Phase 1 study of LP-108 as monotherapy and in combination with azacitidine in patients with relapsed or refractory myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML).

Authors

null

Alison R. Walker

The Ohio State University Wexner Medical Center, Columbus, OH

Alison R. Walker , Juan Miguel Bergua Burgues , Pau Montesinos , Dale Bixby , Naval Guastad Daver , Marina Konopleva , Stephen Patrick Anthony , Fenlai Tan , Yi Chen , Yu Chen , Yue Shen , Patrick William Burke

Organizations

The Ohio State University Wexner Medical Center, Columbus, OH, Hematology, Hospital San Pedro de Alcantara, Caceres, Spain, Hospital Universitari i Politècnic La Fe, Valencia, Spain, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, Newave Pharmaceuticals, Pleasanton, CA, Univ of Michigan, Ann Arbor, MI

Research Funding

Pharmaceutical/Biotech Company

Background: BCL2 inhibition as a means of targeting intrinsic apoptotic pathways that confer a survival advantage to leukemic blasts has become a key therapeutic strategy for patients with myeloid malignancies. LP-108 is an oral highly potent and selective inhibitor of BCL-2 with comparable or more potent in vitro inhibitory activity as compared to the FDA approved oral BCL-2 inhibitor venetoclax. We propose to investigate LP-108 as monotherapy and in combination with azacitidine in patients with relapsed or refractory (r/r) MDS, CMML or AML. Methods: The primary objectives of the trial are 1.) To determine the safety, tolerability and determine the maximum tolerated dose (MTD) and the recommended phase 2 dose / optimal biological dose (OBD) of LP-108 as a single agent (Arm 1) and in combination with azacitidine (Arm 2) in patients with relapsed/refractory MDS/CMML/AML; 2.) To characterize the pharmacokinetic profile of LP-108 as monotherapy and in combination with a fixed dose of azacitidine. The secondary objectives of the trial are 1.) To evaluate the objective response rate of LP-108 (monotherapy or combination therapy) in r/r MDS/CMML/AML as well as progression free survival, duration of response and overall survival. In Arm 1 patients will be enrolled according to a 3+3 design with escalating doses of LP-108 for a 28 day cycle (firs table). DLTs will be determined in the first 28 days. In Arm 2 patients will be enrolled according to a 3+3 design with escalating doses of LP-108 in combination with a fixed dose of azacitidine (second table). DLTs will be determined in the first 28 days. DLT for both arms is defined as some ≥ Grade 3 non-hematological toxicities or prolonged myelosuppression. Patients may continue treatment until disease progression, unacceptable toxicity, or per investigator discretion. Patients age ≥ 18 years with r/r MDS with excess or blasts or with high or very-high risk disease per the R-IPSS, or r/r MDS for Arm 2, r/r AML, or frontline older and/or unfit AML for Arm 2, or r/r CMML may enroll. Patients with prior hypomethylating agents or venetoclax exposure may enroll. The blast count at the time of starting therapy must be ≤ 30 x 109 cells/L. Hydroxyurea is allowed prior to and during treatment. Ejection fraction ≥ 50% is required. Calculated creatinine clearance shall be ≥ 30 mL/min. Strong CYP3A4 inducers and inhibitors are prohibited. Patients on weak/moderate azole antifungals were allowed to enroll. Enrollment to Arm 1 is complete and there have been no DLTs to date. Enrollment to Arm 2 is pending. Arm 1 Dose Escalation Scheme (LP-108 monotherapy). Clinical trial information: NCT04139434.

Arm 2 dose escalation Scheme (LP-108 and azacitidine).

Cohort
LP-108 Dose
1
100 mg
2
200 mg
3
400 mg
4
600 mg
Cohort
LP-108 Dose
Azacitidine Days 1-7 or days 1-5, 8, 9
1
100 mg
75 mg/m2
2
200 mg
75 mg/m2
3
400 mg
75 mg/m2

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Abstract Details

Meeting

2022 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant

Track

Hematologic Malignancies

Sub Track

Acute Leukemia

Clinical Trial Registration Number

NCT04139434

Citation

J Clin Oncol 40, 2022 (suppl 16; abstr TPS7071)

DOI

10.1200/JCO.2022.40.16_suppl.TPS7071

Abstract #

TPS7071

Poster Bd #

298a

Abstract Disclosures

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