A Phase 1/1b Study Evaluating the Safety, Pharmacokinetics, and Preliminary Efficacy of LP-118 in Subjects With Relapsed or Refractory Hematological Malignancies

  • STATUS
    Recruiting
  • End date
    Aug 1, 2024
  • participants needed
    100
  • sponsor
    Newave Pharmaceutical Inc
Updated on 25 October 2022
platelet count
remission
chronic myeloid leukemia
hematologic malignancy
anemia
tyrosine
lymphoma
multiple myeloma
hydroxyurea
acute leukemia
chronic myelomonocytic leukemia
ejection fraction
leukemia
bone marrow procedure
hematologic disorder
gilbert's syndrome
dexamethasone
refractory acute myeloid leukemia (aml)
blast cells
combination chemotherapy
white blood cells
neutrophil count
chemotherapy regimen
prolymphocytic leukemia
refractory multiple myeloma
aggressive non-hodgkin's lymphoma

Summary

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.

Description

Primary objectives of 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-118 administered once daily (QD) as a single agent dosed orally in adult subjects with relapsed/refractory (low risk tumor lysis) CLL/SLL (Group 1a); relapsed/refractory MF, CMML-2, MDS/MPN, MDS-BP, MDS, AML with WBC ≤ 25 × 109 cells/L (Group 1b); relapsed/refractory NHL, RT, MM, T-PLL (Group 1c); relapsed/refractory ALL (Group 1d); relapsed/refractory (intermediate and high tumor lysis risk) CLL/SLL, NHL, RT, T-PLL (Group 2);

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 (low risk tumor lysis) CLL/SLL (Group 1a); relapsed/refractory MF, CMML-2, MDS/MPN, MDS-BP, MDS, AML with WBC ≤ 25 × 109 cells/L (Group 1b); relapsed/refractory NHL, RT, MM, T-PLL (Group 1c); relapsed/refractory ALL (Group 1d); relapsed/refractory (intermediate and high tumor lysis risk) CLL/SLL, NHL, RT, T-PLL (Group 2);

Details
Condition Non Hodgkin Lymphoma, Richter Transformation, Multiple Myeloma, T-cell-prolymphocytic Leukemia, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, Myeodysplastic Syndrome, Myelodysplastic/Myeloproliferative Neoplasm, Myelofibrosis, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Chronic Myelomonocytic Leukemia-2, Myelodysplastic Neoplasm in Blast Phase
Treatment LP-118
Clinical Study IdentifierNCT04771572
SponsorNewave Pharmaceutical Inc
Last Modified on25 October 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Male or female subjects, ≥ 18 years of age at the time of Screening with the following exception as outlined below
For T cell and B 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
Group 1
Group 1a
Relapsed or refractory low risk tumor lysis CLL/SLL subjects (ALC < 25 x 109 /cells/L and all lymph nodes < 5 cm) who have slowly progressed on irreversible BTK inhibitors while on treatment with these agents, and received at least two prior therapies
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
Group 1b
Or atypical chronic myeloid leukemia (aCML) with Hgb > 10g/dL, WBC count < 50 x 109 cells/L, <10% immature circulating cells
Chronic myelomonocytic leukemia (CMML) with <9% blasts
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
Or MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) with Hgb > 10g/dL
Or myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-UC)
CMML-2 with 10-19% blasts as defined by WHO 2016 revised criteria that is relapsed
and/or refractory to prior HMA therapy
Relapsed and/or refractory MPN-BP as defined by WHO 2016 revised criteria that is transformed MPN with >20% myeloid blasts in the peripheral blood or bone marrow, in the opinion of the Investigator, subjects who have no available therapies known to provide clinical benefits
MDS subjects with refractory anemia with excess blasts (MDS-EB; subtype MDS-EB-1 or MDS-EB-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, refer to Appendix 11; Section 15.13) who have no available therapies known to provide clinical benefit
Subject must have adequate bone marrow (independent of growth factor support), coagulation, renal, and hepatic function, per laboratory reference ranges at Screening as follows
Relapsed or refractory AML subjects (including de novo AML, secondary AML evolving from MDS or MPN or other antecedent hematologic disorder, 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. WBC needs to be ≤ 25 × 109 cells/L at the time of initiating investigational therapy (hydroxyurea is allowed to control WBC prior to and during therapy)
Group 1c
Relapsed or refractory low risk tumor lysis 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 benefit; 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
Low risk tumor lysis 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)
Low risk tumor lysis Richter transformation (RT): previously treated CLL and biopsy-proven Richter transformation with DLBCL histology after receiving at least one regimen for RT
Platelets ≥ 50 x 109/L on day of screening (entry platelet count must be independent of transfusion with 14 days of screening)
Relapsed or refractory multiple myeloma (MM) subjects who have received a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 and have no treatment options available known to provide clinical benefit
Hemostasis criteria: Activated partial thromboplastin time (APPT) and prothrombin
time (PT) ≤ 1.5 × the upper limit of normal (ULN)
Relapsed or refractory ALL with dexamethasone run-in [5 days, dexamethasone 10mg/m2 (divided BID)]
Low risk tumor lysis T-cell prolymphocytic leukemia (T-PLL) subjects who have received one therapy for this and are relapsed or refractory
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
Or r/r ALL in remission but with detectable MRD (MRD +) by any detection method per institution standard of practice
Group 1d
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)
IT chemo (per institutional SOC) is permitted prior to LP-118 C1D1 dosing, and then concomitantly on treatment if in best interest of the subject
Relapsed or refractory ALL subjects with B cell phenotype who have received at least two prior therapeutic 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
Group 2
Relapsed or refractory intermediate and high risk tumor lysis CLL/SLL subjects who have received at least two prior therapies
Relapsed or refractory intermediate and high risk tumor lysis 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 benefit; 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
Intermediate and high risk tumor lysis 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)
Intermediate and high risk tumor lysis Richter transformation (RT): previously treated CLL and biopsy-proven Richter transformation with DLBCL histology after receiving at least one regimen for RT
Intermediate and high risk tumor lysis T-cell prolymphocytic leukemia (T-PLL) subjects who have received one therapy for this and are relapsed or refractory
For Group 1d 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 ≥ 40% by 2D echocardiogram without Doppler
Bone marrow criteria: Group 1 (r/r low risk tumor lysis CLL/SLL (ALC < 25 x 109 cells/L and all lymph nodes < 5 cm), NHL, RT, MM, T-PLL)
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)

Exclusion Criteria

A subject will not be eligible for study participation if he/she meets any of the following
criteria
Adequately treated in situ carcinoma of the cervix uteri
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
Subjects in need of immediate cytoreduction should be excluded
and/or up to 20 mg/day prednisone or equivalent systemic steroids for ongoing GVHD is
Any investigational therapy
permitted)
Live vaccines
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
Inhibitors of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)
Subject with breast cancer or prostate cancer on endocrine therapy with stable
disease
Basal cell carcinoma of the skin or localized squamous cell carcinoma of the
Uncontrolled active systemic infection (bacterial, fungal, viral)
skin
Previous malignancy confined and surgically resected (or treated with other
modalities) with curative intent
Subjects with known and active central nervous system (CNS) involvement at Screening
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 ≤
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)
Continuation of maintenance therapy in patients with adequately treated
malignancy
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)
Cancer with expected survival of 2 years or more or that will not confound
evaluation of LP-118 treatment
disability status of New York Heart Association Class ≥ 2 or associated other
Grade 2 clinically significant AEs of the previous therapy (excluding neuropathy)
significant screening ECG or ultrasonic cardiogram abnormalities, per Investigator's
judgement
Subject has significant a history of congenital long QT syndrome or Torsades de
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
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)
There is a 28 day washout period required for subjects who have had prior CAR-T
treatment if there is no evidence of cytokine release syndrome (CRS) or other
adverse events related to the CAR-T treatment, per discussion with the Medical
Monitor
Subject has baseline prolongation of the heart rate-corrected QT (QTcF) interval ≥ 480
ms (calculated per Fridericia's formula [QTcF = QT/RR(1/3)]) ), a cardiovascular
Pointes, uncontrolled or symptomatic arrhythmias, congestive heart failure, myocardial
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