Clinical trial NCT04883749: Efficacy of Acalabrutinib in Very Old or Frail Patients With Treatment-naïve or Relapsed/Refractory CLL
Official title: CLL-Frail - A Prospective, Multicenter Phase II Trial of Acalabrutinib in Very Old (≥80y) or Frail CLL-Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Lymphoid Leukemia
Keywords: CLL
Lead sponsor: German CLL Study Group
Sponsor class: OTHER
First posted: 2021-05-12
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The aim of this trial is to show the efficacy, safety and feasibility of acalabrutinib in a cohort of CLL-patients ≥80 years or with a FRAIL scale score \>2 (5-item questionnaire to be filled out by the patient)


Eligibility criteria: Inclusion Criteria:

1. Age ≥80 years AND/OR considered too frail for intensive/standard treatment defined by a frailty score of \>2 on the FRAIL scale via the patient´s assessment.
2. Have documented CLL requiring treatment according to iwCLL 2018 criteria
3. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements
4. Glomerular Filtration Rate (GFR) \>30ml/min directly measured with 24hr urine collection, calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 - age) x bodyweight)/ (72 x creatinine), for women x 0, 85) or an equally accurate method (Please note: Patients currently on hemodialysis are excluded from participating in the trial)
5. Adequate liver function as indicated by a total bilirubin ≤ 3 x, Aspartate-Aminotransferase/Alanin-Aminotransferase (AST/ ALT) ≤ 3 x the institutional Upper Limit of Normal (ULN) value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome
6. Adequate marrow function independent of growth factor or transfusion support as follows, unless cytopenia is due to marrow involvement of CLL:

   * Absolute neutrophil count ≥ 1.0 × 10\^9/L
   * Platelet counts ≥ 30 × 10\^9/L; in cases of thrombocytopenia clearly due to marrow involvement of CLL (per the discretion of the investigator); platelet count should be ≥ 10 × 10\^9/L if there is bone marrow involvement
   * Total haemoglobin ≥ 9 g/dL (without transfusion support, unless anaemia is due to marrow involvement of CLL)
7. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA Polymerase Chain Reaction (PCR) is performed every month until 12 months after last month of treatment), negative testing for hepatitis C RNA within 6 weeks prior to registration
8. Life expectancy ≥ 3 months
9. Maximum of 1 previous treatment for CLL
10. In case of a recent previous treatment, patients must have recovered from acute toxicities and treatment regimen must be stopped within the following time periods before start of the study treatment in the CLL-Frail trial:

    * chemotherapy ≥ 28 days
    * antibody treatment ≥ 14 days
    * kinase inhibitors (see also exclusion criterion 6), BCL2-antagonists or immunomodulatory agents ≥ 3 days
    * corticosteroids may be applied until the start of the study therapy, these have to be reduced to an equivalent of ≤ 20 mg prednisolone per day during treatment
11. Signed informed consent and, in the investigator's judgment, able to comply with the study protocol

Exclusion Criteria:

1. \>1 prior CLL-specific therapy (except corticosteroid treatment administered due to necessary immediate intervention; within the last 14 days before start of study treatment, only dose equivalents up to 20 mg prednisolone are permitted)
2. Transformation of CLL to aggressive Non-Hodgkin's Lymphoma (NHL) e.g. Richter's transformation or prolymphocytic leukaemia
3. Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML)
4. Patients with uncontrolled autoimmune haemolytic anaemia or immune thrombocytopenia
5. Prior exposure to acalabrutinib
6. Progression during previous treatment with another BTK inhibitor, and/or presence of known mutations associated with resistance to therapy, e.g. Bruton´s Tyrosine Kinase (BTK) and Phospholipase C Gamma 2 (PLCg2)
7. Uncontrolled concomitant malignancy, i.e. any concomitant malignancy that may compromise the assessment of CLL stage and the response assessment of the study treatment
8. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status \>3
9. Uncontrolled or active infection (including positive SARS-Cov-2 PCR result)
10. Patients with known infection with human immunodeficiency virus (HIV)
11. Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 3 months of screening, or any class 4 cardiac disease as defined by the New York Heart Association Functional Classification at Screening (Please note: Subjects with controlled, asymptomatic atrial fibrillation are allowed to enroll on study)
12. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening
13. Significantly increased risk of bleeding according to the investigator´s evaluation, e.g. due known bleeding diathesis (e.g. von-Willebrandt´s disease or hemophilia), major surgical procedure ≤ 4 weeks or stroke/intracranial hemorrhage ≤ 6 months
14. Use of investigational agents which might interfere with the study drug within 28 days prior to registration for study screening
15. Requirement of therapy with strong CYP3A4 inhibitors/inducers or anticoagulant with phenprocoumon (marcumar) or other vitamin K-antagonists (Please note: Switch to alternative anticoagulants for vitamin K antagonists is permitted)
16. Inability to swallow tablets
17. Legal incapacity
18. Prisoners or subjects who are institutionalized by regulatory or court order
19. Persons who are in dependence to the sponsor or an investigator

Primary outcomes:
measure: Overall response rate (ORR) at initial response assessment
timeFrame: At initial response assessment (approx. 6 months after initiation of therapy)
Secondary outcomes:
measure: ORR at final restaging
timeFrame: At final restaging (approx. 24 months after initiation of therapy)
measure: Overall survival (OS)
timeFrame: Up to 24 month
measure: Progression-free survival (PFS)
timeFrame: Up to 24 month
measure: Event-free survival (EFS)
timeFrame: Up to 24 month
measure: Time to next CLL treatment (TTNT).
timeFrame: Up to 24 month
measure: Safety parameters: Adverse events (AE) and adverse events of special interest (AESI)
timeFrame: Up to 24 month
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
city: Wien
country: Austria
facility: Hanusch Krankenhaus
city: Berlin
country: Germany
facility: Onkologische Schwerpunktpraxis Kurfürstendamm
city: Deggendorf
country: Germany
facility: Donau-Isar-Klinikum Deggendorf Hämatologie/Onkologie
city: Erlangen
country: Germany
facility: Oncoresearch Institut für klinische Studien GbR
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Goslar
country: Germany
facility: Onkologische Kooperation Harz
city: Hamburg
country: Germany
facility: OncoResearch Lerchenfeld
city: Hannover
country: Germany
facility: MediProjekt GBR
city: Kiel
country: Germany
facility: Universitaetsklinikum Schleswig-Holstein Campus Kiel
city: Koblenz
country: Germany
facility: Praxis fuer Haematologie und Onkologie
city: Köln
country: Germany
facility: Universitätsklinik Köln
city: Landshut
country: Germany
facility: H.O.T Praxis Landshut
city: Lübeck
country: Germany
facility: Lübecker Onkologische Schwerpunktpraxis
city: Magdeburg
country: Germany
facility: Gemeinschaftspraxis Haematologie und Onkologie
city: Muenster
country: Germany
facility: Gemeinschaftspraxis für Hämatologie und Onkologie
city: Paderborn
country: Germany
facility: Brüderkrankenhaus St. Josef Paderborn
city: Ravensburg
country: Germany
facility: Gemeinschaftspraxis für Hämatologie und Onkologie
city: Ulm
country: Germany
facility: Universitaetsklinikum Ulm
city: Würzburg
country: Germany
facility: Hämatologisch Onkologische Schwerpunktpraxis
Study officials:
affiliation: Department I of Internal Medicine, University Hospital Cologne
name: Barbara Eichhorst, Prof.
role: PRINCIPAL_INVESTIGATOR
References: