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 | Unknown Phase 1

• 1 other identifier: VEN-A-QUI
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 15

Brief 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

Conditions

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

Keywords

Acute myeloid Leukaemia; Newly Diagnosed

Outcome Measures

Primary Outcomes (2)

• 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)

• 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 Outcomes (23)

• CR/CRi rate

  After cycle 1 and after cycle 4, being each cycle of 28 days

• Overall survival (OS)

  Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.

• 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.

• Event-free survival (EFS)

  1, 2 and 3 years.

• Disease-free survival (DFS)

  1, 2 and 3 years.

Study Arms (2)

AZA-Based

EXPERIMENTAL

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).

Drug: Azacitidine; Drug: Venetoclax; Drug: Quizartinib

LDAC-Based

EXPERIMENTAL

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).

Drug: Cytarabine; Drug: Venetoclax; Drug: Quizartinib

Interventions

Azacitidine DRUG

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

AZA-Based

Venetoclax DRUG

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

AZA-Based

Quizartinib DRUG

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

AZA-Based

Cytarabine DRUG

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

LDAC-Based

Eligibility Criteria

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

You may qualify if:

• Newly diagnosed AML.
• Morphological diagnosis of AML (WHO criteria 2008).
• 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)
• ECOG performance status ≤ 3.
• 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).
• 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.
• 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.

You may not qualify if:

• Age \<60 years.
• Genetic diagnosis of acute promyelocytic leukemia.
• 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.
• Serum creatinine ≥ 2.5 mg/dL or creatinine clearance \< 30 mL/min (unless it is attributable to AML activity).
• Bilirubin, SGPT or SGOT \> 3 times the upper normal limit (unless it is attributable to AML activity).
• 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.
• Contraindications for Quizartinib or Venetoclax.
• History of known CNS leukemia, including cerebrospinal fluid positive for AML blasts.
• 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
• Prior treatment with other FLT3-ITD or BCL-2 inhibitors.
• Known uncontrolled or significant cardiovascular disease, including any of the following:
• Bradycardia of less than 50 beats per minute, unless the subject has a pacemaker;
• QTcF interval \>450 msec;
• Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome);
• Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg;

Sponsors & Collaborators

• PETHEMA Foundation: lead

Study Sites (15)

Hospital Universitario Príncipe de Asturias

Alcalá de Henares, Spain

NOT YET RECRUITING

Hospital Clínic

Barcelona, Spain

RECRUITING

Hospital San Pedro de Alcántara

Cáceres, Spain

RECRUITING

Hospital Universitario de Jerez de La Frontera

Jerez de la Frontera, Spain

RECRUITING

Hospital de León (Complejo Asistencial Universitario de León)

León, Spain

RECRUITING

Hospital Universitari Arnau de Vilanova de Lleida

Lleida, Spain

RECRUITING

Hospital Universitario Infanta Leonor

Madrid, Spain

NOT YET RECRUITING

Hospital Universitario La Zarzuela

Madrid, Spain

RECRUITING

Hospital Universitario Puerta de Hierro Majadahonda

Majadahonda, Spain

NOT YET RECRUITING

Hospital de Sant Joan de Deu (Manresa)

Manresa, Spain

RECRUITING

Hospital Clinico Universitario Virgen de La Arrixaca

Murcia, Spain

RECRUITING

Hospital Universitari Son Espases

Palma de Mallorca, Spain

RECRUITING

Hospital Universitario Marques de Valdecilla

Santander, Spain

RECRUITING

Hospital Universitari Mutua de Terrassa

Terrassa, Spain

RECRUITING

Hospital Universitario y Politécnico La Fe

Valencia, Spain

RECRUITING

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  BACKGROUND

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Azacitidine; venetoclax; quizartinib; Cytarabine

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; Arabinonucleosides

Study Officials

• Pau Montesinos, MD

  Hospital Universitario La Fe

  PRINCIPAL INVESTIGATOR

• Juan Bergua, MD

  Hospital San Pedro Alcántara

  PRINCIPAL INVESTIGATOR

• Carmen López-Carrero García

  Fundación PETHEMA

  STUDY CHAIR

Central Study Contacts

Olga Garcia Calduch

CONTACT

0034 609 128 678; olga.garcia.calduch@fundacionpethema.es

Carmen López-Carrero García

CONTACT

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: November 17, 2020
• First Posted: December 29, 2020
• Study Start: November 4, 2020
• Primary Completion: November 1, 2024
• Study Completion: November 1, 2024
• Last Updated: September 8, 2022

Record last verified: 2022-09

Locations

ES (15)