Dose-Escalation Study of Oral Administration of LP-108 as Monotherapy and in Combination With Azacitidine in Patients With Relapsed or Refractory MDS, CMML, or AML

NCT04139434 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: LP-108P
• Study Type: interventional
• Target: 32
• Locations: 2 countries
• Sites: 7

Brief Summary

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

Conditions

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

Keywords

AML; MDS; CMML; relapse; refractory; LP-108

Outcome Measures

Primary Outcomes (5)

• Maximum Tolerated Dose (MTD)

  up to 13 cycles (one cycle has 4 weeks)

• Recommended Phase 2 dose (RP2D)

  up to 13 cycles (one cycle has 4 weeks)

• The pharmacokinetic (PK) profile of LP-108: Maximum Plasma Concentration [Cmax]

  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)

• The PK profile of LP-108: Area Under the Curve [AUC]

  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)

• The PK profile of LP-108: Time at Maximum Concentration [Tmax]

  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 Outcomes (7)

• Objective Response Rate (ORR) for AML

  up to 13 cycles (one cycle has 4 weeks)

• ORR for MDS

  up to 13 cycles (one cycle has 4 weeks)

• ORR for CMML

  up to 13 cycles (one cycle has 4 weeks)

• Progression-Free Survival (PFS)

  up to 13 cycles (one cycle has 4 weeks)

• Duration of Response (DOR)

  up to 13 cycles (one cycle has 4 weeks)

Study Arms (2)

Dose Escalation Phase: LP-108 monotherapy

EXPERIMENTAL

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

Dose Expansion Phase: LP-108 in combination with azacitidine

EXPERIMENTAL

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 in combination with azacitidine at 75 mg/m2.

Drug: LP-108 and azacitidine

Interventions

LP-108 DRUG

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.

Dose Escalation Phase: LP-108 monotherapy

LP-108 and azacitidine DRUG

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, with azacitidine at the standard dose of 75 mg/m2 on Day 1 - Day 7 of each 28-day cycle (weekly schedule) or on Days 1-5, 8, 9 of each 28-day cycle (5-2-2 schedule), according to institutional guidelines.

Dose Expansion Phase: LP-108 in combination with azacitidine

Eligibility Criteria

• Age: 18 Years+
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 in the opinion of the Investigator; Or relapsed and/or refractory MDS subjects in whom the Investigators feel would benefit from Arm 2.
• Relapsed and/or primary refractory AML as defined by WHO 2016 revised criteria; Or frontline older and/or unfit AML subjects in whom the Investigators feel would benefit from Arm 2.
• 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.
• Subject's prior therapies may include other BCL2 inhibitors and other HMA agents for Arm 2.
• Blast count ≤ 30 × 10\^9 cells/L at the time of initiating investigational therapy (hydroxyurea is allowed to control blast 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) ≥ 30 mL/min using 24-hour CrCl OR Cockcroft-Gault formula (using actual body weight)
• UK and EU only: Estimated glomerular filtration rate (GFR) ≥ 30 mL/min/1.73m2 using the modification of diet in renal disease (MDRD) equation.
• 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 2D echocardiogram without Doppler.

You may not qualify if:

• 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 shorter) 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.
• There is 28-day washout period required for subject 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 received the following medications or therapies within 7 days or 5 half-lives (whichever is shorter) 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).
• Immunosuppressive drugs (equivalent to \>10mg prednisone) for underlying autoimmune or rheumatologic conditions.
• All statins as they could inhibit bilirubin uptake transporter OATP1B1 and OATP1B3 (the washout period should always be 5 half-lives) (see Appendix 11)
• Subject has baseline prolongation of the corrected QTc \> 480 ms (calculated per Fridericia's formula \[QTc = QT/RR (1/3)\].
• 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:

Sponsors & Collaborators

• Newave Pharmaceutical Inc: lead

Study Sites (7)

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

University of Cincinnati

Cincinnati, Ohio, 45221, United States

Location

Ohio State Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

MD Anderson Cancer Center

Huston, Texas, 77030, United States

Location

Institut Català d'oncologia - ICO Badalona

Badalona, Barcelona, 08916, Spain

Location

Hospital San Pedro de Alcántara

Cáceres, Cáceres, 10003, Spain

Location

Instituto de Investigación Sanitaria La Fe

Valencia, Valencia, CP 46026, Spain

Location

MeSH Terms

Conditions

Recurrence; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute

Interventions

Azacitidine

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: A classic "3+3" design will be used to establish dose-limiting toxicity (DLT), MTD, and RP2D.

Study Record Dates

• First Submitted: October 18, 2019
• First Posted: October 25, 2019
• Study Start: July 6, 2020
• Primary Completion: December 19, 2025
• Study Completion: December 19, 2025
• Last Updated: January 23, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (4); ES (3)