Study of Oral Administration of LP-168 in Patients With Relapsed or Refractory B-cell Malignancies.

A Phase I, Multicenter, Open-Label, Dose-escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Clinical Activity of Orally Administered LP-168 in Subjects With Relapsed or Refractory B-cell Malignancies.

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.

The primary objectives for the study are to assess the safety and tolerability profile, determine the maximum tolerated dose (MTD), and/or the recommended Phase 2 dose (RP2D) of LP-168 administered once or twice daily as a single agent dosed orally in adult subjects with relapsed/refractory B-cell Malignancies (CLL/SLL, WM, FL, MCL, MZL, DLBCL, HCL); and to characterize the pharmacokinetics (PK) profile of LP-168 in adult subjects with relapsed/refractory B-cell Malignancies (CLL/SLL, WM, FL, MCL, MZL, DLBCL, HCL).

Secondary objectives of the study are to evaluate preliminary efficacy regarding the effect of LP-168 on progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) in adult subjects with relapsed/refractory B-cell Malignancies (CLL/SLL, WM, FL, MCL, MZL, DLBCL, HCL).

Once the MTD is declared and the RP2D is established, additional subjects will be enrolled in a cohort expansion phase (Phase 1b).

Inclusion Criteria:

A subject will be eligible for study participation if he/she meets the following criteria:

• 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.

• Subject must have adequate coagulation, renal, and hepatic function, per local laboratory reference ranges at Screening as follows:

  • 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.
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 ×ULN; Bilirubin ≤ 1.5 × ULN (except subjects with Gilbert's Syndrome, who may have a bilirubin > 1.5 × ULN, per discussion between the Investigator and the Medical Monitor).

• Subjects must have adequate bone marrow independent of growth factor support per local laboratory reference range at screening as follows:

  • Absolute Neutrophil Count (ANC) ≥1000/uL;
  • An exception is for subjects with an ANC<1000/uL and bone marrow heavily infiltrated with underlying disease (approximately 60% or more) may use growth factor to achieve the ANC eligibility criteria per discussion between the Investigator and the Medical Monitor.
  • Platelet count ≥ 50,000/µL - OR - Platelet count ≥ 20,000/ µL if thrombocytopenia is clearly due to CLL disease under study (per Investigator discretion)
  • Hemoglobin ≥8.0g/dL, and can be achieved by transfusion

Exclusion Criteria:

A subject will not be eligible for study participation if he/she meets any of the following criteria.

• Subject has received any of the following therapies within 14 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug, or has not recovered to ≤ Grade 1 clinically significant adverse effect(s)/toxicity(s) of the previous therapy (other than alopecia):

  • 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.

• Subject has received the following medications or therapies within 7 days prior to the first dose of study drug:

  • Steroid therapy (at dosages equivalent to prednisone >20 mg/day) for anti-neoplastic intent (except as noted in exclusion criteria #3);
  • Cytochrome P450, family 3, subfamily A (CYP3A4) strong inhibitors and strong CYP2C8 inducers/inhibitors.
  • Potent CYP3A4 inducers such as rifampin, carbamazepine, phenytoin, and St. John's wort.

• Subjects require treatment with systemic acid-reducing agents including H-2-receptor antagonists and proton pump inhibitors with the following exceptions:

  • Proton pump inhibitors should be discontinued at least 7 days prior and held throughout the study
  • If concurrent use of an H2 blocking agent is necessary, it must be administered only between 2 and 3 hours after the dose of LP-168. If not taken during this time, the dose of H2 blocking agents should not be taken again until 2-3 hours after the next dose of LP-168.
  • If concurrent use of a local antacid is necessary, it must be administered 2 or more hours before and/or 2 or more hours after the dose of LP-168.

• Subject has significant screening electrocardiogram (ECG) abnormalities including. 2nd degree AV block type II 3rd degree block, Grade 2 or higher bradycardia, and corrected QT interval (QTc) ≥ 480ms.

• Serum amylase > 1.5 × ULN or serum lipase > 1.5 × ULN.

• Subject has any history of Richter's transformation for Phase 1a portion of the trial.

• Subjects who have undergone autologous/allogeneic hematopoietic stem cell transplantation (HSCT) therapy within 90 days of the first dose of LP-168, or patients on immunosuppressive therapy post-HSCT at the time of Screening, or currently with clinically significant graft-versus-host disease (GVHD) as per treating physician (Patients in relapse after allogeneic transplantation must be off treatment with systemic immunosuppressive agents for at least 4 weeks. The use of topical steroids and/or up to 20 mg/day prednisone or equivalent systemic steroids for ongoing GVHD is permitted.

• Subject has a history of other active malignancies other than B-cell malignancies within the past 3 years prior to study entry, with the exception of:

  • Adequately treated in situ carcinoma of the cervix uteri;
  • Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
  • Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.

• Subject requires anticoagulation with Warfarin.