Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations
- Conditions
- Myelodysplastic Syndrome (MDS)Myeloproliferative Neoplasms (MPNs)Acute Myeloid Leukemia (AML)Chronic Myelomonocytic Leukemia (CMML)
- Interventions
- Registration Number
- NCT04603001
- Lead Sponsor
- Eli Lilly and Company
- 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
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 260
-
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.
-
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 > 38.5ÂșC 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.
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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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort 2 LY3410738 Patients with R/R AML harboring an IDH1 R132 mutation who have not received a prior IDH inhibitor. Dose Escalation Arm B (Monotherapy) LY3410738 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. Cohort 1 LY3410738 Patients with relapsed/refractory (R/R) AML harboring an IDH1 R132 mutation who have received a prior IDH inhibitor. Cohort 3 LY3410738 Patients with R/R MDS, chronic myelomonocytic leukemia (CMML) or other advanced hematologic malignancy harboring an IDH1 R132 mutation. Dose Escalation Arm C (LY3410738, Venetoclax, and Azacitidine) LY3410738 Patients with no prior venetoclax therapy and not requiring a strong CYP3A4 inhibitor for active treatment within 7 days of starting LY3410738. Cohort 4 LY3410738 Patients with R/R AML, MDS, CMML or other advanced hematologic malignancy harboring IDH2 mutations. Dose Escalation Arm A (Monotherapy) LY3410738 Patients not requiring a strong cytochrome P450 3A4 (CYP3A4) inhibitor. Cohort 5 LY3410738 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. Dose Escalation Arm C (LY3410738, Venetoclax, and Azacitidine) Azacitidine Patients with no prior venetoclax therapy and not requiring a strong CYP3A4 inhibitor for active treatment within 7 days of starting LY3410738. Dose Escalation Arm C (LY3410738, Venetoclax, and Azacitidine) Venetoclax Patients with no prior venetoclax therapy and not requiring a strong CYP3A4 inhibitor for active treatment within 7 days of starting LY3410738. Cohort 5 Venetoclax 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. Cohort 5 Azacitidine 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.
- Primary Outcome Measures
Name Time Method To determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) Up to 30 months For Dose Escalation
To assess the activity of LY3410738 as measured by the overall response rate (ORR) per the Investigator assessment Up to 30 months For Dose Expansion
- Secondary Outcome Measures
Name Time Method To assess the activity of LY3410738 as measured by the overall response rate (ORR) per Investigator assessment Up to 30 months For Dose Escalation
To assess the activity of LY3410738 by Complete Remission (CR) Rate (CRR) plus partial hematologic recovery (AML patients) Up to 30 months For Dose Expansion
To characterize the pharmacodynamic properties of LY3410738 as expressed by change in 2-HG oncometabolite levels in plasma Up to 30 months For Dose Escalation
To characterize the pharmacokinetics (PK) properties of LY3410738 by collecting and evaluating serum at protocol specified time points Up to 30 months For Dose Expansion
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 Up to 30 months For Dose Escalation
To assess the activity of LY3410738 as measured by Best Overall Response (BOR) per Investigator assessment Up to 30 months For Dose Expansion
To assess the activity of LY3410738 by Duration of Response Up to 30 months For Dose Expansion
To assess the activity of LY3410738 by Hematologic improvement in patients with MDS Up to 30 months For Dose Expansion
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 Up to 30 months For Dose Expansion
To characterize the pharmacodynamic properties of LY3410738 as expressed by change in 2-HG oncometabolite levels in plasma. Up to 30 months For Dose Expansion
Trial Locations
- Locations (37)
Roswell Park Cancer Institute
đșđžBuffalo, New York, United States
University of Chicago Hospital
đșđžChicago, Illinois, United States
Massachusetts General Hospital
đșđžBoston, Massachusetts, United States
City of Hope National Medical Center
đșđžDuarte, California, United States
The Alfred Hospital
đŠđșMelbourne, Victoria, Australia
Cliniques universitaires Saint-Luc
đ§đȘBrussels, Belgium
Jewish General Hospital
đšđŠMontrĂ©al, Quebec, Canada
Rambam Medical Center
đźđ±Haifa, Israel
National Taiwan University Hospital
đšđłTaipei, Taiwan
Singapore General Hospital
đžđŹSingapore, Singapore
Clinico Y Provincial Barcelona
đȘđžBarcelona, Spain
Asan Medical Center
đ°đ·Seoul, Seoul-teukbyeolsi [Seoul], Korea, Republic of
National University Cancer Institute
đžđŹSingapore, Singapore
Hospital Universitario La Fe de Valencia
đȘđžValencia, Spain
Samsung Medical Center
đ°đ·Seoul, Seoul-teukbyeolsi [Seoul], Korea, Republic of
Seoul National University Hospital
đ°đ·Seoul, Korea, Republic of
Hospital Universitario FundaciĂłn JimĂ©nez DĂaz
đȘđžMadrid, Spain
China Medical University Hospital
đšđłTaichung City, Taiwan
Vanderbilt University Medical Center
đșđžNashville, Tennessee, United States
University of California, Davis - Health Systems
đșđžSacramento, California, United States
H Lee Moffitt Cancer Center
đșđžTampa, Florida, United States
UCLA Medical Center
đșđžLos Angeles, California, United States
Northwestern University
đșđžChicago, Illinois, United States
Memorial Sloan Kettering Cancer Center
đșđžNew York, New York, United States
University of North Carolina at Chapel Hill
đșđžChapel Hill, North Carolina, United States
Peter MacCallum Cancer Centre
đŠđșMelbourne, Victoria, Australia
University of Texas MD Anderson Cancer Center
đșđžHouston, Texas, United States
Linear Clinical Research
đŠđșNedlands, Western Australia, Australia
BC Cancer Vancouver
đšđŠVancouver, British Columbia, Canada
Helsinki University Hospital - Comprehensive Cancer Center (HYKS - SyöpÀkeskus)
đ«đźHelsinki, Finland
Institut Paoli-Calmettes
đ«đ·Marseille, France
Princess Margaret Hospital
đšđŠToronto, Ontario, Canada
Hopital Saint Louis
đ«đ·Paris, France
Centre hospitalier universitaire de Haut Leveque
đ«đ·Pessac Cedex, France
Centre Hospitalier Lyon Sud
đ«đ·Pierre Benite Cedex, France
Institut Claudius Regaud
đ«đ·Toulouse cedex 9, France
Medizinische Hochschule Hanover
đ©đȘHannover, Niedersachsen, Germany