LOXO-IDH-20001

Critères d’inclusion: Vous pouvez participer si

1. At least 18 years of age or age of majority, if higher per local regulations.
2. Advanced IDH mutant hematologic malignancy including:
• AML according to the World Health Organization (WHO) 2016 criteria
• Myelodysplastic syndrome (MDS) with excess blasts (subtype MDS-EB-1 or MDS-EB-2) or considered high- or very-high-risk by the Revised International Prognostic Scoring System (IPSS-R)
• Other relapsed and/or primary refractory hematologic cancers (e.g. chronic
myelomonocytic leukemia, myeloproliferative neoplasms [myelofibrosis,
essential thrombocythemia, polycythemia vera]), who fulfill the
inclusion/exclusion criteria may be considered on a case-by-case basis, with
approval of the medical monitor.
3. Patients must have received prior therapy as follows:
Dose Escalation
• Patients must be refractory to, or intolerant of, established therapy known to
provide clinical benefit for their condition or who, in the opinion of the
investigator, are not candidates for such therapy.
Dose Expansion
• Patients with AML must have either relapsed disease per ELN 2017 criteria or
refractory disease defined as:
o no CR or CRi after induction chemotherapy OR
o no CR or CRi for those patients who were not candidates for intensive induction who received either demethylating agents [single agent or in combination] or low dose cytarabine [single agent or in combination].
• Patients with all other hematologic malignancies including MDS must have disease that is refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition or who, in the opinion of the investigator, are not candidates for such therapy.
4. Blasts at least 5% in bone marrow.
5. Patients must have a qualifying IDH1 R132, IDH2 R140 or IDH2 R172 mutation
6. Eastern Cooperative Oncology Group (ECOG) 0-2
7. Adequate hepatic and renal organ function
8. Ability to swallow capsules
9. Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation
10. 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.

Critères d’exclusion: Vous ne pouvez pas participer si

1. 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 (Hydroxyurea is allowed throughout the study for the control of peripheral leukemia blasts in patients with white blood cell [WBC] counts >30,000/µL).
2. Major surgery within 4 weeks prior to planned start of LY3410738.
3. 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. Patients on prophylaxis or chronic therapy for a controlled chronic infection are eligible. At the discretion of the investigator and with approval of the sponsor’s medical monitor, patients with documented tumor fever may be enrolled.
4. Another concurrent malignancy requiring active therapy.
5. Active central nervous system involvement.
6. Any unresolved toxicities from prior therapy greater than CTCAE v5.0 Grade 2 at the time of starting study treatment except for alopecia.
7. History of hematopoietic stem cell transplant (HSCT) or CAR-T therapy within 60 days of the first dose of LY3410738, or with any of the following:
• ongoing immunosuppressive therapy post HSCT or CAR-T therapy at the time of screening. The use of low dose corticosteroids ≤ 10 mg prednisone or equivalent is permitted; the use of topical steroids for ongoing skin graft-versus-host-disease (GVHD) is also permitted;
• clinically significant GVHD;
• need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity > Grade 1 from CAR-T therapy.
8. Clinically significant cardiovascular disease:
• History of myocardial infarction within 6 months prior to planned start of LY3410738
• New York Heart Association (NYHA) Class III or IV congestive heart failure
• Unstable angina
• LVEF <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within 28 days of C1D1
• Known history of severe and/or uncontrolled ventricular arrhythmia within 6 months prior to planned start of LY3410738
• Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec on at least 2/3 consecutive electrocardiograms (ECGs), and mean QTcF
> 470 msec on all 3 ECGs, during screening
9. Active hepatitis B (HBV)
10. Active hepatitis C virus (HCV)
11. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug.
12. Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or strong p-gp inhibitor, with the exception of patients being treated with allowed antifungal inhibitors of CYP3A4
(Appendix I) who are being evaluated for Arm B.
13. Treatment with proton pump inhibitor (PPIs) within 7 days of starting LY3410738.
14. 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.
15. Known human immunodeficiency virus (HIV), excluded due to potential drug-drug interactions between anti-retroviral medications and LY3410738
16. Pregnancy, lactation or plan to breastfeeding during the study or within 30 days of the last dose of study intervention

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17. Known hypersensitivity to any of the components of LY3410738 or its formulation.

• Cliniques Universitaires Saint-Luc