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Zanubrutinib With Obinutuzumab in Untreated Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

ConditionsChronic Lymphocytic LeukemiaSmall Lymphocytic Lymphoma
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorPETHEMA Foundation

About this trial

The goal of this phase II randomized open label study is to compare the rate of complete remission (CR) with undetectable minimal residual disease (uMRD) obtained with zanubrutinib in combination with obinutuzumab with two different schedules of administration of obinutuzumab (starting obinutuzumab at cycle 2 or 12 months) in patients with previously untreated Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). There is scarce information about which is the most appropriate schedule of combining the BTKi and the anti-CD20 monoclonal antibody, and whether treatment can be safely stopped in those patients attaining deep responses (CR with uMRD) remains to be determined.

Response will be assessed after 20 cycles of treatment for the primary objective of the study. Patients attaining uMRD will stop treatment with zanubrutinib, whereas the rest of patients will continue on treatment with zanubrutinib until progression, unacceptable toxicity, or trial completion, whichever comes first.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Adult patients with previously untreated CLL defined following IWCLL criteria (Hallek, 2018).

Must understand and voluntarily sign an informed consent form.

Age ≥ 18 years at the time of signing the informed consent form and must be able to adhere to the study visit schedule and other protocol requirements.

Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia.

Disqualifiers

Prior treatment for CLL.

Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative could be eligible if they have an undetectable HBV DNA (negative polymerase chain reaction (PCR) <20 IU). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded.

Estimated Glomerular Filtration Rate (Cockcroft-Gault Appendix C) ≤30 mL/min/1.73m2.

Absolute neutrophil count (ANC) < 1.0 X 109/L.

Trial design

Design model

Parallel

Treatments tested in this trial

  • Zanubrutinib Oral Product

    Drug

    Zanubrutinib drug product is supplied as 80 mg strengths in capsules for oral administration. In both arms A and B, zanubrutinib 320 mg will be taken qDay with or without food. Patients will take zanubrutinib with water at approximately the same time every day.

  • Obinutuzumab

    Drug

    Each dose of obinutuzumab is 1000 mg administered intravenously, per institutional standards, with the exception of the first infusion in Cycle 2 (arm A) or Cycle 13 (arm B). It is recommended that the initial 1000 mg dose be administered over Day 1 (100 mg) and Day 2 (900 mg). For subjects who tolerate the initial 100 mg dose well and required no dose interruption or modification of the infusion rate, the treating physician may opt to administer the remaining 900 mg on Day 1. Arm A: patients will receive obinutuzumab on days 1 (100 mg), 2 (or day 1 continued, 900 mg), 8 and 15 (1000 mg) of the cycle 2 of zanubrutinib treatment, and on the day 1 of cycles 3-7 (1000 mg). Arm B: patients will receive obinutuzumab on days 1 (100 mg), 2 ( (or day 1 continued, 900 mg), 8 and 15 (1000 mg) of the cycle 13 of zanubrutinib treatment, and on the day 1 of cycles 14-18 (1000 mg).

Treatment groups

106 Participants
are divided into 2 treatment groups
Group A: Arm Zanubrutinib+early ObinutuzumabExperimental treatment 2 interventions
Group B: Arm Zanubutinib+late ObinutuzumabExperimental treatment 2 interventions

Trial outcomes

Primary outcomes

1

Rate of Complete Remission (CR) with undetectable Measurable Residual Disease (uMRD).

To compare the rates of complete remission (CR) with undetectable minimal residual disease (uMRD, assessed by flow cytometry in bone marrow with a value \<10-4 \[0.01%\] tumour cells for being considered as negative) between both arms A and B. Response will be assessed after 20 cycles of treatment for the primary outcome measure. Patients attaining uMRD will stop treatment with zanubrutinib, whereas the rest of patients will continue on treatment with zanubrutinib until progression, unacceptable toxicity, or trial completion, whichever comes first. Patients who achieve an uMRD in bone marrow beyond C20, will also be allowed to stop the treatment. The IWCLL guidelines (Hallek, 2018) will be used to measure response in CLL subjects.

Time frame
7.5 Years

Secondary outcomes

1

Overall response rate (ORR)

Includes the following categories: Complete Remission (CR); CR with incomplete marrow recovery (CRi); Partial Remission (PR), and partial response with lymphocytosis. The IWCLL guidelines (Hallek, 2018) will be used to measure response in CLL subjects. Overall response assessment will include evaluation of physical exams, recording of symptoms, and haematological evaluations. OR will be assessed on Day 1 Cycle 2, on Day 1 of Cycles 3 to 12, and on Day 1 of Cycles 13, 15, 17, 19, 21, and 23, and then every 3 cycles to disease progression or study closure.

Time frame
7.5 Years
2

Measurable Residual Disease (MRD) analysis

In cycle 20, MRD should be analysed in peripheral blood and in the bone marrow by flow-cytometry. Patients with uMRD should be followed every 6 months during 24 months and then every 12 months for MRD by peripheral blood flow cytometry. Patients with detectable MRD and without lymphocytosis (lymphocyte count \< 4.0 X 109/L) should be followed every 6 months for MRD by peripheral blood flow cytometry during 24 months and then every 12 months. In addition, a further bone marrow MRD assessment should be performed at any time during follow-up when the patient has cleared MRD from the peripheral blood. MRD will also be evaluated in PB by flow-cytometry at cycle 9 in arm A (2 cycles after finalizing obinutuzumab).

Time frame
7.5 Years
3

Progression-Free Survival (PFS)

Defined as the time from randomization until symptomatic disease progression (as defined by the updated iwCLL-guidelines) or death by any cause, whichever occurs first.

Time frame
7.5 Years
4

Overall Survival (OS)

Defined as the time from the date of first dose of study drug to the date of the subject's death. If the subject is alive or the vital status is unknown, then the subject's data will be censored at the date the subject was last known to be alive. After progression, patients will be followed every 6 months to assess survival status and the start of subsequent cancer therapies until death, patient withdrawal, loss to follow-up, or study termination, whichever comes first.

Time frame
7.5 Years

Other outcomes

Sponsors and contacts

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PETHEMA Foundation

Lead sponsor

Source ClinicalTrials.gov
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