Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations

Acute Myeloid Leukemia (AML) Clinical Trial

Official title:

A Phase 1 Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04603001
• Other study ID #: LOXO-IDH-20001
• Secondary ID: 2020-002830-33I9
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: December 1, 2020
• Est. completion date: May 2025

Study information

• Verified date: June 2024
• Source: Eli Lilly and Company
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is an open-label, multi-center Phase 1 study of LY3410738, an oral, covalent isocitrate dehydrogenase (IDH) inhibitor, in patients with IDH1 and/or IDH2-mutant advanced hematologic malignancies who may have received standard therapy

Description:

This study includes 2 parts: dose escalation and dose expansion. The dose escalation will enroll eligible patients with select IDH-mutant advanced hematologic malignancies. Once the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of LY3410738 is established, the dose expansion will begin and enroll into 5 cohorts to further evaluate safety and clinical activity

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 260
• Est. completion date: May 2025
• Est. primary completion date: July 3, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Advanced IDH mutant hematologic malignancy including:

-- For Dose Escalation Arm C and Dose Expansion Cohort 5:

• Patients with newly diagnosed AML who are 75 years or older or have comorbidities that preclude the use of intensive chemotherapy

• Patients with R/R AML (US only)

• Patients must have received prior therapy

• Blasts at least 5% in bone marrow.

• Patients must have a qualifying IDH1 R132, IDH2 R140 or IDH2 R172 mutation

• Eastern Cooperative Oncology Group (ECOG) 0 to 2

• Adequate organ function

• Ability to swallow capsules or tablets

• Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation

• Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following the last dose of study treatment.

Exclusion Criteria:

• Investigational agent or anticancer therapy within 2 weeks or 5 half-lives, whichever is shorter; or investigational monoclonal antibody within 4 weeks prior to planned start of LY3410738

• For Dose Escalation Arm C and Dose Expansion Cohort 5:

• Prior venetoclax treatment is not allowed.

• Patients are allowed to receive up to 1 cycle of single agent azacitidine or azacitidine plus venetoclax while waiting for results of locally obtained molecular profiling, including IDH1/IDH2 mutational status, prior to starting on study.

• Major surgery within 4 weeks prior to planned start of LY3410738.

• Active, uncontrolled clinically significant systemic bacterial, viral, fungal or parasitic infection or an unexplained fever > 38.5ºC during Screening or on the first day of study drug administration.

• Another concurrent malignancy requiring active therapy.

• Active central nervous system involvement

• Any unresolved toxicities from prior therapy greater than CTCAE v5.0 Grade 2 at the time of starting study treatment except for alopecia.

• History of hematopoietic stem cell transplant (HSCT) or chimeric antigen receptor T-cell (CAR-T) therapy within 60 days of the first dose of LY3410738.

• Clinically significant cardiovascular disease

• Active hepatitis B virus (HBV)

• Active hepatitis C virus (HCV)

• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug

• Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or P- glycoprotein (P-gp) inhibitor, with the exception of patients being treated with allowed antifungal inhibitors of CYP3A4

• Treatment with proton pump inhibitor (PPIs) within 7 days of starting LY3410738

• Any serious underlying medical or psychiatric condition (e.g. alcohol or drug abuse), dementia or altered mental status or any issue that would impair the ability of the patient to understand informed consent or that in the opinion of the Investigator would contraindicate the patient's participation in the study or confound the results of the study

• Known human immunodeficiency virus (HIV), excluded due to potential drug-drug interactions between antiretroviral medications and LY3410738

• Pregnancy, lactation or plan to breastfeeding during the study or within 90 days of the last dose of study intervention

• Known hypersensitivity to any of the components of LY3410738 or its formulation

Related Conditions & MeSH terms

• Acute Myeloid Leukemia (AML)
• Chronic Myelomonocytic Leukemia (CMML)
• Hematologic Neoplasms
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• Myelodysplastic Syndrome (MDS)
• Myelodysplastic Syndromes
• Myeloproliferative Disorders
• Myeloproliferative Neoplasms (MPNs)
• Neoplasms
• Preleukemia

Intervention

Drug:
• LY3410738
Oral LY3410738
• Venetoclax
Oral venetoclax
• Azacitidine
Subcutaneous or intravenous azacitidine

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Linear Clinical Research	Nedlands	Western Australia
Belgium	Cliniques universitaires Saint-Luc	Brussels
Canada	Jewish General Hospital	Montréal	Quebec
Canada	Princess Margaret Hospital	Toronto	Ontario
Canada	BC Cancer Vancouver	Vancouver	British Columbia
Finland	Helsinki University Hospital - Comprehensive Cancer Center (HYKS - Syöpäkeskus)	Helsinki
France	Institut Paoli-Calmettes	Marseille
France	Hopital Saint Louis	Paris
France	Centre hospitalier universitaire de Haut Leveque	Pessac Cedex
France	Centre Hospitalier Lyon Sud	Pierre Benite Cedex
France	Institut Claudius Regaud	Toulouse cedex 9
Germany	Medizinische Hochschule Hanover	Hannover	Niedersachsen
Israel	Rambam Medical Center	Haifa
Korea, Republic of	Asan Medical Center	Seoul	Seoul-teukbyeolsi [Seoul]
Korea, Republic of	Samsung Medical Center	Seoul	Seoul-teukbyeolsi [Seoul]
Korea, Republic of	Seoul National University Hospital	Seoul
Singapore	National University Cancer Institute	Singapore
Singapore	Singapore General Hospital	Singapore
Spain	Clinico Y Provincial Barcelona	Barcelona
Spain	Hospital Universitario Fundación Jiménez Díaz	Madrid
Spain	Hospital Universitario La Fe de Valencia	Valencia
Taiwan	China Medical University Hospital	Taichung City
Taiwan	National Taiwan University Hospital	Taipei
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Hospital	Chicago	Illinois
United States	City of Hope National Medical Center	Duarte	California
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	UCLA Medical Center	Los Angeles	California
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	University of California, Davis - Health Systems	Sacramento	California
United States	H Lee Moffitt Cancer Center	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Eli Lilly and Company	Loxo Oncology, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Finland,  France,  Germany,  Israel,  Korea, Republic of,  Singapore,  Spain,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D)	For Dose Escalation	Up to 30 months
Primary	To assess the activity of LY3410738 as measured by the overall response rate (ORR) per the Investigator assessment	For Dose Expansion	Up to 30 months
Secondary	To determine the safety profile and tolerability of LY3410738 including acute and chronic toxicities by collecting and evaluating adverse events and treatment emergent adverse events	For Dose Escalation	Up to 30 months
Secondary	To characterize the pharmacokinetics (PK) properties of LY3410738 by collecting and evaluating serum at protocol specified time points	For Dose Escalation	Up to 30 months
Secondary	To characterize the pharmacodynamic properties of LY3410738 as expressed by change in 2-HG oncometabolite levels in plasma	For Dose Escalation	Up to 30 months
Secondary	To assess the activity of LY3410738 as measured by the overall response rate (ORR) per Investigator assessment	For Dose Escalation	Up to 30 months
Secondary	To assess the activity of LY3410738 as measured by Best Overall Response (BOR) per Investigator assessment	For Dose Expansion	Up to 30 months
Secondary	To assess the activity of LY3410738 by Complete Remission (CR) Rate (CRR) plus partial hematologic recovery (AML patients)	For Dose Expansion	Up to 30 months
Secondary	To assess the activity of LY3410738 by Duration of Response	For Dose Expansion	Up to 30 months
Secondary	To assess the activity of LY3410738 by Hematologic improvement in patients with MDS	For Dose Expansion	Up to 30 months
Secondary	To determine the safety profile and tolerability of LY3410738 including acute and chronic toxicities by collecting and evaluating Adverse events and treatment emergent adverse events	For Dose Expansion	Up to 30 months
Secondary	To characterize the pharmacokinetics (PK) properties of LY3410738 by collecting and evaluating serum at protocol specified time points	For Dose Expansion	Up to 30 months
Secondary	To characterize the pharmacodynamic properties of LY3410738 as expressed by change in 2-HG oncometabolite levels in plasma.	For Dose Expansion	Up to 30 months

External Links

•   Study of LY3410738 in Patients with Advanced Blood Cancers with a Change in the IDH1 or IDH2 Gene