A Phase 1/2 Open-label Study to Investigate the Safety of Sonrotoclax Ramp-up Schedule(s) in Adult Patients With Hematological Malignancies.
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Enrollment
- 258
- Locations
- 33
- Primary Endpoint
- Number of Participants who Experience Tumor Lysis Syndrome (TLS)
Study Overview
Brief Summary
The purpose of this study is to establish the safety of novel dosing and ramp-up schedules for sonrotoclax in participants with hematological malignancies.
Detailed Description
This study will test the safety of novel sonrotoclax dosing with gradual increases of sonrotoclax dose over specified periods until the intended target daily dose is reached. The focus will be on tumor lysis syndrome (TLS) and related toxicity signals.
Sonrotoclax is a drug that works by blocking a protein called B-cell lymphoma-2 (BCL-2). When sonrotoclax blocks BCL-2 it slows down or stops the growth of tumor cells and helps them die. This can lead to improvements in patients with certain malignant diseases including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). The start of treatment with BCL-2 inhibitor requires a gradual ramp-up over the first weeks to avoid potential consequences of initial tumor cell breakage and the release of cell content in the bloodstream. Several ramp-up schedules have already been explored, and this study aims to optimize the dosing ramp-up schedule that may be beneficial to patients and caregivers. Zanubrutinib is a commercialized product that works by blocking a protein called Bruton's tyrosine kinase (BTK) and controlling the activity and survival of malignant B cells. Zanubrutinib has received approval in over 65 countries/regions worldwide for the treatment of adult participants with B-cell malignancies, including CLL and MCL.
This study will take place at multiple centers worldwide. The overall time to participate in this study is approximately 17 months for treatment-naïve (TN) CLL participants or approximately 32 months for relapsed/refractory (R/R) MCL participants.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Stable Eastern Cooperative Oncology Group (ECOG) Performance Status ≤
- •Adequate organ function and no very recent transfusion or blood growth factor
- •Participants of childbearing potential must be willing to use a highly effective method of birth control and refrain from egg donation for the duration of the study and for ≥ 7 days after the last dose of sonrotoclax or 1 month after the last dose of zanubrutinib, whichever is later.
- •Only for participants with Chronic Lymphocytic Leukemia (CLL):
- •Confirmed diagnosis of CLL, based on Hallek et al 2018, and requiring treatment due to certain features of their disease
- •At least 1 measurable lesion based on computed tomography (CT)/magnetic resonance imaging (MRI) and no history of prolymphocytic leukemia or Richter's transformation.
- •Only for participants with Mantle cell lymphoma (MCL):
- •Historically confirmed diagnosis of MCL based on the World Health Organization 2022 classification of Haematolymphoid Tumors (WHO-HEAM5) or based on International Consensus Classification (ICC).
- •Relapsed or refractory to the last line of therapy and have received at least 1 prior line of systemic therapy. Note: A line of therapy is considered ≥ 2 consecutive cycles of a systemic anticancer regimen. Patients with prior BTKi therapy should not have progressed during treatment or relapsed within 12 months after BTKi discontinuation.
- •Measurable disease defined as ≥ 1 nodal lesion that is > 1.5 cm in longest diameter, or ≥ 1 extranodal lesion that is > 1 cm in longest diameter.
Exclusion Criteria
- •Participants unable to comply with the requirements of the protocol
- •Serologic status reflecting active viral hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
- •Positive HIV serology (HIVAb) status unless certain conditions are met.
- •Participants with any major surgical procedure ≤ 28 days before first dose of study treatment
- •Prior systemic treatment for the CLL
- •Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring treatment
- •Prior exposure to a BCL-2 inhibitor
- •NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
Arms & Interventions
Arms: 1C and 2B: Zanubrutinib + Sonrotoclax for R/R MCL
Participants will receive zanubrutinib alone, followed by a combination with sonrotoclax initiated with a ramp-up according to each schedule defined in the protocol, for a total of 27 cycles of 28 days (including the phase of sonrotoclax ramp-up), then will continue on zanubrutinib alone until progression of their disease or other treatment discontinuation criteria.
Intervention: Zanubrutinib (Drug)
Arms: 1A,1B and 2A: Zanubrutinib + Sonrotoclax for TN CLL
Participants will receive zanubrutinib alone, followed by a combination with sonrotoclax initiated with a ramp-up according to each schedule defined in the protocol. The total treatment duration is of 15 cycles of 28 days (including the phase of sonrotoclax dose ramp-up)
Intervention: Zanubrutinib (Drug)
Arms: 1C and 2B: Zanubrutinib + Sonrotoclax for R/R MCL
Participants will receive zanubrutinib alone, followed by a combination with sonrotoclax initiated with a ramp-up according to each schedule defined in the protocol, for a total of 27 cycles of 28 days (including the phase of sonrotoclax ramp-up), then will continue on zanubrutinib alone until progression of their disease or other treatment discontinuation criteria.
Intervention: Sonrotoclax (Drug)
Arms: 1A,1B and 2A: Zanubrutinib + Sonrotoclax for TN CLL
Participants will receive zanubrutinib alone, followed by a combination with sonrotoclax initiated with a ramp-up according to each schedule defined in the protocol. The total treatment duration is of 15 cycles of 28 days (including the phase of sonrotoclax dose ramp-up)
Intervention: Sonrotoclax (Drug)
Outcomes
Primary Outcomes
Number of Participants who Experience Tumor Lysis Syndrome (TLS)
Time Frame: Approximately 4 months
TLS will be defined by Howard criteria during the schedule-limiting toxicity (SLT) evaluation window
Secondary Outcomes
- Number of Participants with Adverse Events (AEs)(Approximately 4 months)
- Number of Participants with Dose Modifications During the SLT Evaluation Window(Approximately 4 months)