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

NCT ID: NCT05641259

Last Updated: 2024-02-02

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 198 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-02-14
• Study Completion Date: 2025-12-31

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.

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.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

LP-108

Intervention Type: DRUG

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

Azacitidine

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

LP-108

Intervention Type: DRUG

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

Azacitidine

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

LP-108

Intervention Type: DRUG

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

Azacitidine

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

LP-108

Intervention Type: DRUG

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

Azacitidine

Intervention Type: DRUG

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

Interventions

LP-108

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

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Guangzhou Lupeng Pharmaceutical Company LTD.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Depei Wu, PhD

Role: STUDY_CHAIR

First Affiliated Hospital of Soochow University

Xudong Wei, PhD

Role: PRINCIPAL_INVESTIGATOR

Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital

Qiubai Li, PhD

Role: PRINCIPAL_INVESTIGATOR

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

Li Wang, PhD

Role: PRINCIPAL_INVESTIGATOR

First Affiliated Hospital of Chongqing Medical University

Fei Li, PhD

Role: PRINCIPAL_INVESTIGATOR

The First Affiliated Hospital of Nanchang University

Xiaojing Yan, PhD

Role: PRINCIPAL_INVESTIGATOR

First Hospital of China Medical University

Locations

The First Affiliated Hospital of Nanchang University

Nanchang, , China

Site Status: RECRUITING

First Affiliated Hospital of Soochow University

Suzhou, , China

Site Status: RECRUITING

Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital

Zhengzhou, , China

Site Status: RECRUITING

Countries

China

Central Contacts

Yue Shen, PhD

Role: CONTACT

yshen@lupengbio.com

86-020-31605119

Facility Contacts

Fei Li

Role: primary

Depei Wu

Role: primary

Fei Li

Role: primary

References

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Reference Type: RESULT

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Reference Type: RESULT

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Reference Type: RESULT

PMID: 25624319 (View on PubMed)

Other Identifiers

LP-108-CN102

Identifier Type: -

Identifier Source: org_study_id