CLINICAL TRIAL / NCT04771572
Study of Oral Administration of LP-118 in Patients With Relapsed or Refractory CLL, SLL, MDS, MDS/MPN, AML, CMML-2, MPN-BP, ALL, MF, NHL, RT, MM or T-PLL.
- Interventional
- Recruiting
- NCT04771572
Contact Information
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.
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 × 10^9 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 × 10^9 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);
Gender
All
Age Group
13 Years and up
Accepting Healthy Volunteers
No
Inclusion Criteria:
- Male or female subjects, ≥ 18 years of age at the time of Screening with the following
exception as outlined below:
o 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;
Group 1b
- 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;
- 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;
- Chronic myelomonocytic leukemia (CMML) with <9% blasts;
- Or atypical chronic myeloid leukemia (aCML) with Hgb > 10g/dL, WBC count < 50 x
109 cells/L, <10% immature circulating cells;
- 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;
- 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;
- 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;
- Low risk tumor lysis T-cell prolymphocytic leukemia (T-PLL) subjects who have received
one therapy for this and are relapsed or refractory;
Group 1d
- Relapsed or refractory ALL with dexamethasone run-in [5 days, dexamethasone 10mg/m2
(divided BID)];
- Or r/r ALL in remission but with detectable MRD (MRD +) by any detection method per
institution standard of practice;
- 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.
- Relapsed or refractory ALL subjects with age between 13 - 18 years and have body
weight ≥ 40kg, 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
progressed, 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 progressed.
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.
- 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 low risk tumor lysis CLL/SLL (ALC < 25 x 109
cells/L and all lymph nodes < 5 cm), 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)
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).
Exclusion Criteria:
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;
- Continuation of maintenance therapy in patients with adequately treated
malignancy;
- 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.
- Cancer with expected survival of 2 years or more or that will not confound
evaluation of LP-118 treatment
- 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 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).
- 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
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.