MK-1026-011 (​BELLWAVE-011)

Adults (≥18) with untreated, active CLL/SLL needing therapy (iwCLL features), measurable burden, ECOG 0–2, oral intake ability, required central del(17p)/TP53 testing, adequate organ function; controlled HBV/HCV/HIV allowed per protocol.

1) Confirmed CLL/SLL with active disease requiring treatment; at least 1 treatment-trigger criterion (eg, progressive marrow failure/anemia-thrombocytopenia, massive/progressive/symptomatic splenomegaly or lymphadenopathy, progressive lymphocytosis/LDT <6 months, steroid-refractory autoimmune cytopenias, symptomatic extranodal involvement, or constitutional symptoms). 2) At least 1 marker of disease burden: measurable nodal disease (>1.5 cm by CT/MRI), ALC >4×10^9/L, platelets <100×10^9/L, or hemoglobin <11 g/dL (baseline ALC must be known). 3) Provision of peripheral blood, bone marrow aspirate and/or lymph node sample for central del(17p)/TP53 status before randomization; mutant and wild-type are eligible if central results are conclusive per protocol rules. 4) ECOG performance status 0–2 within 7 days before randomization. 5) Able to swallow/retain oral medication (nemtabrutinib not permitted via J-PEG tube). 6) HBsAg-positive participants eligible if on antiviral therapy ≥4 weeks and HBV DNA undetectable before randomization; continue antiviral management per guidance. 7) History of HCV allowed if HCV RNA undetectable at screening and curative antiviral therapy completed ≥4 weeks pre-randomization. 8) HIV allowed if all met: CD4 >350/µL, viral load undetectable per local testing, stable ART ≥4 weeks, and ART not including strong CYP3A4 inducers. 9) Adequate organ function within 7 days before randomization (hematologic, renal, hepatic, coagulation thresholds per Table 4). 10) Any sex/gender, age ≥18. 11) Participants assigned male sex at birth with sperm production capability: protocol-specified contraception/abstinence requirements. 12) Participants assigned female sex at birth: not pregnant/breastfeeding; if POCBP, highly effective contraception/abstinence, negative pregnancy test, and protocol-specified post-treatment contraception/breastfeeding restrictions. 13) Documented informed consent (and assent when applicable); optional FBR consent. 14) EU-specific consent provisions apply where relevant (see protocol Appendix 7).

Active HBV/HCV, GI malabsorption risk, Richter/CNS involvement, recent AIDS-defining infection, major cardiovascular risk (incl. uncontrolled HTN/QTc prolongation), severe bleeding history, recent active second malignancy, prior systemic CLL/SLL therapy, prohibited concomitant drugs, active systemic infection.

1) Active HBV/HCV infection (per protocol HBV/HCV inclusion exceptions). 2) GI dysfunction likely to affect absorption (eg, gastric bypass/gastrectomy). 3) Richter transformation or active CNS involvement by CLL/SLL. 4) AIDS-defining opportunistic infection within 12 months pre-screening. 5) Clinically significant cardiovascular disease, including: MI or unstable angina within 6 months; NYHA III/IV heart failure; significant arrhythmias; QTcF above protocol threshold; Mobitz II/III block without permanent pacemaker; uncontrolled hypertension (per protocol BP criteria). 6) Hypersensitivity to nemtabrutinib, or contraindication to ibrutinib/acalabrutinib (eg, Child-Pugh C hepatic impairment), or relevant excipients. 7) History of severe bleeding disorder. 8) Additional progressing malignancy or malignancy requiring active treatment within past 2 years (protocol-defined exceptions include certain curatively treated skin/in situ lesions and selected low-risk early prostate cancer scenarios). 9) Any prior systemic anticancer therapy for CLL/SLL. 10) Current treatment with prohibited agents: P-gp substrates with narrow therapeutic index, strong CYP3A inducers, strong CYP3A inhibitors (with protocol-specified washout and notes). 11) Prior radiotherapy within 2 weeks before study intervention (limited palliative non-CNS exceptions allowed with timing constraints). 12) Live/live-attenuated vaccine within 30 days before first dose. 13) Investigational agent/device exposure within 4 weeks before study intervention. 14) Any condition/lab abnormality/circumstance that may confound results or make participation not in participant’s best interest per investigator judgment. 15) Active infection requiring systemic therapy (including IV antibiotics during screening; rescreen allowed after completion). 16) Psychiatric or substance abuse disorder interfering with protocol compliance. 17) Not adequately recovered from major surgery or ongoing surgical complications. 18) Country/region-specific exclusions may apply (Appendix 7).