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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)

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ClinicalTrials.gov Identifier: NCT04139434
Recruitment Status : Recruiting
First Posted : October 25, 2019
Last Update Posted : April 2, 2021
Sponsor:
Information provided by (Responsible Party):
Newave Pharmaceutical Inc

Brief Summary:
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)

Condition or disease Intervention/treatment Phase
AML/MDS CMML Relapse Refractory Acute Lymphoblastic Leukemia Relapse Leukemia Relapsed Adult AML Drug: LP-108 Phase 1

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 ORR for AML, MDS, CMML, PFS, DOR, and OS

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: A classic "3+3" design will be used to establish dose-limiting toxicity (DLT), MTD, and RP2D.
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : July 6, 2020
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : December 2022


Arm Intervention/treatment
Experimental: Dose Escalation Phase
Three to 6 subjects per treatment cohort will be assigned to receive sequentially higher oral doses of LP-108 on a once daily schedule for 28 days (a "Cycle" starting at a dose of 100 mg.
Drug: LP-108
For the dose escalation phase, LP-108 will be given once daily at the following dose levels: 100 mg QD, 200 mg QD, 400 mg QD, 600 mg QD, 800 mg QD, 1000 mg QD.

Experimental: Dose Expansion Phase
Additional subjects will be recruited to further explore the safety, tolerability, PK, and efficacy in specific subject subgroups. One or more RP2D may be explored.
Drug: LP-108
For the dose expansion phase, LP-108 will be given once daily dose at the Recommended Phase 2 Dose (RP2D).




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: up to 13 cycles (one cycle has 4 weeks) ]
  2. Recommended Phase 2 dose (RP2D) [ Time Frame: up to 13 cycles (one cycle has 4 weeks) ]
  3. The pharmacokinetic (PK) profile of LP-108: Maximum Plasma Concentration [Cmax] [ Time Frame: At Cycle 1 Day 1 (24 h PK), Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 22, Cycle 2 Day 1 (24 h PK) ]
  4. The PK profile of LP-108: Area Under the Curve [AUC] [ Time Frame: At Cycle 1 Day 1 (24 h PK), Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 22, Cycle 2 Day 1 (24 h PK) ]
  5. The PK profile of LP-108: Time at Maximum Concentration [Tmax] [ Time Frame: At Cycle 1 Day 1 (24 h PK), Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 22, Cycle 2 Day 1 (24 h PK) ]

Secondary Outcome Measures :
  1. Objective Response Rate (ORR) for AML [ Time Frame: up to 13 cycles (one cycle has 4 weeks) ]
    Assessment will be based on revised recommendations of the ELN 2017.

  2. ORR for MDS [ Time Frame: up to 13 cycles (one cycle has 4 weeks) ]
    Assessment will be based on the proposed International Working Group 2006 criteria for MDS patients.

  3. ORR for CMML [ Time Frame: up to 13 cycles (one cycle has 4 weeks) ]
    Assessment will be based on international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) for CMML patients.

  4. Progression-Free Survival (PFS) [ Time Frame: up to 13 cycles (one cycle has 4 weeks) ]
    PFS is defined as the time from start of treatment until objective disease progression or death, whichever occurs first.

  5. Duration of Response (DOR) [ Time Frame: up to 13 cycles (one cycle has 4 weeks) ]
    DOR is for all subjects achieving an objective response.

  6. Event-Free Survival (EFS) [ Time Frame: up to 13 cycles (one cycle has 4 weeks) ]
    EFS is defined as the time from the start of LP-108 therapy until the earliest date of refractory disease or relapse.

  7. Overall Survival (OS) [ Time Frame: up to 13 cycles (one cycle has 4 weeks) ]
    Overall survival is defined as the time from treatment initiation until death from any cause.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

  • 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 revised criteria and/or MDS with high- or very high-risk (risk score > 4.5) per the Revised International Prognostic Scoring System (IPSS-R) (Greenberg et al. 2012) 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 2016 revised criteria 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.
  • White blood cell (WBC) count ≤ 25 × 109 cells/L at the time of enrollment (hydroxyurea is allowed to control WBC count prior to and during therapy).
  • Subject must have adequate coagulation, renal, and hepatic function.

    • 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 Cockcroft-Gault formula (using actual body weight)
    • 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).
  • Adequate cardiac function defined as: shortening fraction of ≥ 27% by echocardiogram, or ejection fraction of ≥ 50% by echocardiogram or radionuclide angiogram (nuclear medicine analysis).

Exclusion Criteria:

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

  • Subjects with a diagnosis of promyelocytic leukemia/retinoic acid receptor alpha (PML-RARA) or non-PML-RARA rearranged acute promyelocytic leukemia (APL).
  • 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).
  • Subject has received any of the following therapies within 14 days or 5 half-lives (whichever is longer) prior to the first dose of study drug, or has not recovered to ≤ Grade 1 clinically significant adverse effect(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.
  • Subject has received the following medications or therapies within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study drug:

    • Cytochrome P450, family 3, subfamily A (CYP3A4) strong inhibitors (see Appendix 10 for strong CYP3A4 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 CYP3A4 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).
  • Subject has corrected QTc > 480 ms.
  • 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
  • Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

    • Uncontrolled systemic infection (bacterial, fungal, viral)
    • Known active or poorly controlled human immunodeficiency virus or active hepatitis B or C infection
    • 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).
  • 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 successful lumbar punctures without cytologic evidence of leukemia may be included after discussion and approval of the 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).
  • Subjects with immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.
  • Requires treatment with

    • Systemic acid-reducing agents including H-2-receptor antagonists and proton pump inhibitors
    • Sensitive CYP2C8 substrates (such as montelukast, pioglitazone, repaglinide, rosiglitazone) or CYP2C8 substrates with a narrow therapeutic index (eg, amiodarone, fosphenytoin, paclitaxel, penprocoumon, phenytoin)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04139434


Contacts
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Contact: Ann Vollmer, BA (925) 989 4601 avollmer@newavepharma.com
Contact: Stephen Anthony, DO s.anthony@newavepharma.com

Locations
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United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
United States, Ohio
The Ohio State Comprehensive Cancer Center- James Cancer Hospital and Solove Research Institute Recruiting
Columbus, Ohio, United States, 43210
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
Newave Pharmaceutical Inc
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Responsible Party: Newave Pharmaceutical Inc
ClinicalTrials.gov Identifier: NCT04139434    
Other Study ID Numbers: LP-108P
First Posted: October 25, 2019    Key Record Dates
Last Update Posted: April 2, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Newave Pharmaceutical Inc:
AML
MDS
CMML
relapse
refractory
LP-108
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid, Acute
Preleukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Myelodysplastic Syndromes
Recurrence
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease Attributes
Pathologic Processes
Myelodysplastic-Myeloproliferative Diseases