| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| High Risk Chronic Lymphocytic Leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Long term cancer of the blood |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| To assess whether ACP-196 is non-inferior to ibrutinib with respect to progression-free survival (PFS) based on independent review committee (IRC) assessment in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) with high-risk prognostic markers. |
|
| E.2.2 | Secondary objectives of the trial |
Efficacy:
To evaluate the benefit/risk of ACP-196 versus ibrutinib in terms of:
•Grade ≥ 3 infections
•Richter’s transformation
•Atrial fibrillation
•Overall survival (OS)
Safety Objectives:
•Safety and tolerability including AEs of interest and laboratory assessments
Exploratory Objectives:
•IRC-assessed ORR per IWCLL 2008 criteria (through protocol version 5.0)
•Investigator-assessed PFS and ORR per IWCLL 2008 criteria
•Improvement and/or resolution of disease-related symptoms
•Improvement in incidence of diarrhea, major bleeding events, lymphocytosis, and second primary malignancy
•Patient-reported outcome (PRO) by various scales will not be collected as of protocol version 6.0
•Medical resource utilization (MRU) will not be collected as of protocol version 6.0
•Summarized plasma concentrations of acalabrutinib at specified time points. PK parameters estimated, as appropriate
•Potential predictive biomarkers and mechanisms of resistance for the disease |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Men and women ≥ 18 years of age.
•Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
•Diagnosis of CLL that meets published diagnostic criteria (Hallek 2008):
oMonoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥ 1 B-cell marker (CD19, CD20, or CD23) and CD5.
oProlymphocytes may comprise ≤ 55% of blood lymphocytes.
oPresence of ≥ 5 x 10^9 B lymphocytes/L (5000 μL) in the peripheral blood (at any point since diagnosis); this applies to CLL only.
•Must have ≥ 1 of the following high-risk prognostic factors:
oPresence of 17p del by central laboratory
oPresence of 11q del by central laboratory
•Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment:
oEvidence 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).
oMassive (ie, ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly
oMassive nodes (ie, ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
oProgressive lymphocytosis with an increase of > 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 (ALC) 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 10^9/L (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.
oAutoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
oConstitutional symptoms documented in the subject’s chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease related symptoms or signs:
-Unintentional weight loss ≥ 10% within the previous 6 months before Screening.
-Significant fatigue (ie, ECOG performance status 2 or worse; inability to work or perform usual activities).
-Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without evidence of infection.
-Night sweats for > 1 month before Screening without evidence of infection.
•Must have received ≥ 1 prior therapies for CLL.
•Meet the following laboratory parameters:
oAbsolute neutrophil count (ANC) ≥ 750 cells/μL (0.75 x 10^9/L) or ≥ 500 cells/μL (0.50 x 10^9/L) in subjects with documented bone marrow involvement and independent of growth factor support 7 days before assessment.
oPlatelet count ≥ 30,000 cells/μL (30 x 10^9/L) without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded.
oSerum aspartate transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT) ≤ 3.0 x upper limit of normal (ULN).
oTotal bilirubin ≤ 1.5 x ULN.
oEstimated creatinine clearance (ie, estimated glomerular filtration rate [eGFR] using Cockcroft-Gault) ≥ 30 mL/min.
•Able to receive all outpatient treatment, all laboratory monitoring, and all radiologic evaluations at the institution that administers study drug for the entire study.
•Women who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after last dose of acelabrutinib or 90 days after the last dose of ibrutinib, whichever is longer.
•Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 2 days after the last dose of acalabrutinib or 90 days after the last dose of ibrutinib, whichever is longer.
•Men must agree to refrain from sperm donation during the study and for 2 days after the last dose of acalabrutinib or 90 days after the last dose of ibrutinib, whichever is longer.
•Must be willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations). Note vulnerable subjects, as defined in the International Conference on Harmonisation (ICH) GCP, are not allowed on this protocol (eg, prisoners or institutionalized subjects). |
|
| E.4 | Principal exclusion criteria |
•Known central nervous system (CNS) lymphoma or leukemia.
•Known prolymphocytic leukemia or history of, or currently suspected, Richter’s syndrome.
•Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP) defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (> 20 mg daily of prednisone daily or equivalent).
•Prior exposure to ibrutinib or to a B-cell receptor (BCR) inhibitor (eg, Bruton tyrosine kinase [Btk] inhibitors or phosphoinositide-3 [PI3] kinase inhibitors or Syk inhibitors) or a BCL-2 inhibitor (eg, ABT-199).
•Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days before first dose of study drug.
•Corticosteroid use > 20 mg within 1 week before first dose of study drug, except as indicated for other medical conditions such as inhaled steroid for asthma, topical steroid use, or as premedication for administration of study drug or contrast. For example, 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 count lowering are excluded.
•Prior radio- or toxin-conjugated antibody therapy.
•Prior allogeneic stem cell transplant or autologous transplant.
•Major surgery within 4 weeks before first dose of study drug.
•History of prior malignancy except for the following:
oMalignancy treated with curative intent and with no evidence of active disease present for more than 3 years before Screening and felt to be at low risk for recurrence by treating physician
oAdequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer
oAdequately treated cervical carcinoma in situ without current evidence of disease
•Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or QTc > 480 msec at screening.
•Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
•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 ongoing intravenous anti-infective treatment.
•Known history of infection with human immunodeficiency virus (HIV).
•Serologic status reflecting active hepatitis B or C infection. Subjects with 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 before randomization. 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 before randomization.
•History of bleeding diathesis (eg, hemophilia, von Willebrand disease).
•Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.
•Requires treatment with a strong cytochrome CYP3A4 inhibitor/inducer.
•Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole)
•Breastfeeding or pregnant.
•Concurrent participation in another therapeutic clinical trial.
• Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To assess whether ACP-196 is non-inferior to ibrutinib with respect to progression-free survival (PFS) based on independent review committee (IRC) assessment in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) with high-risk prognostic markers. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
To compare between ACP-196 and ibrutinib in terms of:
•Incidence of Grade ≥ 3 infections
•Incidence of Richter’s transformation
•Incidence of atrial fibrillation
•OS
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 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 | 22 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 95 |
| 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 |
| Israel |
| New Zealand |
| United States |
| Turkey |
| Belgium |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| 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 | 11 |
| 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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