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

Chronic Lymphocytic Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01722487
• Other study ID #: PCYC-1115-CA
• Secondary ID: 2012-003967-23
• Status: Completed
• Phase: Phase 3
• First received: October 29, 2012
• Last updated: November 27, 2017
• Start date: March 2013
• Est. completion date: May 2015

Study information

• Verified date: October 2017
• Source: Pharmacyclics LLC.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 269
• Est. completion date: May 2015
• Est. primary completion date: May 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years and older

Eligibility

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

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

3. 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

4. Measurable nodal disease by computed tomography (CT)

5. ECOG performance status of 0-2

6. Life expectancy > 4 months from randomization

7. 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)

8. 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

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

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

11. 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

12. 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

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

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

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

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

14. Serologic status reflecting active hepatitis B or C infection

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

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

17. Requirement for anticoagulation with warfarin

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

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Small Lymphocytic Lymphoma

Intervention

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.
• 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.

Locations

Country	Name	City	State
Australia	Site Reference ID/Investigator #163	Bedford Park	South Australia
Australia	Site Reference ID/Investigator #193	Box Hill	Victoria
Australia	Site Reference ID/Investigator #556	Clayton	Victoria
Australia	Site Reference ID/Investigator #501	Fitzroy	Victoria
Australia	Site Reference ID/Investigator #715	Frankston	Victoria
Australia	Site Reference ID/Investigator #558	Geelong	Victoria
Australia	Site Reference ID/Investigator #170	Heidelberg	Victoria
Australia	Site Reference ID/Investigator #555	Hobart	Tasmania
Australia	Site Reference ID/Investigator #654	Kogarah	New South Wales
Australia	Site Reference ID/Investigator #503	Woolloongabba	Queensland
Belgium	Site Reference ID/Investigator #561	Antwerpen
Belgium	Site Reference ID/Investigator #628	Brugge	West-Vlaanderen
Belgium	Site Reference ID/Investigator #184	Brussells
Belgium	Site Reference ID/Investigator #164	Bruxelles	Brussells
Belgium	Site Reference ID/Investigator #560	Gent	Oost-Vlaanderen
Belgium	Site Reference ID/Investigator #559	Leuven	Vlaams Brabant
Belgium	Site Reference ID/Investigator #727	Yvoir	Namur
Canada	Site Reference ID/Investigator #157	Calgary	Alberta
Canada	Site Reference ID/Investigator #018	Edmonton	Alberta
Canada	Site Reference ID/Investigator #159	Ottawa	Ontario
China	Site Reference ID/Investigator #670	Beijing
China	Site Reference ID/Investigator #673	Beijing
China	Site Reference ID/Investigator #674	Guangzhou	Guangdong
China	Site Reference ID/Investigator #675	Hangzhou	Zhejiang
China	Site Reference ID/Investigator #671	Nanjing	Jiangsu
Czechia	Site Reference ID/Investigator #562	Brno
Czechia	Site Reference ID/Investigator #564	Hradec Kralove	Kralovehradecky Kraj
Czechia	Site Reference ID/Investigator #566	Plzen-Lochotin
Ireland	Site Reference ID/Investigator #570	Dublin
Ireland	Site Reference ID/Investigator #572	Dublin
Ireland	Site Reference ID/Investigator #571	Galway
Israel	Site Reference ID/Investigator #573	Haifa
Israel	Site Reference ID/Investigator #576	Haifa
Israel	Site Reference ID/Investigator #577	Jerusalem
Israel	Site Reference ID/Investigator #578	Nahariya
Israel	Site Reference ID/Investigator #575	Peta? Tiqwa
Israel	Site Reference ID/Investigator #574	Ramat Gan
Italy	Site Reference ID/Investigator #580	Bologna
Italy	Site Reference ID/Investigator #523	Milano
Italy	Site Reference ID/Investigator #581	Milano
Italy	Site Reference ID/Investigator #584	Milano
Italy	Site Reference ID/Investigator #524	Modena
Italy	Site Reference ID/Investigator #582	Novara	Piemonte
Italy	Site Reference ID/Investigator #527	Padova	Veneto
Italy	Site Reference ID/Investigator #583	Roma	Lazio
Italy	Site Reference ID/Investigator #522	Rozzano	Milano
New Zealand	Site Reference ID/Investigator #588	Auckland
New Zealand	Site Reference ID/Investigator #663	Auckland
New Zealand	Site Reference ID/Investigator #589	Christchurch	Canterbury
New Zealand	Site Reference ID/Investigator #586	Hamilton	Waikato
New Zealand	Site Reference ID/Investigator #587	Wellington
Poland	Site Reference ID/Investigator #592	Brzozowie	Podkarpackie
Poland	Site Reference ID/Investigator #591	Chorzow
Poland	Site Reference ID/Investigator #529	Gdansk
Poland	Site Reference ID/Investigator #531	Lodz
Poland	Site Reference ID/Investigator #590	Lublin	Lubelskie
Russian Federation	Site Reference ID/Investigator #707	Ryazan
Russian Federation	Site Reference ID/Investigator #304	Yaroslavl
Spain	Site Reference ID/Investigator #533	Barcelona
Spain	Site Reference ID/Investigator #534	Barcelona
Spain	Site Reference ID/Investigator #535	Barcelona
Spain	Site Reference ID/Investigator #604	Barcelona
Spain	Site Reference ID/Investigator #537	Madrid
Spain	Site Reference ID/Investigator #536	Majadahonda	Madrid
Turkey	Site Reference ID/Investigator #606	Ankara
Turkey	Site Reference ID/Investigator #608	Ankara
Turkey	Site Reference ID/Investigator #599	Istanbul
Turkey	Site Reference ID/Investigator #601	Izmir
Turkey	Site Reference ID/Investigator #714	Izmir
Turkey	Site Reference ID/Investigator #602	Kayseri
Ukraine	Site Reference ID/Investigator #597	Cherkasy	Cherkas'ka Oblast
Ukraine	Site Reference ID/Investigator #594	Dnipropetrovsk	Dnipropetrovs'ka Oblast'
Ukraine	Site Reference ID/Investigator #725	Kharkiv	Kharkivs'ka Oblast
Ukraine	Site Reference ID/Investigator #596	Lviv	L'vivs'ka Oblast
Ukraine	Site Reference ID/Investigator #598	Simferopol	Respublika Krym
Ukraine	Site Reference ID/Investigator #595	Vinnytsia	Vinnyts'ka Oblast
Ukraine	Site Reference ID/Investigator #724	Zhytomyr	Zhytomyrs'ka Oblast'
United Kingdom	Site Reference ID/Investigator #721	Birmingham
United Kingdom	Site Reference ID/Investigator #551	Bournemouth	Dorset
United Kingdom	Site Reference ID/Investigator #607	Cardiff	South Glamergon
United Kingdom	Site Reference ID/Investigator #549	Colchester	Essex
United Kingdom	Site Reference ID/Investigator #550	Leeds	Yorkshire
United Kingdom	Site Reference ID/Investigator #544	London	England
United Kingdom	Site Reference ID/Investigator #548	Nottingham
United Kingdom	Site Reference ID/Investigator #668	Oxford	England
United Kingdom	Site Reference ID/Investigator #367	Southampton
United States	Site Reference ID/Investigator #387	Ann Arbor	Michigan
United States	Site Reference ID/Investigator #125	Atlanta	Georgia
United States	Site Reference ID/Investigator #126	Chicago	Illinois
United States	Site Reference ID/Investigator #734	Columbus	Ohio
United States	Site Reference ID/Investigator #047	Duarte	California
United States	Site Reference ID/Investigator #656	Goldsboro	North Carolina
United States	Site Reference ID/Investigator #032	Houston	Texas
United States	Site Reference ID/Investigator #408	La Jolla	California
United States	Site Reference ID/Investigator #381	Laredo	Texas
United States	Site Reference ID/Investigator #712	Las Vegas	Nevada
United States	Site Reference ID/Investigator #071	Louisville	Kentucky
United States	Site Reference ID/Investigator #350	New Hyde Park	New York
United States	Site Reference ID/Investigator #050	Pittsburgh	Pennsylvania
United States	Site Reference ID/Investigator #677	Portland	Oregon
United States	Site Reference ID/Investigator #127	Rochester	New York
United States	Site Reference ID/Investigator #221	Saint Louis	Missouri
United States	Site Reference ID/Investigator #653	San Antonio	Texas
United States	Site Reference ID/Investigator #720	Santa Rosa	California
United States	Site Reference ID/Investigator #404	Seattle	Washington
United States	Site Reference ID/Investigator #038	Stanford	California
United States	Site Reference ID/Investigator #731	Walla Walla	Washington
United States	Site Reference ID/Investigator #307	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Pharmacyclics LLC.	Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  China,  Czechia,  Ireland,  Israel,  Italy,  New Zealand,  Poland,  Russian Federation,  Spain,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	PFS (Progression Free Survival)	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	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.
Secondary	Overall Survival (OS)	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.	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.
Secondary	ORR (Overall Response Rate)	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.	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.
Secondary	Proportion of Sustained Hemoglobin Improvement	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.	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.
Secondary	Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia	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.	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.
Secondary	Proportion of Sustained Platelet Improvement	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.	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.
Secondary	Proportion of Sustained Platelet Improvement in Subjects With Baseline Thrombocytopenia	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.	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.

External Links

•   www.pharmacyclics.com