Clinical trial conducted to evaluate the effectiveness of a combination of drugs called venetoclax and rituximab adapted to the state of minimal residual disease in patients with untreated chronic lymphocytic leukemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Polish Adult Leukemia Group

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

24 Feb 2022 → ongoing

Decision date (initial)

2024-12-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AbbVie, Inc.

External identifiers

EU CT number

2024-518494-34-00

EudraCT number

2019-004613-14

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy, Pharmacogenomic

To demonstrate that VR treatment strategy leads to 35% of complete response (CR) or complete response with incomplete hematological recovery (CRi) according to IWCLL 2018 guidelines with undetectable (<10-4) MRD in bone marrow (as determined by flow cytometry) at the completion of therapy.

Secondary objectives 6

1. Efficacy: To evaluate rates of overall response (ORR; defined as complete response [CR], complete response with incomplete hematological recovery [CRi], and partial response [PR]), PR, and CR and CRi at disease assessment time points
2. Efficacy: To determine progression-free survival (PFS), the duration of response (DOR) and time to next treatment (TTNT)
3. Efficacy: To evaluate overall survival (OS)
4. Efficacy: To evaluate OR, PR, CR, and CRi rates, PFS, DOR, TTNT and OS in patients with TP53 deletion/mutation
5. Efficacy: To estimate the rate of uMRD (MRD <10-4) in the peripheral blood at 12 months from treatment completion
6. Safety: To evaluate the safety and tolerability of treatment by assessment of incidence and severity of any adverse events/serious adverse events, adverse events Grade ≥3 (including laboratory toxicities Grade ≥ 3)

Conditions and MedDRA coding

Chronic lymphocytic leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Signed Informed Consent Form
2. Ability and willingness to comply with the requirements of the study protocol
3. Patient must have diagnosis of CLL or SLL that meets published 2018 IWCLL NCI-WG criteria
4. No prior treatment for CLL or SLL including chemotherapy, BTK inhibitor therapy, venetoclax, small molecule signaling inhibitor, or monoclonal antibody therapy
5. Patient must have an indication for treatment according to published 2018 IWCLL NCI-WG criteria
6. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2
7. Adequate hematologic function independent of growth factor or transfusion support, per local laboratory reference range at screening (unless caused by underlying disease, as established by extensive bone marrow involvement or as a result of hypersplenism secondary to the involvement of the spleen by lymphoma per the investigator) defined as follows: o Hemoglobin ≥ 9 g/dL; o Absolute neutrophil count ≥ 1.0 × 109/L; o Platelet count ≥ 50 × 109/L
8. Adequate renal function, per local laboratory reference range at screening, as indicated by: o Calculated creatinine clearance ≥ 30 mL/min using 24-hour Creatinine Clearance or modified Cockcroft-Gault equation (eCCR; with the use of ideal body mass [IBM] instead of mass)
9. Adequate liver function, per local laboratory reference range at screening, as indicated by: o AST and ALT ≤ 2.5 × ULN o Total bilirubin ≤ 1.5 × ULN (or ≤ 3 × ULN for patients with documented Gilbert syndrome)
10. No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation
11. No current use of corticosteroids. EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is permitted
12. No previous autoimmune complications (e.g. autoimmune hemolytic anemia or immune thrombocytopenia) that have developed since the initial diagnosis of CLL and have required treatment with high dose corticosteroids (e.g. equivalent of > 20 mg/day of prednisone), monoclonal antibody-based therapy, or chemotherapy. Prior use of corticosteroids for reasons other than treatment of autoimmune complications of CLL is allowed
13. No major surgery within 4 weeks (28 days) of first dose of study drug or minor surgery within 3 days of first dose of study drug
14. No radiation therapy ≤ 4 weeks prior to study treatment initiation
15. Patient must be able to receive xanthine oxidase inhibitor or rasburicase for tumor lysis syndrome (TLS) prophylaxis
16. Negative pregnancy test (serum βHCG) for women of childbearing potential (including pre-menopausal women who have had a tubal ligation) and for all women not meeting the definition of postmenopausal (≥ 24 months of amenorrhea), and who have not undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy. For all other women, documentation must be present in medical history confirming that the patient is not of childbearing potential. o Female patients who are not surgically sterile or postmenopausal must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the study. o Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy

Exclusion criteria 13

1. Richter's transformation confirmed by biopsy
2. History of other malignancy that could affect compliance with the protocol or interpretation of results o Patients with a history of curatively treated basal or squamous cell carcinoma or Stage 1 melanoma of the skin or in situ carcinoma of the cervix are eligible. o Patients with a malignancy that has been treated with surgery alone with curative intent will be included. Individuals in documented remission without treatment for (> / =) 2 years prior to enrollment may be included at the discretion of the investigator.
3. Uncontrolled active systemic infection (viral, bacterial, and fungal)
4. Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection confirmed by polymerase chain reaction (PCR) test from respiratory tract specimen (e.g. nasopharyngeal swab)
5. Known positive serology for human immunodeficiency virus (HIV), due to potential drug-drug interactions between anti-retroviral medications and the study drugs
6. Active hepatitis C, defined by the detectable hepatitis C ribonucleic acid (RNA) in plasma by polymerase chain reaction (PCR)
7. Patient is pregnant or breast-feeding
8. Malabsorption syndrome or other condition that precludes enteral route of administration
9. An individual organ/system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system (note that symptoms related to CLL should not be included in the patient’s screening CIRS score). Investigators should consult the General Rules for Severity Rating as well as the Organ-Specific Categories when assigning scores for certain conditions (i.e., pulmonary embolism) and consider the level of morbidity associated with a patient’s condition
10. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study
11. Patients who have received strong and moderate CYP3A inhibitors and/or CYP3A inducers within 7 days prior to the first dose of venetoclax, patients who consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax
12. Patients who require use of warfarin (due to potential drug-drug interactions that may potentially increase the exposure of warfarin). Patients may be eligible if able to be taken off warfarin and started on an alternative anticoagulant
13. Patients with evidence of any of the following conditions: o New York Heart Association Functional Classification III or IV congestive heart failure o History of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration o Recent infection requiring systemic treatment; need to have completed anti-biotic therapy > 14 days before the first dose of study drug o Cerebral vascular accident or intracranial bleed within the last 6 months o Known active chronic hepatitis C o Positive serology for hepatitis B defined as a positive test for hepatitis B surface antigen (HBsAg); in addition, if negative for HBsAg but hepatitis B core antibody (HBcAb) positive (regardless of hepatitis B surface antibody [HBsAb] status), a hepatitis B deoxyribonucleic acid (DNA) test will be performed and, if positive the subject will be ineligible; if the hepatitis B DNA test is negative (i.e. viral load undetectable) then the individual is eligible; if a patient who is HBsAg negative, HBcAb positive, and hepatitis B DNA negative is enrolled, they should be considered for either prophylactic anti-viral therapy or careful monitoring for HBV reactivation. Patients who have protective titers of HBsAb after vaccination or prior but cured hepatitis B are eligible.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The proportion of patients who will achieve a CR or CRi with bone marrow MRD assessed by flow cytometry less than 10-4 at the end of treatment.

Secondary endpoints 10

1. Overall Response Rate (ORR) Percentage of Participants with Best Overall Response (ORR)(defined as complete response [CR], CR [CRi], nodular partial response [nPR], PR) as assessed by investigator determined using iwCLL guidelines
2. Percentage of participants with MRD less than 10-4 in peripheral blood at 12 months following end of treatment
3. Duration of Responses (DOR) [time frame: response up to disease progression or death, whichever occurs first (up to approximately 5 years)].
4. Progression-Free Survival (PFS) [ time frame: baseline up to disease progression or death, whichever occurs first (up to approximately 5 years)] Investigator-Assessed Progression-Free Survival (PFS) determined using standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines
5. Overall Survival (OS) [time Frame: Baseline up to death (up to approximately 5 years)]
6. Time to Next Anti-CLL Treatment (TTNT) [time frame: baseline up to next treatment or death from any cause, whichever occurs first (up to approximately 5 years)]
7. Quality of life (QOL) of subjects during therapy. Changes from baseline in QOL measures assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30).
8. Evaluation of safety of VR treatment comprising all grades adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE, v.5.0).
9. To develop innovative, machine-learning-based algorithms to assess the prediction of response to VR treatment in CLL (as a probability of selected categories of response supported by rationale) based on patients’ electronic health records.
10. To identify gut microbiota associated biomarkers that predict risk of development treatment-related toxicities (mainly infections) and kinetics and depth of response including undetectable MRD.

Investigational products

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

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Polish Adult Leukemia Group

Sponsor organisation

Polish Adult Leukemia Group

Address

Ul. Wybrzeze Armii Krajowej 15

City

Gliwice

Postcode

44-102

Country

Poland

Scientific contact point

Organisation

Polish Adult Leukemia Group

Contact name

Clinical Trial Information Desk

Public contact point

Organisation

Polish Adult Leukemia Group

Contact name

Clinical Trial Information Desk

Third parties 1

Locations

1 EU/EEA country · 10 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 7 files

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

Application history

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