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

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia (AML); Chronic Myelomonocytic Leukemia (CMML); Myelodysplastic Syndrome (MDS); Myeloproliferative Neoplasms (MPNs)
• Intervention / Treatment: Drug: LY3410738; Drug: Venetoclax; Drug: Azacitidine

Detailed 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

• Study Type: Interventional
• Enrollment (Estimated): 260
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Patient Advocacy; Phone Number: 855-569-6305; Email: clinicaltrials@loxooncology.com

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
    • Melbourne, Victoria, Australia, 3000
      • Peter Maccallum Cancer Centre
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Linear Clinical Research
• Belgium
  • Brussels, Belgium, 1200
    • Cliniques universitaires Saint-Luc
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BC Cancer Vancouver
  • Ontario
    • Toronto, Ontario, Canada, M5G2M9
      • Princess Margaret Hospital
  • Quebec
    • Montréal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
• Finland
  • Helsinki, Finland, 00290
    • Helsinki University Hospital - Comprehensive Cancer Center (HYKS - Syöpäkeskus)
• France
  • Marseille, France, 13273
    • Institut Paoli-Calmettes
  • Paris, France, 75010
    • Hopital Saint Louis
  • Pessac Cedex, France, 33604
    • Centre hospitalier universitaire de Haut Leveque
  • Pierre Benite Cedex, France, 69495
    • Centre Hospitalier Lyon Sud
  • Toulouse cedex 9, France, 31059
    • Institut Claudius Regaud
• Germany
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Medizinische Hochschule Hanover
• Israel
  • Haifa, Israel, 3109601
    • Rambam Medical Center
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul-teukbyeolsi [Seoul]
    • Seoul, Seoul-teukbyeolsi [Seoul], Korea, Republic of, 05505
      • Asan Medical Center
    • Seoul, Seoul-teukbyeolsi [Seoul], Korea, Republic of, 06351
      • Samsung Medical Center
• Singapore
  • Singapore, Singapore, 169608
    • Singapore General Hospital
  • Singapore, Singapore, 119228
    • National University Cancer Institute
• Spain
  • Barcelona, Spain, 8036
    • Clinico Y Provincial Barcelona
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz
  • Valencia, Spain, 46026
    • Hospital Universitario La Fe de Valencia
• Taiwan
  • Taichung City, Taiwan, 40447
    • China Medical University Hospital
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
    • Sacramento, California, United States, 95817
      • University of California, Davis - Health Systems
  • Florida
    • Tampa, Florida, United States, 33612-9497
      • H Lee Moffitt Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • New York
    • Buffalo, New York, United States, 14263-0002
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina at Chapel Hill
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation Arm A (Monotherapy); Patients not requiring a strong cytochrome P450 3A4 (CYP3A4) inhibitor.	Drug: LY3410738; Oral LY3410738
Experimental: Dose Escalation Arm B (Monotherapy); Patients requiring a strong CYP3A4 inhibitor for active management or prevention of a lifethreatening condition, such as an azole administered to prevent invasive fungal infection.	Drug: LY3410738; Oral LY3410738
Experimental: Dose Escalation Arm C (LY3410738, Venetoclax, and Azacitidine); Patients with no prior venetoclax therapy and not requiring a strong CYP3A4 inhibitor for active treatment within 7 days of starting LY3410738.	Drug: LY3410738; Oral LY3410738; Drug: Venetoclax; Oral venetoclax; Drug: Azacitidine; Subcutaneous or intravenous azacitidine
Experimental: Cohort 1; Patients with relapsed/refractory (R/R) AML harboring an IDH1 R132 mutation who have received a prior IDH inhibitor.	Drug: LY3410738; Oral LY3410738
Experimental: Cohort 2; Patients with R/R AML harboring an IDH1 R132 mutation who have not received a prior IDH inhibitor.	Drug: LY3410738; Oral LY3410738
Experimental: Cohort 3; Patients with R/R MDS, chronic myelomonocytic leukemia (CMML) or other advanced hematologic malignancy harboring an IDH1 R132 mutation.	Drug: LY3410738; Oral LY3410738
Experimental: Cohort 4; Patients with R/R AML, MDS, CMML or other advanced hematologic malignancy harboring IDH2 mutations.	Drug: LY3410738; Oral LY3410738
Experimental: Cohort 5; Patients with newly diagnosed AML, R/R AML, or other advanced hematologic malignancy harboring IDH1 and/or IDH2 mutations with no prior venetoclax therapy. Strong CYP3A4 inhibitor allowed but not required.	Drug: LY3410738; Oral LY3410738; Drug: Venetoclax; Oral venetoclax; Drug: Azacitidine; Subcutaneous or intravenous azacitidine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D)	For Dose Escalation	Up to 30 months
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
To assess the activity of LY3410738 as measured by the overall response rate (ORR) per Investigator assessment	For Dose Escalation	Up to 30 months
To assess the activity of LY3410738 as measured by Best Overall Response (BOR) per Investigator assessment	For Dose Expansion	Up to 30 months
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
To assess the activity of LY3410738 by Duration of Response	For Dose Expansion	Up to 30 months
To assess the activity of LY3410738 by Hematologic improvement in patients with MDS	For Dose Expansion	Up to 30 months
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
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
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

Collaborators and Investigators

• Sponsor: Eli Lilly and Company
• Collaborators: Loxo Oncology, Inc.
• Investigators: Study Director: Yin Zhang, MD, Loxo Oncology

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2020
• Primary Completion (Actual): July 3, 2023
• Study Completion (Estimated): May 1, 2024

Study Registration Dates

• First Submitted: October 12, 2020
• First Submitted That Met QC Criteria: October 21, 2020
• First Posted (Actual): October 26, 2020

Study Record Updates

• Last Update Posted (Actual): September 1, 2023
• Last Update Submitted That Met QC Criteria: August 31, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; MPN; Myeloproliferative Neoplasms; AML; MDS; Myelodysplastic Syndrome; IDH; IDH1; Advanced Hematologic Malignancies; CMML; IDH2; Chronic Myelomonocytic Leukemia; isocitrate dehydrogenase; AG-221; Enasidenib; Loxo; LY3410738; R132; R140; R172; 2-hydroxyglutarate; 2-HG; Blasts; Relapsed/refractory AML; R/R AML; Advanced Hematologic Cancers; Ivosidenib; AG-120; Vorasidenib; AG-881; Olutasidenib; FT-2102; BAY1436032; DS-1001; IDH-305; Arginine 132; Arginine 140; Arginine 172
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms by Site; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Neoplasms; Myelodysplastic Syndromes; Hematologic Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myeloproliferative Disorders; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Venetoclax; Azacitidine
• Other Study ID Numbers: LOXO-IDH-20001; 2020-002830-33 (EudraCT Number); I9Y-OX-JDHB (Other Identifier: Eli Lilly and Company)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No