Phase-I/II trial for relapsed or refractory AML patients combining cytarabine and mitoxantrone with venetoclax (TUD-RELAX1-070)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Technische Universitaet Dresden

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

6 Apr 2020 → 24 Sep 2025

Decision date (initial)

2024-10-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-514018-12-00

EudraCT number

2018-003025-28

ClinicalTrials.gov

NCT04330820

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

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.

Conditions and MedDRA coding

female and male adult patients with acute myeloid leukemia (AML) at first or second relapse after intensive chemotherapy including allogeneic stem cell transplantation or primary refractory to standard induction chemotherapy who are eligible for intensive salvage treatment

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Signed Informed consent
2. AML according to WHO criteria, excluding APL
3. Relapsed after first or second CR, including relapse after allogeneic stem cell transplantation (dose escalation and expansion phase)
4. Only expansion phase: 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 equivalent treatment (e.g. CPX351) Note: Primary refractory disease is defined by either ≥ 20% myeloid blasts on early response assessment around day 15 after start of the most recent induction, or by ≥ 5% myeloid blasts after blood count recovery after start of the most recent induction, respectively.
5. Age 18-75 years
6. Fit for intensive chemotherapy, defined by - ECOG 0-2, life expectancy > 3 months - Adequate hepatic function (ALAT/ASAT/Bilirubin ≤2.5 x ULN ) - Adequate renal function assessed by creatinine < 1.5 x ULN OR creatinine clearance (by Cockcroft Gault Formula) ≥ 50 mL/min
7. Patient is afebrile and hemodynamically stable for at least 72 hours at the time of study medication initiation.
8. 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.
9. Women must fulfill at least one of the following criteria in order to be eligible for trial inclusion: o Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with Serum FSH > 40 U/ml) o Postoperative (i.e. 6 weeks) after bilateral ovariectomy with or without hysterectomy o Women of childbearing potential must have a negative serum pregnancy test performed within 7 days before the first dose of study drug. o 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. o Sexual abstinence o Vasectomy of the sexual partner

Exclusion criteria 19

1. Acute promyelocytic leukemia (AML M3)
2. CNS involvement or subjects with extramedullary disease only
3. Known hypersensitivity to any agent given in association with this study including cytarabine or mitoxantrone
4. Intended hematopoietic stem cell transplantation planned as early conditioning from aplasia without previous blood count recovery
5. Cumulative previous exposure to anthracyclines of >410 mg/m2 doxorubicin equivalents
6. Acute GVHD ≥ grade 2, extensive chronic GVHD or requiring systemic immunosuppressive therapy
7. 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)
8. Inability to swallow oral medications
9. Any malabsorption condition
10. Cardiovascular disability status of New York Heart Association 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.
11. Chronic respiratory disease that requires continuous oxygen use.
12. White blood cell count > 25 × 109/L Note: Hydroxyurea is permitted to meet this criterion.
13. AML relapse treatment with any investigational or commercial drug within 14 days before enrolment. Hydroxyurea is allowed until enrolment to control peripheral WBC counts.
14. 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
15. 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 Events (CTCAE), Version 5.0
16. 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)
17. History of clinically significant liver cirrhosis (e.g., Child-Pugh class B and C).
18. 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.
19. Live-virus vaccines given within 28 days prior to the initiation of study treatment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase I (Escalation part): Maximum tolerated dose of cytarabine in combination with venetoclax plus mitoxantrone in the framework of a 3+3 design
2. Phase II (Expansion part): CR/CRi rate

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Technische Universitaet Dresden

Sponsor organisation

Technische Universitaet Dresden

Address

Mommsenstrasse 11, Raecknitz/zschertnitz Raecknitz/zschertnitz

City

Dresden

Postcode

01069

Country

Germany

Scientific contact point

Organisation

Technische Universitaet Dresden

Contact name

Prof. Dr. Christoph Röllig

Public contact point

Organisation

Technische Universitaet Dresden

Contact name

Prof. Dr. Christoph Röllig

Locations

1 EU/EEA country · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications