Trial for Relapsed or Refractory AML Patients Combining Cytarabine and Mitoxantrone With Venetoclax (RELAX)

Phase 1

Active, not recruiting

• Conditions: Relapsed Adult AML; Refractory AML
• Interventions: Drug: Venetoclax Oral Tablet

• Registration Number: NCT04330820
• Lead Sponsor: Technische Universität Dresden

Brief Summary

This is an open-label Phase I dose-escalation study of oral venetoclax in combination with increasing cytarabine doses plus mitoxantrone to define the safety profile and MTD of cytarabine in subjects with a histologically or cytologically confirmed acute myeloid leukemia who are refractory or suffered a relapse. This study will be conducted at multiple centers in Germany.

Detailed Description

* To determine safety, tolerability, maximum tolerated dose, and recommended phase II dose of venetoclax in combination with increasing cytarabine doses plus fixed dose mitoxantrone in subjects with a relapsed or refractory AML considered fit for intensive salvage therapy.

* To assess the preliminary efficacy of venetoclax in combination with increasing cytarabine doses plus fixed dose mitoxantrone in subjects with a relapsed or refractory AML considered fit for intensive salvage therapy.

Study Timeline

• Study First Submitted: 2020-03-19
• Study First Submitted QC: 2020-03-30
• Study First Posted: 2020-04-02
• Study Start: 2020-04-06
• Primary Completion: 2023-10-11
• Status Verified: 2024-02
• Last Update Submitted: 2024-02-27
• Last Update Posted: 2024-02-28
• Study Completion: 2025-08

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 55

Inclusion Criteria

Not provided

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Exclusion Criteria

• Acute promyelocytic leukemia (AML M3)
• CNS involvement or subjects with extramedullary disease only
• Known hypersensitivity to excipients of the preparation or any agent given in association with this study including cytarabine or mitoxantrone
• Intended hematopoietic stem cell transplantation planned as early conditioning from aplasia without previous blood count recovery
• Cumulative previous exposure to anthracyclines of >410 mg/m2 doxorubicin equivalents
• Acute GVHD ≥ grade 2, extensive chronic GVHD or requiring systemic immunosuppressive therapy within 2 weeks prior to start of study treatment
• HIV infection (due to potential drug-drug interactions between antiretroviral medications and venetoclax, as well as anticipated venetoclax mechanism-based lymphopenia that may potentially increase the risk of opportunistic infections).
• Inability to swallow oral medications
• Any malabsorption condition
• Cardiovascular disability status of New York Heart Association (NYHA) Class ≥ 2.

Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.

• Chronic respiratory disease that requires continuous oxygen use.
• White blood cell count > 25 × 109/L. Note: Hydroxyurea is permitted to meet this criterion.
• AML relapse treatment with any investigational or commercial drug within 14 days before enrolment. Hydroxyurea is allowed until enrolment to control peripheral WBC counts. Toxic effects of previous investigational drug treatment have to recover to Grade <2.
• Substance abuse, medical, psychological, or social conditions that may interfere with the subject's cooperation with the requirements of the trial or evaluation of the study results
• Acute non-hematologic toxicities from any prior anti-leukemia therapy or from previous investigational drugs that have not resolved to Grade <2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Evens (CTCAE), Version 5.0
• Pregnant or breastfeeding women. Breastfeeding has to be discontinued before onset of and during treatment and should be discontinued for at least 3 months after end of treatment.
• History of active or chronic infectious hepatitis unless serology demonstrates clearance of infection (Occult or prior hepatitis B virus (HBV) infection (defined as negative hepatitis B surface antigen and positive total hepatitis B core antibody) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing. Patients who have protective titers of hepatitis B surface antibody after vaccination or prior but cured hepatitis B are eligible. Patients positive for hepatitis C virus antibody are eligible provided PCR is negative for HCV RNA.)
• History of clinically significant liver cirrhosis (e.g., Child-Pugh class B and C).
• Live-virus vaccines given within 28 days prior to the initiation of study treatment

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Venetoclax+Cytarabin+ Mitoxantron	Venetoclax Oral Tablet	The treatment plan combines a fixed dose of venetoclax and mitoxantrone with increasing doses of cytarabine (V-MAC).

Primary Outcome Measures

Name	Time	Method
CR/CRi rate	appr. 12 months	preliminary efficacy of venetoclax in combination with increasing cytarabine doses plus fixed dose mitoxantrone
Maximum tolerated dose (= recommended phase II dose) of cytarabine in combination with venetoclax plus mitoxantrone	appr. 9 months	number of dose limiting toxicities related to venetoclax per cohort

Secondary Outcome Measures

Name	Time	Method
Relapse-free survival	appr. 48 months	number of participants alive without relapse
Relapse	appr. 48 months	Cumulative incidence of relapse
Mortality	appr. 48 months	Early mortality (within 14 and 30 days)
incidence and severity of adverse Events [safety and tolerability]	appr. 48 months	number and grade of Adverse Events assessed by CTCAE v5.0
remission	appr. 48 months	Duration of Remission and Depth of remission (MRD)
Proportion of allogeneic stem cell transplantation	appr. 48 months	number of allogeneic stem cell transplantation following response
Overall survival	appr. 48 months	number of patients alive

Trial Locations

Locations (12)

Klinikum Augsburg, Medizinische Klinik II; 🇩🇪 Augsburg, Germany

Universitätsklinikum Münster, Medizinische Klinik A; 🇩🇪 Münster, Germany

Universitätsklinikum Dresden, Medizinische Klinik I; 🇩🇪 Dresden, Germany

Klinikum Chemnitz, Krankenhaus Küchwald, Klinik für Innere Medizin III; 🇩🇪 Chemnitz, Germany

Universitätsklinikum Essen; Zentrum für Innere Medizin; 🇩🇪 Essen, Germany

Rotkreuzklinikum München, III. Medizinische Abteilung-Hämatologie und Onkologie; 🇩🇪 München, Germany

Universitätsklinikum Frankfurt am Main, Medizinische Klinik II; 🇩🇪 Frankfurt am Main, Germany

Universitätsklinikum Marburg; 🇩🇪 Marburg, Germany

Universitätsklinikum Schleswig-Holstein Campus Kiel, Klinik für Innere Medizin II; 🇩🇪 Kiel, Germany

Klinikum Nürnberg Nord, Klinik für Innere Medizin 5; 🇩🇪 Nürnberg, Germany

Universitätsklinikum Würzburg, Comprehensive Cancer Center Mainfranken; 🇩🇪 Würzburg, Germany

Robert-Bosch-Krankenhaus Hämatologie, Onkologie und Palliativmedizin; 🇩🇪 Stuttgart, Germany