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Clinical Trial to Assess the Efficacy and Toxicity of Induction and Consolidation With CPX-351 for Patients Aged 60 to 75 Years With Secondary or High-risk Acute Myeloid Leukemia (LAMVYX)

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ClinicalTrials.gov Identifier: NCT04230239
Recruitment Status : Recruiting
First Posted : January 18, 2020
Last Update Posted : January 18, 2020
Sponsor:
Information provided by (Responsible Party):
PETHEMA Foundation

Brief Summary:
This protocol corresponds to a prospective, multicentre, open label, phase II study designed to evaluate the efficacy of CPX-351 in elderly patients with secondary or high-risk AML. The clinical trial is divided into pre-treatment, treatment (induction and consolidation cycles) and follow-up periods and consists of a single arm group. Patients will be enrolled at diagnosis to follow the treatment arm. After that will start induction chemotherapy with CPX-351 regimen (14 days maximum screening period). Once a patient have been evaluated for response and recovered from major complications, he/she will start second course (consolidation 1), unless the bone marrow and peripheral blood assessment is showing less than a complete response, then a second induction may be offered. If a CR or CRi is obtained after the second induction course, patients will start the third course after a rest and recovery period. Patients aged between 60 and 65 years old are recommended to undergo an allo-SCT after first consolidation if they are considered fit for this procedure and they have a full matched related or unrelated donor. Patients aged between 65 and 70 years old can be proposed for an allo-SCT in CR/CRi if they have a composite HSCT co-morbidity index /age less than 4 and a suitable fully matched related donor. In patients over 70 years old, an allo-SCT in first CR should be avoided although the decision should be taken on an individual basis. Patients with CR/CRi who are not considered for an allo-SCT, will follow 6 maintenance cycles with modified courses of CPX-351 schedule. Patients showing unacceptable toxicity along all therapeutic phases that, in consideration of the investigator, will be prematurely discontinued. All patients will be followed-up for survival. The study will be analyzed on an intention to treat basis. Bone marrow and response assessments will be done after each induction and consolidation course, and every 3 months during the first 12 months after starting maintenance therapy. Patients will be followed-up for a minimum period of 1 year after the enrolment of the last patient. Additionally, after the end of the trial, patients will be followed-up for 2 years in order to verify survival and the evolution of the disease. Study design allows a maximum of 59 patients.

Condition or disease Intervention/treatment Phase
Newly Diagnosed Secondary or High Risk AML Drug: CPX-351 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 59 participants
Intervention Model: Single Group Assignment
Intervention Model Description:

This protocol corresponds to a prospective, multicenter, open-label, phase II study to assess efficacy of CPX-351 in elderly patients (60 to 75 years of age) with newly diagnosed high risk AML. In the context of this protocol, a treatment cycle is defined as the first day of study drug administration (Day 1) up to and including the day before the first day of the treatment cycle immediately afterwards. The treatment cycles will begin after Day 42 but no later than Day 80, counting from Day 1 of the treatment cycle immediately before.

Treatment cycles may be administered while the patient is hospitalized. Patients will receive a maximum of 4 treatment cycles (up to 2 inductions and 2 consolidations) and 6 maintenance cycles. Clinical conditions in the care of patients with acute leukemia require the need for flexibility. However, deviations from the study treatment defined in this section must be prospectively discussed with the coordinator.

Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Phase II, Multicentre, Open Label Clinical Trial to Assess the Efficacy and Toxicity of Induction and Consolidation With CPX-351 for Patients Aged 60 to 75 Years With Secondary or High-risk Acute Myeloid Leukemia
Actual Study Start Date : December 26, 2019
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : December 2022


Arm Intervention/treatment
Experimental: CPX-351 Drug: CPX-351

CPX-351 has IV administration Vyxeos contains 2.2 mg/mL and 5 mg/mL powder for concentrate for solution for infusion of Daunorubicin and cytarabine.

Each vial contains 44 mg of daunorubicin and 100 mg of cytarabine. After reconstitution, the solution contains 2.2 mg/mL daunorubicin and 5 mg/mL cytarabine





Primary Outcome Measures :
  1. To evaluate the CR/CRi rate after induction with CPX-351 [ Time Frame: After 1 or 2 cycles of induction (between 12 and 16 weeks approximately) ]
    The primary endpoint of the study is to evaluate the CR/CRi rate after induction with CPX-351. The responses for CR, CRi, PR, therapeutic failure, and disease recurrence are defined for this study based on the revised recommendations of the International Working Group for response criteria.


Secondary Outcome Measures :
  1. Incidence of Treatment-Adverse Events (Safety and Tolerability) of the CPX-351 induction regimen. [ Time Frame: The induction cycles (up to 2 cycles) will have a mean estimated duration of 6 weeks per cycle. Safety/toxicity assessments will be done in day 1, 8, 15, 22, 29 and 36 of the induction cycles. ]
    Incidence and description of adverse events occurred during induction regimen.

  2. To evaluate the effect of priming with G-CSF with the CPX-351 regimen [ Time Frame: Priming with G-CSF will be done in the induction cycles (up to 2 cycles) and in the consolidation cycles (up to 2 cycles) that will have an an estimated duration of 6 weeks per cycle. ]
    Differences of leukocytes values (x10^9/L) from baseline values, will be checked in order to know the effect of priming with G-CSF

  3. Incidence of Treatment-Adverse Events (Safety and Tolerability) of the CPX-351 consolidation regimen [ Time Frame: Safety/toxicity assessments will be done in day 1, 8, 15, 22, 29 and 36 of the consolidation cycles ]
    Incidence and description of adverse events occurred during consolidation regimen.

  4. Incidence of Treatment-Adverse Events (Safety and Tolerability) of the CPX-351 maintenance regimen [ Time Frame: Safety/toxicity assessments will be done every 2 weeks during the manteinance cycles (24 to 40 weeks of maintenance). ]
    Incidence and description of adverse events occurred during maintenance regimen.

  5. Overall survival [ Time Frame: Estimated 1, 2 and 3 year OS ]
  6. Event-free, disease-free, and relapse free survival (RFS), as well as on the duration of remission and cumulative incidence of relapse [ Time Frame: 1, 2 and 3 years ]
  7. Incidence of hematologic and non-hematologic adverse events occurred during the study. [ Time Frame: At 9 months, which is approximately the estimated mean treatment time. ]
    Incidence and description of hematologic and non-hematologic adverse events occurred during the study.

  8. To evaluate the impact on the quality of life, using the European Quality of Life-5 Dimensions (EQ5D) form, in patients treated with CPX-351 [ Time Frame: The cycles will have a mean estimated duration of 6 weeks and Quality of life questionnaire following EQ-5D will be performed at screening, after induction (day 36), after consolidation 2 ( day 36 of cycle 3) and/or prior to allo-SCT ]
    European Quality of Life-5 Dimensions (EQ-5D)

  9. To evaluate the impact on the use of medical resources during induction and consolidation phase. [ Time Frame: The cycles will have a mean estimated duration of 6 weeks and patients may have up to 2 cycles of induction and up to 2 cycles of consolidation. ]
    Frequencies and descriptions of medical resources (antibiotics, transfusions, etc)

  10. To evaluate the quality of CR (by study of minimal residual disease percentages in the bone marrow using multiparametric flow cytometry) [ Time Frame: After first cycle of induction (6 weeks) and after consolidation 1 (cycle 2: 6 weeks after consolidation 1 onset) only in patients achieving CR/CRi after consolidation 1 ]
  11. To evaluate early mortality (first 60 days) in patients initially treated with CPX-351 [ Time Frame: Day 60 ]
  12. To compare the results with a matched-paired historical cohort of the PETHEMA registry [ Time Frame: Once the study is completed ( an average of 30 months through study completion) ]
    Comparison of the different results between patients included in the CPX-351 trial and a retrospective cohort of patients with similarities characteristics at diagnosis (paired analysis). For this purposes, data will be obtained from the retrospective control cohort of the PETHEMA Epidemiologic Registry of Adult AML. Patients will be matched by age (≤65 vs >65, secondary AML vs therapy-related AML vs high-risk according to 2017ELN).

  13. To assess the rate of allo-SCT [ Time Frame: After consolidation 1 (aprox 12 weeks) or after consolidation 2 (aprox 18 weeks) ]
  14. To evaluate 100 day mortality after allo-SCT [ Time Frame: 100 day after allo-SCT ]
  15. To assess compliance of the maintenance schedule [ Time Frame: After maintenance (aprox 36 weeks) ]
    Measure the number and percentage of patients that start maintenance cycles, and how many discontinues during the manteinance phase or complete all manteinance according to protocol



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   60 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent in accordance with national, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure. Informed consent form must be signed by the patient and the investigator.
  2. Age 60 to 75 years at the time of diagnosis of AML.
  3. Newly confirmed diagnosed of AML according to WHO 2008 criteria.
  4. Secondary or high risk AML, defined as one of the following:

    • t-AML: documentation of prior cytotoxic therapy or radiation therapy for an unrelated disease in a discharge summary or pharmacy records or radiation therapy records
    • MDSAML: bone marrow documentation of MDS prior to diagnosis of AML (could have been treated previously with hypomethylating or standard chemotherapy)
    • CMMoLAML: bone marrow documentation of CMMoL prior to diagnosis of AML (could have been treated previously with hypomethylating or standard chemotherapy)
    • de novoAML with FISH or cytogenetic changes linked to MDS per WHO 2016 criteria.
  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
  6. Ability to adhere to the study visit schedule and other protocol requirements.
  7. Laboratory values fulfilling the following:

    • Serum creatinine < 2.0 mg/mL
    • Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or total bilirubin < 3 times the upper limit of normal (ULN, subjects with elevated liver enzymes related to disease were instructed to contact the Sponsor) (subjects with Gilbert's Syndrome were instructed to contact the sponsor).
  8. Subjects with second malignancies in remission may have been eligible if there was clinical evidence of disease stability for a period ≥ 6 months off cytotoxic chemotherapy, documented by imaging, tumor marker studies at screening. Subjects maintained on long-term nonchemotherapy treatment such as hormonal therapy were eligible.
  9. Cardiac ejection fraction ≥ 50% assessed by echocardiography or MUGA.
  10. Eligible to receive intensive chemotherapy.
  11. Female patients of child-bearing potential must have a negative serum pregnancy test at screening and agree to use reliable methods of contraception for three months after their last dose of medication. Male patients must use a reliable method of contraception (if sexually active with a female of child-bearing potential).
  12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures

Exclusion Criteria:

  1. Patients with genetic diagnosis of acute promyelocytic leukemia.
  2. Age <60 years or >75 years.
  3. Blastic phase of bcr/abl chronic myeloid leukemia.
  4. Patients with de novo AML without FISH or cytogenetic changes linked to MDS per WHO 2016 criteria.
  5. Clinical evidence of active central nervous system (CNS) leukemia.
  6. Subjects with active (uncontrolled, metastatic) second malignancies.
  7. Any major surgery or radiation therapy in 4 weeks.
  8. Subjects with myocardial impairment of any cause (eg, cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (Class III or IV staging).
  9. Uncontrolled infection; subjects with an infection receiving treatment (antibiotic, antifungal, or antiviral treatment) could be entered into the study provided the subject was respiratory and hemodynamically stable for ≥ 72 hours.
  10. Current evidence of invasive fungal infection (blood or tissue culture); subjects with recent fungal infection must have had subsequent negative cultures to be eligible; known HIV (new testing not required) or evidence of active hepatitis B or C infection (with rising transaminase values).
  11. Hypersensitivity to cytarabine, daunorubicin or liposomal products.
  12. 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.
  13. Serum creatinine ≥ 20 mg/dL (unless it is attributable to AML activity).
  14. Bilirubin, alkaline phosphatase, or SGOT > 3 times the ULN (unless it is attributable to AML activity).
  15. Subjects with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent).
  16. History of Wilson's disease or other copper-metabolism disorder.
  17. Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent and until toxicity from this has resolved to grade 1 or less; if the half-life of the agent is unknown, patients must wait 4 weeks prior to first dose of study treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04230239


Contacts
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Contact: Olga García Calduch 0034 609128678 olga.garcia.calduch@fundacionpethema.es

Locations
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Spain
Institut Català D'Oncologia-Hospital Germans Trias I Pujol Not yet recruiting
Badalona, Spain
Contact: Susana Vives Polo         
Institut Català D'Oncologia - Hospital Duran I Reynals Not yet recruiting
Bellvitge, Spain
Contact: Montserrat Arnan Sangerman         
Hospital San Pedro de Alcántara Not yet recruiting
Cáceres, Spain
Contact: Juan Miguel Bergua Burgués         
Hospital Universitario Reina Sofía Not yet recruiting
Córdoba, Spain
Contact: Josefina Serrano López         
Hospital Universitario de Gran Canaria Dr. Negrín Not yet recruiting
Las Palmas, Spain
Contact: Carlos Rodríguez Medina         
Hospital Universitario Lucus Augusti Not yet recruiting
Lugo, Spain
Contact: Maria Esperanza Lavilla Rubira         
Hospital Ramón Y Cajal Not yet recruiting
Madrid, Spain
Contact: Pilar Herrera Puente         
Hospital Universitario 12 de Octubre Not yet recruiting
Madrid, Spain
Contact: Pilar Martínez Sánchez         
Hospital Universitario Central de Asturias Not yet recruiting
Oviedo, Spain
Contact: Teresa Bernal del Castillo         
Hospital General Del H.U. Virgen Del Rocío Not yet recruiting
Sevilla, Spain
Contact: José Antonio Pérez Simón         
Hospital Clínico Universitario de Valencia Not yet recruiting
Valencia, Spain
Contact: Mar Tormo Díaz         
Hospital Universitario Y Politécnico La Fe Recruiting
Valencia, Spain
Contact: Rebeca Rodríguez Veiga         
Sponsors and Collaborators
PETHEMA Foundation
Investigators
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Principal Investigator: Pau Montesinos Fernández, PhD Hospital Universitario La Fe
Principal Investigator: José Antonio Pérez Simón, PhD Hospitales Universitarios Virgen del Rocío
Study Chair: Carmen López-Carrero García Fundación Pethema

Publications:
Lancet JE, Uy GL, Cortes JE, et al. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol 34, 2016 (suppl; abstr 7000).

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Responsible Party: PETHEMA Foundation
ClinicalTrials.gov Identifier: NCT04230239    
Other Study ID Numbers: LAMVYX
2018-004353-24 ( EudraCT Number )
First Posted: January 18, 2020    Key Record Dates
Last Update Posted: January 18, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by PETHEMA Foundation:
Secondary AML
High risk AML
Additional relevant MeSH terms:
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Leukemia, Myeloid, Acute
Neoplasm Metastasis
Leukemia
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Neoplastic Processes
Pathologic Processes