Evaluation of a treatment with acalabrutinib in very old (=80 years) or frail patients with chronic lymphocytic leukemia

Phase 1

• Conditions: Patients with CLL requiring treatment; MedDRA version: 21.1Level: PTClassification code 10008958Term: Chronic lymphocytic leukaemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2020-002142-17-AT
• Lead Sponsor: niversity of Cologne

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2021-07-26
• Last Update Posted: 24 June 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 53

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 criteria14.
3.Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
4.GFR >30ml/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault (for men: GFR ˜ ((140 – age) x body-weight)/ (72 x creatinine), for women x 0, 85) or an equally accurate method.
a.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, AST/ ALT = 3 x the institu-tional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syn-drome.
6.Adequate marrow function independent of growth factor or transfusion support as fol-lows, unless cytopenia is due to marrow involvement of CLL:
a.Absolute neutrophil count = 1.0 × 10^9/L.
b.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.
c.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 PCR is performed every month/every three months if persistently negative until 12 months after last month of treat-ment), 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:
a.chemotherapy = 28 days
b.antibody treatment = 14 days
c.kinase inhibitors (see also exclusion criterion 6), BCL2-antagonists or immuno-modulatory agents = 3 days
d.corticosteroids may be applied until the start of the study therapy, these have to be reduced to an equivalent of = 20mg prednisolone per day during treatment
11.Signed informed consent and, in the investigator’s judgment, able to comply with the study protocol.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 1
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 52

Exclusion Criteria

1.>1 prior CLL-specific therapy (corticosteroid treatment is not counted as prior treatment; within the last 10 days before start of study treatment, only corticosteroid dose equivalents up to 20 mg prednisolone are permitted).
2.Transformation of CLL to aggressive NHL (Richter’s transformation or pro-lymphocytic leukaemia).
3.Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML).
4.Patients with uncontrolled autoimmune haemolytic anaemia or immune thrombocyto-penia.
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 and Phospholipase C Gamma 2 (PLCg2)
a.Please note: Patients with a progression during previous treatment with an-other BTK inhibitor, as well as patients with a known resistance mutation (e.g. BTK-/PLCg2) are excluded from study participation. However, patients who progressed after termination of treatment with other BTK inhibitors or who stopped treatment due to intolerance are eligible for participation.
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) >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 Classifica-tion at screening.
i.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
i.Please note: Switch to alternative anticoagulants for vitamin K antago-nists 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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of this trial aims to show the efficacy of acalabrutinib in a cohort of CLL-patients =80 years or with a FRAIL scale score >2 via the patient’s own assessment.;Secondary Objective: The secondary objective of this trial is to show the safety of acalabrutinib as well as feasibility of conducting a trial in this so far underrepresented patient group;Primary end point(s): Overall response rate (ORR) at initial response assessment (cycle 7, day 1 = approx. 6 months after initiation of therapy). ;Timepoint(s) of evaluation of this end point: The primary endpoint can be analysed as soon as all enrolled patients who did not discontinue prematurely have achieved the initial response assessment at cycle 7 day 1 (= approx. 6 months after initiation of therapy). This will trigger the time point of the analysis of the primary and secondary endpoints.