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

• ClinicalTrials.gov Identifier: NCT04330820
• Recruitment Status: Recruiting
• First Posted: April 2, 2020
• Last Update Posted: January 13, 2023
• Sponsor: Technische Universität Dresden
• Collaborator: AbbVie
• Information provided by (Responsible Party): Technische Universität Dresden

Tracking Information

• First Submitted Date: March 19, 2020
• First Posted Date: April 2, 2020
• Last Update Posted Date: January 13, 2023
• Actual Study Start Date: April 6, 2020
• Estimated Primary Completion Date: June 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 5, 2020)

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

Original Primary Outcome Measures (submitted: March 30, 2020)

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

Current Secondary Outcome Measures (submitted: March 30, 2020)

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

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: March 30, 2020)

• Identification of biomarkers predicting CR/CRi achievement [ Time Frame: appr. 48 months ]
  Baseline samples from all patients with be sequenced for genes which have been associated with response to venetoclax treatment. The panel will include TP53, WT1, PDGFRB, ASXL1, and EZH2. Testing for additional markers may be added triggered by new scientific evidence.
• clonal architecture of hematopoiesis [ Time Frame: appr. 48 months ]
  We will test for changes of the clonal architecture of hematopoiesis during therapy and maintenance treatment. This will be done by NGS using a gene panel including TP53, DNMT3A, ASXL1, TET2, JAK2, RUNX1, SF3B1, and EZH2.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Trial for Relapsed or Refractory AML Patients Combining Cytarabine and Mitoxantrone With Venetoclax (RELAX)
• Official Title: Phase-I/II Trial for Relapsed or Refractory AML Patients Combining Cytarabine and Mitoxantrone With Venetoclax (RELAX)
• 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 Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description:

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).

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Relapsed Adult AML
• Refractory AML

Intervention

Drug: Venetoclax Oral Tablet

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.

Other Name: Cytarabin

Study Arms

Experimental: Venetoclax+Cytarabin+ Mitoxantron

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

Intervention: Drug: Venetoclax Oral Tablet

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 11, 2023): 54
• Original Estimated Enrollment (submitted: March 30, 2020): 60
• Estimated Study Completion Date: April 2025
• Estimated Primary Completion Date: June 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria for both escalation and expansion phase:

• 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.

• Women must fulfill at least one of the following criteria in order to be eligible for trial inclusion:

  • 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.

Note: At present, it is not known whether the effectiveness of hormonal contraceptives is reduced by venetoclax. For this reason, women should use a barrier method in addition to hormonal contraceptive methods.

• Sexual abstinence
• Vasectomy of the sexual partner

Inclusion criteria applying for expansion phase (Phase II) only:

• Primary refractory after 1-2 cycles of standard induction chemotherapy (100 to 200 mg/m2 cytarabine over 7-10 days plus anthracycline or mitoxantrone over 3 days) or 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

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
• Treatment with strong and moderate CYP3A inhibitors (see Appendix 1) during screening
• 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
• 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Christoph Röllig, Prof. (MD); +49 351 458 3775; christoph.roellig@ukdd.de

Contact: Martin Wermke, MD; +49 351 7566; martin.wermke@uniklinikum-dresden.de

• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT04330820
• Other Study ID Numbers: TUD-RELAX1-070
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Technische Universität Dresden
• Original Responsible Party: Same as current
• Current Study Sponsor: Technische Universität Dresden
• Original Study Sponsor: Same as current
• Collaborators: AbbVie

Investigators

• Principal Investigator: Christoph Röllig, Prof. (MD); Technische Universität Dresden (TUD)

• PRS Account: Technische Universität Dresden
• Verification Date: January 2023