Clinical Trial to Assess the Safety and Tolerability of the Combination of Low-dose Cytarabine or Azacitidine Plus Venetoclax and Quizartinib in Newly Diagnosed AML Patients Aged Equal or More Than 60 Years Old

Leukemia, Myeloid, Acute Clinical Trial

Official title:

A Phase I-II, Multicentre, Open Label 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04687761
• Other study ID #: VEN-A-QUI
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: November 4, 2020
• Est. completion date: November 2024

Study information

• Verified date: September 2022
• Source: PETHEMA Foundation
• Contact: Olga Garcia Calduch
• Phone: 0034 609 128 678
• Email: olga.garcia.calduch[@]fundacionpethema.es
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A phase I-II trial based on the combination of three drugs regimen LDAC or Azacitidine + Venetoclax + Quizartinib that in this population could be well tolerated by a sequential type administration. The first objective is to achieve rapid control of the disease, using two different schemes, one based in Azacitidine and the other in LDAC, by dose escalation in phase I of the trial. The second goal is to prevent relapse through a maintenance schedule. Phase II will study the efficacy and safety of the recommended dose for Phase II

Description:

The prognosis of AML in elderly patients remain very poor and without significant advances in last decades. AML is a heterogeneous disease in which many altered molecular pathways could contribute to the disease. Thus, curative approaches have been based on highly eradicating regimens using high-dose chemotherapy. However, the low rate of CRs and the high rate of deaths due to toxicity and relapses in elderly patients should stimulate the development of new regimens that overcome these therapeutic obstacles. In recent years, there are a series of new drugs under development that allow the design of sequential combination therapies in this vulnerable population. These drugs have an acceptable toxicity profile and are apparently effective in monotherapy or even in combination, being able to improve the CR rate in this population. The investigators hypothesize that the combination of two targeted drugs that have different mechanisms of action could be capable of breaking the viability of leukemic cells as well as their proliferative qualities, and therefore prolong survival. In this way, the combined action of a pro-apoptotic agent (Venetoclax) and an antiproliferative agent (Quizartinib) could produce a powerful antileukemic effect, preventing the adaptive escape mechanisms of leukemic cells. The investigators have designed a phase I-II trial based on the combination of three drugs regimen LDAC or Azacitidine + Venetoclax + Quizartinib that in this population could be well tolerated by a sequential type administration. The first objective is to achieve rapid control of the disease, using two different schemes, one based in Azacitidine and the other in LDAC, by dose escalation in phase I of the trial. The second goal is to prevent relapse through a maintenance schedule. Phase II will study the efficacy and safety of the recommended dose for Phase II.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 84
• Est. completion date: November 2024
• Est. primary completion date: November 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

Inclusion Criteria:

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 (see Section 0).

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:

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:

1. Bradycardia of less than 50 beats per minute, unless the subject has a pacemaker;

2. QTcF interval >450 msec;

3. Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome);

4. Systolic blood pressure =180 mmHg or diastolic blood pressure =110 mmHg;

5. History of clinically relevant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes);

6. 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);

7. History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to Screening;

8. History of New York Heart Association Class 3 or 4 heart failure;

9. Known history of left ventricular ejection fraction (LVEF) =45% or less than the institutional lower limit of normal;

10. 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.

Related Conditions & MeSH terms

• Age More 60yr
• De Novo
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Azacitidine
AZA 75 mg/m2/daily SC days 1 to 7 or on a 5-on/2-off [weekend]/2-on schedule in 28-day cycle
• Venetoclax
Venetoclax (ramp-up) 400 mg/daily oral days 1 to 28
• Quizartinib
Quizartinib 40 mg/daily oral, days, 8 to 28
• Cytarabine
Low-dose subcutaneous cytarabine (LDAC) 20 mg/m2/daily SC, days 1 to 10
• Venetoclax
Venetoclax (ramp-up) 600 mg/daily oral, days 1 to 28
• Quizartinib
Quizartinib 40 mg/daily oral, days 8 to 28

Locations

Country	Name	City	State
Spain	Hospital Universitario Príncipe de Asturias	Alcalá De Henares
Spain	Hospital Clínic	Barcelona
Spain	Hospital San Pedro de Alcántara	Cáceres
Spain	Hospital Universitario de Jerez de La Frontera	Jerez De La Frontera
Spain	Hospital de León (Complejo Asistencial Universitario de León)	León
Spain	Hospital Universitari Arnau de Vilanova de Lleida	Lleida
Spain	Hospital Universitario Infanta Leonor	Madrid
Spain	Hospital Universitario La Zarzuela	Madrid
Spain	Hospital Universitario Puerta de Hierro Majadahonda	Majadahonda
Spain	Hospital de Sant Joan de Deu (Manresa)	Manresa
Spain	Hospital Clinico Universitario Virgen de La Arrixaca	Murcia
Spain	Hospital Universitari Son Espases	Palma De Mallorca
Spain	Hospital Universitario Marques de Valdecilla	Santander
Spain	Hospital Universitari Mutua de Terrassa	Terrassa
Spain	Hospital Universitario y Politécnico La Fe	Valencia

Sponsors (1)

Lead Sponsor	Collaborator
PETHEMA Foundation

Country where clinical trial is conducted

Spain, 

References & Publications (23)

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* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase I: Recommended phase 2 dose (RP2D)	Recommended phase 2 dose (RP2D) of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules	Approximately 6 months after first patient first visit (FPFV)
Primary	Phase II: CR/Cri rate of AZA based and LDAC based	CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.; Patients will receive 4 consecutive cycles of treatment (approximately every 28 days). After the first 4 cycles, depending on the response and tolerance to treatment, the patient will continue receiving treatment in maintenance cycles until one of these situations occurs: disease progression, lack of clinical benefit, hematological relapse, unacceptable toxicity.	Aproximatey 3 years after FPFV
Secondary	CR/CRi rate	To evaluate the CR/CRi rate after 1 and 4 cycles of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.	After cycle 1 and after cycle 4, being each cycle of 28 days
Secondary	Overall survival (OS)	Overall survival will be defined as the number of days from the start of treatment to the date of death. Subjects that have not died will be censored at the last known date to be alive. To estimate 1, 2 and 3 years event-free, disease-free, and relapse-free survival, as well as on the cumulative incidence of relapse.	Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
Secondary	Overall hematologic and non-hematologic toxicity	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).	Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
Secondary	Event-free survival (EFS)	EFS will be defined as the time from enrollment until the date of progressive disease, relapse from CR or CRi, failure to achieve CR or CRi at 6 months after initiation of treatment, or death from any cause. If a specified event does not occur, subjects will be censored at the date of last disease follow-up. Data for subjects without any disease assessments performed after enrollment will be censored at the date of enrollment.	1, 2 and 3 years.
Secondary	Disease-free survival (DFS)	DFS will be defined as the time from achieving CR or CRi until the date of relapse or death from any cause, whichever occurs first.	1, 2 and 3 years.
Secondary	Relapse-free survival (RFS)	RFS will be defined as the time from achieving CR or CRi until the date of relapse.	1, 2 and 3 years.
Secondary	Cumulative incidence of relapse	Estimation of cumulative incidence of relapse	1, 2 and 3 years.
Secondary	Impact on the quality of life assessed by EuroQoL Group EQ-5D-5L	The impact on the quality of life will be assessed using the EuroQoL Group EQ-5D-5L instrument.	At the screening, after cycle 2, after cycle 6, and after cycle 12, being each cycle of 28 days; and through study completion, an average of 48 months.
Secondary	Impact on the quality of life assessed by EORTC QLQ-C30	The impact on the quality of life will be assessed using the EORTC QLQ-C30 instrument.	at the screening, after 6 cycles, after 12 cycles since start of therapy, being each cycle of 28 days; and through study completion, an average of 48 months
Secondary	Use of medical resources during treatment phase	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).	At the end of treatment phase: after cycle 4, being each cycle of 28 days.
Secondary	Quality of CR	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).	After cycle 1, cycle 4 and then every 3 cycles during the first 2 years after start of the therapy (each cycle of 28 days).
Secondary	CRh rate	To evaluate the CRh rate in AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.	Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
Secondary	Early mortality	To evaluate early mortality rate in AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.	First 30 and 60 days
Secondary	CR/Cri rate of AZA based and LDAC based, in secondary AML subset	CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.	Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
Secondary	CR/Cri rate of AZA based and LDAC based, in CBF subset	CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.	Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
Secondary	CR/Cri rate of AZA based and LDAC based, in FLT3-ITD subset	CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.	Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
Secondary	CR/Cri rate of AZA based and LDAC based, in NPM1 subset	CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.	Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
Secondary	CR/Cri rate of AZA based and LDAC based, in P53 subset	CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.	Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
Secondary	CR/Cri rate of AZA based and LDAC based, in IDH1/IDH2 subset	CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.	Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
Secondary	MRD negativity rate in the BM	To evaluate the MRD negativity rate in the BM using MPFC and NGS-MRD, as part of analysis of biomarkers.	After cycle 1, cycle 4 and then every 3 cycles, being each cycle of 28 days.
Secondary	MRD negativity rate in PB	To evaluate the MRD negativity rate in PB using NGS-MRD, as part of analysis of biomarkers.	After cycle 1, cycle 4 and then every 3 cycles, being each cycle of 28 days.
Secondary	Natural Killer (NK) cell phenotypes and functions (immune recovery) analysis.	Natural Killer (NK) substudy to analyse NK cell phenotypes and functions, as part of biomarker analysis.	At screening and after first and fourth cycles of treatment, being each cycle of 28 days.
Secondary	Baseline and relapse molecular characterization by NGS.	Baseline and relapse molecular characterization by next generation sequencing (NGS), as part of biomarker analysis.	At baseline and at through study completion due to relapse/resistance, an average of 48 months.