PreVent-ACaLL

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rigshospitalet

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Jun 2024 → ongoing

Decision date (initial)

2024-06-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

AbbVie · AstraZeneca AB · Novo Nordisk Foundation

External identifiers

EU CT number

2024-511072-33-00

EudraCT number

2019-000270-29

ClinicalTrials.gov

NCT03868722

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Pharmacokinetic

Primary Objective phase 2 part:
Grade ≥3-Infection-free survival in the treatment arm compared to the
observation arm 12 weeks after finishing treatment (24 weeks after
treatment initiation). This is a non-inferiority analysis as detailed in the
statistical analysis plan to assure safety of the combination treatment in
this preemptive trial population.
Primary Objective optional phase 3 part:
Grade ≥3-infection free and CLL-treatment-free survival 2 years after
enrollment

Secondary objectives 9

1. Grade ≥3-infection free and CLL-treatment-free survival at end of treatment, 1 year and 2 years after enrollment
2. Rate of overall survival (OS) and cause of death
3. Treatment free survival
4. Rate and CTCAE V5.0 grade of infections
5. Response rate and duration according to IWCLL criteria
6. Treatment related adverse events, type, frequency and severity during and for 2 years after treatment
7. Immune function as assessed by immune phenotyping, functional TruCulture assays and measurements of cytokine levels
8. MRD levels in bone marrow and peripheral blood
9. Quality of life during and for 2 years after treatment, QLQC30 and CLL16

Conditions and MedDRA coding

Chronic Lymphocytic Leukemia

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. CLL diagnosed according to IWCLL criteria within one year prior to randomization
2. High risk of infection and/or progressive treatment within 2 years according to CLL-TIM
3. IWCLL treatment indication not fulfilled
4. Life expectancy > 2 years
5. Age at least 18 years
6. Ability and willingness to provide written informed consent and adhere to study procedures and treatment
7. Adequate bone marrow function as indicated by platelets above 100 x 10E9, hemoglobin above 10 g/dL and neutrophils above 1 x 10E9
8. Creatinine clearance above 30 mL/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault
9. Adequate liver function as indicated by a total bilirubin≤ 2 x, AST or ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome.
10. 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 until 12 months after last treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration (signature date on informed consent).
11. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.
12. Woman of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 30 days after the last dose of investigational drugs.
13. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
14. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information.

Exclusion criteria 23

1. Prior CLL treatment (including monoclonal antibodies, chemotherapy, small molecules, including CD20 antibodies, BTK inhibitors and bcl-2 inhibitors for any indication)
2. Transformation of CLL (Richter’s transformation)
3. Previous autoimmune disease as AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura) treated with immune suppression or uncontrolled AIHA or ITP
4. History of progressive multifocal leukoencephalopathy
5. HIV infection (a negative test required)
6. Known active infection
7. Malignancies other than CLL requiring systemic therapies (except anti-hormonal therapies) or considered to impact survival
8. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers or anticoagulant therapy with vitamin K antagonists
9. History of bleeding disorders or current platelet inhibitors or anticoagulant therapy
10. History of clinically significant cardiovascular disease such as arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening (counting from signature date on informed consent), or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec at screening.
11. History of stroke or intracranial hemorrhage within 6 months prior to (signature date on informed consent).
12. Use of investigational agents which might interfere with the study drug within 28 days prior to first day of treatment/C1D1.
13. Vaccination with live vaccines within 28 days prior to first day of treatment/C1D1.
14. Major surgery less than 30 days before start of treatment. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
15. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.
16. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment; further pregnancy testing will be performed regularly).
17. Fertile men or women of childbearing potential unless: surgically sterile or ≥ 2 years after the onset of menopause or willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 30 days after the end of study treatment.
18. Legal incapacity.
19. Persons who are in dependence to the sponsor or an investigator
20. Persons not considered fit for the trial by the investigator
21. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
22. Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) > 2x ULN.
23. Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Grade ≥3-Infection-free survival in the treatment arm compared to the observation arm 12 weeks after finishing treatment (24 weeks after treatment initiation). This is a non-inferiority analysis as detailed in statistical analysis plan to assure safety of the combination treatment in this preemptive trial population.

Secondary endpoints 7

1. Grade ≥3-infection free, CLL-treatment-free survival at end of treatment, 1 year and 2 years after enrollment
2. Overall survival and cause of death
3. Treatment free survival
4. Rate and CTCAE grade of infections
5. Response rate and duration according to IWCLL criteria
6. Treatment related adverse events, type, frequency and severity during and for 2 years after treatment
7. Immune function as assessed by immune phenotyping, functional TruCulture assays and measurements of cytokine levels

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rigshospitalet

Sponsor organisation

Rigshospitalet

Address

Blegdamsvej 9

City

Copenhagen Oe

Postcode

2100

Country

Denmark

Scientific contact point

Organisation

Rigshospitalet

Contact name

Carsten Utoft Niemann

Public contact point

Organisation

Rigshospitalet

Contact name

Carsten Utoft Niemann

Third parties 2

Locations

3 EU/EEA countries · 8 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 19 files

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

Application history

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