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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04603001
Recruitment Status : Recruiting
First Posted : October 26, 2020
Last Update Posted : June 28, 2022
Sponsor:
Collaborator:
Loxo Oncology, Inc.
Information provided by (Responsible Party):
Eli Lilly and Company

Study Description
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Brief Summary:
This is an open-label, multi-center Phase 1 study of LY3410738, an oral, covalent IDH inhibitor, in patients with IDH1 and/or IDH2-mutant advanced hematologic malignancies who have received standard therapy

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) Myelodysplastic Syndrome (MDS) Chronic Myelomonocytic Leukemia (CMML) Myeloproliferative Neoplasms (MPNs) Drug: LY3410738 Phase 1

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 4 cohorts to further evaluate safety and clinical activity
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 220 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations
Actual Study Start Date : December 1, 2020
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Dose Escalation Arm A (Monotherapy)
Patients not requiring a strong 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: Cohort 1
Patients with 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


Outcome Measures
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Primary Outcome Measures :
  1. To determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) [ Time Frame: Up to 30 months ]
    For Dose Escalation

  2. To assess the activity of LY3410738 as measured by the overall response rate (ORR) per the investigator assessment [ Time Frame: Up to 30 months ]
    For Dose Expansion


Secondary Outcome Measures :
  1. 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 [ Time Frame: Up to 30 months ]
    For Dose Escalation

  2. To characterize the pharmacokinetics (PK) properties of LY3410738 by collecting and evaluating serum at protocol specified time points [ Time Frame: Up to 30 months ]
    For Dose Escalation

  3. To characterize the pharmacodynamic properties of LY3410738 as expressed by change in 2-HG oncometabolite levels in plasma [ Time Frame: Up to 30 months ]
    For Dose Escalation

  4. To assess the activity of LY3410738 as measured by the overall response rate (ORR) per investigator assessment [ Time Frame: Up to 30 months ]
    For Dose Escalation

  5. To assess the activity of LY3410738 as measured by Best Overall Response per investigator assessment [ Time Frame: Up to 30 months ]
    For Dose Expansion

  6. To assess the activity of LY3410738 by Complete Response Rate plus partial hematologic recovery (AML patients) [ Time Frame: Up to 30 months ]
    For Dose Expansion

  7. To assess the activity of LY3410738 by Duration of Response [ Time Frame: Up to 30 months ]
    For Dose Expansion

  8. To assess the activity of LY3410738 by Hematologic improvement in patients with MDS [ Time Frame: Up to 30 months ]
    For Dose Expansion

  9. 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 [ Time Frame: Up to 30 months ]
    For Dose Expansion

  10. To characterize the pharmacokinetics (PK) properties of LY3410738 by collecting and evaluating serum at protocol specified time points [ Time Frame: Up to 30 months ]
    For Dose Expansion

  11. To characterize the pharmacodynamic properties of LY3410738 as expressed by change in 2-HG oncometabolite levels in plasma. [ Time Frame: Up to 30 months ]
    For Dose Expansion


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Advanced IDH mutant hematologic malignancy
  • 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) 0-2
  • 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
  • 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 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-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 anti-retroviral 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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04603001


Contacts
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Contact: Patient Advocacy 833-LOXO-IDH clinicaltrials@loxooncology.com

Locations
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Sponsors and Collaborators
Eli Lilly and Company
Loxo Oncology, Inc.
Investigators
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Study Director: Yin Zhang, MD Loxo Oncology
More Information
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Additional Information:

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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT04603001    
Other Study ID Numbers: LOXO-IDH-20001
2020-002830-33 ( EudraCT Number )
I9Y-OX-JDHB ( Other Identifier: Eli Lilly and Company )
First Posted: October 26, 2020    Key Record Dates
Last Update Posted: June 28, 2022
Last Verified: June 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Eli Lilly and Company:
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
Additional relevant MeSH terms:
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Leukemia
Neoplasms
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Hematologic Neoplasms
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
 Myelodysplastic Syndromes
Myeloproliferative Disorders
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms by Site
Myelodysplastic-Myeloproliferative Diseases