Multicenter Parallel 2 Cohort Phase 2 Study of LP-168 and Obinutuzumab for Previously Treated, and T474 Gatekeeper Mutant Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and Variants of This.
Diagnosis of CLL or SLL meeting criteria established in the 2018 iwCLL criteria and requiring treatment. Patients with variation in flow cytometry findings will be allowed to enroll if cytogenetics and/or mutational studies are supportive of CLL/SLL variant.
Cohort 1: One or more prior therapies for CLL/SLL including BCL2 inhibitor (BCL2i), and/or chemotherapy and/or BTK inhibitor (BTKi).
Cohort 2: Treatment with a prior BTKi (covalent and noncovalent) and have a BTK gatekeeper mutation in the T474 coordinate.
Age ≥18 years.
Patients with active Richter's transformation.
Any anti-cancer therapy including chemotherapy, biologic or immunotherapy, radiotherapy, etc.
Any investigational therapy, including targeted small molecule agents.
For patients who come off BCR antagonist treatment (BTK inhibitors, PI3K inhibitors, etc.), allow washout for 5 half-lives as these patients progress quickly after treatment discontinuation and then remain eligible (steroids may be given during the washout to allow for disease control, see d below for details).
Parallel
LP-168
DrugPatients will receive LP-168 200 mg daily beginning day 1 of therapy for 12 cycles.
Obinutuzumab
DrugPatients will with LP-168 and then receive obinutuzumab for a total of 6 cycles, beginning cycle 7, days 1, 2, 8 and 15, and then day 1 of cycles 8-12. A minimum of 12 cycles of therapy will be administered.
Complete remission/ Complete remission with incomplete count (CR/CRi) defined by the IWCLL 2018 criteria
To assess the complete response (CR), complete response with incomplete marrow recovery (CRi) rate of LP-168 + obinutuzumab in each cohort following 12 cycles of treatment.
Overall response rate- defined by the IWCLL 2018 criteria
To assess the overall response rate to LP-168 (CR, CRi, PR, PR-L and nPR) in each cohort of CLL/SLL following 6 cycles of treatment. Each patient will be assigned one of the following categories: 1) complete response, 2) partial response/Partial response with lymphocytosis or nodular partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). Note: By arbitrary convention, category 9 usually designates the "unknown" status of any type of data in a clinical database.
Safety and tolerability - CTCAE
To assess the safety and tolerability of LP-168 given with obinutuzumab. We will monitor further for SAEs (CTCAE grade \>=3) continuously on trial by cohort. The exception is the first 6 patients enrolled (irrespective of cohort) will be evaluated as well for safety of the combination with respect to DLTs as defined by this protocol. Patients will be monitored for regular safety outside the combination using the toxicity monitoring Table 8, given we already have data confirming the safety of the single agent LP-168.
Undetectable minimal residual disease (MRD) complete remission (CR) after completion of cycle 12 of therapy defined by negative leukemia cell to the 10-6 using Clonoseq.
To assess the rate of undetectable measurable residual disease (uMRD), defined by negative leukemia cell to the 10-6 using NGS technique (Clonoseq).
Duration of response (DOR), progression free survival (PFS) and overall survival (OS) of patients receiving LP-168 together with obinutuzumab in each cohort of patients.
DOR defined as the time from receiving first treatment to disease progression or death for patients who achieve complete or partial response, PFS defined as the interval between the first treatment day to the first sign of disease progression or death from any cause, and OS, defined as time from starting treatment until death, all measured at completion of LP-168 with obinutuzumab treatment.
Signaling measured by immunoblot analysis
Signaling:will isolate CD19+ CLL cells and perform immunoblot analysis for phospho BTK (pBTK)/BTK, pPCLG2/PLCG2, pAKT/AKT and pERK/ERK. at Screening, Baseline pre-treatment, Cycle 1 Day 8, Cycle 6 Day 1, and Cycle 12 Day 1 of therapy in cohort 2.
Chemokines production measurement at specific timepoints
Broad range of chemokines ( CCL3, CCL4, TNF-alpha, and BAFF )production will be measured at Screening, Baseline pre-treatment, Cycle 1 Day 8, Cycle 6 Day 1, and Cycle 12 Day 1 of therapy in cohort 2.
Extracellular vesicles (EVs) production measured by the number of vesicles produced in CLL cells
The number of vesicles produced in CLL cells at Screening, Baseline pretreatment (before C1D1 dosing), Cycle 1 Day 8, Cycle 1 Day 28, and the end of Cycles 6 and 12 of therapy for cohort 2
Immune cell function by profiling of specific surface markers on immune cells,
Immune cell function studies at Screening, Baseline, end of Cycle 1, 6, and 12 by profiling of specific surface markers on immune cells,
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Zulfa Omer
Lead sponsor
University of Cincinnati
Sponsor institution
Newave Pharmaceutical Inc
Collaborator
