E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) |
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E.1.1.1 | Medical condition in easily understood language |
Leukemia (CLL) or Lymphoma (SLL) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060669 |
E.1.2 | Term | B-cell chronic lymphocytic leukemia/prolymphocytic leukemia/small lymphocytic lymphoma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To monitor progression-free survival (PFS)
• To continue treatment and safety assessment of patients randomized to Arm B (ibrutinib) in Study PCYC-1115-CA (the parent study) who have not progressed at the time of parent study closure
• To follow patients for long-term outcome
• To capture overall response rate (ORR), duration of response (DOR), PFS, and overall survival (OS), and time to next therapy
• To fulfill long-term follow-up requirements of randomized patients after closure of the parent study, including OS |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Randomized in the parent study, PCYC-1115-CA
2. Informed consent for Study PCYC-1116-CA
3. IRC-confirmed PD in the parent study or closure of the parent study
To receive second-line ibrutinib, patients must meet all of the following criteria:
1. IRC-confirmed disease progression in the parent study (PCYC-1115-CA), or for patients who did not progress in the parent study, investigator-determined disease progression in the extension study (PCYC 1116-CA)
2. Received at least 3 cycles of chlorambucil therapy
3. Documented, protocol-defined reason for chlorambucil discontinuation:
• No evidence of response in radiographically assessed disease parameters at Cycle 5 compared to baseline; no further response (defined as failure to reach at least a PR, or a plateau of response with no further improvement of disease parameters) after at least 6 cycles; could not tolerate treatment (a situation defined by the recurrence of toxicity of at least Grade 3 despite appropriate dose reductions and optimal symptomatic management); or maximum treatment of 12 cycles with chlorambucil
4. Demonstrates continuation of adequate organ function, performance status, and other criteria, as follows:
• Eastern Cooperative Oncology Group (ECOG) status of 0-2
• Adequate hematologic function, defined as absolute neutrophil count (ANC) ≥ 0.75 x109/L (independent of growth factor support in the preceding 7 days) and platelet count ≥ 30 x 109/L (independent of transfusion or growth factor support in the preceding 7 days)
• 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 xULN (unless due to Gilbert's syndrome)
• Adequate renal function, defined as an estimated glomerular filtration rate ≥ 30 mL/min using the Cockcroft-Gault equation
• Patients must have recovered from acute toxicities due to prior chemotherapy, radiotherapy, investigational drugs or experimental treatments (non-hematologic toxicities have resolved to a NCI CTCAE [version 4.0] Grade of ≤2) prior to receiving next line ibrutinib on this study
5. Meets at least 1 of the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria for active disease requiring treatment (Hallek 2008):
• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 10 g/dL), and/or thrombocytopenia (platelets < 100,000/μL)
• Massive (≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly
• Massive nodes (at least 10 cm longest diameter), progressive, or symptomatic lymphadenopathy
• Progressive lymphocytosis with an increase of more than 50% 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 (see definitions below) that is poorly responsive to corticosteroids or other standard therapy
(Definitions: Autoimmune hemolytic anemia is defined by at least 1 marker of hemolysis [indirect bilirubin above the 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 1 marker of direct or indirect autoimmune mechanism [positive direct antiglobulin for IgG or C3d, cold agglutinins] [Ding 2007]. Autoimmune thrombocytopenia is defined by platelets ≤ 100,000/μL and increased megakaryocytes on the bone marrow examination.)
• Constitutional symptoms, defined as 1 or more of the following disease-related symptoms or signs, documented in the patient’s record prior to randomization:
o Unintentional weight loss > 10% within 6 months prior to screening
o Significant fatigue (inability to work or perform usual activities)
o Fevers > 100.5°F or 38.0°C for 2 or more weeks prior to screening without evidence of infection
o Night sweats for more than 1 month prior to screening without evidence of infection
6. Obtained the sponsor’s approval for second-line ibrutinib therapy |
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E.4 | Principal exclusion criteria |
To receive second-line ibrutinib, patients must meet NONE of the following criteria:
1. Disease progression involving the central nervous system (CNS) or transformation to another histology
2. Intervening chemotherapy, immunotherapy, or investigational agent specifically to treat CLL if administered before date of IRC confirmed
progressive disease
3. In the 4 weeks before dosing, radiation therapy, major surgery, or receipt of an investigational drug
4. Requirement for treatment with a strong CYP3A inhibitor
5. Uncontrolled systemic infection or requirement for intravenous (IV) antibiotics
6. Noncompliance on the parent study |
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E.5 End points |
E.5.1 | Primary end point(s) |
• PFS on first-line therapy
• PFS after initiation of subsequent anticancer therapy (PFS2)
• Overall survival
• Time to next treatment
• ORR and DOR
• Safety as measured by all AEs and SAEs
• Disease outcome following cessation of ibrutinib therapy after attainment of minimal residual disease (MRD)-negative remission in those patients receiving ibrutinib as secondline therapy |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Disease assessment measures collected until 25 cycles after the start of treatment in patients taking chlorambucil in the parent. Study assessments occur on Day 1 of every 4th cycle (ie Cycles 13 17 21 25 counting from Cycle 1 Day 1 in the parent study) starting from Cyle 30 onwards, the assessment then occur every 6 cycles until patient experiences PD or study is closed by the Sponsor.
Disease assessment measures collected until 25 cycles after the start of treatment in patietns taking ibrutininb in the parent. Study assessments
occur on Day 1 of every 4th cycle (counting from Cycle 1 Day 1 in the parent study) starting from Cyle 30 onwards the assessment then occur
every 12 cycles (every 12 months for pre-PD follow-up) until patient experiences PD or study is closed by the Sponsor. |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 66 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Canada |
China |
Czech Republic |
Ireland |
Israel |
Italy |
New Zealand |
Poland |
Russian Federation |
Spain |
Turkey |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 10 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |