This is a phase I, multi-center, open-label, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics and clinical activity of LP-168 in subjects with relapsed or refractory B-cell malignancies. LP-168 is a small molecule inhibitor.
Subjects are eligible with B-cell malignancies, WM, FL, MCL, MZL, DLBCL, HCL, CLL, SLL, based upon 2016 updated WHO classification. Those subjects with WM, FL, MCL, DLBCL, or HCL must have received at least 2 prior systemic therapies.
Low-grade B-cell lymphomas as follicular Grade 1, 2, or 3A, marginal zone or small lymphocytic lymphoma.
Activated partial thromboplastin time (APTT) and prothrombin time (PT) not to exceed 1.5 × ULN
Calculated creatinine clearance (CrCl) ≥ 60 mL/min using 24-hour CrCl OR Cockcroft-Gault formula.
Any anti-cancer therapy including chemotherapy, biologic or immunotherapy, radiotherapy, etc;
Any investigational therapy, including targeted small molecule agents.
For CLL subjects who come off BCR antagonists (BTK inhibitors, PI3K inhibitors, etc.) treatment, allow washout for 2 days as these subjects progress quickly after treatment discontinuation and then remain eligible (steroids may be given during these two days to allow disease control).
Subjects who require immediate cytoreduction. However, subjects may receive up to two days of steroids for symptoms of impending organ impairment and remain eligible.
Sequential
LP-168
DrugFor the dose escalation phase, LP-168 will be given once or twice daily at the following dose levels:100 mg QD,150 mg QD, 100 mg BID, 300 mg QD, 150 mg BID, 450 mg QD, 225 mg BID, 600 mg QD, 800 mg QD, and 1000 mg QD.
LP-168
DrugFor the dose expansion phase, subjects will receive once or twice daily dose of LP-168 at the Recommended Phase 2 Dose (RP2D). The RP2D may be as high as the MTD and will be determined following evaluation of Phase I Dose Escalation results.
Maximum Tolerated Dose (MTD)
When more than 1 DLT occurs in ≤ 6 subjects in a dosing cohort, dose escalation will be stopped and this dose level will be identified as the non-tolerated dose. Doses between the non-tolerated dose and the preceding lower dose, where ≤ 1 DLT occurred, may be explored to more precisely define the MTD.
Recommended Phase 2 dose (RP2D)
The RP2D may be as high as the MTD or a lower dose and will be selected in discussion with the Investigators and the Sponsor based on longer term safety data, preliminary efficacy data, and PK data.
Pharmacokinetic (PK) profile of LP-168
Maximum Plasma Concentration \[Cmax\]
Pharmacokinetic (PK) profile of LP-168
Area Under the Curve \[AUC\]
Progression-Free Survival (PFS)
PFS is measured from the time of first study drug administration until the first date that recurrent or progressive disease is objectively documented.
Objective Response Rate (ORR)
ORR is defined as the sum of complete response (CR) and partial remission rates.
Duration of Response (DOR)
The duration of overall response is measured from the time measurement criteria are met for CR or PR (which is first recorded) until the first date that recurrent or progressive disease is objectively documented
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