This is a phase 2 study of Epcoritamab as a consolidation therapy for 2nd generation BTKi +/- Obinutuzumab in CLL/SLL patients or patients with variants of this.
Diagnosis of CLL or SLL meeting the established 2018 iwCLL diagnostic criteria or variant of CLL/SLL and has received a 2nd generation BTKi (acalabrutinib or zanubrutinib) +/- obinutuzumab for a minimum of 12 months as first line therapy.
Attainment of Partial Response or greater with a 2nd generation BTKi (acalabrutinib or zanubrutinib) +/- obinutuzumab but detectable disease in blood or bone marrow by NGS ClonoSEQ.
Age ≥18 years.
ECOG performance status ≤2 (or Karnofsky ≥60%, see Appendix D).
Obtaining a CR or nodal PR with no detectable disease in blood or bone marrow after treatment with a 2nd generation BTKi (acalabrutinib or zanubrutinib) +/- obinutuzumab as assessed by Adaptive's NGS ClonoSEQ.
Absence of CD20 expression on CLL cells at pre-treatment.
Received any prior treatment ever with a CD3×CD20 bispecific antibody.
Organ transplant recipients are excluded except those with no active graft versus host disease (GVHD) requiring treatment within 12 months of beginning treatment on study.
Single group
Epcoritamab
DrugEpcoritamab is the investigational product under study in combination with SOC drugs in this protocol. During C1, epcoritamab will be initiated using step-up dosing (SUD) C1D1 .16mg, C1D8 .8mg, C1D15 3 mg, C1D22 24 mg vs 48 mg (full dose) during safety lead in to determine the RP2D. On Cycles 2-3 the RP2D (24mg vs 48 mg) will be administered on Days 1, 8, 15, 22. Then Cycles 4-9 RP2D will be administered on Days 1 \& 15. Then Cycle 10-12 RP2D on Day 1 of each cycle. Epcoritamab is administered subcutaneously. The SOC BTKi are oral medications administered daily during the trial period.
uMRD CR as defined by negative leukemia cells to the 10^6
uMRD CR as defined by negative leukemia cells to the 10\^6 after 12 cycles of consolidative therapy with epcoritamab measured by Adaptive's NGS MRD assay (ClonoSEQ) in patients who have attained a partial response or better with detectable disease after acalabrutinib or zanubrutinib +/- obinutuzumab treatment for a minimum of 12 cycles of therapy
Safety measured by CTCAE v. 5.
Safety of epcoritamab given together with acalabrutinib or zanubrutinib in patients with CLL/SLL reported as frequency and severity of adverse events using CTCAE v. 5.
uMRD CR defined by negative leukemia cells to the 10^6 using NGG ClonoSEQ
uMRD CR defined by negative leukemia cells to the 10\^6 using NGG ClonoSEQ after 6 cycles of consolidation with epcoritamab.
T-cell subsets levels measured by flow-cytometry
T-cell subsets levels (include T-regulatory cells, TH17 T-cells, effector memory T-cells, central memory T-cells, naïve T-cells, and cytotoxic T-cells) at baseline, Day 1, Day 8, C2D1, C4D1, C7D1 and C12 D28 of consolidation with epcoritamab.
PFS defined as the interval between the first treatment day to the first sign of disease progression or death from any cause of patient
PFS defined as the interval between the first treatment day to the first sign of disease progression or death from any cause after receiving 12 cycles of consolidative epcoritamab.
T-cell cytotoxicity against primary pretreatment CLL cells
T-cell cytotoxicity against primary pretreatment CLL identified by INF-gamma production in presence of ex-vivo incubated CLL cells at baseline, Day 1, Day 8, Day 29 of Cycle 1, end of Cycle 3, Cycle 6 and Cycle 12 of consolidation with epcoritamab.
T-cell proliferation against primary pretreatment CLL cells
T-cell proliferation against primary pretreatment CLL cells through identifying different T cell cells receptor(TCR) using next generation sequencing at baseline, Day 1, Day 8, Day 29 of Cycle 1, end of Cycle 3, Cycle 6 and Cycle 12 of consolidation with epcoritamab.
Cytokine production against autologous CLL cells
Cytokine levels ( e.g. IL-6, TNF-alpha) produced using flow cytometry against CLL cells at baseline, Day 1, Day 8, Day 29 of Cycle 1, end of Cycle 3, Cycle 6 and Cycle 12 of consolidation with epcoritamab.
Tumor features of patients who respond to epcoritamab therapy and then relapse following receipt of this treatment.
To determine pre-treatment and serial tumor features changes including development of new mutations and change in genomics through whole exon sequencing and single cell sequecning that are associated with response in CLL patients receiving epcoritamab at the following timepoints Screening, Baseline pre-treatment on C1D1, C1D8, C2D1, C4D1, C7D1, end of C12 (or at EOT) and Relapse.
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