Zanubrutinib, Obinutuzumab, Sonrotoclax (BOSon) or BGB-16673, Obinutuzumab, Sonrotoclax (DOSon) in TN CLL/SLL

A Multicenter Phase 2 Study of Zanubrutinib, Obinutuzumab, and Sonrotoclax (BOSon) or Tacabrutideg (BGB-16673), Obinutuzumab, and Sonrotoclax (DOSon) in Treatment-Naïve Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

The purpose of this study is to determine the proportion of participants who achieve undetectable measurable residual disease (uMRD) in previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational [drug/device/intervention] to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The U.S. Food and Drug Administration (FDA) has approved sonrotoclax for the treatment of patients with mantle cell lymphoma. However, the U.S. FDA has not approved sonrotoclax for the treatment of patients with CLL/SLL.

The U.S. FDA has approved zanubrutinib and obinutuzumab as a treatment option for CLL/SLL.

The U.S. FDA has not approved tacabrutideg (BGB-16673).

The combinations of zanubrutinib, obinutuzumab, and sonrotoclax (BOSon regimen) or tacabrutideg (BGB-16673), obinutuzumab, and sonrotoclax (DOSon) are not an approved regimen for CLL or SLL and are investigational in this study.

Zanubrutinib blocks a protein in B-cells (immune cells) called Bruton tyrosine kinase (BTK). BTK helps CLL/SLL cells live and grow. By blocking BTK, zanubrutinib may slow down or stop the activity of CLL/SLL cells, which can lead to improvement in the symptoms associated with CLL/SLL.

Tacabrutideg (BGB-16673) degrades a protein in B-cells (immune cells) called Bruton tyrosine kinase (BTK). BTK helps CLL/SLL cells live and grow. By degrading BTK, tacabrutideg may slow down or stop the activity of CLL/SLL cells, which can lead to improvement in the symptoms associated with CLL/SLL.

Obinutuzumab is a drug that targets a protein called CD20, which is found on the surface of B cells, the white blood cells that are affected by CLL/SLL. When obinutuzumab attaches to CD20, it directly both destroys the B cells and makes them more "visible" to the immune system. The immune system then attacks and destroys the cancerous B cells.

Sonrotoclax blocks a protein called B-cell lymphoma-2 (Bcl-2). Bcl-2 helps certain blood cancer cells live and replicate. By blocking Bcl-2, sonrotoclax can slow or stop blood cancer cells replicating and allow natural cell death to occur, thereby causing blood cancer cell death.

This research study uses the clonoSEQ test to detect measurable residual disease (MRD). The U.S. Food and Drug Administration (FDA) has approved the clonoSEQ MRD test for patients with CLL/SLL. However, using this test to guide the duration of therapy is investigational in this study. Although we hope that this test can be used to provide a more personalized treatment plan for participants with CLL/SLL, there is also a risk that this results in some participants receiving more or less treatment than they otherwise would receive.

In this research study, we are hoping to learn how safe and effective the combinations of BOSon (zanubrutinib, obinutuzumab and sonrotoclax) or DOSon (tacabrutideg, obinutuzumab and sonrotoclax) are for people who require therapy for CLL/SLL.

It is expected that about 80 people will take part in this research study, including 40 people treated with BOSon and 40 people treated with DOSon.

Inclusion Criteria:

• Participant must have CLL or SLL (WHO criteria).

• Participant must require treatment according to iwCLL guidelines.

• Participants must have no prior systemic therapy for CLL or SLL, except:

  • Prior local radiation for symptomatic disease is permitted.
  • Short course systemic corticosteroids is permissible for disease control, improvement of performance status, or non-cancer indication. However, duration of steroid course must be ≤14 days with maximum daily dose of ≤100 mg prednisone, ≤20 mg dexamethasone, or equivalent, and must be discontinued prior to study treatment (last dose may be administered up until the morning of / prior to study treatment). Inhaled steroids, topical steroids, and replacement / stress corticosteroids are permitted independent of above rules. In cases of autoimmune complications of CLL (e.g., ITP or AIHA), steroid usage is permitted.

• Age ≥18 years.

• ECOG performance status of 0, 1 or 2.

• Participants must meet the following organ and marrow function as defined below:

  • absolute neutrophil count ≥1,000/µL without growth factor support (filgrastim within 5 days or PEGfilgrastim within 10 days of test), unless clearly due to disease under study (per investigator)
  • platelets ≥75,000/µL, or ≥20,000/µL if clearly due to disease under study (per investigator)
  • total bilirubin ≤2 x institutional upper limit of normal (ULN), or ≤3 x institutional ULN if due to Gilbert's syndrome, or with PI approval if clearly due to disease under study
  • AST(SGOT)/ALT(SGPT) ≤2.5 x × institutional ULN
  • CrCl or GFR ≥30 mL/min as estimated by the Cockcroft-Gault equation, the CKD-EPI equation, or as measured by 24-hour urine collection

• For females of childbearing potential, a serum pregnancy test must be negative within screening period.

• For female patients of childbearing potential: agreement to use highly effective form(s) of contraception (i.e., one that results in a low failure rate [<1% per year] when used consistently and correctly) or remain abstinent (refrain from heterosexual intercourse) during the treatment period and to continue its use for ≥ 30 days after the last dose of zanubrutinib or BGB-16673 or ≥ 7 days after the last dose of sonrotoclax, and for ≥18 months fter the last dose of obinutuzumab (whicher is later).

  • A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (>12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.
  • Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Hormonal contraceptive methods must be supplemented by a barrier method.
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

• For men with a female partner of childbearing potential or a pregnant female partner: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom in addition to 1 of the highly effective methods of contraception listed below, from the time of taking the first dose of study drug , during the treatment period and to continue its use for ≥ 30 days after the last dose of zanubrutinib or BGB-16673 or ≥ 7 days after the last dose of sonrotoclax, and for ≥18 months fter the last dose of obinutuzumab (whicher is later).

  --The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

• Willingness to not donate or bank sperm or oocytes during the entire study treatment period and after treatment discontinuation for for ≥ 30 days after the last dose of zanubrutinib or BGB-16673 or ≥ 7 days after the last dose of sonrotoclax, and for ≥18 months fter the last dose of obinutuzumab (whicher is later).

• Ability to understand and the willingness to sign a written informed consent document. (Providing consents in as many languages as possible is encouraged)

Exclusion Criteria:

• Known histologic transformation from CLL or SLL to an aggressive lymphoma (i.e., Richter's transformation).

• Known central nervous system involvement with CLL or SLL.

• Other diagnosis of active malignancy or systemic therapy within 2 years of study treatment. Note: An active malignancy or systemic therapy within 2 years for another malignancy, whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Also, local/regional therapy with curative intent such as surgical resection or localized radiation at any timepoint is permitted.

• Any uncontrolled illness that in the opinion of the investigator would preclude administration of study therapy (e.g., significant active infections, hypertension, angina, arrhythmias, pulmonary disease, or autoimmune dysfunction).

• Congestive heart failure, New York Heart Association III/IV. Unstable angina within 3 months before screening, myocardial infarction within 6 months before screening. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes). Heart rate-corrected QT interval > 480 milliseconds based on Fridericia's formula corrected for bundle branch block as appropriate. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place.

• Receipt of a live-virus vaccine within 28 days prior to initiation of study treatment or need for live-virus vaccine at any time during study treatment.

• Active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds).

• Known bleeding diathesis. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention.

• Prior major surgical procedure within 4 weeks of study, or anticipation of need for a major surgical procedure during the course of the study.

• Known CNS hemorrhage or stroke within 6 months of the study.

• History of progressive multifocal leukoencephalopathy.

• History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C infection.

  • Patients with a history of HIV infection that is well controlled on antiretroviral therapy are eligible if all of the following criteria are met: (1) undetectable HIV viral load by standard clinical assay AND (2) CD4+ T cell count of >/=200 cells/microliter). NOTE: Many HIV regimens are excluded based on drug interactions, and concomitant antiretroviral therapy must be acceptable per protocol.
  • Participants with occult or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is undetectable, and if the participant is willing to take appropriate anti-viral prophylaxis as indicated and HBV DNA monitoring on study.
  • Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.

Known condition or other clinical situation resulting in inability to swallow oral medications, or that would impair absorption of oral medications.

• Participant in a separate investigational therapeutic trial unless authorized by the PI.
• Concurrent therapy with, or administration within 5 half-lives 14 days prior to the first dose of study drug (whichever is shorter), with moderate or strong inhibitors or inducers of CYP3A.
• Concomitant use of warfarin or warfarin derivatives.
• Concomitant use of dual antiplatelet therapy.
• Prior systemic therapy for CLL or SLL, except for localized radiation or corticosteroids as per 3.1.3.
• Prior anti-CD20 monoclonal antibody therapy for any indication (malignant or non-malignant).
• Participants with a contraindication to obinutuzumab based on known hypersensitivity (IgE-mediated) reaction to obinutuzumab or to any of its excipients. Hypersensitivity to zanubrutinib or sonrotoclax.
• Consumption of one or more of the following within 3 days prior to the first dose of study drug: grapefruit or grapefruit products, Seville oranges including marmalade containing Seville oranges, or Star fruit (carambola).
• Known psychiatric illness or social situation that would interfere with study adherence.
• Pregnant women are excluded from this study given potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued prior to the first dose of study drug if the mother is treated.
• Uncontrolled autoimmune anemia and/or autoimmune thrombocytopenia (eg, idiopathic thrombocytopenia purpura), e.g., with need for ongoing corticosteroid treatment (see 3.2.24).
• Requires ongoing need for corticosteroid treatment. NOTE: Systemic corticosteroids must be fully tapered off/stopped before first study drug.
• Uncontrolled hypertension at Screening, defined as systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg by ≥ 2 consecutive measurements. In patients NOT meeting these parameters for uncontrolled hypertension, repeat blood pressure measurement is NOT required for eligibility.
• Prior invasive fungal infections, except if patient agrees to receive secondary antifungal prophylaxis during the entire treatment period (Cohort 2 Only).
• Patients with known contraindication to azole antifungal agents, including hypersensitivity reactions (Cohort 2 Only).