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

NCT04330820 | Active Not Recruiting Phase 1

• 1 other identifier: TUD-RELAX1-070
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 12

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.

Conditions

Relapsed Adult AML; Refractory AML

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose (= recommended phase II dose) of cytarabine in combination with venetoclax plus mitoxantrone

  number of dose limiting toxicities related to venetoclax per cohort

  appr. 9 months

• CR/CRi rate

  preliminary efficacy of venetoclax in combination with increasing cytarabine doses plus fixed dose mitoxantrone

  appr. 12 months

Secondary Outcomes (7)

• remission

  appr. 48 months

• Relapse

  appr. 48 months

• Relapse-free survival

  appr. 48 months

• Mortality

  appr. 48 months

• Proportion of allogeneic stem cell transplantation

  appr. 48 months

Other Outcomes (2)

• Identification of biomarkers predicting CR/CRi achievement

  appr. 48 months

• clonal architecture of hematopoiesis

  appr. 48 months

Study Arms (1)

Venetoclax+Cytarabin+ Mitoxantron

EXPERIMENTAL

The treatment plan combines a fixed dose of venetoclax and mitoxantrone with increasing doses of cytarabine (V-MAC).

Drug: Venetoclax Oral Tablet

Interventions

Venetoclax Oral Tablet DRUG

This study will investigate the combination of a fixed maximum venetoclax dose with increasing cytarabine doses plus mitoxantrone in a fixed dose in phase I. In Phase II cytarabine will be given at MDT or RP2D that assessed in phase I. The venetoclax dose of 400 mg will be reached by a ramp up over 3 days. Parallel chemotherapy with cytarabine and mitoxantrone will start on day 3.

Also known as: Cytarabin

Venetoclax+Cytarabin+ Mitoxantron

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained before screening.
• AML according to WHO-2016 criteria, excluding acute promyelocytic leukemia
• Relapsed from first or second CR after 1-2 cycles of standard induction chemotherapy (which must have included cytarabine with an anthracycline or anthracenedione), including relapse after allogeneic stem cell transplantation (dose escalation and expansion part)
• Age 18-75 years
• Fit for intensive chemotherapy, defined by
• ECOG 0-2, life expectancy \> 3months
• Adequate hepatic function: ALAT/ASAT/Bilirubin ≤2.5 x ULN\*
• unless considered due to leukemic organ involvement Note: Subjects with Gilbert's Syndrome may have a bilirubin \> 2.5 × ULN per discussion between the investigator and Coordinating investigator.
• Adequate renal function assessed by serum creatinine ≤ 1.5x ULN OR creatinine clearance (by Cockcroft Gault formula) ≥ 50 mL/min
• Patient is afebrile and hemodynamically stable for at least 72 hours at the time of study medication initiation.
• Male subjects must agree to refrain from unprotected sex and sperm donation from time point of signing the informed consent until 30 days after the last dose of study drug.
• Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with Serum FSH \> 40 U/ml)
• Postoperative (i.e. 6 weeks) after bilateral ovariectomy with or without hysterectomy
• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days before the first dose of study drug.
• Continuous and correct application of a contraception method with a Pearl Index of \<1% (e.g. implants, depots, oral contraceptives, intrauterine device - IUD) from time point of signing the informed consent until 30 days after the last dose of study drug.

You may not qualify if:

• 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

Sponsors & Collaborators

• Technische Universität Dresden: lead
• AbbVie: collaborator

Study Sites (12)

Klinikum Augsburg, Medizinische Klinik II

Augsburg, 86156, Germany

Location

Klinikum Chemnitz, Krankenhaus Küchwald, Klinik für Innere Medizin III

Chemnitz, 09113, Germany

Location

Universitätsklinikum Dresden, Medizinische Klinik I

Dresden, 01307, Germany

Location

Universitätsklinikum Essen; Zentrum für Innere Medizin

Essen, 45122, Germany

Location

Universitätsklinikum Frankfurt am Main, Medizinische Klinik II

Frankfurt am Main, 60590, Germany

Location

Universitätsklinikum Schleswig-Holstein Campus Kiel, Klinik für Innere Medizin II

Kiel, 24105, Germany

Location

Universitätsklinikum Marburg

Marburg, 35033, Germany

Location

Rotkreuzklinikum München, III. Medizinische Abteilung-Hämatologie und Onkologie

München, 80634, Germany

Location

Universitätsklinikum Münster, Medizinische Klinik A

Münster, 48149, Germany

Location

Klinikum Nürnberg Nord, Klinik für Innere Medizin 5

Nuremberg, 90419, Germany

Location

Robert-Bosch-Krankenhaus Hämatologie, Onkologie und Palliativmedizin

Stuttgart, 70376, Germany

Location

Universitätsklinikum Würzburg, Comprehensive Cancer Center Mainfranken

Würzburg, 97080, Germany

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Christoph Röllig, Prof. (MD)

  Technische Universität Dresden (TUD)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The phase I part will be conducted according to the enhanced algorithms of a 3+3H design (Ji et al. J Clin Oncol 2013). The phase II part will be performed as single stage study adopting the A'Hern design (A'Hern Stat Med 2001).

Study Record Dates

• First Submitted: March 19, 2020
• First Posted: April 2, 2020
• Study Start: April 6, 2020
• Primary Completion: October 11, 2023
• Study Completion: August 1, 2025
• Last Updated: February 28, 2024

Record last verified: 2024-02

Locations

DE (12)