Summary
The purpose of the study is to assess the safety, pharmacokinetics, and preliminary efficacy of AMX-883 monotherapy in participants with acute myeloid leukaemia (AML) and high-risk myelodysplastic syndrome (MDS) and in combination with anticancer agents in participants with AML.
Detailed Description
This is a modular, Phase 1, open-label, multi-centre dose-escalation study investigating AMX-883 in participants with relapsed/refractory AML and high-risk MDS. The study comprises Module 1, which will evaluate AMX-883 as monotherapy and in combination with posaconazole.
Module 1 consists of three parts:
* Part A consists of the monotherapy dose escalation cohorts and investigation of the food-effect at selected dose(s).
* Part B consists of AMX-883 in combination with posaconazole dose escalation cohorts.
Other modules may be added by protocol amendment. The study aims to establish optimal dosing and preliminary efficacy data to support further clinical development of AMX-883.
Eligibility Criteria
Age Range: 18 years to No maximum
Inclusion Criteria:
* Participants with relapsed or refractory AML who have failed all available standard therapies or relapsed or refractory high-risk MDS with BM blasts 10-19%
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Adequate washout from prior therapies
* Adequate kidney and liver function
* Female participants of childbearing potential must use highly effective contraception for at least 120 days, or 27 weeks (applicable to the United Kingdom \[UK\] only), after last dose, and male participants must agree to use barrier contraception and avoid sperm donation for at least 120 days after last dose
* If enrolled in M1B: Participant must have no documented contraindication to treatment with posaconazole before start of treatment
Exclusion Criteria:
* Diagnosis of acute promyelocytic leukaemia or chronic myelogenous leukaemia in blast crisis
* Clinically active central nervous system (CNS) leukaemia
* Receiving immunosuppressive therapy post HSCT
* History of another malignancy that is active, progressing, or has required systemic treatment within the past 2 years
* Presence of \>Grade 1 active graft versus host disease within 4 weeks prior to C1D1
* Significant cardiovascular disease
* Family history of sudden cardiac death before 40 years of age or a family history of long QT syndrome
* Clinically significant electrolyte imbalances (e.g., hypokalaemia, hypomagnesaemia, hypocalcaemia) that may contribute to QT interval prolongation
* Clinically significant bradycardia (\<50 beats per minute) that is symptomatic or causes haemodynamic instability
* Major surgery within 4 weeks prior to C1D1 or inadequate recovery from prior surgery
* Uncontrolled intercurrent illness
* Inability to fast, swallow, ingest, or absorb oral medication due to a pre-existing condition
* History of interstitial lung disease or pneumonitis requiring systemic corticosteroid treatment
* Requirement for medications with a known risk of Torsades de Pointes that cannot be discontinued prior to study treatment
* Detectable human immunodeficiency virus (HIV) viral load (applicable to rest of the world)
* Known history of human immunodeficiency virus (HIV)-1/2 antibodies with an HIV ribonucleic acid (RNA) viral load ≥50 copies/mL, cluster of differentiation (CD)4+ lymphocyte count \<350 cells/µL, a history of an acquired immunodeficiency syndrome-defining opportunistic infection within the past 12 months, on the same anti-HIV medications for \<12 weeks or further changes in the number or type of antiretroviral drugs in the regimen could be anticipated in the next 12 weeks (applicable to UK only)
* Known serologic status reflecting active hepatitis B or C infection
* Active uncontrolled systemic fungal, bacterial, viral, or other infection or a condition predisposing to severe infection