Acalabrutinib in Patients With Chronic Lymphocytic Leukemia With Direct Oral Anticoagulation (CICERO) (CICERO)

A Non-interventional, Prospective, Open-label, Observational Study Evaluating the Effectiveness and Safety of Acalabrutinib (Calquence®) in Patients With Chronic Lymphocytic Leukemia (CLL) Receiving Direct Oral Anticoagulation (DOAC).

The goal of CICERO is to investigate the clinical outcome with a particular focus on prospective data on safety using acalabrutinib (+/- obinutuzumab) in CLL patients receiving co-medication with DOACs (edoxaban, rivaroxaban, dabigatran, apixaban) irrespective of treatment line.

Study Overview

• Status: Recruiting
• Conditions: CLL
• Intervention / Treatment: Drug: Calquence; Drug: Calquence

Detailed Description

The non-interventional study (NIS) CICERO will collect real-world data to explore acalabrutinib (+/- obinutuzumab) in adult CLL patients (irrespective of treatment line) who receive co-medication with DOACs. The primary focus of the study is to investigate the incidence proportion of bleeding events. Due to the mostly elderly CLL patient population, CLL patients often suffer from multiple cardiovascular comorbidities including atrial fibrillation (AF), deep vein thrombosis (DVT) or pulmonary embolism (PE) which make anticoagulation mandatory.

Up to now, no systematic and prospective evaluation on interactions of BTKis and DOACs has been conducted.

In Order to assess bleeding events, a questionnaire will be used to document if bleeding events occurred in-between visits in routine care. Patients will be asked at each visit if distinct events occurred in the time between the last visit until the current visit and discuss the questionnaire with the physician to determine of any (S)AE occurred until end of acalabrutinib treatment.

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Daniel Kummer, Dr.; Phone Number: +49761152420; Email: Cicero@iomedico.com

Study Locations

• Germany
  • Thüringen
    • Saalfeld, Thüringen, Germany, 07318
      • Recruiting
      • Prof. Dr. Fenchel & Dr. Winkler MVZ Träger GbR
      • Contact: Klaus Fenchel, Prof. Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult patients with CLL receiving acalabrutinib (+/- obinutuzumab) and co-medication with DOAC.

Description

Inclusion Criteria:

• 18 years of age or older
• Patients with chronic lymphocytic leukemia (CLL) and decision for treatment with acalabrutinib (+/- obinutuzumab) according to current SmPC as assessed by the treating physician or already started treatment with acalabrutinib (+/- obinutuzumab) according to current SmPC no longer than 6 weeks ago
• Other concomitant disease resulting in medical need of or already under treatment with direct oral anticoagulant (DOAC) treatment with edoxaban (Lixiana®) or rivaroxaban (Xarelto®) or dabigatran (Pradaxa®) or apixaban (Eliquis®) according to the respective current SmPC.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Signed, written informed consent.

Exclusion Criteria:

• Combination of acalabrutinib with other substances than obinutuzumab for CLL treatment
• Participation in an interventional clinical trial with acalabrutinib

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
first-line therapy; Patients enrolled for first-line acalabrutinib (+/- obinutuzumab).	Drug: Calquence; acalabrutinib (+/- obinutuzumab) according to Calquence® SmPC.; Drug: Calquence; acalabrutinib according to Calquence® SmPC.
later-line therapy; Pre-treated patients enrolled for later-line acalbrutinib therapy.	Drug: Calquence; acalabrutinib (+/- obinutuzumab) according to Calquence® SmPC.; Drug: Calquence; acalabrutinib according to Calquence® SmPC.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence proportion of patients with major bleeding event according to Schulman et al.	Bleeding event is defined as major according to Schulmann et al., if it is fatal (contributes to death) and/or symptomatic in a critical area or organ (such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome) and/or causing a decrease in hemoglobin of 2 g/dL (1.24 mmol/l) or more or requires a transfusion of 2 or more units of whole blood or red blood cells. Incidence proportion (cumulative incidence) is calculated as the number of patients with bleeding event while on treatment (+30 days safety follow-up), divided by the number of patients in the full analysis population.	Baseline until end of acalabrutinib treatment (+ 30 days safety follow-up); up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Therapy decision making	Frequencies of parameters affecting therapy choice.	Baseline
Previous therapies	Frequencies and percentages of previous therapies	Baseline
Incidence proportion of clinically relevant non-major (CRNM) bleeding events	CRNM bleeding is defined as bleeding that does not meet the criteria for major bleeding according to Schulman et al. but is associated with the need for medical intervention and/or personal contact with a physician and/or hospitalization or increase in level of care.	Baseline, up to 36 months
Major (according to Schulman et al.) and/or CRNM bleeding events.	Incidence proportion of major (according to Schulman et al.) and/or CRNM bleeding events.	Baseline, up to 36 months
Any bleeding event.	Incidence proportion of any bleeding event.	Baseline, up to 36 months
Incidence proportion of major bleeding according to Ghia et al.	Major bleeding according to Ghia et al. is defined as any serious OR grade ≥3 hemorrhage OR central nervous system (CNS) hemorrhage of any grade, excluding immune thrombocytopenic purpura.	Baseline, up to 36 months
Time to first Occurrence of major bleeding events	Time to first occurrence of major (according to Schulman et al.) bleeding events.	Baseline, up to 36 months
Incidence proportion of central nervous system (CNS) bleeding events	Frequencies of patients with CNS bleeding events.	Baseline, up to 36 months
Patient safety regarding mortality	Mortality from all causes during acalabrutinib therapy.	Baseline, up to 36 months
Patient safety in terms of interactions with effectiveness of DOAC	Rate of any new or recurrent ischemic stroke or arterial systemic embolism or venous thromboembolic events.	Baseline, up to 36 months
VTE (venous thromboembolism)-related death	Incidence proportion of VTE-related death.	Baseline, up to 36 months
Overall response rate (ORR)	ORR is defined as proportion of patients with any response (partial or complete remission) overall.	Baseline, up to 36 months
Progression-free survival (PFS)	Time from start of acalabrutinib to occurrence of progressive disease or death from any cause, whichever comes first.	Baseline, up to 36 months
Overall survival (OS)	OS is defined as time from first administration of acalabrutinib to death from any cause.	Baseline, up to 36 months
Acalabrutinib (+/- obinutuzumab) treatment: Duration	Analysis of treatment duration of acalabrutinib using descriptive statistics.	Baseline, up to 36 months
Acalabrutinib (+/- obinutuzumab) treatment: Dose intensity	Analysis of dose intensity of acalabrutinib treatment with reference to the SmPC (absolute and relative) using descriptive statistics.	Baseline, up to 36 months
Obinutuzumab treatment: Duration	Analysis of treatment duration of obinutuzumab using descriptive statistics	Baseline, up to 36 months
Reasons for end of treatment of obinutuzumab	Frequencies and percentages of reasons for end of obinutuzumab treatment.	Baseline, up to 36 months
Types of DOAC	Type of DOAC used (edoxaban, rivaroxaban, dabigatran and apixaban).	Baseline, up to 36 months
Reasons for DOAC treatment	Frequencies and precentages of reasons for DOAC treatment.	Baseline, up to 36 months
DOAC treatment: Duration	Analysis of DOAC treatment duration using descriptive statistics.	Baseline, up to 36 months
DOAC treatment: Dose modifications	Frequencies and percentages of dose modifications of DOAC treatment.	Baseline, up to 36 months
DOAC treatment: Reasons for dose modifications	Frequencies and percentages of reasons for dose modifications of DOAC treatment.	Baseline, up to 36 months
DOAC treatment: Reasons for end of treatment	Frequencies and percentages of reasons for end of DOAC treatment.	Baseline, up to 36 months
Time from onset to DOAC to start of acalabrutinib	Assessment of time from onset of DOAC to start of acalabrutinib therapy using descriptive statistics.	Baseline, up to 36 months
Concomitant medication	Frequency of concomitant medication other than DOAC.	Baseline, up to 36 months

Collaborators and Investigators

• Sponsor: iOMEDICO AG
• Collaborators: AstraZeneca
• Investigators: Study Chair: Klaus Fenchel, Prof. Dr., Onkologische Praxisklinik Hämatologie/ Onkologie und Gerinnungsstörungen

Publications and helpful links

General Publications

• Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.
• Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, Kaplan P, Kraychok I, Illes A, de la Serna J, Dolan S, Campbell P, Musuraca G, Jacob A, Avery E, Lee JH, Liang W, Patel P, Quah C, Jurczak W. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Sep 1;38(25):2849-2861. doi: 10.1200/JCO.19.03355. Epub 2020 May 27.

Study record dates

Study Major Dates

• Study Start (Actual): October 12, 2022
• Primary Completion (Estimated): October 12, 2025
• Study Completion (Estimated): October 12, 2025

Study Registration Dates

• First Submitted: August 19, 2022
• First Submitted That Met QC Criteria: August 25, 2022
• First Posted (Actual): August 26, 2022

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 22, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: CLL; DOAC; Acalabrutinib (+/- Obinutuzumab)
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Leukemia; Leukemia, B-Cell; Chronic Disease; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Acalabrutinib
• Other Study ID Numbers: IOM-100473

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No