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

NCT ID: NCT02942758

Last Updated: 2024-05-08

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-04-10
• Study Completion Date: 2020-03-25

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

low-dose AZA / ATRA / Pioglitazone

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

Group Type: EXPERIMENTAL

low-dose Azacitidine

Intervention Type: DRUG

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

Pioglitazone

Intervention Type: DRUG

Pioglitazone 45 mg p.o. continuously from day 1

ATRA

Intervention Type: 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.

standard-dose AZA

standard-dose azacitidine (75mg/m²/d)

Group Type: ACTIVE_COMPARATOR

standard-dose AZA

Intervention Type: DRUG

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

Interventions

low-dose Azacitidine

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

Intervention Type: DRUG

Pioglitazone

Pioglitazone 45 mg p.o. continuously from day 1

Intervention Type: DRUG

ATRA

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.

Intervention Type: DRUG

standard-dose AZA

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

Intervention Type: DRUG

Other Intervention Names

Vidaza; Actos; All-trans-retinoic acid; Vesanoid; Vidaza

Eligibility Criteria

Inclusion Criteria

1. 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

2. 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).

3. Age ≥ 60; no upper age limit

4. ECOG performance status of ≤ 2 at screening

5. 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.

6. 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.

7. 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.

8. Signed written informed consent.

Exclusion Criteria

1. Known or suspected hypersensitivity to the study drugs and/or any excipients

2. Patients with acute promyelocytic leukemia exhibiting t(15;17)(q22;q12); PML-RARA, or with variant translocations

3. Acute myeloid leukemia (AML) with isocitratdehydrogenase (IDH) 1 or 2 mutations if results are available from the central AMLSG reference laboratories

4. ECOG performance status > 2

5. Inadequate cardiac, hepatic and/or renal function at Screening Visit defined as:

1. heart failure NYHA II-IV

2. unstable angina pectoris

3. total bilirubin, ALT, AST > 2.5 x upper normal serum level

4. Creatinine > 1.5 x upper normal serum level

6. Active central nervous system involvement

7. Uncontrolled infection

8. Uncontrolled diabetes mellitus

9. 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)

10. 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

11. Severe neurological or psychiatric disorder interfering with ability of giving an informed consent

12. Known or suspected active alcohol or drug abuse

13. Known positive for HIV, active HBV or HCV infection

14. No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician and/or other physicians involved in the treatment of the patient about study participation.

15. Treatment with any other clinical study drug within 14 days before the first administration of the investigational drugs or at any time during the study

16. Breast feeding woman or women with a positive pregnancy test at Screening Visit

17. Male patients with a female partner of childbearing potential not willing 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 for 3 months following the last study treatment.

• Minimum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Anticancer Fund, Belgium

OTHER

Sponsor Role: collaborator

Celgene

INDUSTRY

Sponsor Role: collaborator

University Hospital Regensburg

OTHER

Sponsor Role: lead

Responsible Party

Simone Thomas

Dr. med.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Simone Thomas, Dr.

Role: PRINCIPAL_INVESTIGATOR

University Hospital Regensburg

Locations

University Hospital Regensburg

Regensburg, , Germany

Countries

Germany

References

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.

Reference Type: DERIVED

PMID: 30542286 (View on PubMed)

Other Identifiers

AMLSG26-16

Identifier Type: -

Identifier Source: org_study_id