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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Acerta Pharma B.V.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

30 Sep 2015 → ongoing

Decision date (initial)

2024-05-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Acerta Pharma B.V.

External identifiers

EU CT number

2023-509347-27-00

EudraCT number

2014-005530-64

ClinicalTrials.gov

NCT02477696

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacogenomic, Therapy, Pharmacodynamic, Pharmacokinetic

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 leukaemia (CLL) with high-risk prognostic markers.

Secondary objectives 3

1. Efficacy: To evaluate the benefit/risk of acalabrutinib versus ibrutinib in terms of: 1. Grade ≥ 3 infections 2. Richter’s transformation 3. Atrial fibrillation 4. OS
2. Safety Objectives: - Safety and tolerability including AEs of interest and laboratory assessments
3. Exploratory Objectives: 1. IRC-assessed ORR per IWCLL 2008 criteria (through protocol version 5.0) 2. Investigator-assessed PFS and ORR per IWCLL 2008 criteria 3. Improvement and/or resolution of disease-related symptoms 4. Improvement in incidence of diarrhea, major bleeding events, lymphocytosis, and second primary malignancy 5. Patient-reported outcome (PRO) by various scales will not be collected as of protocol version 6.0 6. Medical resource utilization (MRU) will not be collected as of protocol version 6.0 7. Summarized plasma concentrations of acalabrutinib at specified time points. PK parameters estimated, as appropriate 8. Potential predictive biomarkers and mechanisms of resistance for the disease

Conditions and MedDRA coding

High Risk Chronic Lymphocytic Leukaemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Men and women ≥ 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 ≥ 1 B-cell marker (CD19, CD20, or CD23) and CD5. b. Prolymphocytes may comprise ≤ 55% of blood lymphocytes. c. Presence of ≥ 5 x 109 B lymphocytes/L (5000 μL) in the peripheral blood (at any point since diagnosis); this applies to CLL only.
4. Must have ≥ 1 of the following high-risk prognostic factors: a. Presence of 17p del by central laboratory. b. Presence of 11q del by central laboratory.
5. Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment: a. 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). b. Massive (ie, ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly. c. Massive nodes (ie, ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy. d. Progressive lymphocytosis with an increase of > 50% over a 2-month period or a LDT of < 6 months. LDT may be obtained by linear regression extrapolation of 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 109/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. e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy. f. Constitutional symptoms documented in the subject’s chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease-related symptoms or signs: i. Unintentional weight loss ≥ 10% within the previous 6 months before Screening. ii. Significant fatigue (ie, ECOG performance status 2 or worse; inability to work or perform usual activities). iii. Fevers > 100.5°F or 38.0°C for ≥ 2 weeks before Screening without evidence of infection. iv. Night sweats for > 1 month before Screening without evidence of infection.
6. Must have received ≥ 1 prior therapies for CLL.
7. Meet the following laboratory parameters: a. ANC ≥ 750 cells/μL (0.75 x 109/L) or ≥ 500 cells/μL (0.50 x 109/L) in subjects with documented bone marrow involvement, and independent of growth factor support 7 days before assessment. b. Platelet count ≥ 30,000 cells/μL (30 x 109/L) without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded. c. Serum AST/SGOT and ALT/SGPT ≤ 3.0 x ULN. d. Total bilirubin ≤ 1.5 x ULN. e. Estimated creatinine clearance (ie, eGFR using Cockcroft-Gault) ≥ 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 contraception while on the study and for 2 days after the last dose of acalabrutinib or 90 days after the last dose of ibrutinib, whichever is longer.
10. 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.
11. 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.
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 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).

Exclusion criteria 23

1. Subjects will be ineligible for this study if they meet any of the following criteria: - 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 (> 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 > 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.
7. Prior radio- or toxin-conjugated antibody therapy.
8. Prior allogeneic stem cell transplant or autologous transplant.
9. Major surgery within 4 weeks before first dose of study drug.
10. History of prior malignancy except: 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 malign 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 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.
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 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.
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 CYP3A inhibitor/inducer.
20. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole), applicable only to those subjects receiving Acalabrutinib capsules.
21. Breastfeeding or pregnant.
22. Concurrent participation in another therapeutic clinical trial.
23. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 1

1. 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Acerta Pharma B.V.

Sponsor organisation

Acerta Pharma B.V.

Address

Kloosterstraat 9

City

Oss

Postcode

5349 AB

Country

Netherlands

Scientific contact point

Organisation

Acerta Pharma B.V.

Contact name

Global Clinical Lead

Public contact point

Organisation

Acerta Pharma B.V.

Contact name

Global Clinical Lead

Third parties 3

Locations

2 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications