Acute Myeloid Leukemia, in Relapse, Acute Myeloid Leukemia, Refractory, Refractory/Relapse Acute Myeloid Leukemia
Conditions
Keywords
Acute Myeloid Leukemia, Relapsed, Refractory, Ceramide, AML, NanoLiposome, Relapsed/Refratory Acute Myleoid Leukemia, NanoLiposomes, Safety, CNL, Ceraxa
Brief summary
The study objective is to evaluate patient safety for patients with refractory and relapsed AML being treated with Ceramide NanoLiposome (CNL) .
Detailed description
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 the AML came back (refractory or relapsed AML, aka RR-AML). This study seeks to determine the right dose to start with in later studies when CNL is combined with other drugs in potential future studies. 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 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, or 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.
Interventions
DRUGCeramide NanoLiposome (Ceraxa)
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.
Sponsors
Keystone Nano, Inc
University of Virginia
Milton S. Hershey Medical Center
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single group assignment
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent is obtained prior to conducting any study-specific screening procedures. 2. Willing and able to understand the nature of this study and to comply with the study and follow-up procedures. 3. Age and Disease: ≥ 18 years of age with refractory or relapsed AML Refractory AML: Patients who fail to achieve a complete remission (CR) or a complete remission with incomplete count recovery (CRi) after one or more ines of AML directed therapy. Relapsed AML: Patients who achieved a complete remission (CR) or a complete remission with incomplete count recovery (CRi) 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). 4. Eastern Cooperative Oncology Group (ECOG) performance status must be ≤2. 5. ECOG performance status must be ≤2 6. Peripheral white blood cell (WBC) count \<30,000/µL. For cyto-reduction, the following are allowed to reduce WBC count to \< 30,000/µL: * hydroxyurea is allowed during screening and through the end of Cycle, * cytarabine is allowed during screening but not after registration and should be limited 1 g/m2 or less from time of consent to registration. 7. 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) ≤ 3 × ULN if not attributed to leukemia, or ≤ 5 x ULN if attributed to leukemia * Creatinine clearance \> 60 mL/min.
Exclusion criteria
Patients meeting any of the following criteria are ineligible for study entry: 1. 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. 2. Patients may not be receiving any other concurrent investigational agents during study treatment and not for at least within one week prior to starting study treatment. 3. Since the teratogenic potential of this combination is currently unknown, females who are pregnant or lactating are excluded. 4. History of any other malignancies within the preceding 12 months before registration with the exception of in-situ cancer, non-muscle invasive bladder cancer, non-metastatic prostate cancer, basal or squamous cell skin cancer. 5. 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. 6. Evidence of isolated extramedullary disease. 7. Acute Promyelocytic Leukemia. 8. AML with active central nervous system (CNS) involvement (as determined by study investigator). 9. Severe infection requiring treatment that would interfere with study drug(s) or study participation in the opinion of the treating investigator. 10. Past Hematopoietic stem cell transplant (HSCT) with graft vs host disease, immunosuppression other than low dose prednisone (10 mg) (or equivalent does of another immunosuppressant) within the 4 weeks before registration. 11. All adverse reactions from prior therapy must have recovered to Grade ≤ 1 or acceptable baseline per treating investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients with Dose Limiting Toxicities as defined in Protocol Section 13.5 | At the end of the the first cycle of administration (each cycle is 28 days) | Dose Limiting Toxicities within the first cycle of CNL monotherapy. See section 13.5 of Protocol for the complete list of Dose Limiting Toxicities |
| Number of Patients with Adverse Events | Through study completion, an average of 24 weeks | Number of Patients with Adverse Events |
| Severity of Adverse Events | Through study completion, an average of 24 weeks | Severity of Adverse Event As Described in Protocol |
| Duration of Adverse Events | Length of Adverse Events as measured in days, measured through study completion, an average of 24 weeks | Duration of Adverse Events, As Described in Protocol, measured in days |
| Duration of therapy | Through study completion, an average of 24 weeks | Duration of therapy provided as measured in days |
| Dose Levels achieved during study | Through study completion, an average of 24 weeks | Dose levels administered in milligrams per m2 |
| Concentration Max (C Max) | Through cycle one, 28 days (each cycle is 28 days) | Maximum Serum Concentration measured, in nanograms/milliliter |
| Time to Maximum Study Drug (T Max) | Through cycle one, 28 days (each cycle is 28 days) | Time to maximum concentration measured, in minutes |
| Half Life of Study Drug | Through cycle one, 28 days (each cycle is 28 days) | Time for drug to be reduced to half of the starting concentration (in minutes) |
| Study Drug Clearance | Through cycle one, 28 days (each cycle is 28 days) | The Amount of Study Drug Cleared per unit time (Nanograms/Minute) |
| Ratio of C16/C24 Ceramides | After one cycle of therapy (Day 28) | Ratio of Ceramide 16 to Ceramide 24 (ng of C16/ng of C18) from bone marrow biopsy |
| Clinical Response - Complete Response | After Cycle Two (56 days) | Complete Response |
| Clinical Response - Complete Response with Incomplete Hematologic Recovery (CRi) | After Cycle Two (56 days) | Complete Response with Incomplete Hematological Recovery as defined by blasts in bone marrow |
| Clinical Response - Partial Remission | After Cycle Two (56 days) | Partial Remission (as defined by blasts in bone marrow) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients with Grade 3 or 4 Adverse Events | Through study completion, an average of 24 weeks | Grade 3 and 4 adverse events as defined by CTCAE v5.0 |
| Overall Response | Through study completion, an average of 24 weeks, and up to 24 weeks afterwards (total of 48 weeks) | 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 |
| Event Free Survival | From registration to 24 weeks after completion of experimental drug treatment | 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 |
| Overall Survival | From registration to 24 weeks following drug administration | Overall survival (OS) |
| Quality of Life according to EORTC Quality of Life Questionnaire (QLQ) 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 | Quality of life according to EORTC Quality of Life Questionnaire C30 |
Countries
United States
Contacts
CONTACTJames H Adair, Ph.D.
CONTACTBernadette M Adair, BS
STUDY_DIRECTORDaniel Vlock, MD
Keystone Nano, Inc
STUDY_CHAIRChristopher Prior, Ph.D.
Keystone Nano
Outcome results
None listed