ASSURE

ASSURE is a Phase 3b, Multicenter, Open-Label, Single-Arm Study of Acalabrutinib in Subjects with Chronic Lymphocytic Leukaemia.

Chronic Lymphocytic Leukemia

Chronic lymphocytic leukaemia (also called CLL) is a type of blood cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). CLL usually gets worse slowly and is one of the most common types of leukaemia in adults, often occurring during or after middle age.

Participants on the ASSURE trial will receive an oral capsule of Acalabrutinib treatment for an intended 48 cycles (28 days per cycle).

Inclusion Criteria:

Men and women ≥18 years of age
Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2018):
- Monoclonal B-cells that are clonally co expressing > 1 B-cell markers (CD19, 20, 23) and CD5
- Prolymphocytes comprising <55% blood lymphocytes
- Presence of > 5 x 109 B lymphocytes in peripheral blood
Active disease (per IWCLL 2018 criteria) meeting at least 1 of the following:
- Evidence of progressive marrow failure as manifested by developing worsening anaemia or thrombocytopenia
- Massive progressive or symptomatic splenomegaly. (>6cm)
- Massive nodes – progressive or symptomatic lymphadenopathy (>10cm)
- Progressive lymphocytosis with an increase >50% over 2 months or lymphocyte doubling time of <6 months
- Autoimmune anaemia and/or thrombocytopenia that is poorly responsive to standard therapy
- B-symptoms (systemic) documented in subject’s chart with supportive objective measurements defined as >1 of the following:
  – Unintentional weight loss >10% in previous 6 months
  – ECOG of >2
  – High fever > 38.0c for >2 weeks before screening
  – Night sweats >1 month before screening without evidence of infection
Must meet one of the following criteria: (3 cohorts)
- Have received no prior therapy for CLL and meet 1 of the following:
  – A score of > 6 on the Cumulative Illness Rating scale (CIRS)
  – Creatinine clearance of 30-69mL/min
  – Have previously received prior therapy and have either R/R CL
  – Have received prior BTKi therapy (i.e. defined as a subject who discontinued a BTKi for any reason except disease progression) for CLL5.
- ECOG of <26.
- Female of childbearing potential, sexually active with a non-sterilized male partner be using >1 highly effective method of contraception. (From screening to 2 days post Study)Fluorescence in situ hybridization (FISH) within 60 days before or during screening reflecting presence or absence of chromosome 17, 13q, 11q deletion, trisomy of chromosome 12 along with percentage of cells with deletion, along with TP53 sequencing. AND Molecular analysis detection of IGHV mutation status at any time since diagnosis – Both of which results are to be back by C1D1
- Subject must be willing adhere to the Protocol visit schedule, understand and comply with protocol requirements and provide written IFC and authorization to use protected health data

Exclusion Criteria

Prior disease progression while on a BTKi for any other malignant or non-malignant condition
Prior malignancy other than CLL (except for Basal/Squamous cell skin cancer, in situ cancer, early stage prostate cancer, or other cancer from which subject has been disease free for >2 years)
History of progressive multifocal leukoencephalopathy
Significant cardiovascular disease (symptomatic arrhythmias, congestive heart failure, myocardial infarction (within 6 months of screening)) or any class 3-4 cardiac disease as per NY heart association functional classification, or corrected QT interval >480msec at screening. (NOTE: Subjects with rate-controlled, asymptomatic atrial fibrillation are allowed to enroll in the study)
Malabsorption syndrome affecting GI function, resection of stomach, extensive small bowel resection, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery
Evidence of Richter’s Transformation (development of high-grade non-Hodgkin lymphoma).
Central nervous system involvement by CLL.
Known history of HIV, serologic status showing active Hep B, or Hep C and Subjects who have received live attenuated vaccine within 4 weeks of first dose of study treatment.
Uncontrolled autoimmune hemolytic anaemia or idiopathic thrombocytopenia purpura defined as declining haemoglobin or platelet count secondary to autoimmune destruction within screening period or requirement of high dose steroids (>20mg daily of prednisone or equivalent for longer than 2 weeks).
History of stroke or intracranial haemorrhage within 6 months of first study dose.
History of bleeding diathesis (eg. Haemophilia or von Willebrand disease).
Presence of GI ulcer diagnosed within 3 months of screening
Major surgical procedure within 4 weeks of first study dose
Requires treatment with Proton-pump inhibitors. (Subjects who switch to H2-receptor antagonists or antacids are eligible)
Subjects requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists within 7 days of first study dose
Absolute Neutrophil count of <0.50 x 109/L or platelet count <30 x 109/L unless proven due to CLL
Total bilirubin, or aspartate aminotransferase, or alanine aminotransferase > 3x ULN, unless proven due to Gilberts syndrome
Estimated creatinine of < 30mL/min
Breastfeeding or pregnant
Received any chemotherapy, external beam radiation, investigational drug or any other anti-CLL therapy within 30 days of first study dose
Concurrent participation in another study
History of Interstitial lung disease (ILD)
Requiring long term treatment with strong cytochrome (CYP3A), or use of strong – medium cytochromes within 7 days of first study dose