CLL-Frail - A prospective, multicenter phase II trial of acalabrutinib in very old (≥80y) or frail CLL-Patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Of Cologne

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 May 2021 → 8 May 2025

Decision date (initial)

2024-04-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

AstraZeneca

External identifiers

EU CT number

2023-507002-14-00

EudraCT number

2020-002142-17

ClinicalTrials.gov

NCT04883749

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

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 objectives 8

1. ORR at final restaging (cycle 25, day 1 = approx. 24 months af-ter initiation of therapy).
2. Overall survival (OS).
3. Progression free survival (PFS).
4. Event-free survival (EFS).
5. Duration of response.
6. Time to next CLL treatment (TTNT).
7. Feasibility parameters: o Modification of treatment and reasons. o Treatment discontinuation: early discontinuation of treatment and reasons. o Treatment exposure: total cumulative dose, dose intensity, time on treatment (any dose), time on treatment (full dose), days with 0 dose.
8. Safety parameters: Type, frequency, and severity of o adverse events (AEs) and o adverse events of special interest (AESI) and adverse events of particular interest (AEPI) including falls and delirium as typical adverse geriatric outcomes and their relationship to study treatment.

Conditions and MedDRA coding

treatment-naïve or relapsed/refractory chronic lymphocytic leukemia

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

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. 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 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, AST/ ALT ≤ 3 x the institutional 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: i. Absolute neutrophil count ≥ 1.0 × 10^9/L. ii. 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. iii. 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 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 treat-ment in the CLL-Frail trial: i. chemotherapy ≥ 28 days, ii. antibody treatment ≥ 14 days, iii. kinase inhibitors (see also exclusion criterion 6), BCL2-antagonists or immuno-modulatory agents ≥ 3 days, iv. 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.

Exclusion criteria 19

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 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 in the 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall response rate (ORR) at initial response assessment (cycle 7, day 1 = approx. 6 months after initiation of therapy).

Secondary endpoints 8

1. ORR at final restaging (cycle 25, day 1 = approx. 24 months after initiation of therapy).
2. Overall survival (OS).
3. Progression free survival (PFS).
4. Event-free survival (EFS).
5. Duration of response.
6. Time to next CLL treatment (TTNT).
7. Feasibility parameters: o Modification of treatment and reasons. o Treatment discontinuation: early discontinuation of treatment and reasons. o Treatment exposure: total cumulative dose, dose intensity, time on treatment (any dose), time on treatment (full dose), days with 0 dose.
8. Safety parameters: Type, frequency, and severity of o adverse events (AEs) and o adverse events of special interest (AESI) and adverse events of particular interest (AEPI) including falls and delirium as typical adverse geriatric outcomes and their relationship to study treatment.

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Of Cologne

Sponsor organisation

University Of Cologne

Address

Albertus-Magnus-Platz 1

City

Cologne

Postcode

50923

Country

Germany

Scientific contact point

Organisation

University Of Cologne

Contact name

Barbara Eichhorst

Public contact point

Organisation

University Of Cologne

Contact name

Barbara Eichhorst

Third parties 7

Locations

2 EU/EEA countries · 16 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 29 files

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

Application history

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