| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 17.1 |
| 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 |
|
| 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 evaluate the efficacy of PCI-32765 compared with chlorambucil
based on the Independent Review Committee (IRC) assessment of
progression-free survival (PFS) in patients 65 years of age or older
with treatment-naive chronic lymphocytic leukemia (CLL) or small
lymphocytic lymphoma (SLL) |
|
| E.2.2 | Secondary objectives of the trial |
To compare the treatment groups in terms of the following:
Efficacy
• Overall response rate (ORR) according to International Workshop
on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria, as assessed by the IRC
• Rate of minimal residual disease (MRD)-negative complete responses (CRs)
• Overall survival (OS)
• Fatigue measured by Functional Assessment of Chronic Illness
Therapy-Fatigue (FACIT-F)
• Hematological improvement measured by hemoglobin and platelet
counts
Safety
• To evaluate the safety and tolerability of PCI-32765 compared with chlorambucil |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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/μLor hemoglobin < 10 g/dL
• Clinically apparent autoimmune cytopenia (autoimmune hemolytic
anemia or immune thrombocytopenia): Autoimmune hemolytic anemia is defined by at least one marker of hemolysis indirect bilirubin above the upper limit of normal (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 one marker of direct or indirect autoimmune mechanism (positive direct antiglobulin for IgG or C3d, cold agglutinins) (Ding 2007).; Immune thrombocytopenia is defined by
platelets ≤ 100,000/μL and increased megakaryocytes on the bone
marrow exam.
• Eastern Cooperative Oncology Group (ECOG) performance score = 1 or 2
2. Diagnosis of CLL/SLL that meets published diagnostic criteria (Hallek 2008):
• Monoclonal B cells (either kappa or lambda light chain restricted) that are clonally coexpressing at least 1 B-cell marker (CD19 or CD20) and CD5.
• Prolymphocytes may comprise no more than 55% of blood lymphocytes.
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 (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), or 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
(defined in Inclusion Criterion 1) that is poorly responsive to corticosteroids or other standard therapy (but see Exclusion Criterion 4).
• Constitutional symptoms, defined as one or more of the following disease-related symptoms or signs, documented in the patient’s record prior to randomization:
− unintentional weight loss > 10% within 6 months prior to screening
− significant fatigue (inability to work or perform usual activities)
− fevers > 100.5°F or 38.0°C for 2 or more weeks prior to screening without evidence of infection
− night sweats for more than 1 month prior to screening without evidence of infection
4. Measurable nodal disease by computed tomography (CT), defined as at least 1 lymph node > 1.5 cm in the longest diameter in a site that has not been previously irradiated. An irradiated lesion may be assessed for measurable disease only if there has been documented progression in that lesion since radiotherapy has ended.
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 ULN, and total bilirubin ≤ 1.5 x ULN (unless due to Gilbert’s syndrome).
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. |
|
| E.4 | Principal 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 chromosome17: del (17p13.1), as defined by del 17p 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, such as those patients with a declining hemoglobin level or platelet count secondary to autoimmune destruction within the 4 weeks prior to first dose of study drug, or the need for daily prednisone ≥ 20 mg daily (or corticosteroid equivalent) to control the autoimmune disease.
5. Any previous treatment (chemotherapy, radiotherapy, and/or monoclonal antibodies) intended specifically to treat CLL/SLL.
6. Received any immunotherapy, live vaccine, or investigational drug within 4 weeks prior to randomization.
7. Corticosteroid use > 20 mg prednisone daily (or corticosteroid equivalent, see Appendix M) 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), 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, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York HeartAssociation Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
11. Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (including malabsorption syndrome, resection of the small bowel, or poorly controlled inflammatory bowel disease).
12. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection, and without improvement despite appropriate antibiotics or other treatment), or requirement for intravenous (IV) antibiotics.
13. Known history of infection with human immunodeficiency virus (HIV).
14. Active hepatitis B or C infection. Patients who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative
polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
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, in the investigator’s opinion, could compromise the patient’s safety or put the study at risk.
17. Requirement for anticoagulation with warfarin.
18. Requirement for treatment with a strong CYP3A4/5 inhibitor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS as assessed by IRC review according to IWCLL criteria (Hallek 2008) with modification for treatment-related lymphocytosis (Hallek 2012). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| (a) after all enrolled patients have received a minimum of 12 months of treatment and/or follow-up, and (b) either 81 confirmed progression or death events have occurred or 15 months have elapsed after the last patient was randomized -whichever comes first. |
|
| E.5.2 | Secondary end point(s) |
Efficacy
• ORR defined as the proportion of patients who achieve CR, CRi, nPR, or PR per IWCLL 2008 criteria over the course of the study as assessed by the IRC
• Rate of MRD-negative CRs
• OS
• Change from baseline FACiT-Fatigue score
• Rate of hematological improvement
Safety
• Incidence of 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 a European Medicines Agency (EMA) recommendation, where progressive disease (PD), death and non-response at 4 months after randomization are defined as events. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| (a) after all enrolled patients have received a minimum of 12 months of treatment and/or follow-up, and (b) either 81 confirmed progression or death events have occurred or 15 months have elapsed after the last patient was randomized—whichever comes first. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 7 |
| 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 |
|
| 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
|
| The database will be locked at the point that all enrolled patients have had the opportunity to complete 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. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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 |
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