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

NCT05641259 | Recruiting Phase 1

• 1 other identifier: LP-108-CN102
• Study Type: interventional
• Target: 198
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia

Outcome Measures

Primary Outcomes (10)

• Maximum Tolerated Dose(MTD)

  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)

  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

  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

  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

  Maximum plasma concentration (Cmax) of LP-108.

  Up to 24 hours post dose

• Tmax of LP-108

  Time to maximum plasma concentration (Tmax) of LP-108.

  Up to 24 hours post dose

• t1/2 of LP-108

  The terminal elimination half-life (t1/2).

  Up to 24 hours post dose

• AUC0-t of LP-108

  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

  Apparent clearance (CL/F) of LP-108.

  Up to 24 hours post dose

• Vd/F of LP-108

  Apparent volume of distribution of LP-108.

  Up to 24 hours post dose

Secondary Outcomes (7)

• Objective Response Rate (ORR)

  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)

  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)

  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)

  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)

  Measured from the date of the first CR/CRi to the date of earliest disease progression or death, and assessed up to 24 months.

Study Arms (4)

Dose Escalation

EXPERIMENTAL

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; Drug: Azacitidine

Safety Expansion

EXPERIMENTAL

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; Drug: Azacitidine

Efficacy Expansion [AML]

EXPERIMENTAL

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; Drug: Azacitidine

Efficacy Expansion [MDS&CMML]

EXPERIMENTAL

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; Drug: Azacitidine

Interventions

LP-108 DRUG

Oral administration for 21 or 28 days on a 28-day cycle

Dose Escalation; Efficacy Expansion [AML]; Efficacy Expansion [MDS&CMML]; Safety Expansion

Azacitidine DRUG

Subcutaneous administration for 7 days on a 28-day cycle at the dose of 75mg/m2 2-2.5h hours after LP-108.

Dose Escalation; Efficacy Expansion [AML]; Efficacy Expansion [MDS&CMML]; Safety Expansion

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Guangzhou Lupeng Pharmaceutical Company LTD.: lead

Study Sites (3)

The First Affiliated Hospital of Nanchang University

Nanchang, China

RECRUITING

First Affiliated Hospital of Soochow University

Suzhou, China

RECRUITING

Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital

Zhengzhou, China

RECRUITING

Related Publications (3)

• Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Lowenberg B, Bloomfield CD. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017 Jan 26;129(4):424-447. doi: 10.1182/blood-2016-08-733196. Epub 2016 Nov 28.

  PMID: 27895058 RESULT

• Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. doi: 10.1182/blood-2005-10-4149. Epub 2006 Apr 11.

  PMID: 16609072 RESULT

• Savona MR, Malcovati L, Komrokji R, Tiu RV, Mughal TI, Orazi A, Kiladjian JJ, Padron E, Solary E, Tibes R, Itzykson R, Cazzola M, Mesa R, Maciejewski J, Fenaux P, Garcia-Manero G, Gerds A, Sanz G, Niemeyer CM, Cervantes F, Germing U, Cross NC, List AF; MDS/MPN International Working Group. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. 2015 Mar 19;125(12):1857-65. doi: 10.1182/blood-2014-10-607341. Epub 2015 Jan 26.

  PMID: 25624319 RESULT

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic

Interventions

Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

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 Officials

• Depei Wu, PhD

  First Affiliated Hospital of Soochow University

  STUDY CHAIR

• Xudong Wei, PhD

  Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital

  PRINCIPAL INVESTIGATOR

• Qiubai Li, PhD

  Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

  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

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Yue Shen, PhD

CONTACT

86-020-31605119; yshen@lupengbio.com

Study Design

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

Model Details: This is a Phase 1 study with a dose escalation design and an expansion cohort.

Study Record Dates

• First Submitted: November 17, 2022
• First Posted: December 7, 2022
• Study Start: February 14, 2023
• Primary Completion: December 31, 2024
• Study Completion: December 31, 2025
• Last Updated: February 2, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

CN (3)