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

Acute Myeloid Leukemia, in Relapse Clinical Trial

— KNAN2001  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04716452
• Other study ID #: KNAN2001
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: June 1, 2024
• Est. completion date: December 1, 2024

Study information

• Verified date: October 2023
• Source: Keystone Nano, Inc
• Contact: James H Adair, Ph.D.
• Phone: 814-360-4654
• Email: jadair[@]pendreabio.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 18
• Est. completion date: December 1, 2024
• Est. primary completion date: September 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia, in Relapse
• Acute Myeloid Leukemia, Refractory
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Ceramide 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.

Locations

Country	Name	City	State
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Penn State University Hershey Medical Center	Hershey	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
Keystone Nano, Inc	Milton S. Hershey Medical Center, University of Virginia

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	Number of Patients with Adverse Events	Number of Patients with Adverse Events	Through study completion, an average of 24 weeks
Primary	Severity of Adverse Events	Severity of Adverse Event As Described in Protocol	Through study completion, an average of 24 weeks
Primary	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
Primary	Duration of therapy	Duration of therapy provided as measured in days	Through study completion, an average of 24 weeks
Primary	Dose Levels achieved during study	Dose levels administered in milligrams per m2	Through study completion, an average of 24 weeks
Primary	Concentration Max (C Max)	Maximum Serum Concentration measured, in nanograms/milliliter	Through cycle one, 28 days (each cycle is 28 days)
Primary	Time to Maximum Study Drug (T Max)	Time to maximum concentration measured, in minutes	Through cycle one, 28 days (each cycle is 28 days)
Primary	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)
Primary	Study Drug Clearance	The Amount of Study Drug Cleared per unit time (Nanograms/Minute)	Through cycle one, 28 days (each cycle is 28 days)
Primary	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)
Primary	Clinical Response - Complete Response	Complete Response	After Cycle Two (56 days)
Primary	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)
Primary	Clinical Response - Partial Remission	Partial Remission (as defined by blasts in bone marrow)	After Cycle Two (56 days)
Secondary	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
Secondary	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)
Secondary	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
Secondary	Overall Survival	Overall survival (OS)	From registration to 24 weeks following drug administration
Secondary	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