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Dose-escalation Study of Oral Administration of LP-108 in Patients With Relapsed or Refractory Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML)

NCT04139434

Description:

A Phase 1, Multi-center, Open-label, Dose Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Clinical Activity of Orally Administered LP-108 in Subjects with Relapsed or Refractory Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML)

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
  • Refractory Anemia with Excess Blasts-1
  • Refractory Anemia with Excess Blasts-2
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Dose-escalation Study of Oral Administration of LP-108 in Patients With Relapsed or Refractory Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML)
  • Official Title: A Phase 1, Multicenter, Open-label, Dose-escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Clinical Activity of Orally Administered LP-108 in Subjects With Relapsed or Refractory Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML)

Clinical Trial IDs

  • ORG STUDY ID: LP-108P
  • NCT ID: NCT04139434

Conditions

  • AML/MDS
  • CMML
  • Relapse
  • Refractory Acute Lymphoblastic Leukemia
  • Relapse Leukemia
  • Relapsed Adult AML

Interventions

DrugSynonymsArms
LP-108Cohort 1

Purpose

A Phase 1, Multi-center, Open-label, Dose Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Clinical Activity of Orally Administered LP-108 in Subjects with Relapsed or Refractory Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML)

Detailed Description

      The primary objectives are to assess the safety and tolerability profile, determine the
      maximum tolerated dose (MTD), and/or the recommended Phase 2 dose (RP2D) of LP-108
      administered daily as a single agent dosed orally in adult subjects with relapsed/refractory
      MDS/CMML/AML; to characterize the pharmacokinetics (PK) profile of LP-108 in adult subjects
      with relapsed/refractory MDS/CMML/AML.

      Secondary objectives are to evaluate preliminary efficacy regarding the effect of LP-108
      (monotherapy or combination therapy) on objective response rate (ORR) for AML (including rate
      of complete remission [CR]with or without minimal residual disease [MRD], CR with incomplete
      platelet recovery [CRp], CR with incomplete blood count recovery [CRi], morphologic
      leukemia-free state (MLFS), and partial remission [PR]), and ORR for MDS (CR with or without
      persistent dysplasia, PR, and marrow CR), and ORR for CMML (including CR, complete
      cytogenetic remission, PR, marrow response, and clinical benefit), progression-free survival
      (PFS), duration of response (DOR) (for all subjects achieving an objective response),
      event-free survival (EFS), and overall survival (OS) for AML, MDS and CMML.

      Exploratory objectives are to explore blood borne biomarkers that may influence development
      of hematological malignancy and/or response to treatment (where response is defined broadly
      to include efficacy, tolerability, or safety); to study genes/genetic variation that may
      influence PK or response (ie, absorption, distribution, metabolism, excretion, safety,
      tolerability, and efficacy) to treatment, and/or genetic drivers of hematological malignancy
      such as AML, MDS, and CMML; to explore the relationship between PK and selected endpoints
      (ie, blood borne biomarkers), where deemed appropriate.

      Once the MTD is declared and the RP2D is established, additional subjects will be enrolled in
      a cohort expansion phase (Phase 1b) that might adapt combination therapies with other agents
      such as hypomethylating agents (HMA), and in the United States and ex-US sites.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1ExperimentalDose 100mg
  • LP-108
Cohort 2ExperimentalDose 200mg
  • LP-108
Cohort 3ExperimentalDose 400mg
  • LP-108
Cohort 4ExperimentalDose 600mg
  • LP-108
Cohort 5ExperimentalDose 800mg
  • LP-108
Cohort 6ExperimentalDose 1000mg
  • LP-108

Eligibility Criteria

        Inclusion Criteria:

        A subject will be eligible for study participation if he/she meets the following criteria:

          1. Male or female subjects, ≥ 18 years of age at the time of Screening.

          2. Eligible subject must have an advanced hematologic malignancy including:

               -  MDS with refractory anemia with excess blasts (RAEB; subtype RAEB-1 or RAEB-2) as
                  defined by World Health Organization (WHO) 2016 and/or MDS with high- or very
                  high-risk per the Revised International Prognostic Scoring System (IPSS-R)
                  (Greenberg et al. 2012) (Appendix 8) that is relapsed or refractory to prior
                  therapy for MDS, or the subject is intolerant to established therapy known to
                  provide clinical benefit for their condition (ie, subjects must not be candidates
                  for regimens known to provide clinical benefit), according to the treating
                  physician and with approval of the Medical Monitor;

               -  Relapsed and/or primary refractory AML as defined by WHO 2016 revised criteria;

               -  CMML (with ≥ 5% blasts in bone marrow) as defined by WHO that is relapsed and/or
                  refractory and that, in the opinion of the Investigator, requires treatment or
                  that has exhausted treatment options that would be considered standard of care.

          3. White blood cell (WBC) count ≤ 25 × 109 cells/L at the time of enrollment (hydroxyurea
             is allowed to control white count prior to and during therapy).

          4. Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2.

          5. Predicted life expectancy of ≥ 3 months.

          6. Subject must have adequate coagulation, renal, and hepatic function, per laboratory
             reference ranges at Screening as follows:

               -  Activated partial thromboplastin time and prothrombin time not to exceed 1.5 ×
                  the upper limit of normal (ULN);

               -  Calculated creatinine clearance (Cr Cl) ≥ 60 mL/min using 24-hour CrCl OR
                  modified Cockcroft-Gault formula (using ideal body mass [IBM] instead of mass):

             CrCl = (140-Age) x IBM (kg) x [1.0 if Male, 0.85 if Female] 72 x Serum Creatinine
             (mg/dL)

             Or, if serum creatinine is in μmol/L:

             CrCl = (140-Age) x IBM (kg) x [1.23 if Male, 1.04 if Female] Serum Creatinine (μmol/L)

             IBM should be calculated:

             IBM = [(height cm - 154) x 0.9] + (50 if Male, 45.5 if Female)

             • 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).

          7. Adequate cardiac function defined as: shortening fraction of ≥ 27% by echocardiogram,
             or ejection fraction of ≥ 50% by echocardiogram or radionuclide angiogram (nuclear
             medicine analysis).

          8. Females of childbearing potential and non-sterile males must practice at least 1 of
             the following methods of birth control with their partner(s) throughout the study and
             for 90 days after discontinuing study drug:

               -  Total abstinence from sexual intercourse as the preferred lifestyle of the
                  subject; periodic abstinence is not acceptable;

               -  Surgically sterile partner(s) by vasectomy, bilateral orchiectomy, bilateral
                  tubal ligation, bilateral oophorectomy or hysterectomy

               -  Intrauterine device

               -  Double-barrier method including contraceptive sponge, diaphragm or cervical cap
                  with spermicidal jellies or cream and a condom

               -  Hormonal contraceptives (oral, parenteral, vaginal ring or transdermal) for at
                  least 1 month prior to study drug administration.

          9. Females of childbearing potential (ie, non-postmenopausal for at least 2 years or
             surgically sterile) must have a negative pregnancy result as follows:

               -  At Screening on a serum sample obtained within 14 days prior to the first study
                  drug administration, and

               -  Prior to dosing on a urine or serum sample obtained on the first day of study
                  drug administration if it has been > 7 days since obtaining the serum pregnancy
                  test results in Screening.

         10. Male subjects must refrain from sperm donation, from initial study drug administration
             until 90 days after the last dose of study drug.

         11. Subject must be able to understand and voluntarily sign and date an informed consent,
             approved by an IEC/IRB, prior to any protocol-related procedures.

        Exclusion Criteria:

        A subject will not be eligible for study participation if he/she meets any of the following
        criteria.

          1. Subjects with known hypersensitivity to any of the components of LP-108.

          2. Subjects with a diagnosis of promyelocytic leukemia/retinoic acid receptor alpha
             (PML-RARA) or non-PML-RARA rearranged acute promyelocytic leukemia (APL).

          3. Subjects who have undergone hematopoietic stem cell transplantation (HSCT) within 60
             days of the first dose of LP-108, or subjects on immunosuppressive therapy post-HSCT
             at the time of Screening, or with clinically significant graft-versus-host disease
             (GVHD). (Subjects in relapse after allogeneic transplantation must be off calcineurin
             inhibitors 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).

          4. Subject has received any of the following therapies within 28 days or 5 half-lives
             (whichever is longer) prior to the first dose of study drug, or has not recovered to
             less than Grade 1 clinically significant adverse effect(s)/toxicity(s) of the previous
             therapy:

               -  Any anti-cancer therapy including chemotherapy, hormonal therapy, biologic or
                  immunotherapy, targeted small molecule agents, etc. (corticosteroid therapy < 20
                  mg/day prednisone equivalent for < 14 days at time of study treatment and
                  hydroxyurea cytoreduction therapy according to institutional guidelines to treat
                  disease associated symptoms are permitted).

               -  Any investigational therapy.

          5. Subject has received the following medications or therapies within 7 days prior to the
             first dose of study drug:

               -  Cytochrome P450, family 3, subfamily A (CYP3A) and CYP2D6, CYP1A2, CYP2C19 strong
                  inhibitors (see Appendix 10 for strong inhibitors). In Phase 1b of this trial,
                  the criterion regarding CYP3A4 strong inhibitors will be removed at time of
                  amendment of the trial when Phase 1b is to be initiated. The amendment will
                  include recommendations on concomitant dosing of LP-108 and strong CYP3A4
                  inhibitors such as azole antifungal agents, PK monitoring for the initial weeks
                  on study, as well as closer safety monitoring for subjects.

               -  Strong CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's
                  wort

               -  Inhibitors of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)
                  (see Appendix 11 for P gp and BCRP inhibitors).

               -  Sensitive CYP2C8 substrates (such as montelukast, pioglitazone, repaglinide,
                  rosiglitazone) or CYP2C8 substrates with a narrow therapeutic index (eg,
                  amiodarone, fosphenytoin, paclitaxel, penprocoumon, phenytoin).

               -  Systemic acid reducing agents, including antacids, H-2-receptor antagonists, and
                  proton pump inhibitors.

          6. Subject has consumed grapefruit, grapefruit products, Seville oranges (including
             marmalade containing Seville oranges) or Star fruit within 3 days prior to the first
             dose of study drug.

          7. Subject has a significant history of renal, neurologic, psychiatric, pulmonary,
             endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease that, in
             the opinion of the Investigator, would adversely affect his/her participation in this
             study. For subjects who have required a surgical intervention for any above diseases
             within the past 6 months, a discussion with the Investigator and the Medical Monitor
             is needed.

          8. Subject has a cardiovascular disability status of New York Heart Association Class ≥
             2.

          9. Subject has QTc > 480 ms.

         10. Subject has a history of other malignancies other than the eligible hematologic
             malignancy within the past 1 year 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.

         11. Subject exhibits evidence of other clinically significant uncontrolled condition(s)
             including, but not limited to:

               -  Uncontrolled systemic infection (bacterial, fungal)

               -  Known active or poorly controlled of human immunodeficiency virus or active
                  hepatitis B or C

               -  Unexplained fever > 38.5°C during the Screening period or on their first day of
                  study drug administration (at the discretion of the Investigator, if the fever is
                  considered related to the subject's malignancy may be enrolled).

         12. A female subject is pregnant or breast-feeding.

         13. Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions
             that, in the opinion of the Investigator, may limit the ingestion or gastrointestinal
             absorption of drugs administered orally.

         14. Subjects who are not amenable to serial bone marrow aspiration/biopsy, peripheral
             blood sampling, and urine sampling during the study (the diagnosis and evaluation of
             hematologic malignancy can be made by bone marrow core biopsy when an aspiration is
             unobtainable and/or is not a part of the standard of care; bone marrow biopsy is
             required in case of "dry tap" or unevaluable aspiration usually due to diluted
             hemodiluted specimen).

         15. Subjects with known and active central nervous system (CNS) involvement (radiographic
             or cytologic) at Screening; subjects with history of CNS involvement who have no
             symptoms suggestive of CNS disease and have had at least 2 success lumbar punctures
             without cytologic evidence of leukemia may be included after discussion and approval
             of Medical Monitor. (Evaluation of cerebrospinal fluid is only required if there is a
             clinical suspicion of CNS involvement by leukemia during screening in subjects without
             a history of CNS involvement).

         16. Subjects with immediate life-threatening, severe complications of leukemia such as
             uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
             intravascular coagulation.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:up to 13 cycles (one cycle has 4 weeks)
Safety Issue:
Description:When more than 1 DLT occurs in ≤ 6 subjects in a dosing cohort, dose escalation will be stopped and this dose level will be identified as the non-tolerated dose. Doses between the non-tolerated dose and the preceding lower dose, where ≤ 1 DLT occurred, may be explored to more precisely define the MTD.

Secondary Outcome Measures

Measure:Objective Response Rate (ORR) for AML
Time Frame:up to 13 cycles (one cycle has 4 weeks)
Safety Issue:
Description:Assessment will be based on revised recommendations of the ELN 2017.
Measure:ORR for MDS
Time Frame:up to 13 cycles (one cycle has 4 weeks)
Safety Issue:
Description:Assessment will be based on the proposed International Working Group 2006 criteria for MDS patients.
Measure:ORR for CMML
Time Frame:up to 13 cycles (one cycle has 4 weeks)
Safety Issue:
Description:Assessment will be based on international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) for CMML patients.
Measure:Progression-Free Survival (PFS)
Time Frame:up to 13 cycles (one cycle has 4 weeks)
Safety Issue:
Description:PFS is defined as the time from start of treatment until objective disease progression or death, whichever occurs first.
Measure:Duration of Response (DOR)
Time Frame:up to 13 cycles (one cycle has 4 weeks)
Safety Issue:
Description:DOR is for all subjects achieving an objective response.
Measure:Event-Free Survival (EFS)
Time Frame:up to 13 cycles (one cycle has 4 weeks)
Safety Issue:
Description:EFS is defined as the time from the start of LP-108 therapy until the earliest date of refractory disease or relapse.
Measure:Overall Survival (OS)
Time Frame:up to 13 cycles (one cycle has 4 weeks)
Safety Issue:
Description:Overall survival is defined as the time from treatment initiation until death from any cause.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Newave Pharmaceutical Inc

Trial Keywords

  • BCL-2 inhibitor
  • AML
  • MDS
  • CMML
  • relapse
  • refractory
  • LP-108

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