study of oral administration of lp-168 in patients with relapsed or refractory b-cell malignancies.

Conditions: CLL/SLL; Waldenstrom Macroglobulinemia; Follicular Lymphoma; Diffuse Large B Cell Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Hairy Cell Leukemia

Summary: 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).

Eligibility criteria:
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.