Study of Oral Administration of LP-118 in Patients With Relapsed or Refractory NHL, RT, MM, T-PLL, Acute Leukemia (AML, ALL), MDS, MDS/MPN, and MF

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Brief Title

Study of Oral Administration of LP-118 in Patients With Relapsed or Refractory NHL, RT, MM, T-PLL, Acute Leukemia (AML, ALL), MDS, MDS/MPN, and MF

Official Title

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

Brief 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.
    

Detailed 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 NHL, RT, MM, T-PLL (Group 1) and acute leukemia (AML, ALL), MDS, MDS/MPN,
      MF (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 NHL, RT, MM, T-PLL (Group 1); and acute leukemia
      (AML, ALL), MDS, MDS/MPN, MF (Group 2
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Maximum Tolerated Dose (MTD)

Secondary Outcome

 Progression-Free Survival (PFS)

Condition

Non Hodgkin Lymphoma

Intervention

LP-118

Study Arms / Comparison Groups

 Dose Escalation Phase
Description:  Phase 1a dose-escalation will begin with group 1 and proceed until DLT is observed and MTD is established, or until an RP2D is established. Subjects enrolled in the 10 mg dose cohort will receive 10 mg LP-118 once daily. Subjects enrolled in the 20 mg dose cohort will receive 10 mg LP-118 for the first day, followed by 20 mg LP-118 once daily thereafter. Subjects enrolled in the rest of the dose cohorts will follow 3+3 study design, starting with an accelerated step-up dosing schedule until they reach the designated target dose (50 mg, 100 mg, 200 mg, 300 mg, or 400 mg). Once the MTD or RP2D is established for group 1, the phase 1a dose escalation can proceed for group 2. The starting dose level for group 2 will be one dose level below the MTD or RP2D established for group 1.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

100

Start Date

August 23, 2021

Completion Date

August 1, 2024

Primary Completion Date

August 1, 2024

Eligibility Criteria

        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 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).

        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;

               -  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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, (925) 989 4601, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04771572

Organization ID

LP-118-US-I01


Responsible Party

Sponsor

Study Sponsor

Newave Pharmaceutical Inc


Study Sponsor

, , 


Verification Date

September 2021