A Randomized, Multicenter, Open-Label, Non-Inferiority, Phase 3 Study of ACP-196 Versus Ibrutinib in Previously Treated Subjects with High Risk Chronic Lymphocytic Leukemia
Philip A. Thompson
The goal of this clinical research study is to learn if ACP-196 is able to control CLL and SLL as well as ibrutinib. The safety of ACP-196 will also be studied.
Disease Group: Leukemia
Treatment Agent: ACP-196,Ibrutinib
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Acerta Pharma BV
Primary Objective: 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. The IRC will use the International Workshop on Chronic Lymphocytic Leukemia Criteria (IWCLL, Hallek 2008) with incorporation of the clarification for treatment-related lymphocytosis (Cheson 2012), hereafter referred to as IWCLL 2008 criteria. Secondary Objectives: To evaluate the benefit:risk of ACP-196 versus ibrutinib in terms of: Grade 3 infections Richter's transformation (RT) Atrial fibrillation (AF) Overall survival (OS) Safety Objectives: Safety and tolerability including adverse events of interest and laboratory assessments Exploratory Objectives: IRC-assessed overall response rate (ORR) per IWCLL 2008 criteria 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 secondary malignancy Patient-reported outcome (PRO) by various scales Medical resource utilization (MRU) Pharmacokinetic (PK) characteristics of ACP-196 in subjects with CLL to determine which, if any, covariates (eg, age, sex, body size, race) influence exposure to ACP-196 Identification of potential predictive biomarkers and mechanisms of disease resistance.
IRB Review and Approval Date: 06/23/2016
Recruitment Status: Open
Projected Accrual: 500
1) Eligible subjects will be considered for inclusion in this study if
they meet all of the following criteria: (1) Men and women greater than
or equal to 18 years of age.
2) ECOG performance status of 0 to 2.
3) Diagnosis of CLL that meets published diagnostic criteria (Hallek 2008): (a) Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing greater than or equal to 1 B-cell marker (CD19, CD20, or CD23) and CD5. (b) Prolymphocytes may comprise less than or equal to 55% of blood lymphocytes. (c) Presence of >or= 5000 B lymphocytes/microL in peripheral blood, at any point since diagnosis.
4) Must have greater than or equal to 1 of the following high-risk prognostic factors: (i) Presence of 17p del by central laboratory. (ii) Presence of 11q del by central laboratory.
5) Meets at least 1 IWCLL 2008 criterion for requiring treatment: a) Marrow failure: hemoglobin <10 g/dL and/or platelets <100 x 10^9/L. b) Massive (>o/=6cm below costal margin), progressive or symptomatic splenomegaly c) Massive (>/=10cm in max diameter), progressive or symptomatic lymphadenopathy. d) Progressive lymphocytosis; increase >50% over 2 months or LDT of <6 months. If initial blood lymphocyte count is <30x10^9/L, LDT should not be used as a single parameter to define need for treatment. e) Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids or standard therapy. f) Disease-related constitutional symptoms - >/=1 of: i) Unintentional weight loss of >/=10% within the previous 6 months before screening. ii) Significant fatigue (ie ECOG PS 2; inability to work or perform usual activities). iii) Fevers >100.5°F (38.0°C) for at least 2 weeks before screening, without evidence of infection. iii) Night sweats for >1 month before screening not due to infection.
6) Must have received greater than or equal to 1 prior therapies for CLL.
7) Meet the following laboratory parameters: (a) ANC greater than or equal to 750 cells/microL (0.75 x 10^9/L) or greater than or equal to 500 cells/microL (0.50 x 10^9/L) in subjects with documented bone marrow involvement, and independent of growth factor support 7 days before assessment. (b) Platelet count greater than or equal to 30,000 cells/microL (30 x 10^9/L) without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded. (c) Serum AST/SGOT and ALT/SGPT less than or = 3.0 x ULN. (d) Total bilirubin less than or equal to 1.5 x ULN. (e) Estimated creatinine clearance (ie, eGFR using Cockcroft-Gault) greater than or equal to 30 mL/min.
8) Able to receive all outpatient treatment, all laboratory monitoring, and all radiologic evaluations at the institution that administers study drug for the entire study.
9) Women who are sexually active and can bear children must agree to use highly effective forms of contraction while on the study and for 90 days after the last dose of ACP-196 or ibrutinib. Highly effective forms of contraception are defined in Section 6.2.11
10) Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of ACP-196 or ibrutinib. Highly effective forms of contracpetion are defined in Section 6.2.11.
11) Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of ACP-196 or ibrutinib.
12) 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 subject 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).
1) Subjects will be ineligible for this study if they meet any of the
following criteria: (1) Known CNS lymphoma or leukemia.
2) Known prolymphocytic leukemia or history of, or currently suspected, Richter’s syndrome.
3) Uncontrolled AIHA or ITP defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (greater than 20 mg daily of prednisone daily or equivalent).
4) Prior exposure to ibrutinib or to a BCR inhibitor (eg Btk or PI3 kinase or Syk inhibitors) or a BCL-2 inhibitor (eg, ABT-199).
5) Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days before first dose of study drug.
6) Corticosteroid use greater than 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. Subjects requiring steroids at daily doses greater than 20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for leukemia control or white blood cell count lowering are excluded.
7) Prior radio- or toxin-conjugated antibody therapy.
8) Prior allogeneic stem cell or autologous transplant.
9) Major surgery within 4 weeks before first dose of study drug.
10) History of prior malignancy except for the following: (a) Malignancy 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 (b) Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer (c) Adequately treated cervical carcinoma in situ without current evidence of disease
11) Significant cardiovascular disase such as uncontrolled or symptiomatic arrhythmias, congestive heart failure, or myocardial infarction with 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Function Classification, or corrected QT interval (QTc) >480msec at screening.
12) 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.
13) 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.
14) Known history of infection with HIV.
15) 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 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.
16) History of stroke or intracranial hemorrhage within 6 months before randomization.
17) History of bleeding diathesis (eg, hemophilia, von Willebrand disease).
18) Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.
19) Requires treatment with a strong CYP3A4 inhibitor/inducer.
20) Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
21) Breast feeding or pregnant.
22) Concurrent participation in another therapeutic clinical trial.
23) Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
Information and next steps
Philip A. Thompson
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