Low-dose AZA, Pioglitazone, ATRA Versus Standard-dose AZA in Patients >=60 Years With Refractory AML

NCT02942758 | Terminated Phase 2 DMC

• 1 other identifier: AMLSG26-16
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

Diagnosis: Acute myeloid leukemia refractory to intensive induction chemotherapy; Age ≥ 60 years, no upper age limit; Study drug: low-dose azacitidine, pioglitazone, ATRA; Safety Run-In Phase; randomized Phase II, open-label

• Safety Run-In Phase: Based on a 3 + 3 modified design, the tolerable dose of ATRA for the randomized phase II is defined.
• Phase II: Experimental Arm: low-dose azacitidine, pioglitazone, ATRA; Standard Arm: standard-dose azacitidine; in both arms patients can receive further cycles (with no limit to the number given) as long as clinically appropriate

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (1)

• overall Survival

  3 years

Secondary Outcomes (10)

• complete remission (CR) rate

  3 years

• complete remission with incomplete blood count recovery (CRi) rate

  3 years

• partial remission (PR) rate

  3 years

• hematological improvement (HI) rate

  3 years

• cumulative incidence of relapse (CIR)

  3 years

Study Arms (2)

low-dose AZA / ATRA / Pioglitazone

EXPERIMENTAL

low-dose azacitidine (75 mg/d), ATRA, pioglitazone

Drug: low-dose Azacitidine; Drug: Pioglitazone; Drug: ATRA

standard-dose AZA

ACTIVE COMPARATOR

standard-dose azacitidine (75mg/m²/d)

Drug: standard-dose AZA

Interventions

low-dose Azacitidine DRUG

Azacitidine 75 mg/d s.c. for 7 days, repeated 28-day treatment cycle

Also known as: Vidaza

low-dose AZA / ATRA / Pioglitazone

Pioglitazone DRUG

Pioglitazone 45 mg p.o. continuously from day 1

Also known as: Actos

low-dose AZA / ATRA / Pioglitazone

ATRA DRUG

ATRA \*45 mg/m² p.o. from day 1 to 28, 15 mg/m² from day 29 continuously; \*this regimen will be chosen for the first dose to be evaluated.

Also known as: All-trans-retinoic acid; Vesanoid

low-dose AZA / ATRA / Pioglitazone

standard-dose AZA DRUG

Azacitidine 75 mg/m²/d s.c. for 7 days, repeated 28-day treatment cycle

Also known as: Vidaza

standard-dose AZA

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with confirmed diagnosis of acute myeloid leukemia (AML) who are refractory\* to induction therapy and not eligible for further intensive induction therapy based on documented medical reasons (e.g. disease characteristics or patient characteristics), or
• Patients with confirmed diagnosis of acute myeloid leukemia (AML) who are refractory\* to induction therapy and not immediate candidates for allogeneic HSCT (bridge to transplant is allowed)
• \*refractory to induction therapy is defined as no CR, no CRi and no PR (according to standard criteria, see Section 11.2.3) after at least one intensive induction therapy including at least 5 days of cytarabine 100-200 mg/m² continuously or an equivalent regimen with cytarabine with total dose not less than 500 mg/m² per cycle and at least 2 days of an anthracycline (e.g. daunorubicin, idarubicin).
• Age ≥ 60; no upper age limit
• ECOG performance status of ≤ 2 at screening
• To control hyperleukocytosis or extramedullary involvement, medication with hydroxyurea is allowed up to 24h before start of study treatment. In case of hyperleukocytosis hydroxyurea should be given and start of study treatment should be delayed until leukocyte counts are \< 20 x 10\^9/L.
• Female subjects of childbearing potential\* may participate, providing they meet the following conditions:
• Have a negative pregnancy test (serum or urine with a sensitivity of at least 25 mIU/mL; local laboratory) within 72 hours prior to starting study therapy. They must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices true abstinence\*\* from heterosexual contact.
• Agree to practice true abstinence\*\* from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with two effective methods of contraception (e.g., oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) without interruption during the study therapy (including dose interruptions), and for 3 months after discontinuation of study drugs.
• A female subject of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).
• True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
• Male patients with a female partner of childbearing potential must agree to abstain from sexual intercourse or to the use of at least two effective contraceptive methods (e.g., synthetic condoms with spermicide, etc) at screening and throughout the course of the study and should avoid fathering a child during the course of the study and for 3 months following the last study treatment.
• Signed written informed consent.

You may not qualify if:

• Known or suspected hypersensitivity to the study drugs and/or any excipients
• Patients with acute promyelocytic leukemia exhibiting t(15;17)(q22;q12); PML-RARA, or with variant translocations
• Acute myeloid leukemia (AML) with isocitratdehydrogenase (IDH) 1 or 2 mutations if results are available from the central AMLSG reference laboratories
• ECOG performance status \> 2
• Inadequate cardiac, hepatic and/or renal function at Screening Visit defined as:
• heart failure NYHA II-IV
• unstable angina pectoris
• total bilirubin, ALT, AST \> 2.5 x upper normal serum level
• Creatinine \> 1.5 x upper normal serum level
• Active central nervous system involvement
• Uncontrolled infection
• Uncontrolled diabetes mellitus
• Patients with a "currently active" second malignancy requiring active therapy other than non-melanoma skin cancers (except for hormonal/antihormonal treatment, e.g. in prostate or breast cancer)
• Patients with "currently active" bladder cancer or bladder cancer in their history, patients with risk factors for bladder cancer (e.g. exposure to aromatic amines or heavy tobacco smoker), or macrohematuria of unknown origin
• Severe neurological or psychiatric disorder interfering with ability of giving an informed consent

Sponsors & Collaborators

• University Hospital Regensburg: lead
• Anticancer Fund, Belgium: collaborator
• Celgene: collaborator

Study Sites (1)

University Hospital Regensburg

Regensburg, 93053, Germany

Location

Related Publications (1)

• Klobuch S, Steinberg T, Bruni E, Mirbeth C, Heilmeier B, Ghibelli L, Herr W, Reichle A, Thomas S. Biomodulatory Treatment With Azacitidine, All-trans Retinoic Acid and Pioglitazone Induces Differentiation of Primary AML Blasts Into Neutrophil Like Cells Capable of ROS Production and Phagocytosis. Front Pharmacol. 2018 Nov 27;9:1380. doi: 10.3389/fphar.2018.01380. eCollection 2018.

  PMID: 30542286 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Azacitidine; Pioglitazone; Tretinoin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Thiazolidinediones; Thiazoles; Sulfur Compounds; Azoles; Vitamin A; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Diterpenes; Pigments, Biological; Biological Factors

Study Officials

• Simone Thomas, Dr.

  University Hospital Regensburg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr. med.

Study Record Dates

• First Submitted: October 18, 2016
• First Posted: October 24, 2016
• Study Start: April 10, 2017
• Primary Completion: March 25, 2020
• Study Completion: March 25, 2020
• Last Updated: May 8, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)