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

NCT01722487 | Completed Phase 3 Results

• 2 other identifiers: PCYC-1115-CA2012-003967-23
• Study Type: interventional
• Target: 269
• Locations: 16 countries
• Sites: 108

Brief Summary

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

Conditions

Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma

Keywords

CLL, SLL

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Overall Survival (OS)

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

• ORR (Overall Response Rate)

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

• Proportion of Sustained Hemoglobin Improvement

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

• Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia

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

• Proportion of Sustained Platelet Improvement

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

Study Arms (2)

Ibrutinib

EXPERIMENTAL

Ibrutinib will be supplied as hard gelatin 140-mg capsules for oral (PO) administration. Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily. The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an outpatient basis. Ibrutinib will be dispensed to patients in bottles at each visit.

Drug: Ibrutinib

Chlorambucil

ACTIVE COMPARATOR

Chlorambucil will be supplied as 2-mg tablets for PO administration. Chlorambucil is administered orally on Days 1 and 15 of each 28-day cycle.The starting dosage (Cycle 1) is 0.5 mg/kg. If well tolerated, the Chlorambucil dose can be increased starting at Cycle 2, with increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg.

Drug: Chlorambucil

Interventions

Ibrutinib DRUG

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.

Ibrutinib

Chlorambucil DRUG

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.

Chlorambucil

Eligibility Criteria

• Age: 65 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• 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
• Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria (Hallek 2008)
• 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
• Measurable nodal disease by computed tomography (CT)
• ECOG performance status of 0-2
• Life expectancy \> 4 months from randomization

You may not qualify if:

• Known involvement of the central nervous system by lymphoma or leukemia
• History or current evidence of Richter's transformation or prolymphocytic leukemia
• 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
• Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura
• Any previous treatment (chemotherapy, radiotherapy, and/or monoclonal antibodies) intended specifically to treat CLL/SLL
• Received any immunotherapy, vaccine, or investigational drug within 4 weeks prior to randomization
• 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.
• Major surgery within 4 weeks prior to randomization
• 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
• Currently active, clinically significant cardiovascular disease or a history of myocardial infarction within 6 months prior to randomization
• Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function
• Uncontrolled active systemic fungal, bacterial, viral, or other infection or requirement for intravenous (IV) antibiotics

Sponsors & Collaborators

• Pharmacyclics LLC.: lead
• Janssen Research & Development, LLC: collaborator

Study Sites (108)

Site Reference ID/Investigator #047

Duarte, California, 91010, United States

Location

Site Reference ID/Investigator #408

La Jolla, California, 92093, United States

Location

Site Reference ID/Investigator #720

Santa Rosa, California, 95403, United States

Location

Site Reference ID/Investigator #038

Stanford, California, 94305, United States

Location

Site Reference ID/Investigator #125

Atlanta, Georgia, 30318, United States

Location

Site Reference ID/Investigator #126

Chicago, Illinois, 60637, United States

Location

Site Reference ID/Investigator #071

Louisville, Kentucky, 40207, United States

Location

Site Reference ID/Investigator #307

Worcester, Massachusetts, 01655, United States

Location

Site Reference ID/Investigator #387

Ann Arbor, Michigan, 48109, United States

Location

Site Reference ID/Investigator #221

St Louis, Missouri, 63110, United States

Location

Site Reference ID/Investigator #712

Las Vegas, Nevada, 89169, United States

Location

Site Reference ID/Investigator #350

New Hyde Park, New York, 11042, United States

Location

Site Reference ID/Investigator #127

Rochester, New York, 14642, United States

Location

Site Reference ID/Investigator #656

Goldsboro, North Carolina, 27534, United States

Location

Site Reference ID/Investigator #734

Columbus, Ohio, 43219, United States

Location

Site Reference ID/Investigator #677

Portland, Oregon, 97227, United States

Location

Site Reference ID/Investigator #050

Pittsburgh, Pennsylvania, 15232, United States

Location

Site Reference ID/Investigator #032

Houston, Texas, 77030, United States

Location

Site Reference ID/Investigator #381

Laredo, Texas, 78041, United States

Location

Site Reference ID/Investigator #653

San Antonio, Texas, 78229, United States

Location

Site Reference ID/Investigator #404

Seattle, Washington, 98109, United States

Location

Site Reference ID/Investigator #731

Walla Walla, Washington, 99362, United States

Location

Site Reference ID/Investigator #654

Kogarah, New South Wales, 2217, Australia

Location

Site Reference ID/Investigator #503

Woolloongabba, Queensland, 4102, Australia

Location

Site Reference ID/Investigator #163

Bedford Park, South Australia, 5042, Australia

Location

Site Reference ID/Investigator #555

Hobart, Tasmania, 7000, Australia

Location

Site Reference ID/Investigator #193

Box Hill, Victoria, 3128, Australia

Location

Site Reference ID/Investigator #556

Clayton, Victoria, 3168, Australia

Location

Site Reference ID/Investigator #501

Fitzroy, Victoria, 3065, Australia

Location

Site Reference ID/Investigator #715

Frankston, Victoria, 3199, Australia

Location

Site Reference ID/Investigator #558

Geelong, Victoria, 3220, Australia

Location

Site Reference ID/Investigator #170

Heidelberg, Victoria, 3084, Australia

Location

Site Reference ID/Investigator #164

Brussels, Brussells, 1200, Belgium

Location

Site Reference ID/Investigator #727

Yvoir, Namur, 5530, Belgium

Location

Site Reference ID/Investigator #560

Ghent, Oost-Vlaanderen, 9000, Belgium

Location

Site Reference ID/Investigator #559

Leuven, Vlaams Brabant, 3000, Belgium

Location

Site Reference ID/Investigator #628

Bruges, West-Vlaanderen, 8000, Belgium

Location

Site Reference ID/Investigator #561

Antwerp, 2060, Belgium

Location

Site Reference ID/Investigator #184

Brussells, 1000, Belgium

Location

Site Reference ID/Investigator #157

Calgary, Alberta, T2N 4N2, Canada

Location

Site Reference ID/Investigator #018

Edmonton, Alberta, T6G 1Z2, Canada

Location

Site Reference ID/Investigator #159

Ottawa, Ontario, K1H 8L6, Canada

Location

Site Reference ID/Investigator #674

Guangzhou, Guangdong, 510060, China

Location

Site Reference ID/Investigator #671

Nanjing, Jiangsu, 210029, China

Location

Site Reference ID/Investigator #675

Hangzhou, Zhejiang, 31003, China

Location

Site Reference ID/Investigator #670

Beijing, 100142, China

Location

Site Reference ID/Investigator #673

Beijing, 100191, China

Location

Site Reference ID/Investigator #564

Hradec Králové, Královéhradecký kraj, 500 05, Czechia

Location

Site Reference ID/Investigator #562

Brno, 625 00, Czechia

Location

Site Reference ID/Investigator #566

Plzen-Lochotin, 304 60, Czechia

Location

Site Reference ID/Investigator #572

Dublin, 7, Ireland

Location

Site Reference ID/Investigator #570

Dublin, 8, Ireland

Location

Site Reference ID/Investigator #571

Galway, ST4 6QG, Ireland

Location

Site Reference ID/Investigator #573

Haifa, 31048, Israel

Location

Site Reference ID/Investigator #576

Haifa, 31096, Israel

Location

Site Reference ID/Investigator #577

Jerusalem, 91031, Israel

Location

Site Reference ID/Investigator #578

Nahariya, 22100, Israel

Location

Site Reference ID/Investigator #575

Petah Tikva, 49100, Israel

Location

Site Reference ID/Investigator #574

Ramat Gan, 52621, Israel

Location

Site Reference ID/Investigator #583

Rome, Lazio, 00161, Italy

Location

Site Reference ID/Investigator #522

Rozzano, Milano, 20089, Italy

Location

Site Reference ID/Investigator #582

Novara, Piedmont, 28100, Italy

Location

Site Reference ID/Investigator #527

Padua, Veneto, 35128, Italy

Location

Site Reference ID/Investigator #580

Bologna, 40138, Italy

Location

Site Reference ID/Investigator #584

Milan, 20122, Italy

Location

Site Reference ID/Investigator #523

Milan, 20132, Italy

Location

Site Reference ID/Investigator #581

Milan, 20162, Italy

Location

Site Reference ID/Investigator #524

Modena, 41100, Italy

Location

Site Reference ID/Investigator #589

Christchurch, Canterbury, 8011, New Zealand

Location

Site Reference ID/Investigator #586

Hamilton, Waikato Region, 3240, New Zealand

Location

Site Reference ID/Investigator #663

Auckland, 0622, New Zealand

Location

Site Reference ID/Investigator #588

Auckland, 1023, New Zealand

Location

Site Reference ID/Investigator #587

Wellington, 6021, New Zealand

Location

Site Reference ID/Investigator #590

Lublin, Lublin Voivodeship, 20-081, Poland

Location

Site Reference ID/Investigator #592

Brzozowie, Podkarpackie Voivodeship, 36.200, Poland

Location

Site Reference ID/Investigator #591

Chorzów, 40, Poland

Location

Site Reference ID/Investigator #529

Gdansk, 80-952, Poland

Location

Site Reference ID/Investigator #531

Lodz, 93-510, Poland

Location

Site Reference ID/Investigator #707

Ryazan, 390039, Russia

Location

Site Reference ID/Investigator #304

Yaroslavl, 150062, Russia

Location

Site Reference ID/Investigator #536

Majadahonda, Madrid, 28222, Spain

Location

Site Reference ID/Investigator #534

Barcelona, 08035, Spain

Location

Site Reference ID/Investigator #533

Barcelona, 08036, Spain

Location

Site Reference ID/Investigator #535

Barcelona, 08041, Spain

Location

Site Reference ID/Investigator #604

Barcelona, 08908, Spain

Location

Site Reference ID/Investigator #537

Madrid, 28050, Spain

Location

Site Reference ID/Investigator #608

Ankara, 06500, Turkey (Türkiye)

Location

Site Reference ID/Investigator #606

Ankara, 06590, Turkey (Türkiye)

Location

Site Reference ID/Investigator #599

Istanbul, 34390, Turkey (Türkiye)

Location

Site Reference ID/Investigator #714

Izmir, 35040, Turkey (Türkiye)

Location

Site Reference ID/Investigator #601

Izmir, 35340, Turkey (Türkiye)

Location

Site Reference ID/Investigator #602

Kayseri, 38039, Turkey (Türkiye)

Location

Site Reference ID/Investigator #598

Simferopol, Autonomous Republic of Crimea, 95023, Ukraine

Location

Site Reference ID/Investigator #597

Cherkasy, Cherkasy Oblast, 18009, Ukraine

Location

Site Reference ID/Investigator #594

Dnipropetrovsk, Dnipropetrovsk Oblast, 49102, Ukraine

Location

Site Reference ID/Investigator #725

Kharkiv, Kharkivs’ka Oblast’, 61070, Ukraine

Location

Site Reference ID/Investigator #596

Lviv, Lviv Oblast, 79044, Ukraine

Location

Site Reference ID/Investigator #595

Vinnytsia, Vinnytsia Oblast, 21018, Ukraine

Location

Site Reference ID/Investigator #724

Zhytomyr, Zhytomyr Oblast, 10022, Ukraine

Location

Site Reference ID/Investigator #551

Bournemouth, Dorset, BH7 7DW, United Kingdom

Location

Site Reference ID/Investigator #544

London, England, SE5 9RS, United Kingdom

Location

Site Reference ID/Investigator #668

Oxford, England, OX3 7LE, United Kingdom

Location

Site Reference ID/Investigator #549

Colchester, Essex, CO4 5JL, United Kingdom

Location

Site Reference ID/Investigator #607

Cardiff, South Glamergon, CF14 4XW, United Kingdom

Location

Site Reference ID/Investigator #550

Leeds, Yorkshire, LS9 7TF, United Kingdom

Location

Site Reference ID/Investigator #721

Birmingham, B9 5SS, United Kingdom

Location

Site Reference ID/Investigator #548

Nottingham, NG5 1PB, United Kingdom

Location

Site Reference ID/Investigator #367

Southampton, SO16 6YD, United Kingdom

Location

Related Publications (9)

• Abuhelwa AY, Almansour SA, Brown JR, Al-Shamsi HO, Abuhelwa Z, Kharaba Z, Bustanji Y, Semreen MH, Ali S, Alhuraiji A, McKinnon RA, Sorich MJ, Alzoubi KH, Hopkins AM. Statin use and survival in CLL/SLL treated with ibrutinib: pooled analysis of 4 randomized controlled trials. Blood Adv. 2025 Jul 22;9(14):3566-3575. doi: 10.1182/bloodadvances.2024015287.

  PMID: 40266025 DERIVED

• Barr PM, Owen C, Robak T, Tedeschi A, Bairey O, Burger JA, Hillmen P, Dearden C, Grosicki S, McCarthy H, Li JY, Offner F, Moreno C, Jermain M, Zhou C, Hsu E, Szoke A, Kipps TJ, Ghia P. Many People With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Benefit From Ibrutinib Treatment Up To 8 Years: A Plain Language Summary. Future Oncol. 2023 Jan 9. doi: 10.2217/fon-2022-0898. Online ahead of print.

  PMID: 36617990 DERIVED

• Barr PM, Owen C, Robak T, Tedeschi A, Bairey O, Burger JA, Hillmen P, Coutre SE, Dearden C, Grosicki S, McCarthy H, Li JY, Offner F, Moreno C, Zhou C, Hsu E, Szoke A, Kipps TJ, Ghia P. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022 Jun 14;6(11):3440-3450. doi: 10.1182/bloodadvances.2021006434.

  PMID: 35377947 DERIVED

• Burger JA, Robak T, Demirkan F, Bairey O, Moreno C, Simpson D, Munir T, Stevens DA, Dai S, Cheung LWK, Kwei K, Lal I, Hsu E, Kipps TJ, Tedeschi A. Up to 6.5 years (median 4 years) of follow-up of first-line ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and high-risk genomic features: integrated analysis of two phase 3 studies. Leuk Lymphoma. 2022 Jun;63(6):1375-1386. doi: 10.1080/10428194.2021.2020779. Epub 2022 Jan 11.

  PMID: 35014928 DERIVED

• Allan JN, Shanafelt T, Wiestner A, Moreno C, O'Brien SM, Li J, Krigsfeld G, Dean JP, Ahn IE. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022 Feb;196(4):947-953. doi: 10.1111/bjh.17984. Epub 2021 Dec 5.

  PMID: 34865212 DERIVED

• Coutre SE, Byrd JC, Hillmen P, Barrientos JC, Barr PM, Devereux S, Robak T, Kipps TJ, Schuh A, Moreno C, Furman RR, Burger JA, O'Dwyer M, Ghia P, Valentino R, Chang S, Dean JP, James DF, O'Brien SM. Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies. Blood Adv. 2019 Jun 25;3(12):1799-1807. doi: 10.1182/bloodadvances.2018028761.

  PMID: 31196847 DERIVED

• Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, Bartlett NL, Burger JA, Hillmen P, Coutre S, Devereux S, Grosicki S, McCarthy H, Li J, Simpson D, Offner F, Moreno C, Zhou C, Styles L, James D, Kipps TJ, Ghia P. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018 Sep;103(9):1502-1510. doi: 10.3324/haematol.2018.192328. Epub 2018 Jun 7.

  PMID: 29880603 DERIVED

• Brown JR, Moslehi J, O'Brien S, Ghia P, Hillmen P, Cymbalista F, Shanafelt TD, Fraser G, Rule S, Kipps TJ, Coutre S, Dilhuydy MS, Cramer P, Tedeschi A, Jaeger U, Dreyling M, Byrd JC, Howes A, Todd M, Vermeulen J, James DF, Clow F, Styles L, Valentino R, Wildgust M, Mahler M, Burger JA. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017 Oct;102(10):1796-1805. doi: 10.3324/haematol.2017.171041. Epub 2017 Jul 27.

  PMID: 28751558 DERIVED

• Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O'Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ; RESONATE-2 Investigators. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015 Dec 17;373(25):2425-37. doi: 10.1056/NEJMoa1509388. Epub 2015 Dec 6.

  PMID: 26639149 DERIVED

Related Links

• www.pharmacyclics.com

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

ibrutinib; Chlorambucil

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals

Results Point of Contact

• Title: Dr. Lori Styles, Medical Monitor
• Organization: Pharmacyclics LLC

lstyles@pcyc.com

+1 (408) 215-3770

Study Officials

• Lori Styles, MD

  Pharmacyclics LLC.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2012
• First Posted: November 6, 2012
• Study Start: March 1, 2013
• Primary Completion: May 1, 2015
• Study Completion: May 1, 2015
• Last Updated: November 30, 2017
• Results First Posted: May 4, 2016

Record last verified: 2017-10

Data Sharing

• IPD Sharing: Will not share

Locations

PL (5); CZ (3); GB (9); BE (7); CN (5); AU (10); IE (3); CA (3); RU (2); TU (6); UA (7); IT (9); NZ (5); US (22); IL (6); ES (6)