Phase 1 Open-label Study of AMX-883 Alone in Participants With AML and High-risk MDS and in Combination in Participants With AML

Phase 1RecruitingNCT07723703

Amphista Therapeutics Ltd54 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Acute Myeloid Leukaemia High Risk Myelodysplastic Syndrome

Interventions

AMX-883DRUG

AMX-883 will be administered orally.

PosaconazoleDRUG

Posaconazole tablets will be administered orally.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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, 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 * 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

Locations (1)

NEXT Oncology Virginia

Fairfax, Virginia, United States

RECRUITING

Outcomes

Primary Outcomes

Number of participants with adverse events (AEs), treatment-emergent adverse events (TEAEs), adverse events of special interests (AESIs) and serious adverse events (SAEs)

To determine the safety and tolerability of AMX-883 in participants with relapsed or refractory AML and high-risk MDS when administered as monotherapy and in combination with posaconazole.

Time frame: Until 30 days after last dose (Approximately 2 years 8 months)

Number of participants with dose limiting toxicities (DLTs)

To determine the maximum tolerated dose (MTD)/optimal biological dose (OBD) and the recommended dose for expansion (RDE) of AMX-883 in participants with relapsed or refractory AML and high-risk MDS when administered as monotherapy and in combination with posaconazole.

Time frame: During Cycle 1 (each cycle will be 28 days)

Secondary Outcomes

Maximum plasma concentration (Cmax)

To characterise the PK (Cmax) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (Cmax) of AMX-883.

Time frame: At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months)

Minimum plasma concentration (Cmin)

To characterise the PK (Cmin) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (Cmin) of AMX-883.

Time frame: At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months)

Time to Cmax (Tmax)

To characterise the PK (Tmax) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (Tmax) of AMX-883.

Central Contacts

Amphista Medical Monitor

CONTACT

mm@amphista.com

Data from ClinicalTrials.gov

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Time frame: At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months)

Terminal plasma half-life (t½λz)

To characterise the PK (t½λz) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (t½λz) of AMX-883.

Time frame: At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months)

Area under the plasma concentration-time curve from zero to infinity (AUCinf)

To characterise the PK (AUCinf) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (AUCinf) of AMX-883.

Time frame: At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months)

Oral plasma clearance (CL/F)

To characterise the PK (CL/F) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (CL/F) of AMX-883.

Time frame: At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months)

Oral volume of distribution during terminal phase (Vz/F)

To characterise the PK (Vz/F) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (Vz/F) of AMX-883.

Time frame: At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months)

Mean residence time (MRT)

To characterise the PK (MRT) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (MRT) of AMX-883.

Time frame: At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months)

Area under the plasma concentration-time curve from zero to tau (AUC0-tau) where tau=12

To characterise the PK (AUC0-tau) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (AUC0-tau) of AMX-883. AUC at other timepoints may also be derived.

Time frame: At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months)

Composite complete remission (CRc) (AML)

CRc is defined as percentage of participants with Complete remission (CR) and complete remission with partial haematologic recovery (CRh) and complete remission with incomplete count recovery (CRi). This will be used to explore early evidence of antileukaemic activity (ALA) of AMX-883 when administered as monotherapy and in combination with posaconazole in participants.