Epacadostat, Cladribine and Cytarabine (ECC) in AML

Study Overview
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Brief Summary
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This trial assess the maximum tolerated dose (MTD) and to characterize dose-limiting toxicities (DLTs) of epacadostat when added to the cladribine/cytarabine chemotherapy in relapsed / refractory AML patients fit for intensive treatment

Detailed Description
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Background and Rationale: Epacadostat (INCB024360) is an Inhibitor of Indoleamine 2,3- dioxygenase 1 (IDO1). Indoleamine 2,3- dioxygenase 1 (IDO1) is a 403 amino acid cytosolic haem enzyme encoded by the INDO gene on human chromosome 8p22. IDO1 is responsible for the catabolism of the essential amino acid tryptophan (trp) to kynurenine (kyn) within immune cells and a subset of tumor cells resulting in inhibition of antitumor cell-mediated immune responses. Increased IDO activity correlates with lower CR rates and shorter OS in AML. Objective: The primary objective is to determine the maximum tolerated dose (MTD) and to characterize dose-limiting toxicities (DLTs) of epacadostat when added to the cladribine/cytarabine chemotherapy in relapsed / refractory AML patients fit for intensive treatment Study Duration: Phase I part will last from 3 to 18 months (permitting the enrolment of minimum of 3 and a maximum of 24 patients).

Official Title
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Epacadostat With Cladribine and Cytarabine (ECC) in Relapsed / Refractory AML Patients Fit for Intensive Chemotherapy; a Phase I Study.

Conditions
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AML, Relapse

Intervention / Treatment
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* Drug: Epacadostat
* Drug: Cladribine
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsed/refractory AML (according to the 2016 World Health Organization (WHO) classification definition of ≥ 20% blasts; Arber et al, 2016) after at least one line of treatment and suitable for intensive treatment (including stem cell transplantation) without severe concurrent infections. Patients must be aged > 18 years, and must have given voluntary written informed consent. Women of childbearing potential having a negative serum pregnancy test at screening or at least within 48 hours before start with epacadostat, and willing to use an effective contraceptive method (intrauterine devices, hormonal contraceptives, contraceptive pill, implants, transdermal patches, hormonal vaginal devices, infusions with prolonged release) during the study and for at least 6 months after the last study drug administration Men willing to use an effective contraceptive method (eg, condom, vasectomy) during the study and for at least 6 months after the last study drug administration. Exclusion Criteria: Prior or concurrent malignancy, except for the following: adequately treated basal cell or squamous cell skin cancer, or any other cancer from which the subject has been disease-free for more than 6 months. APL (acute promyelocytic leukemia) or AML type M3, are excluded from the trial Treatment with any investigational product within 4 weeks before the first administration of epacadostat (INCB024360) Abnormal organ function if not caused by the underlying disease as considered by the treating physician Use of immune-suppressive agents for the past 4 weeks before the first administration of epacadostat (INCB024360). For regular use of systemic corticosteroids, subjects may only be included after stepwise discontinuation to be free of steroids for a minimum of 5 days before the first administration of epacadostat (INCB024360)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dosis finding<br>Epacadostat is given for 2 cycles of 28 days at a dose according to the titration design together with standard chemotherapy (Cladribine and Cytarabine) | Drug: Epacadostat<br>* Epacadostat orally two times daily (BID) for two cycles (28 days each) in combination with standard induction chemotherapy (Cladribine and Cytarabine)<br>Drug: Cladribine<br>* Standard chemotherapy<br>Drug: Cytarabine<br>* Standard chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose finding | To determine the maximum tolerated dose (MTD) and to characterize dose-limiting toxicities (DLTs) of epacadostat | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of morphologic complete remission (CR) | Bone marrow blasts < 5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count > 1.0G/L (1000/μL); platelet count > 100 x G/L (100.000/μL); independence of red cell transfusions. | 60 days | 
| Adverse events | Number of patients experiencing toxicity (Adverse Events) | 100 days | 
| Overall survival | Number of patients alive after 12 months | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, Epacadostat, Cladribine, Cytarabine