A multicentre clinical trial to assess the safety and tolerability of the combination of low-dose cytarabine or azacitidine, plus Venetoclax and Quizartinib in newly diagnosed acute myeloid leukemia patients aged equal or more than 60 years old ineligible for standard induction chemotherapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion PETHEMA, Fundacion PETHEMA

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Nov 2024 → 30 Sep 2025

Decision date (initial)

2024-11-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

PETHEMA Foundation

External identifiers

EU CT number

2024-519275-26-00

EudraCT number

2020-000406-28

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others, Dose response

-For the phase I: to establish the RP2D of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
-For the phase II: to assess and to compare the CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.

Secondary objectives 11

1. To evaluate the CR/CRi rate after 1 and 4 cycles of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
2. To compare the median OS between AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
3. To evaluate the safety and tolerability of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules (overall hematologic and non-hematologic toxicity).
4. To estimate 1, 2 and 3 years event-free, disease-free, and relapse-free survival, as well as on the cumulative incidence of relapse.
5. To evaluate the impact on the quality of life, using the EQ5D and the EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) forms, of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
6. To evaluate the impact on the use of medical resources during treatment phase (ie, antibiotics, transfusions, duration of hospitalization, need of central venous line, use of strong or moderate CYP3A inhibitors and moderate CYP3A inducers).
7. To evaluate the quality of CR (by study of minimal residual disease percentages in the bone marrow (BM) using multiparametric flow cytometry [MPFC] and NGS-MRD).
8. To evaluate the CRh rate in AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
9. To evaluate early mortality (first 30 and 60 days).
10. Separate analyses in secondary AML, CBF, FLT3-ITD, NPM1, P53, and IDH1/IDH2 subsets.
11. Exploration of biomarkers predictive of drug activity and duration of response may be performed. These analyses maybe part of a multi-study assessment to compare responses to the therapies and/or disease state. Potential analyses may include: o To evaluate the MRD negativity rate in the BM using MPFC and NGS-MRD o To evaluate the MRD negativity in PB using NGS-MRD o Immune recovery o Exhaustive biomarker plan including baseline and relapse molecular characterization by next generation sequencing (NGS).

Conditions and MedDRA coding

Newly diagnosed acute myeloid leukemia patients aged equal or more than 60 years old

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Newly diagnosed AML.
2. Morphological diagnosis of AML (WHO criteria 2008).
3. Patient must be considered be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age or co-morbidities defined by the following criteria: 3.1. ≥ 71 years of age; 3.2. ≥ 60 to 70 years of age with at least one of the following co-morbidities:  ECOG Performance Status of 2 or 3;  Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 55% or chronic stable angina;  DLCO ≤ 65% or FEV1 ≤ 65% or significant history of chronic pulmonary obstructive;  Creatinine clearance ≥ 30 mL/min to < 50 ml/min  Moderate hepatic impairment with total bilirubin, SGPT or SGOT > 1.5 to ≤ 3.0 × ULN  Non active/controlled prior neoplastic disease  Any other patient´s comorbidity or disease condition that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Trial Coordinators before study enrollment (e.g, prior MDS or MPS, high-risk cytogenetics)
4. ECOG performance status ≤ 3.
5. Male subjects who are sexually active, must agree, from Study Day 1 through at least 120 days after the last dose of study drug, to practice the protocol specified contraception.
6. Female subjects must be either postmenopausal for at least 1 year before screening OR permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) OR Women of Childbearing Potential (WOCBP) must agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together), or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception). Female subjects of childbearing potential must have negative results for pregnancy test performed and must not be lactating and breastfeeding
7. Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC) prior to the initiation of any screening or study specific procedures, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

Exclusion criteria 20

1. Age <60 years.
2. Genetic diagnosis of acute promyelocytic leukemia.
3. Treated (excluding surgery or hormone-therapy) for another malignancy within 6 months before randomization or previously diagnosed with another malignancy and have any evidence of disease which may compromise the administration of investigational treatment schedule.
4. Presence of any severe psychiatric disease or physical condition that, according to the physician´s criteria, contraindicates the inclusion of the patient into the clinical trial.
5. Serum creatinine ≥ 2.5 mg/dL or creatinine clearance < 30 mL/min (unless it is attributable to AML activity).
6. Bilirubin, SGPT or SGOT > 3 times the upper normal limit (unless it is attributable to AML activity).
7. WBC> 50 x 109/L. Subject should have white blood cell count <50 × 109/L before starting therapy. Patients who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria before starting therapy.
8. Contraindications for Quizartinib or Venetoclax.
9. History of known CNS leukemia, including cerebrospinal fluid positive for AML blasts.
10. Prior treatment with any investigational drug or device within 30 days prior to Randomization (within 2 weeks for investigational or approved immunotherapy) or currently participating in other investigational procedures
11. Prior treatment with other FLT3-ITD or BCL-2 inhibitors.
12. Known uncontrolled or significant cardiovascular disease, including any of the following: a) Bradycardia of less than 50 beats per minute, unless the subject has a pacemaker; b) QTcF interval >450 msec; c) Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome); d) Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg; e) History of clinically relevant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes); f) History of second (Mobitz II) or third degree heart block (subjects with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker); g) History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to Screening; h) History of New York Heart Association Class 3 or 4 heart failure; i) Known history of left ventricular ejection fraction (LVEF) ≤45% or less than the institutional lower limit of normal; j) Complete left bundle branch block;
13. Prior therapy for AML (except hydroxiurea).
14. Subject enrolling into a dose-escalation cohort must not have received a known strong or moderate inducer or inhibitor of cytochrome P450 (CYP) 3A within 7 days before the first Quizartinib or Venetoclax dose. Subject enrolling into a safety expansion cohort must not have received a known strong or moderate inducer or strong inhibitor of CYP3A within 7 days before the first Quizartinib or Venetoclax dose.
15. Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade-containing Seville oranges), or star fruit within 3 days before anticipated first dose of Venetoclax and must consent not to consume through the last dose of Venetoclax.
16. Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy at physician discretion;
17. Known active clinically relevant liver disease (eg, active hepatitis B, or active hepatitis C)
18. Known history of human immunodeficiency virus (HIV).
19. History of hypersensitivity to any excipients in the Quizartinib, Venetoclax or other study medication.
20. Non mutated FLT3-ITD subjects will be considered ineligible during the randomized Phase II after 48 non mutated FLT3-ITD subjects have been randomized.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Phase I: Recommended phase 2 dose (RP2D) of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules -Phase II: CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules

Secondary endpoints 13

1. CR/CRi rate after 1, and 4 cycles
2. Overall survival (OS)
3. Safety and tolerability of the AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules (overall hematologic and non-hematologic toxicity)
4. Event-free survival (EFS)
5. Disease-free survival (DFS)
6. Relapse-free survival (RFS)
7. Quality of life (from the EuroQoL Group EQ-5D-5L and the EORTC QLQ-C30 instruments)
8. Medical resources during treatment phase
9. Minimal residual disease (MRD)
10. CRh rate (Bone marrow blasts <5% with partial hematologic recovery defined as ANC ≥0.5 × 109/L and platelet count ≥50 × 109/L, with no evidence of extramedullary leukemia and cannot be classified as CR)
11. Early mortality (first 30 and 60 days)
12. Separate analyses in secondary AML, CBF, FLT3-ITD, NPM1, P53, and IDH1/IDH2 subsets.
13. Exploration of biomarkers predictive of drug activity and duration of response. Potential analyses may include: o To evaluate the MRD negativity rate in the BM using MPFC and NGS o Immune recovery o Exhaustive biomarker plan including baseline and relapse molecular characterization by NGS

Investigational products

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

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion PETHEMA

Sponsor organisation

Fundacion PETHEMA

Address

Calle Del Professor Martin Lagos Sn

City

Madrid

Postcode

28040

Country

Spain

Scientific contact point

Organisation

Fundacion PETHEMA

Contact name

Dr. Juan José Lahuerta

Public contact point

Organisation

Fundacion PETHEMA

Contact name

Dr. Juan José Lahuerta

Third parties 3

Fundacion PETHEMA

Sponsor organisation

Fundacion PETHEMA

Address

Calle Del Professor Martin Lagos Sn

City

Madrid

Postcode

28040

Country

Spain

Locations

1 EU/EEA country · 5 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 6 files

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

Application history

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