Fludarabine in Combination With Daunorubicin and Cytarabine Liposome in Newly-diagnosed Acute Myeloid Leukemia.

Study Overview
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Brief Summary
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This phase 2 clinical trial will evaluate the effectiveness and safety of fludarabine in combination with CPX-351 in patients with untreated AML. Patients will receive fludarabine and CPX-351 during Induction 1 and 2 as well as 2 cycles of consolidation therapy.

Detailed Description
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This is a phase 2, open label single arm study to look at the effectives and safety of fludarabine in combination with CPX-351 in patients with untreated AML. The rationale for this combination stems from data which indicated that pre-treatment of the THP-1 cell line with fludarabine for 4 hours prior to CPX-351 administration (Flu-CPX) significantly potentiated intracellular ara-CTP accumulation compared to CPX-351 alone. This suggests that fludarabine combined with CPX-351 may have efficacy against leukemic clones that would be resistant to CPX-351 or standard chemotherapy in first induction. It has been demonstrated that treatment with CPX-351 produces superior clinical outcomes in secondary AML likely due to its novel formulation, which results in sustained exposure of the cytotoxic agents cytarabine and daunorubicin in a synergistic 5:1 ratio within the plasma and bone marrow. Fludarabine can potentially improve upon the outcomes observed with CPX-351 monotherapy and 7+3 by enhancing intracellular ara-CTP accumulation from CPX-351. Patients will received fludarabine and CPX-351 for up to 2 cycles of induction and 2 cycles of consolidation.

Official Title
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A Phase II Trial of Fludarabine in Combination With Daunorubicin and Cytarabine Liposome for Adults With Newly-diagnosed Acute Myeloid Leukemia: University of California Hematologic Malignancies Consortium Protocol 1914

Conditions
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AML, Acute Myeloid Leukemia, Adult, AML, Adult

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Vyxeos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed de novo or secondary AML as defined by WHO criteria Intermediate- or poor-risk disease by ELN 2017 criteria Adults 18 years of age or older ECOG performance status of 0, 1, or 2 Able to give informed consent and follow study guidelines Organ function requirements: Adequate renal function defined as creatinine clearance greater than 60 ml/min Adequate hepatic function defined by serum bilirubin less than or equal 2 mg/dL. If serum bilirubin greater than 2 mg/dl and direct bilirubin is less than 30 percent of total bilirubin contact study chair for eligibility exception for Gilbert's syndrome. ALT/AST less than or equal to 3 times the upper limit of normal LVEF 50 percent by echocardiogram or MUGA Patients with history of second malignancies in complete remission and without history of metastasis are eligible if there is clinical evidence of disease stability for a period of greater than 6 months off cytotoxic chemotherapy, documented by imaging, tumor marker studies, etc., at screening. Women of child-bearing potential and men with partners of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 120 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Women of child-bearing potential has negative pregnancy test prior to initiating study drug dosing. Exclusion Criteria: Current or anticipated use of additional investigational agents. Any prior treatment for AML with the exception of corticosteroids, hydroxyurea, and/or leukapheresis to prevent or treat early complications prior to starting study therapy. Permitted prior therapy must be stopped 24 hours prior to starting study therapy. Prior use of hypomethylating agents is permitted for patients with history of antecedent MDS. Last dose of hypomethylating therapy must have been 15 or more days prior to starting study therapy. Toxicities associated with prior MDS therapy must have recovered to grade 1 or less prior to start of treatment. Favorable risk cytogenetics as defined by 2017 ELN risk stratification including acute promyelocytic leukemia Chronic myeloid leukemia in myeloid blast crisis Except for CMML, patients with history of myeloproliferative neoplasms (MPN) (defined as a history of essential thrombocytosis or polycythemia vera, or idiopathic myelofibrosis prior to the diagnosis of AML) or combined MDS/MPN are not eligible Clinical evidence of active CNS leukemia Active or metastatic second malignancy Any major surgery or radiation therapy within four weeks. Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent). Any serious medical condition, laboratory abnormality or psychiatric illness that would prevent obtaining informed consent Patients with myocardial impairment of any cause (e.g. 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) Active or uncontrolled infection. Patients with an infection receiving treatment (antibiotic, antifungal or antiviral treatment) may be entered into the study but must be afebrile and hemodynamically stable for greater than or equal to 72 hrs. Current evidence of invasive fungal infection (blood or tissue culture); patients with recent fungal infection must have subsequent negative culture(s) to be eligible Known HIV infection Active hepatitis B or hepatitis C infection Hypersensitivity to cytarabine, daunorubicin or liposomal products History of Wilson's disease or copper-metabolism disorder Pregnant or breastfeeding Any condition which in the opinion of the investigator will interfere with the ability of the subject to comply with the requirements of the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fludarabine and CPX351<br>Induction 1: Fludarabine 30 mg/m2/day IV on days 1-5 for 5 doses Daunorubicin and cytarabine liposome (CPX-351) daunorubicin 44 mg/m2/day and cytarabine 100 mg/m2/day IV on days 1, 3, 5 (given 4 hours after fludarabine infusion) for 3 doses Induction 2 (residual leukemia after Induction 1): Fludarabine 30 mg/m2/day IV on days 1-3 for 3 doses Daunorubicin and cytarabine liposome (CPX-351) daunorubicin 44 mg/m2/day and cytarabine 100 mg/m2/day IV on days 1, 3 (given 4 hours after fludarabine infusion) for 2 doses Optional consolidation, up to 2 cycles: Daunorubicin and cytarabine liposome (CPX-351) daunorubicin 29 mg/m2/day and cytarabine 65 mg/m2/day IV on days 1, 3 for 2 doses | Drug: Fludarabine<br>* 30mg/m2 days 1 through 5<br>* Other names: Oforta, Fludara;Drug: Vyxeos<br>* 100U/m2 days 1, 3 5 in induction, 65U/m2 days 1 and 3 for consolidation<br>* Other names: CPX-351;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate after induction | Overall response rate after induction, defined as the sum of complete response (CR) rate and complete response with incomplete count recovery (CRi) rate after 1-2 cycles of induction therapy, in accordance with 2017 ELN criteria. | 35 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | Safety and tolerability will be determined by rates of NCI CTCAE 5.0 Grade 3-5 toxicities and rate of discontinuation from study therapy due to intolerance | 6 months | 
| Incidence of Grade 3 Treatment Emergent Adverse Events [Safety and Tolerability] | Safety and tolerability will be determined by rates of NCI CTCAE 5.0 Grade 3 toxicities and rate of discontinuation from study therapy due to intolerance | 6 months | 
| Incidence of Grade 4 Treatment Emergent Adverse Events [Safety and Tolerability] | Safety and tolerability will be determined by rates of NCI CTCAE 5.0 Grade 4 toxicities and rate of discontinuation from study therapy due to intolerance | 6 months | 
| Incidence of Grade 5 Treatment Emergent Adverse Events [Safety and Tolerability] | Safety and tolerability will be determined by rates of NCI CTCAE 5.0 Grade 5 toxicities and rate of discontinuation from study therapy due to intolerance | 6 months | 
| CR Rate | CR rate defined as proportion of patients achieving a CR after 1-2 cycles of induction | 60 days | 
| Overall response rate | Overall response rate (CR +CRi) after 1 cycle of induction | 35 days | 
| Overall survival | Overall survival (OS) at 1 year, with OS defined as time from start of study therapy to death from any cause | 1 year | 
| Overall survival | Overall survival (OS) at 3 years, with OS defined as time from start of study therapy to death from any cause | 3 years | 
| Leukemia-free survival | Leukemia-free survival (LFS) at 1 year, with EFS defined as the time from start of study therapy until failure to attain CR, relapse, or death from any cause | 1 years | 
| Leukemia-free survival | Leukemia-free survival (LFS) at 3 years, with EFS defined as the time from start of study therapy until failure to attain CR, relapse, or death from any cause | 3 years | 
| Event free survival | Event Free Survival (EFS) at 1 year, with EFS defined as the time from start of study therapy until failure to attain CR, relapse, or death from any cause. | 1 year | 
| Event free survival | Event Free Survival (EFS) at 3 years, with EFS defined as the time from start of study therapy until failure to attain CR, relapse, or death from any cause. | 3 years | 
| Platelet Recovery | Platelet recovery, defined as the time from start of study therapy until absolute neutrophil count >1,000/mcl in patients achieving a CR | 60 days | 
| 30-day | 30-day mortality defined as death from any cause within 30 days of starting study therapy | 30 days from start of study therapy | 
| 60-day mortality | 60-day mortality defined as death from any cause within 60 days of starting study therapy | 60 days from start of study therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vyxeos, CPX-351, Fludarabine, Untreated AML