Study of C6 Ceramide NanoLiposome (CNL) in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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The study explores whether Ceramide NanoLiposome (CNL) combined with other conventional cancer-fighting drugs makes them work better.

Detailed Description
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The research team has shown that C6 ceramide nanoliposome (CNL) has anti-cancer activity in laboratory models of AML and that when it is combined with other cancer-fighting drugs, it works better. The primary goal of this study is to evaluate the safety of CNL given without other cancer treatments in patients with AML where either their initial treatment didn't work or it stopped working and your AML came back (refractory or relapsed AML, or RR-AML). This study seeks to determine the right dose to start with in later studies when CNL is combined with other drugs. CNL is given by intravenous (IV) infusion and will be given twice a week in this study. Participants will receive study treatment as long as it is considered safe for them to continue, though their disease status will be checked regularly to make sure that their disease has not gotten worse. Blood samples will be collected at many time-points in order to see how their bodies are responding to the drug and how long it stays in the blood. The first patients in the study will start at one dose of the drug and, if that is shown to be safe, the next group will be treated at a slightly higher dose. Participants will be given CNL by intravenous (IV) infusion twice a week over about 2 hours and then they will be monitored for about 2 hours to make sure they don't have any bad side effects, but initially patients will be required to stay at the site for about 6 hours after the start of the infusion in order to get blood draws to see how long the drug stays active in their system. Participants will have a bone marrow biopsy before their second cycle of drug (after about 1 month) and then again before their third cycle of drug in order to see how their disease is responding. After that, bone marrow biopsies will be about every other cycle based on what the study doctor recommends. If the doctor doesn't think that CNL is helping their disease, of if their doctor decides that it is not safe for them to continue, they will be taken off study treatment. Participants will be followed for safety and disease status for up to 6 months.

Official Title
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Phase I Study of C6 Ceramide NanoLiposome (CNL) in Patients With Relapsed/Refractory Acute Myeloid Leukemia (RR-AML)

Conditions
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Acute Myeloid Leukemia, in Relapse, Acute Myeloid Leukemia, Refractory

Intervention / Treatment
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* Drug: Ceramide NanoLiposome (Ceraxa)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent is obtained prior to conducting any study-specific screening procedures. Willing and able to understand the nature of this study and to comply with the study and follow-up procedures. Age and Disease: ≥ 18 years of age with refractory or relapsed AML Refractory AML: Patients who fail to achieve a complete remission (CR) after one line of AML directed therapy Relapsed AML: Patients who achieved a complete remission (CR) with one or more prior lines of AML directed therapy but then developed a relapse of AML. Note: Patients are eligible even if they have not received intensive induction chemotherapy but have been treated with other AML directed therapy like hypomethylating agents (azacitidine, decitabine). Eastern Cooperative Oncology Group (ECOG) performance status must be ≤2 Peripheral white blood cell (WBC) count <30,000/µL. For cyto-reduction, hydroxyurea is allowed during screening and through Cycle 2, Day 3 to reduce WBC count to < 30,000 µL. Adequate organ function as evidenced by the following laboratory findings: Total bilirubin ≤ 1.5 × upper limit of normal (ULN) or < 3 x ULN for patients with Gilbert-Meulengracht Syndrome Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN Creatinine clearance > 60 mL/min QT-interval corrected according to Fridericia's formula (QTcF) < 450 ms on one electrocardiogram (ECG) at screening Exclusion Criteria: Patients meeting any of the following criteria are ineligible for study entry: Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmias not well controlled with medication, myocardial infarction within the previous 6 months before registration, or psychiatric illness/social situations that would limit compliance with study requirements. Patients may not be receiving any other concurrent investigational agents, or have received any investigational agent within one week of registration. Since the teratogenic potential of this combination is currently unknown, females who are pregnant or lactating are excluded. History of any other malignancies within the preceding 12 months before registration with the exception of in-situ cancer, non-muscle invasive bladder cancer, prostate, basal or squamous cell skin cancer Life-threatening illnesses other than AML, uncontrolled medical conditions or organ system dysfunction that, in the Investigator's opinion, could compromise the patient's safety or put the study outcomes at risk Evidence of isolated extramedullary disease Acute Promyelocytic Leukemia or AML with active central nervous system (CNS) involvement Untreated severe (in the opinion of the treating investigator) infection Active and uncontrolled infection with HIV (viral load is detectable by PCR) Active infection with Hepatitis B virus (HbSAg positive or PCR with detectable viral load) or Hepatitis C virus (viral load detectable by PCR). Past Hematopoietic stem cell transplant (HSCT) with active graft vs host disease, immunosuppression other than low dose prednisone (5 mg), or calcineurin inhibitors within the 4 weeks before registration

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
Interventional Model Description: Single group assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open Label Administration of Ceramide NanoLiposome<br>Ceramide NanoLiposome will be administered by Intravenous Dosing twice per week in accordance with the protocol relative to dose escalation. There is no placebo group or arm of the study. | Drug: Ceramide NanoLiposome (Ceraxa)<br>* Ceramide NanoLiposome will be given by IV twice a week. The dose, which is based on body size, will be increased for the next group of patients if the first group of patients tolerates that dose and it will decrease for the next group if they do not tolerate the dose.<br>* Other names: Ceramide NanoLiposome;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients with Dose Limiting Toxicities as defined in Protocol Section 13.5 | Dose Limiting Toxicities within the first cycle of CNL monotherapy. See section 13.5 of Protocol for the complete list of Dose Limiting Toxicities | At the end of the the first cycle of administration (each cycle is 28 days) | 
| Number of Patients with Adverse Events | Number of Patients with Adverse Events | Through study completion, an average of 24 weeks | 
| Severity of Adverse Events | Severity of Adverse Event As Described in Protocol | Through study completion, an average of 24 weeks | 
| Duration of Adverse Events | Duration of Adverse Events, As Described in Protocol, measured in days | Length of Adverse Events as measured in days, measured through study completion, an average of 24 weeks | 
| Duration of therapy | Duration of therapy provided as measured in days | Through study completion, an average of 24 weeks | 
| Dose Levels achieved during study | Dose levels administered in milligrams per m2 | Through study completion, an average of 24 weeks | 
| Concentration Max (C Max) | Maximum Serum Concentration measured, in nanograms/milliliter | Through cycle one, 28 days (each cycle is 28 days) | 
| Time to Maximum Study Drug (T Max) | Time to maximum concentration measured, in minutes | Through cycle one, 28 days (each cycle is 28 days) | 
| Half Life of Study Drug | Time for drug to be reduced to half of the starting concentration (in minutes) | Through cycle one, 28 days (each cycle is 28 days) | 
| Study Drug Clearance | The Amount of Study Drug Cleared per unit time (Nanograms/Minute) | Through cycle one, 28 days (each cycle is 28 days) | 
| Ratio of C16/C24 Ceramides | Ratio of Ceramide 16 to Ceramide 24 (ng of C16/ng of C18) from bone marrow biopsy | After one cycle of therapy (Day 28) | 
| Clinical Response - Complete Response | Complete Response | After Cycle Two (56 days) | 
| Clinical Response - Complete Response with Incomplete Hematologic Recovery (CRi) | Complete Response with Incomplete Hematological Recovery as defined by blasts in bone marrow | After Cycle Two (56 days) | 
| Clinical Response - Partial Remission | Partial Remission (as defined by blasts in bone marrow) | After Cycle Two (56 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients with Grade 3 or 4 Adverse Events | Grade 3 and 4 adverse events as defined by CTCAE v5.0 | Through study completion, an average of 24 weeks | 
| Overall Response | Overall response of CNL monotherapy in patients with RR-AML: Complete remission (CR) + Complete remission with incomplete count recovery (CRi) + partial response (PR). CR, CRi and PR as defined as European LeukemiaNet 2017 (ELN 2017) response criteria | Through study completion, an average of 24 weeks, and up to 24 weeks afterwards (total of 48 weeks) | 
| Event Free Survival | Event-free survival (EFS): the time from registration until documented refractory disease, relapse after achieving CR/CRi, or death from any cause, whichever is observed first | From registration to 24 weeks after completion of experimental drug treatment | 
| Overall Survival | Overall survival (OS) | From registration to 24 weeks following drug administration | 
| Quality of Life according to EORTC Quality of Life Questionnaire (QLQ) C30 | Quality of life according to EORTC Quality of Life Questionnaire C30 | Prior to starting study treatment, on day 1 of each cycle (each cycle is 28 days), and at end of treatment (which is expected to be 2 to 3 months (cycles) for most patients | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, Relapsed, Refractory, Ceramide, AML, NanoLiposome