Clinical trial NCT04603001: Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations
Official title: A Phase 1 Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Acute Myeloid Leukemia (AML)
Myelodysplastic Syndrome (MDS)
Chronic Myelomonocytic Leukemia (CMML)
Myeloproliferative Neoplasms (MPNs)
Keywords: Loxo
LY3410738
isocitrate dehydrogenase
IDH
IDH1
IDH2
R132
R140
R172
2-hydroxyglutarate
2-HG
Advanced Hematologic Malignancies
Blasts
Acute Myeloid Leukemia
AML
Relapsed/refractory AML
R/R AML
Myelodysplastic Syndrome
MDS
Chronic Myelomonocytic Leukemia
CMML
Myeloproliferative Neoplasms
MPN
Advanced Hematologic Cancers
Ivosidenib
AG-120
Vorasidenib
AG-881
Olutasidenib
FT-2102
BAY1436032
DS-1001
IDH-305
Enasidenib
AG-221
Arginine 132
Arginine 140
Arginine 172
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
First posted: 2020-10-26
Enrollment: 260
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

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

Eligibility criteria: 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

Primary outcomes:
measure: To determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D)
timeFrame: Up to 30 months
measure: To assess the activity of LY3410738 as measured by the overall response rate (ORR) per the Investigator assessment
timeFrame: Up to 30 months
Secondary outcomes:
measure: 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
timeFrame: Up to 30 months
measure: To characterize the pharmacokinetics (PK) properties of LY3410738 by collecting and evaluating serum at protocol specified time points
timeFrame: Up to 30 months
measure: To characterize the pharmacodynamic properties of LY3410738 as expressed by change in 2-HG oncometabolite levels in plasma
timeFrame: Up to 30 months
measure: To assess the activity of LY3410738 as measured by the overall response rate (ORR) per Investigator assessment
timeFrame: Up to 30 months
measure: To assess the activity of LY3410738 as measured by Best Overall Response (BOR) per Investigator assessment
timeFrame: Up to 30 months
measure: To assess the activity of LY3410738 by Complete Remission (CR) Rate (CRR) plus partial hematologic recovery (AML patients)
timeFrame: Up to 30 months
measure: To assess the activity of LY3410738 by Duration of Response
timeFrame: Up to 30 months
measure: To assess the activity of LY3410738 by Hematologic improvement in patients with MDS
timeFrame: Up to 30 months
measure: 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
timeFrame: Up to 30 months
measure: To characterize the pharmacokinetics (PK) properties of LY3410738 by collecting and evaluating serum at protocol specified time points
timeFrame: Up to 30 months
measure: To characterize the pharmacodynamic properties of LY3410738 as expressed by change in 2-HG oncometabolite levels in plasma.
timeFrame: Up to 30 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Sacramento
country: United States
facility: University of California, Davis - Health Systems
state: California
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Hospital
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Linear Clinical Research
state: Western Australia
city: Brussels
country: Belgium
facility: Cliniques universitaires Saint-Luc
city: Vancouver
country: Canada
facility: BC Cancer Vancouver
state: British Columbia
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Helsinki
country: Finland
facility: Helsinki University Hospital - Comprehensive Cancer Center (HYKS - Syöpäkeskus)
city: Marseille
country: France
facility: Institut Paoli-Calmettes
city: Paris
country: France
facility: Hopital Saint Louis
city: Pessac Cedex
country: France
facility: Centre hospitalier universitaire de Haut Leveque
city: Pierre Benite Cedex
country: France
facility: Centre Hospitalier Lyon Sud
city: Toulouse cedex 9
country: France
facility: Institut Claudius Regaud
city: Hannover
country: Germany
facility: Medizinische Hochschule Hanover
state: Niedersachsen
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
state: Seoul-teukbyeolsi [Seoul]
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
state: Seoul-teukbyeolsi [Seoul]
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Singapore
country: Singapore
facility: National University Cancer Institute
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Barcelona
country: Spain
facility: Clinico Y Provincial Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Valencia
country: Spain
facility: Hospital Universitario La Fe de Valencia
city: Taichung City
country: Taiwan
facility: China Medical University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
affiliation: Eli Lilly and Company
name: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
role: STUDY_DIRECTOR
References: