CPX-351+GO in Subjects 55 Years Old, or Older, With AML

Study Overview
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Brief Summary
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This is an open label study to assess the safety and efficacy of CPX-351 in combination with gemtuzumab ozogamicin (GO) as first intensive therapy in older (age >55 years) subjects with newly diagnosed AML who are eligible for intensive induction chemotherapy, or AML subjects who previously failed low-intensity therapy but who would be eligible for high-intensity chemotherapy, with companion cognitive function testing to determine whether this contributes to outcome in these subjects. Subjects may have received prior AML treatment with non-intensive regimens, e.g. hypomethylating agents, low-dose cytarabine, or lenalidomide or a clinical trial drug in combination with hypomethylating agents or low-dose cytarabine, but may not have received intensive AML treatment with anthracyclines and/or infusional cytarabine prior to enrollment on this trial. Subjects may not have been treated with GO or other antibody targeting CD 33 prior to enrollment on this trial. The cohort will include 30 subjects treated with the combination of CPX-351 and GO and is designed to establish the safety and feasibility of the combination. These subjects will be assessed for efficacy and safety. Quality of life will be assessed using the FACT-LEU in all subjects. Cognitive function will be assessed using the Blessed Orientation-Memory-Concentration Test and the Montreal Cognitive Assessment.

Official Title
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Phase I Trial, With an Expansion Cohort, of CPX-351 (Cytarabine:Daunorubicin) Liposome Injection in Combination With Gemtuzumab in Subjects With Acute Myeloid Leukemia >55 Years of Age Who Have Not Been Treated With Intensive Chemotherapy

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: CPX-351
* Drug: Gemtuzumab Ozogamicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and voluntarily give informed consent Age≥55 years at the time of study treatment Pathological diagnosis of AML according to WHO criteria (with >20% blasts in the peripheral blood or bone marrow) including: De novo AML with intermediate or adverse-risk karyotypes (including subjects with karyotypic abnormalities characteristic of MDS), who may have received treatment with low-dose cytarabine, hypomethylating agents, and/or non-intensive chemotherapy-based clinical trial treatments Secondary AML: transformed from prior MDS or MPN, confirmed by bone marrow documentation of prior antecedent hematologic disorder Therapy-related AML: t-AML, requires documented history of prior cytotoxic therapy or ionizing radiotherapy for an unrelated disease Performance status >50% KPS, ECOG 0-2 Laboratory values fulfilling the following: Peripheral blast count is less than 30,000/μL prior to administration of drug Serum creatinine < 2.5 mg/dL Serum total bilirubin < 2.5 mg/dL Serum alanine aminotransferase or aspartate aminotransferase < 3 times the ULN Subjects with elevated liver enzymes and serum creatinine values secondary to AML are eligible after discussion with PI Cardiac ejection fraction ≥ 50% by echocardiography, MUGA, or Cardiac MRI Negative pregnancy test for non-menopausal women ≥ 55 years old Subjects with history of second malignancies in remission may be eligible if there is clinical evidence of disease stability off cytotoxic chemotherapy, documented by imaging, tumor marker studies, etc., at screening. Subjects maintained on long-term non-chemotherapy treatment, e.g., hormonal therapy, are eligible. Exclusion Criteria: Acute promyelocytic leukemia [t(15;17)], AML with karyotype inversion 16 or t(8;21) Clinical or morphologic evidence of active CNS leukemia Prior intensive chemotherapy for AML with anthracycline/cytarabine-based regimens, GO or other antibody targeting CD33 as a single agent and/ or prior HSCT. Subjects may have been treated with commercially available or investigational hypomethylating agents (e.g. decitabine, azacitidine, SGI-110), lenalidomide, or low-dose cytarabine (not to exceed 20 mg/m2 daily for 14 days for ≤ 6 cycles) or on clinical trials with combinations of low-intensity chemotherapy agents. No more than one agent or combination of agents can be given for treatment of AML prior to enrollment onto this protocol. Prior treatment including HMA, systemic chemotherapy, surgery, or radiation therapy must have been completed at least 7 days before start of study treatment or after discussion with PI. Treatment with investigational agents must have been completed at least 14 days prior to study drug treatment. Hydroxyurea is permitted for control of blood counts before the start of study treatment. Toxicities associated with prior therapies must have recovered to grade 1 or less prior to start of study treatment. Subjects 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 Subjects 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. Subjects with an infection receiving treatment (antibiotic, antifungal or antiviral treatment) may be entered into the study but must be afebrile and hemodynamically stable for ≥72 hrs. Subjects with current or recent evidence of invasive fungal infection (blood or tissue culture); subjects with recent fungal infection must have a 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) Hypersensitivity to cytarabine, daunorubicin or liposomal products History of Wilson's disease or other copper-metabolism disorder History of prior bone marrow or solid organ transplantation

Ages Eligible for Study
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Minimum Age: 55 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>CPX-351 : Daunorubicin 44mg/m^2 and cytarabine 100mg/m^2/day on Days 1,3 and 5 (90 minute IV infusion) Gemtuzumab ozogamicin: 3mg/m^2/day on Day 1 (2 hour IV infusion) | Drug: CPX-351<br>* CPX-351 is a liposomal formulation of a fixed combination of the antineoplastic drugs cytarabine and daunorubicin. The two drugs are present inside the liposome in a 5:1 molar ratio. The liposome membrane is composed of distearoylphosphatidylcholine, distearoylphosphatidylglycerol and cholesterol in a 7:2:1 molar ratio.<br>* Other names: Vyxeos;Drug: Gemtuzumab Ozogamicin<br>* Gemtuzumab ozogamicin is a CD-33 directed antibody drug conjugated to calicheamicin. CD 33 is expressed on myeloid leukemic blast cells and on normal hematopoietic cells. The drug is approved for the treatment of newly diagnosed CD 33 positive AML in adults and the treatment of relapsed and refractory CD 33 positive AML in adults. The drug is available for injection 4.5 mg as a lyophilized cake or powder in a single use vial for reconstitution and dilution.<br>* Other names: Mylotarg;|
| Experimental: Cohort B<br>CPX-351: Daunorubicin 44mg/m^2 and cytarabine 100mg/m^2 on Days 1, 3 and 5 (90 minute IV infusion) Gemtuzumab ozogamicin: 3mg/m^2 on Days 1, 4 (2 hour IV infusion) | Drug: CPX-351<br>* CPX-351 is a liposomal formulation of a fixed combination of the antineoplastic drugs cytarabine and daunorubicin. The two drugs are present inside the liposome in a 5:1 molar ratio. The liposome membrane is composed of distearoylphosphatidylcholine, distearoylphosphatidylglycerol and cholesterol in a 7:2:1 molar ratio.<br>* Other names: Vyxeos;|
| Experimental: Cohort C<br>CPX-351: Daunorubicin 44mg/m^2 and cytarabine 100mg/m^2 on Days 1, 3, and 5 (90 minute IV infusion) Gemtuzumab ozogamicin: 3mg/m^2 on Days 1, 4 and 7 (2 hour IV infusion) | Drug: CPX-351<br>* CPX-351 is a liposomal formulation of a fixed combination of the antineoplastic drugs cytarabine and daunorubicin. The two drugs are present inside the liposome in a 5:1 molar ratio. The liposome membrane is composed of distearoylphosphatidylcholine, distearoylphosphatidylglycerol and cholesterol in a 7:2:1 molar ratio.<br>* Other names: Vyxeos;Drug: Gemtuzumab Ozogamicin<br>* Gemtuzumab ozogamicin is a CD-33 directed antibody drug conjugated to calicheamicin. CD 33 is expressed on myeloid leukemic blast cells and on normal hematopoietic cells. The drug is approved for the treatment of newly diagnosed CD 33 positive AML in adults and the treatment of relapsed and refractory CD 33 positive AML in adults. The drug is available for injection 4.5 mg as a lyophilized cake or powder in a single use vial for reconstitution and dilution.<br>* Other names: Mylotarg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasible dose of Gemtuzumab Ozogamicin (GO) in combination with CPX-351 (cytarabine:daunorubicin) in older subjects with AML | The combination of CPX-351 + GO will be declared feasible if at least one dose of GO (day 1, 4, and 7) at 3 mg/m^2 can be safely delivered to subjects. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of the combination of CPX and GO as first intensive therapy in elderly (age ≥55 years) by response rate | The efficacy of the combination of CPX-351 and GO in this population will be assessed by treatment response rate, as determined by bone marrow analysis at Day 14 of each induction and consolidation, and as needed thereafter, up to 5 years. | 5 years | 
| Safety of the combination of CPX and GO in elderly (age ≥55 years) subjects with AML by evaluation of the frequency and severity of adverse events. | The safety of CPX-351 in this population will be assessed by evaluation of the frequency and severity of adverse events. | 5 years | 
| Assessment of Minimal Residual Disease (MRD) response in subjects treated with this combination using multiparameter flow cytometry and next generation sequencing. | MRD is defined as posttherapy persistence of leukemia cells at levels below morphologic detection, and is a prognostic marker of increased risk of relapse and shorter survival in this subject population. | 5 years | 
| Quality of Life Assessment using the Functional Assessment of Cancer Therapy-Leukemia (FACT-LEU). | Leukemia Subscale (LeuS): Range:0-68. To derive: Subtract the answers from 4 for each of the 17 questions, except #s 11 and 12 (these are added without modification). Add values, multiply by 17 and divide by # of questions answered. FACT-Leu total =PWB+SWB+EWB+FWB+LeuS. Range: 0-176. | 5 years | 
| Assessment of the relationship of cognitive function to outcome using the Blessed Orientation-Memory-Concentration Test | The relationship of cognitive function to outcome will be assessed using the Blessed Orientation-Memory-Concentration Test. The score for 6 items are multiplied to yield a weighted score. The higher the total weighted score, the more likely the patient has cognitive disability. Weight scores totaling greater than 10 are generally accepted as an indication of the presence of clinically meaningful cognitive impairment. | 5 years | 
| Assessment of the relationship of cognitive function to outcome using the Montreal Cognitive Assessment (MoCA). | The relationship of cognitive function to outcome will be assessed using the MoCA. The MoCA was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. The total possible score is 30 points; a score of 26 or above is considered normal. | 5 years | 
| CPX-351 as a post-remission (consolidation) therapy | The safety of CPX-351 as a post-remission (consolidation) therapy will be assessed by evaluation of the frequency and severity of adverse events. | 5 years | 
| Rate of morphologic leukemia-free state (MLFS) | The rate of morphologic leukemia-free state (MLFS) will be determined to supplement the efficacy assessment of CPX-351. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, De novo AML, Secondary AML, Therapy-related AML