E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
An Open-label, Single arm, Multicenter Phase 2 Study of the Bruton’s Tyrosine Kinase Inhibitor PCI-32765 (Ibrutinib) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma with 17p Deletion |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003908 |
E.1.2 | Term | B-cell small lymphocytic lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008976 |
E.1.2 | Term | Chronic lymphocytic leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the efficacy of PCI-32765 in terms of ORR according to an Independent Review Committee (IRC) per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria in subjects with relapsed or refractory CLL/Small Lymphocytic Lymphoma (SLL) with 17p deletion as determined by fluorescence in situ hybridization (FISH) as determined by central laboratory analysis, who have received a minimum of 1 prior line of systemic treatment. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate duration of response (DOR; including subjects who achieve a PR with lymphocytosis); and
• To evaluate the safety and tolerability of PCI 32765.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Men or women, at least 18 years of age
• Diagnosis of CLL/SLL meeting published diagnostic criteria:
− monoclonal B cells (either kappa or lambda light chain restricted) that are clonally co-expressing at least 1 B-cell marker (CD19 or CD20) and CD5
− prolymphocytes may comprise no more than 55% of blood lymphocytes
• Documentation of del (17p13.1) confirmed by central laboratory FISH analysis by peripheral blood sample
• Must have relapsed or refractory disease after receiving at least 1 prior line of systemic therapy which included at least 2 cycles of chemotherapy or immunotherapy for CLL/SLL.
• Currently has active disease meeting at least 1 of the following IWCLL criteria24 for requiring treatment:
− evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin <110 g/L) and/or thrombocytopenia (platelets <100 x 109/L)
− 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 LDT of <6 months. Lymphocyte doubling time 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 subjects with initial blood lymphocyte counts of
<30 x 109/L, 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 anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy (also see Exclusion Criteria, Section 4.2)
− documented constitutional symptoms, defined as 1 or more of the following diseaserelated symptoms or signs:
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
• 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.
• Eastern Cooperative Oncology Group performance status of 0 or 1
• Adequate hematologic function, defined as absolute neutrophil count (ANC) ≥0.75 x 109/L (independent of growth factor support for at least 7 days prior to screening) and platelet
count ≥30 x 109/L (independent of transfusion and growth factor support for at least 7 days prior to screening)
• Adequate hepatic function, defined as serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN)
• Total bilirubin ≤1.5 x ULN
• Estimated creatinine clearance ≥30 mL/min using the Cockcroft-Gault equation
• Ability to receive all outpatient treatment, all laboratory monitoring, and all radiological evaluations at the institution that administers the study drug for the entire study
• Male subjects must use an effective barrier method of contraception during the study and for 3 months following the last dose of PCI-32765 if sexually active with a female of
childbearing potential.
• Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 3 days of the first dose of PCI-32765 and agree to use dual methods of contraception during the study and for 1 month following the last dose with PCI-32765. Post-menopausal females (>45 years old and without menses for >1 year) and surgically sterilized females are exempt from this criterion.
• Ability to provide written informed consent and understand and comply with the requirements of the study |
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E.4 | Principal exclusion criteria |
• Known involvement of the central nervous system by lymphoma or leukemia
• History or current evidence of Richter’s transformation or prolymphocytic leukemia
• Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura, such as subjects with a declining hemoglobin level or platelet count secondary to autoimmune
destruction within the 4 weeks prior to first dose of PCI-32765 or the need for daily corticosteroids ≥20 mg daily to control the autoimmune disease
• Prior hematologic stem cell transplantation <6 months from study enrollment or any ongoing GVHD
• Received any chemo- or immunotherapy, radiation therapy, or investigational drug within 4 weeks prior to treatment
• Received 5 or more prior lines of systemic therapy for CLL
• Prior exposure to PCI-32765
• Prior enrollment into a PCI-32765 study (subjects who did NOT receive PCI-32765)
• Corticosteroid use >20 mg prednisone (or equivalent) within 1 week prior to first dose of PCI-32765, with the exception of inhaled steroid for asthma, topical steroid use, etc. Subjects requiring steroids at daily doses
>20 mg prednisone equivalent systemic exposure daily, 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 treatment
• 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 lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer
− Adequately treated cervical carcinoma in situ without current evidence of disease
• Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia; Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to treatment
• Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of
the small bowel, poorly controlled inflammatory bowel disease, etc.)
• Uncontrolled systemic infection or requirement for intravenous (IV) antibiotics
• Known infection with human immunodeficiency virus
• Serologic status reflecting active hepatitis B or C infection. Subjects who are hepatitis B core antibody positive who are surface antigen negative or who are hepatitis C antibody
positive will need to have a negative polymerase chain reaction (PCR) result prior to enrollment. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive
and those who are hepatitis C PCR positive will be excluded.
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment
• Current life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator’s opinion, could compromise the subject’s safety, or put the study at risk
• Requires or has received anticoagulation treatment with warfarin or equivalent Vitamin K antagonists (eg, phenprocoumon) within 28 days of the first dose of PCI-32765
• Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor
• Woman who is breast-feeding |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is ORR, which is defined as the proportion of subjects in the m-ITT population who achieve a CR, CRi, nPR, or PR, per IWCLL 2008 criteria, based on IRC assessment, over the course of the study in subjects with del 17p CLL as confirmed by central laboratory analysis. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis for all efficacy endpoints will be conducted at approximately 6 months after the last subject’s first dose of PCI-32765, and will be based on IRC assessment and the
m-ITT population. |
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E.5.2 | Secondary end point(s) |
The secondary endpoint for efficacy is DOR (including subjects who achieve a PR with lymphocytosis), defined as the interval between the date of initial documentation of a response
including PR with lymphocytosis, and the date of first documented evidence of progressive disease, death, or date of censoring if applicable, for responders only. Subjects who start new anticancer treatment 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 new anticancer therapy. Responders are subjects in the m-ITT population who achieve CR, CRi, PR, or nPR based on
IWCLL response criteria. Non-responders will be excluded from the analysis for DOR. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary analysis for all efficacy endpoints will be conducted at approximately 6 months after the last subject’s first dose of PCI-32765, and will be based on IRC assessment and the
m-ITT population. |
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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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
To evaluate the safety and tolerability of PCI-32765 |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 20 |
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 |
Germany |
New Zealand |
Sweden |
Turkey |
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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30 months from last subject enrolled |
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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 | 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 |