A Phase 1/1b Study Evaluating the Safety, Pharmacokinetics, and Preliminary Efficacy of LP-118 in Subjects With Relapsed or Refractory Hematological Malignancies
This is a Phase 1, multi-center, open-label study with a dose-escalation phase (Phase 1a) and a cohort expansion phase (Phase 1b), to evaluate the safety, tolerability, and PK profile of LP-118 under a once daily oral dosing schedule in up to 100 subjects.
Secondary objectives of the study are to evaluate preliminary efficacy regarding the effect of LP-118 on objective response rate (ORR) using disease specific response criteria, progression-free survival (PFS), and duration of response (DOR), and overall survival (OS) in adult subjects with relapsed/refractory NHL, RT, MM, T-PLL (Group 1); and acute leukemia (AML, ALL), MDS, MDS/MPN, MF (Group 2
18 Years and up
Accepting Healthy Volunteers?
- Male or female subjects, ≥ 18 years of age at the time of Screening with the following exception as outlined below:
• For T cell ALL subjects with age between 13 - 18 years, their body weight shall be ≥ 40 kg (for Phase 1b only).
- Eligible subject must have an advanced hematologic malignancy including:
- Relapsed or refractory NHL (NHL histologies [MZL, FL, WM, DLBCL, ATLL, PTCL, AITL, ALCL, MCL] are to be included per the 2016 World Health Organization [WHO] criteria) subjects, must have histologically documented diagnosis of a non-Hodgkin lymphoma as defined in the WHO classification scheme. Subjects have received at least 2 prior therapies and have no available therapies known to provide clinical benefits; For subjects with indolent NHL (Grade 1~3a FL, MZL) who have received two prior systemic therapies and have relapsed or progressed according to 2014 Lugano; NHL subjects with high risk for Tumor Lysis Syndrome (TLS) are not eligible until an MTD or RP2D is reached in subjects with low or medium risk for TLS;
- Transformed, follicular, MZL, WM (to large cell or aggressive lymphoma) subjects who must have received at least one prior systemic therapy for the transformed lymphoma (unless combination chemotherapy is not appropriate);
- Richter transformation (RT): previously treated CLL and biopsy-proven Richter transformation with DLBCL histology after receiving at least one regimen for RT
- T-cell prolymphocytic leukemia (T-PLL) subjects who have received one therapy for this and are relapsed or refractory; T-PLL subjects with high risk for TLS are not eligible until an MTD or RP2D is reached at subjects with low or medium risk for TLS;
- Relapsed or refractory multiple myeloma (MM) subjects who have received a PI, an IMiD, and an anti-CD38 and have no treatment options available known to provide clinical benefits; MM subjects with high risk for TLS are not eligible until an MTD or RP2D is reached in subjects with low or medium risk for TLS;
- MDS subjects with refractory anemia with excess blasts (RAEB; subtype RAEB-1 or RAEB-2) as defined by WHO 2016 revised criteria and/or MDS with high- or very high-risk (risk score > 4.5) per the Revised International Prognostic Scoring System (IPSS-R) who have no available therapies known to provide clinical benefit;
- Morphologically confirmed diagnosis of MDS/MPN, excluding juvenile myelomonocytic leukemia (JMML), in accordance with WHO 2016 revised criteria, that is relapsed and/or refractory and that, in the opinion of the Investigator, subjects who have no available therapies known to provide clinical benefits;
- Morphologically confirmed diagnosis of MF in accordance with the WHO 2016 revised criteria, that is relapsed, intolerant and/or refractory and that, in the opinion of the Investigator, subjects who have no available therapies known to provide clinical benefits;
- Relapsed or primary refractory AML subjects (including de novo AML, secondary AML evolving from MDS or MPN, and therapy-related AML) as defined by WHO 2016 revised criteria, subjects who have no available therapies known to provide clinical benefits; subjects with prior BCL-2 inhibitor therapy are permitted;
- Relapsed or refractory ALL subjects with B cell phenotype who have received at least two prior regimens (such as multi-agent chemotherapy and/or tyrosine kinase inhibitors including bosutinib, dasatinib, imatinib, nilotinib or ponatinib) and failed, or are currently ineligible/intolerant for CD19-based target therapy (e.g. Blinatumomab); Relapsed or refractory ALL subjects with T cell phenotype who have received at least one prior therapy and failed.
- For Group 2 AML and ALL subjects only, white blood cell (WBC) count ≤ 25 × 109 cells/L at the time of enrollment (glucocorticoids or hydroxyurea is permitted to control WBC count prior to and during therapy).
- Adequate cardiac function defined as shortening fraction of ≥ 27% by echocardiogram, or ejection fraction of ≥ 50% by echocardiogram or radionuclide angiogram (nuclear medicine analysis) if there is history of anthracycline exposure.
- Subject must have adequate bone marrow (independent of growth factor support), coagulation, renal, and hepatic function, per laboratory reference ranges at Screening as follows:
- Bone marrow criteria: Group 1 (r/r NHL, RT, MM, T-PLL):
1. Absolute Neutrophil Count (ANC) ≥ 1 x 109/L (An exception is for subjects with an ANC<1 x 109/L 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),
2. Platelets ≥ 50 x 109/L on day of screening (entry platelet count must be independent of transfusion with 14 days of screening);
- Hemostasis criteria: Activated partial thromboplastin time (APPT) and prothrombin time (PT) ≤ 1.5 × the upper limit of normal (ULN);
- Renal function criteria: Serum creatinine ≤ ULN (per local institution reference range) or Calculated creatinine clearance (Cr Cl) ≥ 60 mL/min using 24-hour CrCl OR by Cockcroft-Gault formula using actual body weight.
- Hepatic function criteria: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × 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).
A subject will not be eligible for study participation if he/she meets any of the following criteria.
- Subjects who have undergone autologous/allogeneic hematopoietic stem cell transplantation (HSCT) therapy within 60 days of the first dose of LP-118, or subjects on immunosuppressive therapy post-HSCT at the time of Screening, or currently with clinically significant graft-versus-host disease (GVHD) as per treating physician (Subjects 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 malignancies within past 12 months that are active and could result in competing risks. These cases shall be discussed with the Medical Monitor with exception below
- Subject with breast cancer or prostate cancer on endocrine therapy with stable disease;
- 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 has received any of the following therapies within 14 days or 5 half-lives (whichever is shorter) prior to the first dose of LP-118, or has not recovered to ≤ Grade 2 clinically significant AEs of the previous therapy (excluding alopecia or neuropathy):
- Any anti-neoplastic therapy including chemotherapy, hormonal therapy, radiotherapy, biologic or immunotherapy, targeted small molecule agents, etc. (corticosteroid therapy < 20 mg/day prednisone equivalent and hydroxyurea cytoreduction therapy according to institutional guidelines to treat disease associated symptoms are permitted);
- For MF subjects who come off JAK2 antagonists, allow washout for 2 days as these subjects progress quickly after treatment discontinuation and remain eligible (steroids may be given during these two days to allow disease control).
- Subjects in need of immediate cytoreduction should be excluded.
- Any investigational therapy.
- Live vaccines
- Subject has received the following medications, therapies or natural products within 7 days prior to the first dose of LP-118:
- Cytochrome P450, family 3, subfamily A (CYP3A) strong inhibitors (itraconazole, etc) or inducers (phenytoin, rifampin, etc);
- Inhibitors of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
- Subject has baseline prolongation of the heart rate-corrected QT (QTc) interval ≥ 480 ms (calculated per Fridericia's formula [QTc = QT/RR(1/3)]) ), a cardiovascular disability status of New York Heart Association Class ≥ 2 or associated other significant screening ECG or ultrasonic cardiogram abnormalities, per Investigator's judgement.
- Subject has significant a history of congenital long QT syndrome or Torsades de pointes, uncontrolled or symptomatic arrhythmias, congestive heart failure, myocardial infarction, stroke or intracranial hemorrhage within 6 months prior to the first dose of LP-118.
- Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
- Uncontrolled active systemic infection (bacterial, fungal, viral);
- Known poorly controlled of human immunodeficiency virus (HIV) or active hepatitis B or C infection (active hepatitis B defined as HBsAg positive, or HBcAb positive with detectable HBV DNA load; active hepatitis C defined as HCV antibody positive with HCV RNA positive);
- Unexplained fever > 38.5°C within 7 days prior to the first dose of study drug administration (at the discretion of the Investigator, if the fever is considered attributed to the subject's malignancy or an explained infection may be enrolled).
- Subjects with known and active central nervous system (CNS) involvement at Screening.