free survival at Month 48) are presented. |
Time Frame | Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]). |
Outcome Measure Data
Analysis Population Description |
---|
High-Risk Population Analysis Set: participants with del17p or TP53 mutation or del 11q or IGHV unmutated at baseline per central lab results. |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 73 | 75 |
Number (95% Confidence Interval) [percentage of participants] |
70.3
62.2%
|
8.0
6.9%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | < 0.0001 |
Comments | ||
Method | Log Rank | |
Comments | The treatment effect was tested with an unstratified log rank test. | |
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.169 | |
Confidence Interval |
(2-Sided) 95% 0.102 to 0.282 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The hazard ratio and its 95% confidence interval were estimated using a Cox regression model with treatment as the only covariate. |
Title | Final Analysis: Rate of Sustained Hemoglobin Improvement |
---|---|
Description | Percentage of participants with sustained hemoglobin improvement, defined as hemoglobin increase ≥ 2 g/dL over baseline continuously for ≥ 56 days without blood transfusions or growth factors. |
Time Frame | Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019). |
Outcome Measure Data
Analysis Population Description |
---|
Intent to Treat population: all randomized participants |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 113 | 116 |
Number [percentage of participants] |
44.2
39.1%
|
44.0
37.9%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.9657 |
Comments | ||
Method | Chi-squared | |
Comments |
Title | Final Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response |
---|---|
Description | Percentage of participants who achieved MRD-negative response, defined as < 1 CLL cell per 10,000 leukocytes as assessed by flow cytometry of a bone marrow aspirate per central laboratory. MRD samples were collected before initiation of subsequent antineoplastic treatment and MRD status was reported by central lab within 5 days after collection date. Participants with missing MRD data were considered non-responders. |
Time Frame | Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019). |
Outcome Measure Data
Analysis Population Description |
---|
Intent to Treat population: all randomized participants |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 113 | 116 |
Number [percentage of participants] |
24.8
21.9%
|
17.2
14.8%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.1612 |
Comments | ||
Method | Chi-squared | |
Comments |
Title | Final Analysis: ORR Based on Investigator Assessment |
---|---|
Description | ORR, defined as the percentage of participants achieving a best overall response of protocol-specified CR, CRi, nPR or PR per investigator assessment at or prior to initiation of subsequent antineoplastic therapy. Assessment of response included physical examination, radiographic imaging, and evaluation of blood and marrow (if applicable), evaluated in accordance with the IWCLL 2008 criteria (Halleck et al). CR, CRi, nPR, and PR required confirmation with 2 consecutive assessments that were at least 56 days apart and no use of blood supportive product and/or growth factor during this period. Kaplan-Meier estimate. |
Time Frame | Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019). |
Outcome Measure Data
Analysis Population Description |
---|
Intent to Treat population: all randomized participants |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 113 | 116 |
Number [percentage of participants] |
91.2
80.7%
|
81.0
69.8%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0273 |
Comments | ||
Method | Chi-squared | |
Comments | ||
Method of Estimation | Estimation Parameter | Rate Ratio |
Estimated Value | 1.125 | |
Confidence Interval |
(2-Sided) 95% 1.013 to 1.250 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Final Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 48 |
---|---|
Description | OS, defined as the time from the date of randomization to the date of death from any cause. All deaths observed as the time of the analysis were considered as events. For participants who were not known to have died at the time of the analysis, OS data were censored at the date last known alive. As the median OS was not reached in either treatment arm at the time of the analysis, Kaplan Meier point estimates of the OS rate (that is, the estimated percentage of participants still surviving at Month 48 [final analysis]) are presented. |
Time Frame | Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]). |
Outcome Measure Data
Analysis Population Description |
---|
Intent to Treat population: all randomized participants |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 113 | 116 |
Number (95% Confidence Interval) [percentage of participants] |
80.5
71.2%
|
81.3
70.1%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.7934 |
Comments | ||
Method | Log Rank | |
Comments | The treatment effect was tested with an unstratified log rank test. | |
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 1.083 | |
Confidence Interval |
(2-Sided) 95% 0.595 to 1.973 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The hazard ratio and its 95% confidence interval were estimated using a Cox regression model with treatment as the only covariate. |
Title | Final Analysis: Rate of Sustained Platelet Improvement |
---|---|
Description | Percentage of participants with platelet counts increase ≥ 50% over baseline continuously for ≥ 56 days without blood transfusion or growth factors. |
Time Frame | Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019). |
Outcome Measure Data
Analysis Population Description |
---|
Intent to Treat population: all randomized participants |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 113 | 116 |
Number [percentage of participants] |
30.1
26.6%
|
14.7
12.7%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0050 |
Comments | ||
Method | Chi-squared | |
Comments |
Title | Final Analysis: PFS Based on Investigator Assessment - Kaplan Meier Landmark Estimates at Month 48 |
---|---|
Description | PFS was defined as time from the date randomization to the date of first investigator-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 48 months (that is, the estimated percentage of participants with progression-free survival at Month 48) are presented. |
Time Frame | Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]). |
Outcome Measure Data
Analysis Population Description |
---|
Intent to Treat population: all randomized participants |
Arm/Group Title | IBR+OB | CLB+OB |
---|---|---|
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. |
Measure Participants | 113 | 116 |
Number (95% Confidence Interval) [percentage of participants] |
74.0
65.5%
|
22.0
19%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | IBR+OB, CLB+OB |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | < 0.0001 |
Comments | ||
Method | Log Rank | |
Comments | The treatment effect was tested with an unstratified log rank test. | |
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.251 | |
Confidence Interval |
(2-Sided) 95% 0.162 to 0.389 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | The hazard ratio and its 95% confidence interval were estimated using a Cox regression model with treatment as the only covariate. |
Adverse Events
Time Frame | From first dose of study drug up to 30 days after the last dose of study drug. Median treatment duration for the IBR+OB arm was 42.3 (IBR) and 4.6 (OB) months. Median treatment duration for the CLB+OB arm was 5.1 (CLB) and 4.6 (OB) months. Final analysis data (data cutoff date: 17 October 2019). | |||
---|---|---|---|---|
Adverse Event Reporting Description | One participant in the CLB+OB arm was randomized but went off study without any treatment. This participant had received baseline assessments and was included in all efficacy analyses but was excluded from safety population, i.e. not at risk for adverse event assessment. | |||
Arm/Group Title | IBR+OB | CLB+OB | ||
Arm/Group Description | 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. | 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 (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 disease progression or unacceptable toxicity. | ||
All Cause Mortality |
||||
IBR+OB | CLB+OB | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 22/113 (19.5%) | 21/115 (18.3%) | ||
Serious Adverse Events |
||||
IBR+OB | CLB+OB | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 69/113 (61.1%) | 41/115 (35.7%) | ||
Blood and lymphatic system disorders | ||||
Anaemia | 1/113 (0.9%) | 2/115 (1.7%) | ||
Aplastic anaemia | 1/113 (0.9%) | 0/115 (0%) | ||
Febrile neutropenia | 5/113 (4.4%) | 7/115 (6.1%) | ||
Leukopenia | 1/113 (0.9%) | 0/115 (0%) | ||
Neutropenia | 2/113 (1.8%) | 0/115 (0%) | ||
Thrombocytopenia | 3/113 (2.7%) | 1/115 (0.9%) | ||
Cardiac disorders | ||||
Acute coronary syndrome | 3/113 (2.7%) | 0/115 (0%) | ||
Acute myocardial infarction | 1/113 (0.9%) | 1/115 (0.9%) | ||
Angina pectoris | 2/113 (1.8%) | 0/115 (0%) | ||
Atrial fibrillation | 6/113 (5.3%) | 0/115 (0%) | ||
Atrial tachycardia | 1/113 (0.9%) | 0/115 (0%) | ||
Cardiac arrest | 2/113 (1.8%) | 0/115 (0%) | ||
Cardiac failure | 1/113 (0.9%) | 0/115 (0%) | ||
Cardiac failure congestive | 1/113 (0.9%) | 0/115 (0%) | ||
Myocardial infarction | 1/113 (0.9%) | 0/115 (0%) | ||
Myocardial ischaemia | 0/113 (0%) | 1/115 (0.9%) | ||
Pericarditis | 1/113 (0.9%) | 0/115 (0%) | ||
Pericarditis constrictive | 0/113 (0%) | 1/115 (0.9%) | ||
Stress cardiomyopathy | 1/113 (0.9%) | 0/115 (0%) | ||
Endocrine disorders | ||||
Goitre | 1/113 (0.9%) | 0/115 (0%) | ||
Eye disorders | ||||
Cataract | 1/113 (0.9%) | 0/115 (0%) | ||
Retinal detachment | 1/113 (0.9%) | 0/115 (0%) | ||
Gastrointestinal disorders | ||||
Abdominal pain | 2/113 (1.8%) | 0/115 (0%) | ||
Constipation | 0/113 (0%) | 1/115 (0.9%) | ||
Diarrhea | 1/113 (0.9%) | 0/115 (0%) | ||
Dyspepsia | 1/113 (0.9%) | 0/115 (0%) | ||
Gastritis | 1/113 (0.9%) | 0/115 (0%) | ||
Haemorrhoids | 1/113 (0.9%) | 0/115 (0%) | ||
Impaired gastric emptying | 1/113 (0.9%) | 0/115 (0%) | ||
Inguinal hernia | 1/113 (0.9%) | 0/115 (0%) | ||
Large intestine polyp | 1/113 (0.9%) | 0/115 (0%) | ||
Nausea | 0/113 (0%) | 2/115 (1.7%) | ||
Oesophageal rupture | 1/113 (0.9%) | 0/115 (0%) | ||
Proctitis | 1/113 (0.9%) | 0/115 (0%) | ||
Small intestinal obstruction | 1/113 (0.9%) | 1/115 (0.9%) | ||
Stomatitis | 1/113 (0.9%) | 0/115 (0%) | ||
General disorders | ||||
Catheter site haematoma | 1/113 (0.9%) | 0/115 (0%) | ||
Death | 2/113 (1.8%) | 0/115 (0%) | ||
Multi-organ disorder | 1/113 (0.9%) | 0/115 (0%) | ||
Pyrexia | 4/113 (3.5%) | 4/115 (3.5%) | ||
Sudden Death | 1/113 (0.9%) | 0/115 (0%) | ||
Hepatobiliary disorders | ||||
Cholecystitis | 0/113 (0%) | 1/115 (0.9%) | ||
Cholelithiasis | 1/113 (0.9%) | 0/115 (0%) | ||
Infections and infestations | ||||
Abscess | 1/113 (0.9%) | 0/115 (0%) | ||
Bacterial sepsis | 1/113 (0.9%) | 0/115 (0%) | ||
Bronchitis | 1/113 (0.9%) | 0/115 (0%) | ||
Bronchopulmonary aspergillosis | 1/113 (0.9%) | 0/115 (0%) | ||
Bursitis infective staphylococcal | 1/113 (0.9%) | 0/115 (0%) | ||
Cellulitis | 1/113 (0.9%) | 0/115 (0%) | ||
Erysipelas | 1/113 (0.9%) | 0/115 (0%) | ||
Escherichia sepsis | 1/113 (0.9%) | 0/115 (0%) | ||
Escherichia urinary tract infection | 1/113 (0.9%) | 0/115 (0%) | ||
Gastroenteritis | 3/113 (2.7%) | 1/115 (0.9%) | ||
Herpes Zoster | 1/113 (0.9%) | 0/115 (0%) | ||
Infective aneurysm | 1/113 (0.9%) | 0/115 (0%) | ||
Listeria sepsis | 1/113 (0.9%) | 0/115 (0%) | ||
Lower respiratory tract infection | 1/113 (0.9%) | 0/115 (0%) | ||
Pharyngitis | 1/113 (0.9%) | 1/115 (0.9%) | ||
Pneumocystis jirovecii pneumonia | 1/113 (0.9%) | 0/115 (0%) | ||
Pneumonia | 8/113 (7.1%) | 5/115 (4.3%) | ||
Pneumonia bacterial | 1/113 (0.9%) | 0/115 (0%) | ||
Pneumonia klebsiella | 1/113 (0.9%) | 0/115 (0%) | ||
Prostate infection | 1/113 (0.9%) | 0/115 (0%) | ||
Respiratory tract infection | 2/113 (1.8%) | 0/115 (0%) | ||
Sepsis | 0/113 (0%) | 2/115 (1.7%) | ||
Septic shock | 2/113 (1.8%) | 0/115 (0%) | ||
Sinusitis fungal | 1/113 (0.9%) | 0/115 (0%) | ||
Soft tissue infection | 1/113 (0.9%) | 0/115 (0%) | ||
Streptococcal bacteraemia | 1/113 (0.9%) | 0/115 (0%) | ||
Upper respiratory tract infection | 1/113 (0.9%) | 0/115 (0%) | ||
Urinary tract infection | 3/113 (2.7%) | 1/115 (0.9%) | ||
Urosepsis | 1/113 (0.9%) | 0/115 (0%) | ||
Vascular device infection | 0/113 (0%) | 1/115 (0.9%) | ||
Injury, poisoning and procedural complications | ||||
Accidental overdose | 0/113 (0%) | 1/115 (0.9%) | ||
Concussion | 1/113 (0.9%) | 1/115 (0.9%) | ||
Craniocerebral injury | 0/113 (0%) | 1/115 (0.9%) | ||
Femur fracture | 2/113 (1.8%) | 0/115 (0%) | ||
Hip fracture | 0/113 (0%) | 1/115 (0.9%) | ||
Incisional hernia | 1/113 (0.9%) | 0/115 (0%) | ||
Infusion related reaction | 2/113 (1.8%) | 8/115 (7%) | ||
Jaw fracture | 1/113 (0.9%) | 0/115 (0%) | ||
Pubis fracture | 1/113 (0.9%) | 0/115 (0%) | ||
Rib fracture | 1/113 (0.9%) | 0/115 (0%) | ||
Spinal compression fracture | 1/113 (0.9%) | 0/115 (0%) | ||
Thoracic vertebral fracture | 1/113 (0.9%) | 0/115 (0%) | ||
Traumatic haematoma | 1/113 (0.9%) | 0/115 (0%) | ||
Upper limb fracture | 1/113 (0.9%) | 0/115 (0%) | ||
Metabolism and nutrition disorders | ||||
Dehydration | 0/113 (0%) | 1/115 (0.9%) | ||
Diabetes mellitus inadequate control | 1/113 (0.9%) | 0/115 (0%) | ||
Hypercalcaemia | 1/113 (0.9%) | 0/115 (0%) | ||
Hypokalaemia | 1/113 (0.9%) | 0/115 (0%) | ||
Hypomagnesaemia | 1/113 (0.9%) | 0/115 (0%) | ||
Hyponatraemia | 0/113 (0%) | 1/115 (0.9%) | ||
Tumour lysis syndrome | 0/113 (0%) | 5/115 (4.3%) | ||
Musculoskeletal and connective tissue disorders | ||||
Arthritis | 1/113 (0.9%) | 0/115 (0%) | ||
Compartment syndrome | 1/113 (0.9%) | 0/115 (0%) | ||
Inclusion body myositis | 1/113 (0.9%) | 0/115 (0%) | ||
Osteoarthritis | 2/113 (1.8%) | 0/115 (0%) | ||
Osteolysis | 0/113 (0%) | 1/115 (0.9%) | ||
Osteonecrosis of jaw | 0/113 (0%) | 1/115 (0.9%) | ||
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
Adenocarcinoma gastric | 1/113 (0.9%) | 0/115 (0%) | ||
Adenocarcinoma of colon | 3/113 (2.7%) | 0/115 (0%) | ||
Basal cell carcinoma | 1/113 (0.9%) | 0/115 (0%) | ||
Benign renal neoplasm | 1/113 (0.9%) | 0/115 (0%) | ||
Chronic lymphocytic leukaemia | 0/113 (0%) | 1/115 (0.9%) | ||
Colorectal cancer | 1/113 (0.9%) | 0/115 (0%) | ||
Colorectal cancer metastatic | 1/113 (0.9%) | 0/115 (0%) | ||
Essential thrombocythaemia | 0/113 (0%) | 1/115 (0.9%) | ||
Invasive ductal breast carcinoma | 1/113 (0.9%) | 0/115 (0%) | ||
Kaposi's sarcoma | 0/113 (0%) | 1/115 (0.9%) | ||
Keratoacanthoma | 0/113 (0%) | 1/115 (0.9%) | ||
Malignant melanoma | 1/113 (0.9%) | 0/115 (0%) | ||
Myelodysplastic syndrome | 1/113 (0.9%) | 0/115 (0%) | ||
Neuroendocrine carcinoma of the skin | 0/113 (0%) | 1/115 (0.9%) | ||
Non-small cell lung cancer | 1/113 (0.9%) | 0/115 (0%) | ||
Osteoma | 1/113 (0.9%) | 0/115 (0%) | ||
Prostate Cancer | 0/113 (0%) | 1/115 (0.9%) | ||
Squamous cell carcinoma | 1/113 (0.9%) | 0/115 (0%) | ||
Nervous system disorders | ||||
Cerebral ischaemia | 1/113 (0.9%) | 0/115 (0%) | ||
Cerebrovascular accident | 2/113 (1.8%) | 0/115 (0%) | ||
Depressed level of consciousness | 1/113 (0.9%) | 0/115 (0%) | ||
Headache | 0/113 (0%) | 1/115 (0.9%) | ||
Ischaemic stroke | 1/113 (0.9%) | 0/115 (0%) | ||
Loss of consciousness | 0/113 (0%) | 1/115 (0.9%) | ||
Seizure | 0/113 (0%) | 1/115 (0.9%) | ||
Syncope | 1/113 (0.9%) | 0/115 (0%) | ||
Transient ischaemic attack | 2/113 (1.8%) | 0/115 (0%) | ||
Psychiatric disorders | ||||
Acute psychosis | 1/113 (0.9%) | 0/115 (0%) | ||
Complete Suicide | 1/113 (0.9%) | 0/115 (0%) | ||
Confusional state | 1/113 (0.9%) | 0/115 (0%) | ||
Renal and urinary disorders | ||||
Acute kidney injury | 2/113 (1.8%) | 1/115 (0.9%) | ||
Nephrolithiasis | 1/113 (0.9%) | 0/115 (0%) | ||
Renal failure | 2/113 (1.8%) | 0/115 (0%) | ||
Urinary retention | 1/113 (0.9%) | 1/115 (0.9%) | ||
Reproductive system and breast disorders | ||||
Benign prostatic hyperplasia | 1/113 (0.9%) | 0/115 (0%) | ||
Uterine prolapse | 1/113 (0.9%) | 0/115 (0%) | ||
Respiratory, thoracic and mediastinal disorders | ||||
Acute respiratory failure | 0/113 (0%) | 1/115 (0.9%) | ||
Bronchitis chronic | 1/113 (0.9%) | 0/115 (0%) | ||
Haemoptysis | 1/113 (0.9%) | 0/115 (0%) | ||
Pleural effusion | 1/113 (0.9%) | 0/115 (0%) | ||
Productive cough | 1/113 (0.9%) | 0/115 (0%) | ||
Pulmonary embolism | 0/113 (0%) | 1/115 (0.9%) | ||
Respiratory failure | 1/113 (0.9%) | 1/115 (0.9%) | ||
Vascular disorders | ||||
Hypertension | 0/113 (0%) | 1/115 (0.9%) | ||
Peripheral ischaemia | 1/113 (0.9%) | 0/115 (0%) | ||
Venous thrombosis limb | 0/113 (0%) | 1/115 (0.9%) | ||
Other (Not Including Serious) Adverse Events |
||||
IBR+OB | CLB+OB | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 112/113 (99.1%) | 111/115 (96.5%) | ||
Blood and lymphatic system disorders | ||||
Anaemia | 19/113 (16.8%) | 29/115 (25.2%) | ||
Increased tendency to bruise | 6/113 (5.3%) | 0/115 (0%) | ||
Neutropenia | 50/113 (44.2%) | 73/115 (63.5%) | ||
Spontaneous haematoma | 10/113 (8.8%) | 1/115 (0.9%) | ||
Thrombocytopenia | 39/113 (34.5%) | 29/115 (25.2%) | ||
Cardiac disorders | ||||
Atrial fibrillation | 16/113 (14.2%) | 0/115 (0%) | ||
Palpitations | 7/113 (6.2%) | 3/115 (2.6%) | ||
Eye disorders | ||||
Cataract | 11/113 (9.7%) | 1/115 (0.9%) | ||
Dry eye | 7/113 (6.2%) | 3/115 (2.6%) | ||
Lacrimation increased | 8/113 (7.1%) | 5/115 (4.3%) | ||
Vision blurred | 9/113 (8%) | 7/115 (6.1%) | ||
Gastrointestinal disorders | ||||
Abdominal pain | 9/113 (8%) | 6/115 (5.2%) | ||
Constipation | 19/113 (16.8%) | 14/115 (12.2%) | ||
Diarrhea | 39/113 (34.5%) | 12/115 (10.4%) | ||
Dyspepsia | 9/113 (8%) | 2/115 (1.7%) | ||
Gastrooesophageal reflux disease | 8/113 (7.1%) | 3/115 (2.6%) | ||
Nausea | 15/113 (13.3%) | 34/115 (29.6%) | ||
Stomatitis | 7/113 (6.2%) | 1/115 (0.9%) | ||
Vomiting | 12/113 (10.6%) | 14/115 (12.2%) | ||
General disorders | ||||
Asthenia | 12/113 (10.6%) | 17/115 (14.8%) | ||
Chills | 7/113 (6.2%) | 10/115 (8.7%) | ||
Fatigue | 22/113 (19.5%) | 19/115 (16.5%) | ||
Oedema peripheral | 14/113 (12.4%) | 8/115 (7%) | ||
Peripheral swelling | 7/113 (6.2%) | 2/115 (1.7%) | ||
Pyrexia | 19/113 (16.8%) | 28/115 (24.3%) | ||
Infections and infestations | ||||
Bronchitis | 8/113 (7.1%) | 2/115 (1.7%) | ||
Cellulitis | 6/113 (5.3%) | 3/115 (2.6%) | ||
Conjunctivitis | 12/113 (10.6%) | 2/115 (1.7%) | ||
Herpes zoster | 6/113 (5.3%) | 3/115 (2.6%) | ||
Nasopharyngitis | 15/113 (13.3%) | 4/115 (3.5%) | ||
Oral herpes | 1/113 (0.9%) | 6/115 (5.2%) | ||
Pneumonia | 12/113 (10.6%) | 5/115 (4.3%) | ||
Respiratory tract infection | 8/113 (7.1%) | 1/115 (0.9%) | ||
Upper respiratory tract infection | 18/113 (15.9%) | 7/115 (6.1%) | ||
Urinary tract infection | 13/113 (11.5%) | 7/115 (6.1%) | ||
Injury, poisoning and procedural complications | ||||
Contusion | 6/113 (5.3%) | 1/115 (0.9%) | ||
Fall | 10/113 (8.8%) | 3/115 (2.6%) | ||
Infusion related reaction | 26/113 (23%) | 61/115 (53%) | ||
Investigations | ||||
Blood creatine increased | 8/113 (7.1%) | 1/115 (0.9%) | ||
Weight decreased | 3/113 (2.7%) | 6/115 (5.2%) | ||
Metabolism and nutrition disorders | ||||
Decreased appetite | 11/113 (9.7%) | 5/115 (4.3%) | ||
Hyperglycaemia | 6/113 (5.3%) | 7/115 (6.1%) | ||
Hyperuricaemia | 15/113 (13.3%) | 0/115 (0%) | ||
Hypokalaemia | 7/113 (6.2%) | 2/115 (1.7%) | ||
Iron deficiency | 9/113 (8%) | 0/115 (0%) | ||
Musculoskeletal and connective tissue disorders | ||||
Arthralgia | 27/113 (23.9%) | 12/115 (10.4%) | ||
Back pain | 21/113 (18.6%) | 12/115 (10.4%) | ||
Muscle spasms | 16/113 (14.2%) | 7/115 (6.1%) | ||
Musculoskeletal pain | 6/113 (5.3%) | 3/115 (2.6%) | ||
Myalgia | 7/113 (6.2%) | 4/115 (3.5%) | ||
Pain in extremity | 12/113 (10.6%) | 10/115 (8.7%) | ||
Nervous system disorders | ||||
Dizziness | 12/113 (10.6%) | 7/115 (6.1%) | ||
Headache | 9/113 (8%) | 13/115 (11.3%) | ||
Tremor | 4/113 (3.5%) | 7/115 (6.1%) | ||
Psychiatric disorders | ||||
Anxiety | 10/113 (8.8%) | 8/115 (7%) | ||
Depression | 7/113 (6.2%) | 1/115 (0.9%) | ||
Insomnia | 13/113 (11.5%) | 5/115 (4.3%) | ||
Renal and urinary disorders | ||||
Haematuria | 6/113 (5.3%) | 0/115 (0%) | ||
Respiratory, thoracic and mediastinal disorders | ||||
Cough | 33/113 (29.2%) | 14/115 (12.2%) | ||
Dyspnoea | 12/113 (10.6%) | 15/115 (13%) | ||
Epistaxis | 7/113 (6.2%) | 9/115 (7.8%) | ||
Oropharyngeal pain | 8/113 (7.1%) | 4/115 (3.5%) | ||
Productive cough | 8/113 (7.1%) | 2/115 (1.7%) | ||
Skin and subcutaneous tissue disorders | ||||
Dry Skin | 7/113 (6.2%) | 0/115 (0%) | ||
Ecchymosis | 7/113 (6.2%) | 0/115 (0%) | ||
Onychoclasis | 7/113 (6.2%) | 0/115 (0%) | ||
Petechiae | 6/113 (5.3%) | 0/115 (0%) | ||
Pruritus | 9/113 (8%) | 4/115 (3.5%) | ||
Rash | 10/113 (8.8%) | 1/115 (0.9%) | ||
Rash maculo-papular | 17/113 (15%) | 2/115 (1.7%) | ||
Vascular disorders | ||||
Hypertension | 22/113 (19.5%) | 5/115 (4.3%) | ||
Hypotension | 1/113 (0.9%) | 6/115 (5.2%) |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Institution/Investigator will not publish without Sponsor prior review and approval Institution/Investigator will not publish until the earlier of (i) results of study are submitted for publication (ii) notification that submission of the multicenter results are no longer planned (iii) 18 months after study termination.
Results Point of Contact
Name/Title | Lori Styles |
---|---|
Organization | Pharmacyclics LLC, An AbbVie Company |
Phone | (408) 215-3770 |
lstyles@pcyc.com |
- PCYC-1130-CA