A Study of CG-806 in Patients With Relapsed or Refractory AML or Higher-Risk MDS

Study Overview
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Brief Summary
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This study is being done to evaluate the safety, tolerability and antitumor activity of oral CG-806 (luxeptinib) for the treatment of patients with Acute Myeloid Leukemia (except APML), secondary AML, therapy-related AML, or higher-risk MDS, whose disease has relapsed, is refractory or who are ineligible for or intolerant of intensive chemotherapy or transplantation.

Detailed Description
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This is a multicenter, open-label, Phase 1 a/b dose escalation study of safety, pharmacodynamics, and pharmacokinetics of CG-806 in ascending cohorts (3+3 design) to determine the MTD or recommended dose in patients with relapsed or refractory Acute Myeloid Leukemia (except APML), secondary AML, therapy-related AML, or higher-risk MDS whose disease has relapsed, is refractory or who are ineligible for or intolerant of intensive chemotherapy or transplantation. This is to be followed by a cohort expansion phase.

Official Title
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A Phase 1a/b Trial of CG-806 in Patients With Relapsed/Refractory Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndromes

Conditions
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Acute Myeloid Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: CG-806


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age ≥18 years Life expectancy of at least 3 months ECOG Performance Status ≤ 2 Patients must be able to swallow capsules Adequate hematologic parameters, unless cytopenias are disease caused Adequate renal, liver and cardiac functions Key Exclusion Criteria: Patients with GVHD requiring systemic immunosuppressive therapy Uncontrolled leptomeningeal disease, auto-immune hemolytic anemia and uncontrolled and clinically significant disease related metabolic disorder Clinically significant leukostasis Treatment with other investigational drugs or receipt of cytotoxic therapy within 14 days prior to first study treatment administration Receipt of cellular immunotherapeutic agents within 4 weeks prior to first study treatment administration

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation and Expansion<br>Dose Escalation and Expansion; CG-806 will be given orally in ascending doses in patients with relapsed or refractory AML or higher-risk MDS (escalation cohort), until the maximum tolerated dose or candidate recommended Phase 2 dose is reached. Followed up by up to 50 patients enrolled in the expansion cohort at the recommended dose. | Drug: CG-806<br>* CG-806 will be given orally in ascending doses starting at 450 mg PO BID until the maximum tolerated dose or candidate recommended Phase 2 dose is reached.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events of CG-806 | Patients will be assessed for adverse events during all cycles of treatment and for dose limiting toxicities in Cycle 1 (28-days). Dose escalation to a higher dose level will be considered if none of the first three patients who complete Cycle 1 (28-days) at a given dose level experience a dose limiting toxicity or if only 1 of 6 patients at a given dose level experience a dose-limiting toxicity. | At the end of Cycle 1 (each cycle is 28 days) | 
| Establish a CG-806 dose that maintains a biologically active plasma concentration | To determine the dose of CG-806 given orally every 12 hours daily that maintains a biologically active plasma concentration during 28-day cycles. | At the end of Cycle 1 (each cycle is 28 days) | 
| Establish a recommended dose for future development of CG-806 | To establish the maximum tolerated dose and/or recommended Phase 2 dose (RP2D) of CG-806 for future clinical trials in patients with AML and other advanced myeloid malignancies. | At the end of Cycle 1 (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics variables including maximum plasma concentration (Cmax). | Pharmacokinetics variables including maximum plasma concentration at various timepoints. | At the end of Cycle 1 (each cycle is 28 days) | 
| Pharmacokinetics variables including minimum plasma concentration (Cmin) | Pharmacokinetics variables including minimum plasma concentration at various timepoints. | At the end of Cycle 1 (each cycle is 28 days) | 
| Pharmacokinetics variables including area under the curve (AUC) | Pharmacokinetics variables including plasma concentration at various timepoints. | At the end of Cycle 1 (each cycle is 28 days) | 
| Pharmacokinetics variables including volume of distribution | Pharmacokinetics variables including plasma concentration at various timepoints. | At the end of Cycle 1 (each cycle is 28 days) | 
| Pharmacokinetics variables including clearance | Pharmacokinetics variables including plasma concentration at various timepoints. | At the end of Cycle 1 (each cycle is 28 days) | 
| Pharmacokinetics variables including plasma half-life. | Pharmacokinetics variables including plasma concentration at various timepoints. | At the end of Cycle 1 (each cycle is 28 days) | 
| To determine the ability of CG-806 to modulate the expression or activity of pharmacodynamic biomarkers of drug effect. | To determine the ability of CG-806 to modulate the expression or activity of pharmacodynamic biomarkers of drug effect. | At the end of Cycle 1 (each cycle is 28 days) | 
| To assess patients for evidence of anti-tumor activity of CG-806 based on hematologic, bone marrow, physical examination, evaluations | To assess patients for evidence of anti-tumor activity of CG-806 based on hematologic, bone marrow, physical examination, and FDG PET-CT imaging evaluations. | At the end of Cycle 1 (each cycle is 28 days) | 
| To determine the Relative Bioavailability of Generation 3 formulation given to up to 18 patients on Cycle 1 Day -3 compared to Generation 1 formulation of study drug given to patients during Cycle 1. | Compare G1 to G3 pharmacokinetics variables including maximum plasma concentration (Cmax) | At the end of Cycle 1 (each cycle is 28 days) | 
| To determine the Relative Bioavailability of Generation 3 formulation given to up to 18 patients on Cycle 1 Day -3 compared to Generation 1 formulation of study drug given to patients during Cycle 1. | Compare G1 to G3 Pharmacokinetics variables including minimum plasma concentration (Cmin) | At the end of Cycle 1 (each cycle is 28 days) | 
| To determine the Relative Bioavailability of Generation 3 formulation given to up to 18 patients on Cycle 1 Day -3 compared to Generation 1 formulation of study drug given to patients during Cycle 1. | Compare G1 to G3 Pharmacokinetics variables including area under the curve (AUC) | At the end of Cycle 1 (each cycle is 28 days) | 
| To determine the Relative Bioavailability of Generation 3 formulation given to up to 18 | Compare G1 to G3 Pharmacokinetics variables including volume of distribution | At the end of Cycle 1 (each cycle is 28 days) | 
| To determine the Relative Bioavailability of Generation 3 formulation given to up to 18 | Compare G1 to G3 Pharmacokinetics variables including clearance | At the end of Cycle 1 (each cycle is 28 days) | 
| Compare G1 to G3 Pharmacokinetics variables including clearance | Compare G1 to G3 Pharmacokinetics variables including plasma half-life. | At the end of Cycle 1 (each cycle is 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARQ 531, F691L, CG-806, Aptose, FLT3, FLT3-ITD, D835Y, BTK, C481S, TP53, NRAS, IDH1, BCL2, Gilteritinib, Quizartinib, Midostaurin, Crenolanib, Venetoclax, Ibrutinib, Acalabrutinib, Zanubrutinib, LOXO-305, AML, Acute Myeloid Leukemia, MDS, Myelodysplastic Syndrome, CLL, Chronic Lymphocytic Leukemia, Resistant, Refractory, Relapsed, Intolerant, Kinase Inhibitor, Non covalent, Luxeptinib