Clinical trial NCT04716452: Study of C6 Ceramide NanoLiposome (CNL) in Patients With Relapsed/Refractory Acute Myeloid Leukemia
Official title: Phase I Study of C6 Ceramide NanoLiposome (CNL) in Patients With Relapsed/Refractory Acute Myeloid Leukemia (RR-AML)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Acute Myeloid Leukemia, in Relapse
Acute Myeloid Leukemia, Refractory
Refractory/Relapse Acute Myeloid Leukemia
Keywords: Acute Myeloid Leukemia
Relapsed
Refractory
Ceramide
AML
NanoLiposome
Relapsed/Refratory Acute Myleoid Leukemia
NanoLiposomes
Safety
Lead sponsor: Keystone Nano, Inc
Sponsor class: INDUSTRY
Collaborators: name: University of Virginia
name: Milton S. Hershey Medical Center
name: National Cancer Institute (NCI)
First posted: 2021-01-20
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single group assignment
Primary purpose: TREATMENT

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

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 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.

Eligibility criteria: 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) 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).
4. Eastern Cooperative Oncology Group (ECOG) performance status must be ≤2
5. 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.
6. 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
7. 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:

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, or have received any investigational agent within one week of registration.
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, prostate, 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 or AML with active central nervous system (CNS) involvement
8. Untreated severe (in the opinion of the treating investigator) infection
9. Active and uncontrolled infection with HIV (viral load is detectable by PCR)
10. Active infection with Hepatitis B virus (HbSAg positive or PCR with detectable viral load) or Hepatitis C virus (viral load detectable by PCR).
11. 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

Primary outcomes:
measure: Number of Patients with Dose Limiting Toxicities as defined in Protocol Section 13.5
timeFrame: At the end of the the first cycle of administration (each cycle is 28 days)
measure: Number of Patients with Adverse Events
timeFrame: Through study completion, an average of 24 weeks
measure: Severity of Adverse Events
timeFrame: Through study completion, an average of 24 weeks
measure: Duration of Adverse Events
timeFrame: Length of Adverse Events as measured in days, measured through study completion, an average of 24 weeks
measure: Duration of therapy
timeFrame: Through study completion, an average of 24 weeks
measure: Dose Levels achieved during study
timeFrame: Through study completion, an average of 24 weeks
measure: Concentration Max (C Max)
timeFrame: Through cycle one, 28 days (each cycle is 28 days)
measure: Time to Maximum Study Drug (T Max)
timeFrame: Through cycle one, 28 days (each cycle is 28 days)
measure: Half Life of Study Drug
timeFrame: Through cycle one, 28 days (each cycle is 28 days)
measure: Study Drug Clearance
timeFrame: Through cycle one, 28 days (each cycle is 28 days)
measure: Ratio of C16/C24 Ceramides
timeFrame: After one cycle of therapy (Day 28)
measure: Clinical Response - Complete Response
timeFrame: After Cycle Two (56 days)
measure: Clinical Response - Complete Response with Incomplete Hematologic Recovery (CRi)
timeFrame: After Cycle Two (56 days)
measure: Clinical Response - Partial Remission
timeFrame: After Cycle Two (56 days)
Secondary outcomes:
measure: Number of Patients with Grade 3 or 4 Adverse Events
timeFrame: Through study completion, an average of 24 weeks
measure: Overall Response
timeFrame: Through study completion, an average of 24 weeks, and up to 24 weeks afterwards (total of 48 weeks)
measure: Event Free Survival
timeFrame: From registration to 24 weeks after completion of experimental drug treatment
measure: Overall Survival
timeFrame: From registration to 24 weeks following drug administration
measure: Quality of Life according to EORTC Quality of Life Questionnaire (QLQ) C30
timeFrame: 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
Other outcomes:
Locations:
city: Hershey
country: United States
facility: Penn State University Hershey Medical Center
state: Pennsylvania
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
Study officials:
affiliation: Keystone Nano, Inc
name: Daniel Vlock, MD
role: STUDY_DIRECTOR
affiliation: Keystone Nano
name: Christopher Prior, Ph.D.
role: STUDY_CHAIR
References:
citation: Barth BM, Wang W, Toran PT, Fox TE, Annageldiyev C, Ondrasik RM, Keasey NR, Brown TJ, Devine VG, Sullivan EC, Cote AL, Papakotsi V, Tan SF, Shanmugavelandy SS, Deering TG, Needle DB, Stern ST, Zhu J, Liao J, Viny AD, Feith DJ, Levine RL, Wang HG, Loughran TP Jr, Sharma A, Kester M, Claxton DF. Sphingolipid metabolism determines the therapeutic efficacy of nanoliposomal ceramide in acute myeloid leukemia. Blood Adv. 2019 Sep 10;3(17):2598-2603. doi: 10.1182/bloodadvances.2018021295.
citation: Morad SAF, MacDougall MR, Abdelmageed N, Kao LP, Feith DJ, Tan SF, Kester M, Loughran TP Jr, Wang HG, Cabot MC. Pivotal role of mitophagy in response of acute myelogenous leukemia to a ceramide-tamoxifen-containing drug regimen. Exp Cell Res. 2019 Aug 15;381(2):256-264. doi: 10.1016/j.yexcr.2019.05.021. Epub 2019 May 18.
citation: Kester M, Bassler J, Fox TE, Carter CJ, Davidson JA, Parette MR. Preclinical development of a C6-ceramide NanoLiposome, a novel sphingolipid therapeutic. Biol Chem. 2015 Jun;396(6-7):737-47. doi: 10.1515/hsz-2015-0129.