A Study to Assess Safety and Preliminary Efficacy of LP-108 Combined With Azacitidine In Subjects With AML, MDS, CMML

February 1, 2024 updated by: Guangzhou Lupeng Pharmaceutical Company LTD.

A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of LP-108, a BCL-2 Inhibitor, Combined With Azacitidine In Subjects With AML, MDS, CMML

This is a Phase 1, open-label, multicenter, dose-escalation & expansion study to evaluate the safety,tolerability and pharmacokinetics (PK) of LP-108, a BCL-2 inhibitor, combined with azacitidine, to determine the dose limiting toxicity (DLT) and the recommended Phase 2 dose (RP2D), and to assess the preliminary efficacy of this combination.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This Phase 1 study will look at different doses and different treatment schedules in order to better understand the effects of the combined regimens on the newly diagnosed or refractory/relapsed adult participants with AML ,MDS or CMML. The procedures include screening for eligibility, study treatments, and blood & bone marrow tests. All the safety events will be record, pharmacokinetic parameters (Tmax, Cmax,T1/2, AUC et al.) will be calculated, response and survival will be assess during the study. Participants will be treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.

Study Type

Interventional

Enrollment (Estimated)

198

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • China
      • Nanchang, China
        • Recruiting
        • The First Affiliated Hospital Of Nanchang University
        • Contact:
          • Fei Li
      • Suzhou, China
        • Recruiting
        • First Affiliated Hospital of Soochow University
        • Contact:
          • Depei Wu
      • Zhengzhou, China
        • Recruiting
        • Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital
        • Contact:
          • Fei Li

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Subject must has a diagnosis of one of the following: relapsed or refractory (R/R) or untreated ineligible for treatment with a standard induction chemotherapy acute myeloid leukemia (AML) ; R/R myelodysplastic syndrome(MDS) or untreated MDS with excess blasts defined as ≥ 5% blasts in either bone marrow or blood or with high risk (high and very high-risk groups according to IPSS-R) ;CMML-1 or 2 by WHO, no requirements for prior therapy.
  • ECOG performance status ≤ 2.
  • Estimated survival ≥ 12 weeks.
  • Baseline white blood cell count (WBC) ≤ 25 x 109/L.
  • Subject must has adequate organ function as defined below: Aspartate transaminase (AST) and alanine transaminase (ALT)≤3 x ULN; Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin); adequate renal function as demonstrated by a creatinine clearance ≤1.5 x ULN ; calculated by the Cockcroft Gault formula; APTT ≤ 1.5 x ULN, INR ≤ 1.5 x ULN.
  • Prior treatment-related toxicities must be grade 1 or baseline except for alopecia.
  • If subject is sexually active, he/she must agree to carry out birth control throughout the study and 90 days after the last dose of LP-108. Subject must agree to have a negative serum β-HCG test result within 7 days prior to study drug.
  • Subject must voluntarily sign and date an informed consent.

Exclusion Criteria:

  • Subject is allergic to LP-108, Azacitidine or excipients, or with poor tolerance to Azacitidine.
  • Subject has received prior therapy with a BH3 mimetic.
  • Subject has acute promyelocytic leukemia.
  • Subject has t(9;22) karyotype abnormality or positive BCR/ABL1 fusion gene.
  • Subject has known and active CNS involvement.
  • Subject has myeloid sarcoma but no bone marrow involvement.
  • Subject has Acute unidentified leukemia.
  • Subject has treatment related MDS or AML.
  • Subject has AML/MDS/CMML with myelofibrosis ≥ grade 2.
  • Subject has received allogeneic Hematopoietic Stem Cell Transplantation (HSCT) or autologous HSCT within 3 months prior to the first dose of study drug.
  • Subject must be at least 4 weeks from antitumor therapy, major surgery, radiation therapy, or participation in other investigational trials.
  • Subject has received a strong and/or moderate CYP3A inhibitor or inducer, P-gp inhibitor or CYP2C8 substrate within 14 days prior to the initiation of study treatment.
  • Subject has received drugs with a potential to cause prolonged QT intervals or torsade de pointes.
  • Administration or consumption of any of the following within 3 days prior to the first dose of study drug: Grapefruit or grapefruit products; Seville oranges (including marmalade containing Seville oranges); Star fruit.
  • Subject has known malignancy within 3 years prior to the first dose of study drug, with the exception of: Adequately treated basal skin cancers, in situ carcinoma of the cervix uteri or breast, localized squamous cell carcinoma.
  • Subject has serious and/or uncontrolled systemic diseases, in the opinion of the investigator, the subject is inappropriate for enrollment into this study (serious active infection with grade ≥ 2(based on CTCAE), high blood pressure that cannot be controlled by medication, diabetes, unstable angina, congestive heart failure, Respiratory diseases requiring continuous oxygen intake, severe vascular embolism, uncontrolled massive bleeding or bleeding from vital organs, severe liver, kidney or metabolic diseases, such as cirrhosis, kidney failure, etc.).
  • Subject has myocardial infarction or stroke within 6 months prior to the first dose of study drug.
  • Subject has a cardiac history including the following: History of CHF requiring treatment or Ejection Fraction <50% or a cardiovascular disability status of New York Heart Association.
  • Subject has uncontrolled and/or active systemic infection (viral, bacterial or fungal).
  • Subject has difficulty to swallow pills or has conditions that affect drug absorption or pharmacokinetics.
  • Strong and/or moderate CYP3A inhibitor or inducer and CYP2C8 substrate cannot be discontinued during the study.
  • Vaccination with live, attenuated vaccines ≤4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study or 4 weeks after the last dose of study drug.
  • Subject has an autoimmune disease that requires immunosuppressive therapy In the opinion of the investigator, the subject is inappropriate for enrollment into this study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Dose Escalation

LP-108: Cycle 0: ramp-up from Day 1, Cycle 1+: at escalating dose levels in participants with AML, MDS or CMML.

Azacitidine: beginning on Day 1 through Day 7 of each Cycle (expect for Cycle 0).

Strong/moderate CYP3A inhibitor and inducer are prohibited. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Drug: LP-108
Oral administration for 21 or 28 days on a 28-day cycle
Drug: Azacitidine
Subcutaneous administration for 7 days on a 28-day cycle at the dose of 75mg/m2 2-2.5h hours after LP-108.
Experimental: Safety Expansion

LP-108: Cycle 0: ramp-up from Day 1, Cycle 1+: Participants with AML, MDS or CMML will be treated with LP-108 to enable selection of the recommended Phase 2 dose (RP2D).

Azacitidine: beginning on Day 1 through Day 7 of each Cycle (expect for Cycle 0).

Strong/moderate CYP3A inhibitor and inducer are prohibited. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Drug: LP-108
Oral administration for 21 or 28 days on a 28-day cycle
Drug: Azacitidine
Subcutaneous administration for 7 days on a 28-day cycle at the dose of 75mg/m2 2-2.5h hours after LP-108.
Experimental: Efficacy Expansion [AML]

LP-108: Cycle 0: ramp-up from Day 1, Cycle 1+: at RP2D level in participants with AML .

Azacitidine: beginning on Day 1 through Day 7 of each Cycle (expect for Cycle 0).

After the completion of Part 1, the Part 2 dose expansion phase will begin. Strong/moderate CYP3A inhibitor and inducer are prohibited. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Drug: LP-108
Oral administration for 21 or 28 days on a 28-day cycle
Drug: Azacitidine
Subcutaneous administration for 7 days on a 28-day cycle at the dose of 75mg/m2 2-2.5h hours after LP-108.
Experimental: Efficacy Expansion [MDS&CMML]

LP-108: Cycle 0: ramp-up, Cycle 1+: at RP2D level in participants with MDS or CMML.

Azacitidine: beginning on Day 1 through Day 7 of each Cycle (expect for Cycle 0).

Strong/moderate CYP3A inhibitor and inducer are prohibited. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Drug: LP-108
Oral administration for 21 or 28 days on a 28-day cycle
Drug: Azacitidine
Subcutaneous administration for 7 days on a 28-day cycle at the dose of 75mg/m2 2-2.5h hours after LP-108.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum Tolerated Dose(MTD)
Time Frame: Up to 42 days after initial dose of study drug at the designated cohort dose.
Standard phase I 3+3 design. The first 3 subjects will be assigned to dose level 1 cohort. If none of the first three subjects experiences DLT, escalation to dose level 2 cohort is permitted. If one of the first three subjects' experiences DLT, a total of six subjects will be required in that dose cohort, and escalation will only be permitted if five of six subjects do not experience DLT. If more than one DLT is observed in the dose level 2 cohort, this will be determined to be the maximally administered dose, and three more subjects will be enrolled in the dose level 1 cohort if only three were previously treated at that dose. Escalation from dose level 2 to level 3 cohort will be with the same method as before. The MTD will be the cohort in which ≤1/6 subjects have dose limiting toxicity at the dose prior to the maximally administered dose. If the dose level 3 cohort has ≤1/6 subjects with a DLT, the MTD will not have been reached.
Up to 42 days after initial dose of study drug at the designated cohort dose.
Recommended Phase 2 Dose(RP2D)
Time Frame: Up to 1.5 years
RP2D will be determined using available safety and pharmacokinetics data upon completion of the dose escalation phase.
Up to 1.5 years
Incidence of AEs
Time Frame: From first dose of study drug to 28 days after last dose of study drug
Type, frequency and severity of AEs, relationship of AEs to study treatment
From first dose of study drug to 28 days after last dose of study drug
Incidence of clinically significant changes in clinical laboratory results
Time Frame: From first dose of study drug to 28 days after last dose of study drug
Clinically significant changes in hematology, chemistry, coagulation and urinalysis tests results.
From first dose of study drug to 28 days after last dose of study drug
Cmax of LP-108
Time Frame: Up to 24 hours post dose
Maximum plasma concentration (Cmax) of LP-108.
Up to 24 hours post dose
Tmax of LP-108
Time Frame: Up to 24 hours post dose
Time to maximum plasma concentration (Tmax) of LP-108.
Up to 24 hours post dose
t1/2 of LP-108
Time Frame: Up to 24 hours post dose
The terminal elimination half-life (t1/2).
Up to 24 hours post dose
AUC0-t of LP-108
Time Frame: Up to 24 hours post dose
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration of LP-108.
Up to 24 hours post dose
CL/F of LP-108
Time Frame: Up to 24 hours post dose
Apparent clearance (CL/F) of LP-108.
Up to 24 hours post dose
Vd/F of LP-108
Time Frame: Up to 24 hours post dose
Apparent volume of distribution of LP-108.
Up to 24 hours post dose

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective Response Rate (ORR)
Time Frame: Measured from Cycle 1 Day 1 to 28 days after last dose of study drug, and assessed up to 24 months.
Response criteria follows the 2017 European Leukemia Net (ELN) recommendations for AML( CR, CRi, PR) , the International Working Group (IWG) response criteria for MDS(CR, PR, marrow CR, HI), the international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults(CR, PR, Marrow response, Clinical benefit).
Measured from Cycle 1 Day 1 to 28 days after last dose of study drug, and assessed up to 24 months.
Progression-Free Survival(PFS) (only for MDS or CMML)
Time Frame: Measured from the date of first dose of study drug to the date of earliest disease progression or death or last visit, and assessed up to 24 months.
PFS is defined as the number of days from the date of the first dose of study drug to the date of earliest disease progression or death.
Measured from the date of first dose of study drug to the date of earliest disease progression or death or last visit, and assessed up to 24 months.
Time to Response(TTR)
Time Frame: Measured from the date of the first dose of study drug to the date of earliest response, and assessed up to 6 months.
TTR is defined as the number of days from the date of the first dose of study drug to the date of earliest response.
Measured from the date of the first dose of study drug to the date of earliest response, and assessed up to 6 months.
Duration of Response(DOR)
Time Frame: Measured from the date of the first remission to the date of earliest disease progression or death, and assessed up to 24 months.
DOR is defined as the number of days from the date of the first remission to the date of earliest disease progression or death.
Measured from the date of the first remission to the date of earliest disease progression or death, and assessed up to 24 months.
DOCR (only for CR/CRi participants)
Time Frame: Measured from the date of the first CR/CRi to the date of earliest disease progression or death, and assessed up to 24 months.
DOCR is defined as the number of days from the date of the first CR/CRi to the date of earliest disease progression or death.
Measured from the date of the first CR/CRi to the date of earliest disease progression or death, and assessed up to 24 months.
Event-free Survival (EFS)
Time Frame: Measured from the date of first dose to the date of earliest evidence of disease progression, initiation of new non-protocol-specified antitumor therapy without documented progression, death, and for up to 5 years after the last subject is enrolled.
EFS is defined as the number of days from the date of first dose to the date of earliest evidence of disease progression/relapse, or initiation of new non-protocol-specified antitumor therapy without documented progression, or death.
Measured from the date of first dose to the date of earliest evidence of disease progression, initiation of new non-protocol-specified antitumor therapy without documented progression, death, and for up to 5 years after the last subject is enrolled.
OS
Time Frame: Measured from the date of date of first dose to the date of death or last visit, and for up to 5 years after the last subject is enrolled.
OS is defined as the number of days from the date of first dose to the date of death.
Measured from the date of date of first dose to the date of death or last visit, and for up to 5 years after the last subject is enrolled.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Guangzhou Lupeng Pharmaceutical Company LTD.

Investigators

  • Study Chair: Depei Wu, PhD, First Affiliated Hospital of Soochow University
  • Principal Investigator: Xudong Wei, PhD, Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital
  • Principal Investigator: Qiubai Li, PhD, Wuhan Union Hospital, China
  • Principal Investigator: Li Wang, PhD, First Affiliated Hospital of Chongqing Medical University
  • Principal Investigator: Fei Li, PhD, The First Affiliated Hospital Of Nanchang University
  • Principal Investigator: Xiaojing Yan, PhD, First Hospital of China Medical University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 14, 2023

Primary Completion (Estimated)

December 31, 2024

Study Completion (Estimated)

December 31, 2025

Study Registration Dates

First Submitted

November 17, 2022

First Submitted That Met QC Criteria

November 29, 2022

First Posted (Actual)

December 7, 2022

Study Record Updates

Last Update Posted (Estimated)

February 2, 2024

Last Update Submitted That Met QC Criteria

February 1, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • LP-108-CN102

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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