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

• ClinicalTrials.gov Identifier: NCT01722487
• Recruitment Status: Completed
• First Posted: November 6, 2012
• Results First Posted: May 4, 2016
• Last Update Posted: November 30, 2017
• Sponsor: Pharmacyclics LLC.
• Collaborator: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Pharmacyclics LLC.

Tracking Information

• First Submitted Date: October 29, 2012
• First Posted Date: November 6, 2012
• Results First Submitted Date: March 31, 2016
• Results First Posted Date: May 4, 2016
• Last Update Posted Date: November 30, 2017
• Study Start Date: March 2013
• Actual Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 31, 2016)

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

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

Original Primary Outcome Measures (submitted: November 2, 2012)

The primary endpoint of this study is PFS as assessed by IRC review according to IWCLL 2008 criteria with modification for treatment-related lymphocytosis [ Time Frame: All enrolled patients have completed at least 12 months of treatment and/or follow-up and either (a) 81 progression or death events have been observed or (b) 15 months have elapsed after the last patient is randomized, whichever occurs first. ]

Assessment of response should include physical examination, radiographic imaging, and evaluation of blood and marrow (if applicable). Patients who withdraw from the study or are considered lost to follow-up without prior documentation of disease progression will be censored on the date of the last adequate disease assessment. Patients who start new anticancer therapy before documentation of disease progression will be censored on the date of the last adequate disease assessment that is on or before the start date of the new anticancer therapy. For patients without an adequate post-baseline disease assessment, PFS will be censored on the date of randomization. Patients who have 2 or more consecutive missing disease assessments immediately before PD or death will be censored for analysis of PFS at the time of last adequate disease assessment. The adequate disease assessment is defined as physical examination and CBC, or CBC and CT scan.

Current Secondary Outcome Measures (submitted: March 31, 2016)

• Overall Survival (OS) [ Time Frame: Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month. ]
  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.
• ORR (Overall Response Rate) [ Time Frame: Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month. ]
  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.
• Proportion of Sustained Hemoglobin Improvement [ Time Frame: Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month. ]
  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.
• Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia [ Time Frame: Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month. ]
  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.
• Proportion of Sustained Platelet Improvement [ Time Frame: Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month. ]
  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.
• Proportion of Sustained Platelet Improvement in Subjects With Baseline Thrombocytopenia [ Time Frame: Analysis was conducted when 15 months had elapsed after the last subject was randomized with cutoff date of 4 May 2015. The median follow-up time is 18 month. ]
  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.

Original Secondary Outcome Measures (submitted: November 2, 2012)

• To measure Efficacy [ Time Frame: Secondary endpoints will be collected for 12 months of treatment and/or follow-up and either (a) 81 progression or death events have been observed or (b) 15 months have elapsed after the last patient is randomized whichever occurs first. ]
  Efficacy ORR defined as the proportion of patients who achieve CR, CR with incomplete bone marrow recovery (CRi), nodular partial response (nPR), or partial response (PR) per IWCLL 2008 criteria over the course of the study as assessed by the IRC. OS Rate of MRD-negative CRs, Change from baseline FACiT-Fatigue score, Rate of hematological improvement in patients with baseline anemia and thrombocytopenia defined by hemoglobin > 11 g/dL or increase ≥ 50% over baseline or platelet count > 100,000/mm3, respectively.
• Safety [ Time Frame: Secondary endpoints will be collected for 12 months of treatment and/or follow-up and either (a) 81 progression or death events have been observed or (b) 15 months have elapsed after the last patient is randomized whichever occurs first. ]
  Safety Incidence of adverse events (AEs) and changes in laboratory variables, vital signs, and ECG. In addition, Event-Free Survival (EFS), will be included as a secondary endpoint in response to European Medicines Agency (EMA) recommendation, where progressive disease (PD), death, and non response at 3 months are defined as events. Non-response is defined as patients who do not have CR, CRi, nPR, PR, or PR with lymphocytosis.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: November 2, 2012)

• To evaluate and compare the treatment groups in terms rate of hematological improvement, changes in disease related symptoms, patient reported outcomes, PK characteristics, medical resource utilization and potential predictive biomarkers. [ Time Frame: Exploratory endpoints will be collected for 12 months of treatment and/or follow-up and either (a) 81 progression or death events have been observed or (b) 15 months have elapsed after the last patient is randomized whichever occurs first. ]
  Rate of hematological improvement in patients with baseline neutropenia, Changes in disease-related symptoms.Changes and differences in PRO measures EORTC QLQ-30 & EQ-5D-5L. The efficacy criteria for the EQ-5D-5L will be the change in weighted utility score from baseline to each assessment, Time to treatment failure, Change in immunoglobulin levels from baseline, Medical resource utilization (MRU) associated with therapy including the number of hospitalizations, emergency department visits, blood product transfusions, and use of hematopoietic growth factors.
• To evaluate and compare the treatment groups in terms rate of hematological improvement, changes in disease related symptoms, patient reported outcomes, PK characteristics, medical resource utilization and potential predictive biomarkers. [ Time Frame: Exploratory endpoints will be collected for 12 months of treatment and/or follow-up and either (a) 81 progression or death events have been observed or (b) 15 months have elapsed after the last patient is randomized whichever occurs first. ]
  PK characteristics of PCI-32765 in patients with CLL/SLL and determination of which, if any, covariates (ie, age, gender, body size, race) influence exposure to ibrutinib, Response based on predictive biomarkers.
• To evaluate and compare the treatment groups in terms rate of hematological improvement, changes in disease related symptoms, patient reported outcomes, PK characteristics, medical resource utilization and potential predictive biomarkers. [ Time Frame: Exploratory endpoints will be collected for 12 months of treatment and/or follow-up and either (a) 81 progression or death events have been observed or (b) 15 months have elapsed after the last patient is randomized whichever occurs first. ]
  Percentage of patients with elevated TSH compared to a normal baseline value Percentage of patients with low free T4 compared to a normal baseline value

Descriptive Information

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

Detailed Description

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

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

• Treatment Arm A: Oral Chlorambucil 0.5 mg/kg on Days 1 and 15 of each 28-day cycle; the dose can be increased, if well tolerated, in increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg; patients receive a minimum of 3 and a maximum of 12 cycles, in the absence of progressive disease or unacceptable toxicity.
• Treatment Arm B: Oral Ibrutinib 420 mg/day Randomization will be stratified on Eastern Cooperative Oncology Group (ECOG) performance status (0,1 versus 2); presence of advanced Rai stage (yes/no), advanced being defined as Stages 3-4; and geographic region: US versus non-US.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Study Arms

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

Publications *

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 4, 2016): 269
• Original Estimated Enrollment (submitted: November 2, 2012): 272
• Actual Study Completion Date: May 2015
• Actual Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 65 Years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, China, Czechia, Ireland, Israel, Italy, New Zealand, Poland, Russian Federation, Spain, Turkey, Ukraine, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01722487
• Other Study ID Numbers: PCYC-1115-CA; 2012-003967-23 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: We share this information with FDA and other authorities for the purposes of analyzing the study but not with other researchers

• Current Responsible Party: Pharmacyclics LLC.
• Original Responsible Party: Same as current
• Current Study Sponsor: Pharmacyclics LLC.
• Original Study Sponsor: Same as current
• Collaborators: Janssen Research & Development, LLC

Investigators

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

• PRS Account: Pharmacyclics LLC.
• Verification Date: October 2017