Leukemia, Myeloid, Acute
Conditions
Brief summary
This is a multi-center, open-label, dose escalation study that will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of liposomal annamycin as a single agent for the treatment of subjects with AML that is refractory to or relapsed after standard induction therapy
Interventions
2-hour intravenous infusion liposomal annamycin daily for 3 consecutive days followed by 18 days off study drug (i.e., one treatment cycle = 21 days).
Sponsors
Moleculin Biotech, Inc.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. A pathologically confirmed diagnosis of AML by World Health Organization (WHO) classification. 2. AML that is refractory to or relapsed after standard induction therapy. 3. Age ≥18 years at the time of signing informed consent. 4. No chemotherapy, radiation, or major surgery within two weeks prior to first dose of study drug and/or recovered from the toxic side effects of that therapy, unless treatment is indicated due to progressive disease. 5. No investigational therapy within four weeks of the first dose of study drug. 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. 7. Adequate laboratory results including the following: 1. Bilirubin ≤1.5 times the upper limit of normal (ULN) unless due to Gilbert Syndrome 2. Serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT) and alkaline phosphatase \<3 times the ULN) unless due to organ involvement 3. Adequate renal function (The Cockcroft-Gault equation will be used to estimate creatinine clearance. This equation is as follows: Creatinine clearance in ml/min = (140 - age) x body weight (kg)/72 x plasma creatinine (mg/dL); multiplied by 0.85 for women. Using this equation, adequate renal function will be deemed to be a creatinine clearance of greater than 60 ml/minute.) 8. Prior anthracycline cumulative dose below 551 mg/m2 or the daunorubicin equivalent which is the recommended non-cardiotoxic level. 9. Subject can understand and sign the informed consent document, can communicate with the investigator, and can understand and comply with the requirements of the protocol. 10. Women of childbearing potential must have a negative serum or urine pregnancy test. 11. All men and women must agree to practice effective contraception during the entire study period and after discontinuing study drug, unless documentation of infertility exists. 1. Sexually active, fertile women must use two effective forms of contraception (abstinence, intrauterine device, oral contraceptive, or double barrier device) from the time of informed consent and until at least 6 months after discontinuing study drug 2. Sexually active men and their sexual partners must use effective contraceptive methods from the time of subject informed consent and until at least 3 months after discontinuing study drug
Exclusion criteria
1. Subjects diagnosed with Acute Promyelocytic Leukemia. 2. Concomitant therapy that includes other chemotherapy that is or may be active against AML except for prophylaxis and/or treatment of opportunistic or other infection with antibiotics, antifungals and/or antiviral agents. 3. Prior mediastinal radiotherapy 4. Any condition which, in the opinion of the Investigator, places the subject at unacceptable risk if he/she were to participate in the study. 5. Positive risk assessment for cardiovascular disease including prior anthracycline cumulative dose more than 50% above recommended non-cardiotoxic levels, left ventricular ejection fraction (LVEF) \<50%, valvular heart disease, or severe hypertension, (see Table 1). Cardiac subjects with a New York Heart Association (NYHA) classification of 3 or 4 will be excluded. (Cardiology consultation should be requested if any question arises about cardiac function.) This also includes subjects with baseline QT/QTc interval \>480 msec, a history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) and using concomitant medications that significantly prolong the QT/QTc interval. 6. Clinically relevant serious co-morbid medical conditions including, but not limited to, active infection, recent (less than or equal to six months) myocardial infarction, unstable angina, symptomatic congestive heart failure, uncontrolled hypertension, uncontrolled cardiac arrhythmias, chronic obstructive or chronic restrictive pulmonary disease, active CNS disease uncontrolled by standard of care, known positive status for human immunodeficiency virus (HIV) and/or active hepatitis B or C, cirrhosis, or psychiatric illness/social situations that would limit compliance with study requirements. 7. Pregnant, lactating, or not using adequate contraception. 8. Known allergy to anthracyclines. 9. Any evidence of mucositis/stomatitis or previous history of severe (≥Grade 3) mucositis from prior therapy. 10. Required use of strong inhibitors and inducers of CYP enzymes and transporters.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting Toxicity | Day 28 | Number of patients with a dose-limiting toxicity (DLT) at each dose evaluated |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics - Area Under the Plasma Concentration | Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after the start of liposomal annamycin infusion on Day 1 and Day 3 | Area under the plasma concentration - time curve (AUC) of annamycin and its metabolite, annamycinol |
| Number of Participants With Anti-leukemic Activity | 15-35 Days after the start of therapy | Determined by acute myeloid leukemia (AML) response rate based on the International Working Group (IWG) Response Criteria in AML (Cheson, 2003). Anti-leukemic Activity measured by bone marrow biopsy/aspirate pre and post treatment. |
Countries
United States
Participant flow
Pre-assignment details
no participants were enrolled in Phase 2
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1: 100 mg/m2/Day Liposomal Annamycin Liposomal Annamycin: 2-hour intravenous infusion liposomal annamycin daily for 3 consecutive days followed by 18 days off study drug (i.e., one treatment cycle = 21 days). | 4 |
| Dose Level 2: 120 mg/m2/Day Liposomal Annamycin Liposomal Annamycin: 2-hour intravenous infusion liposomal annamycin daily for 3 consecutive days followed by 18 days off study drug (i.e., one treatment cycle = 21 days). | 3 |
| Total | 7 |
Baseline characteristics
| Characteristic | Dose Level 1: 100 mg/m2/Day Liposomal Annamycin | Dose Level 2: 120 mg/m2/Day Liposomal Annamycin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 2 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Continuous | 67.0 years STANDARD_DEVIATION 6.73 | 57.0 years STANDARD_DEVIATION 18.19 | 62.7 years STANDARD_DEVIATION 12.71 |
| ECOG Performance Status ECOG - 0 | 0 Participants | 1 Participants | 1 Participants |
| ECOG Performance Status ECOG - 1 | 3 Participants | 1 Participants | 4 Participants |
| ECOG Performance Status ECOG- 2 | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 2 Participants | 6 Participants |
| Region of Enrollment United States | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 |
| other Total, other adverse events | 4 / 4 | 3 / 3 |
| serious Total, serious adverse events | 2 / 4 | 0 / 3 |
Outcome results
Primary
Dose-limiting Toxicity
Number of patients with a dose-limiting toxicity (DLT) at each dose evaluated
Time frame: Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1: 100 mg/m2/Day Liposomal Annamycin | Dose-limiting Toxicity | 0 Participants |
| Dose Level 2 : 120 mg/m2/Day Liposomal Annamycin | Dose-limiting Toxicity | 0 Participants |
Secondary
Number of Participants With Anti-leukemic Activity
Determined by acute myeloid leukemia (AML) response rate based on the International Working Group (IWG) Response Criteria in AML (Cheson, 2003). Anti-leukemic Activity measured by bone marrow biopsy/aspirate pre and post treatment.
Time frame: 15-35 Days after the start of therapy
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1: 100 mg/m2/Day Liposomal Annamycin | Number of Participants With Anti-leukemic Activity | Morphological Leukemia Free State (MLFS) | 0 Participants |
| Dose Level 1: 100 mg/m2/Day Liposomal Annamycin | Number of Participants With Anti-leukemic Activity | Treatment Failure (TF) | 4 Participants |
| Dose Level 2 : 120 mg/m2/Day Liposomal Annamycin | Number of Participants With Anti-leukemic Activity | Morphological Leukemia Free State (MLFS) | 1 Participants |
| Dose Level 2 : 120 mg/m2/Day Liposomal Annamycin | Number of Participants With Anti-leukemic Activity | Treatment Failure (TF) | 2 Participants |
Secondary
Pharmacokinetics - Area Under the Plasma Concentration
Area under the plasma concentration - time curve (AUC) of annamycin and its metabolite, annamycinol
Time frame: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after the start of liposomal annamycin infusion on Day 1 and Day 3
Population: One participant excluded from summary statistics due to high Annamycin concentrations
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Level 1: 100 mg/m2/Day Liposomal Annamycin | Pharmacokinetics - Area Under the Plasma Concentration | Annamycin 100 mg/m2 - Day 1 | 1430 hr*ng/ml | Geometric Coefficient of Variation 19.6 |
| Dose Level 1: 100 mg/m2/Day Liposomal Annamycin | Pharmacokinetics - Area Under the Plasma Concentration | Annamycin 100 mg/m2 - Day 3 | 1610 hr*ng/ml | Geometric Coefficient of Variation 22.4 |
| Dose Level 1: 100 mg/m2/Day Liposomal Annamycin | Pharmacokinetics - Area Under the Plasma Concentration | Annamycin 120 mg/m2 - Day 1 | 2330 hr*ng/ml | Geometric Coefficient of Variation 42 |
| Dose Level 1: 100 mg/m2/Day Liposomal Annamycin | Pharmacokinetics - Area Under the Plasma Concentration | Annamycin 120 mg/m2 - Day 3 | 2880 hr*ng/ml | Geometric Coefficient of Variation 33.3 |
| Dose Level 1: 100 mg/m2/Day Liposomal Annamycin | Pharmacokinetics - Area Under the Plasma Concentration | Annamycinol 100 mg/m2 - Day 1 | 1400 hr*ng/ml | Geometric Coefficient of Variation 43.9 |
| Dose Level 1: 100 mg/m2/Day Liposomal Annamycin | Pharmacokinetics - Area Under the Plasma Concentration | Annamycinol 100 mg/m2 - Day 3 | 1520 hr*ng/ml | Geometric Coefficient of Variation 36.7 |
| Dose Level 1: 100 mg/m2/Day Liposomal Annamycin | Pharmacokinetics - Area Under the Plasma Concentration | Annamycinol 120 mg/m2 - Day 1 | 1370 hr*ng/ml | Geometric Coefficient of Variation 39.5 |
| Dose Level 1: 100 mg/m2/Day Liposomal Annamycin | Pharmacokinetics - Area Under the Plasma Concentration | Annamycinol 120 mg/m2 - Day 3 | 1610 hr*ng/ml | Geometric Coefficient of Variation 67.7 |