Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Cytarabine

Venetoclax

Azacitidine

Quizartinib

Antimetabolites

Antiviral Agents

Immunosuppressive Agents

Immunologic Factors

Enzyme Inhibitors

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

Azacitidine 75 mg/m2/daily SC on a 5-on/2-off \[weekend\]/2-on schedule in 28-day cycle plus Venetoclax (ramp-up) 400 mg/daily oral, days 1 to 28 plus Quizartinib phase I/RP2D mg/daily oral, days 8 to 14-28.

If 1 DLT is observed among these 3 patients, additional 3 subjects will receive the level 2 dose, and it will be recommended in the absence of DLT between them. If \>1 DLT occurs in these 6 level 2 patients, the dose administered in the level 1 will be the RP2D of the AZA-based schedule.

AZA and Venetoclax doses will remain the same in all levels and only the dose of Quizartinib will be modificated according to the following table:

Escalation-Quizartinib dose-Quizartinib duration; Level-2 -30 mg/daily-Days 8 to 14; Level-1 -30 mg/daily-Days 8 to 21; Level1-40 mg/daily Days 8 to 28; Level2-60 mg/daily-Days 8 to 28.

In phase II, patients randomized to this arm, will receive the recommended phase 2 dose (RP2D) regimen of AZA + Venetoclax + Quizartinib regimen (30 patients).

Low-dose subcutaneous cytarabine 20 mg/m2/daily SC, days 1 to 10 plus Venetoclax (ramp-up) 600 mg/daily oral, days 1 to 28 plus Quizartinib phase I/RP2D mg/daily oral, days 8 to 14-28.

If 1 DLT is observed among these 3 patients, additional 3 subjects will receive the level 2 dose, and it will be recommended in the absence of DLT between them. If \>1 DLT occurs in these 6 level 2 patients, the dose administered in the level 1 will be the RP2D of the LDAC-based schedule.

LDAC and Venetoclax doses will remain the same in all levels and only the dose of Quizartinib will be modificated according to the following table:

Escalation-Quizartinib dose-Quizartinib duration; Level-2 -30 mg/daily-Days 8 to 14; Level-1 -30 mg/daily-Days 8 to 21; Level1-40 mg/daily-Days 8 to 28; Level2-60 mg/daily-Days 8 to 28.

In phase II, patients randomized to this arm, will receive the recommended phase 2 dose (RP2D) regimen of LDAC + Venetoclax + Quizartinib regimen (30 patients).

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 (ramp-up) 400 mg/daily oral days 1 to 28

Quizartinib 40 mg/daily oral, days, 8 to 28

Low-dose subcutaneous cytarabine (LDAC) 20 mg/m2/daily SC, days 1 to 10

Venetoclax (ramp-up) 600 mg/daily oral, days 1 to 28

Quizartinib 40 mg/daily oral, days 8 to 28

Olga Garcia Calduch

Carmen López-Carrero García

Julio García Suárez

Jordi Esteve

Juan Miguel Bergua Burgués

Eusebio Martin Chacón

Fernando Ramos

Antoni García Guiñón

Maria Ángeles Foncillas

Daniel García Belmonte

Guiomar Bautista

Cristina Motlló

Joaquin Antonio Gómez Espuch

Antonia Sampol

Mercedes Colorado Araujo

Ferran Vall-Llovera Calmet

Rebeca Rodríguez Veiga

Pau Montesinos, MD

Juan Bergua, MD

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

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.

Phase 1: Study treatment will start at level 1 and therapeutic level will be escalated or descalated depending on the apparition of DLT. DLT will be monitored during cycle 1 and it is defined as any grade 3-4 related extrahematological toxicity or grade 4 neutropenia not recovered on day 56 since C1D1 not attributable to persistent leukemia.

Phase I will consist of two parallel dose escalation cohorts, with consecutive assignment to each group (first patient will be assigned to AZA-based schedule, second to LDAC-based, third to AZA-based, etc).

Phase II includes two treatment arm groups (AZA-based RP2D vs. LDAC-based RP2D). Patients will be enrolled at diagnosis, within a maximum 28 days screening period, will be assessed for eligibility and therefore randomized to follow the assigned treatment arm (open label design). All screening activities will be performed after patient's informed consent form is signed. Patients will start the assigned regimen 48h maximum after randomization.

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

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

Recommended phase 2 dose (RP2D) of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules

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.

To evaluate the CR/CRi rate after 1 and 4 cycles of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.

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.

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).

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.

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.

RFS will be defined as the time from achieving CR or CRi until the date of relapse.

Estimation of cumulative incidence of relapse

The impact on the quality of life will be assessed using the EuroQoL Group EQ-5D-5L instrument.

The impact on the quality of life will be assessed using the EORTC QLQ-C30 instrument.

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).

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).

To evaluate the CRh rate in AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.

To evaluate early mortality rate in AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.

CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.

To evaluate the MRD negativity rate in the BM using MPFC and NGS-MRD, as part of analysis of biomarkers.

To evaluate the MRD negativity rate in PB using NGS-MRD, as part of analysis of biomarkers.

Natural Killer (NK) substudy to analyse NK cell phenotypes and functions, as part of biomarker analysis.

Baseline and relapse molecular characterization by next generation sequencing (NGS), as part of biomarker analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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	NCT04687761	Leukemia, Myelo... De Novo Age More 60yr	Azacitidine Venetoclax Quizartinib Cytarabine Venetoclax Quizartinib	60 Years -	PETHEMA Foundation
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	NCT04687761	Leukemia, Myelo... De Novo Age More 60yr	Azacitidine Venetoclax Quizartinib Cytarabine Venetoclax Quizartinib	60 Years -	PETHEMA Foundation

Spots Global Cancer Trial Database for age more 60yr