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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 : July 8, 2020
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 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.

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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. 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. Once all subjects in a given cohort have reached Cycle 1 Day 28, these data will be reviewed by the Safety Review Committee (SRC) for decisions on dose escalation for a new dose cohort. Subjects will receive once-daily oral dose of LP-108 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal from treatment criterion is noted. Treatment cycles will occur consecutively without interruption, except when necessary to manage AEs. There will be no intra-subject dose escalation.
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: Cohort 1
Dose 100mg
Drug: LP-108
Evaluate safety, tolerability, pharmacokinetics, and clinical activity of orally administered LP-108 in subjects with r/r MDS, CMML, or AML

Experimental: Cohort 2
Dose 200mg
Drug: LP-108
Evaluate safety, tolerability, pharmacokinetics, and clinical activity of orally administered LP-108 in subjects with r/r MDS, CMML, or AML

Experimental: Cohort 3
Dose 400mg
Drug: LP-108
Evaluate safety, tolerability, pharmacokinetics, and clinical activity of orally administered LP-108 in subjects with r/r MDS, CMML, or AML

Experimental: Cohort 4
Dose 600mg
Drug: LP-108
Evaluate safety, tolerability, pharmacokinetics, and clinical activity of orally administered LP-108 in subjects with r/r MDS, CMML, or AML

Experimental: Cohort 5
Dose 800mg
Drug: LP-108
Evaluate safety, tolerability, pharmacokinetics, and clinical activity of orally administered LP-108 in subjects with r/r MDS, CMML, or AML

Experimental: Cohort 6
Dose 1000mg
Drug: LP-108
Evaluate safety, tolerability, pharmacokinetics, and clinical activity of orally administered LP-108 in subjects with r/r MDS, CMML, or AML




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: up to 13 cycles (one cycle has 4 weeks) ]
    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.

  2. Recommended Phase 2 dose (RP2D) [ Time Frame: up to 13 cycles (one cycle has 4 weeks) ]
    The RP2D may be as high as the MTD or a lower dose and will be selected based on longer term safety data, preliminary efficacy data, and PK data.

  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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (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 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.

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
Layout table for location contacts
Contact: Fenlai Tan, M.D., Ph.D. 248-835-9998 tfl@newavepharma.com
Contact: Anna Chen, M.D., Ph.D. 206-335-3820 yu@newavepharma.com

Locations
Layout table for location information
United States, Michigan
University of Michigan Not yet 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, Oregon
Oregon Health and Science University OHSU Knight Cancer Institute Not yet recruiting
Portland, Oregon, United States, 97239
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Principal Investigator: Naval Daver, M.D.         
Principal Investigator: Marina Konopleva, M.D., Ph.D.         
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: July 8, 2020
Last Verified: July 2020
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