A 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 (RESONATE™-2)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Janssen Research & Development, LLC
Information provided by (Responsible Party):
Pharmacyclics
ClinicalTrials.gov Identifier:
NCT01722487
First received: October 29, 2012
Last updated: February 7, 2014
Last verified: January 2014
  Purpose

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


Condition Intervention Phase
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Drug: PCI-32765
Drug: Chlorambucil
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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 (RESONATE™-2)

Resource links provided by NLM:


Further study details as provided by Pharmacyclics:

Primary Outcome Measures:
  • 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. ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • 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. ] [ Designated as safety issue: No ]
    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. ] [ Designated as safety issue: Yes ]
    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.


Other Outcome Measures:
  • 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. ] [ Designated as safety issue: Yes ]
    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. ] [ Designated as safety issue: No ]
    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. ] [ Designated as safety issue: No ]
    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


Estimated Enrollment: 272
Study Start Date: January 2013
Estimated Study Completion Date: February 2016
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PCI-32765
PCI-32765 will be supplied as hard gelatin 140-mg capsules for oral (PO) administration.PCI-32765 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. PCI-32765 will be dispensed to patients in bottles at each visit.
Drug: PCI-32765
PCI-32765 will be supplied as hard gelatin 140-mg capsules for oral (PO) administration.PCI-32765 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. PCI-32765 will be dispensed to patients in bottles at each visit.
Active Comparator: Chlorambucil
Chlorambucil will be supplied as 2-mg tablets for PO administration.Chlorambucil is administered orally on Days 1 and 15 of each 28-day cycle.The starting dosage (Cycle 1) is 0.5 mg/kg. If well tolerated, the chlorambucil dose can be increased starting at Cycle 2, with increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg.
Drug: Chlorambucil
Chlorambucil will be supplied as 2-mg tablets for PO administration.Chlorambucil is administered orally on Days 1 and 15 of each 28-day cycle. The starting dosage (Cycle 1) is 0.5 mg/kg. If well tolerated, the chlorambucil dose can be increased starting at Cycle 2, with increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg.

Detailed Description:

Study design: This is a randomized, multicenter, open-label, Phase 3 study designed to compare the safety and efficacy of PCI-32765 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 PCI-32765 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.
  Eligibility

Ages Eligible for Study:   65 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01722487

Locations
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Pharmacyclics
Janssen Research & Development, LLC
Investigators
Study Director: Lori Styles, MD Pharmacyclics
  More Information

Additional Information:
No publications provided

Responsible Party: Pharmacyclics
ClinicalTrials.gov Identifier: NCT01722487     History of Changes
Other Study ID Numbers: PCYC-1115-CA, 2012-003967-23
Study First Received: October 29, 2012
Last Updated: February 7, 2014
Health Authority: United States: Food and Drug Administration
Australia: Department of Health and Ageing Therapeutic Goods Administration
Belgium: Federal Agency for Medicinal Products and Health Products
Canada: Health Canada
China: Food and Drug Administration
Czech Republic: State Institute for Drug Control
Germany: Federal Institute for Drugs and Medical Devices
Ireland: Irish Medicines Board
Israel: Israeli Health Ministry Pharmaceutical Administration
Italy: The Italian Medicines Agency
New Zealand: Food Safety Authority
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Turkey: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Ukraine: State Pharmacological Center - Ministry of Health

Keywords provided by Pharmacyclics:
CLL, SLL

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Lymphoma
Immune System Diseases
Immunoproliferative Disorders
Leukemia, B-Cell
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Chlorambucil
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014