Details
Title A Phase I/II Study of SEL24 in Patients with Acute Myeloid Leukemia; CLI24-001.
IRB MNGP1917
CC 17-1155
Hospital Main Campus
Stage N/A
Phase Phase 1, Phase 2
Disease Leukemia - Acute Myeloid (AML)
Drug SEL24
Description
This is a Phase I/II, open-label, multi-center, dose escalation study to estimate the MTD (or MAD) of SEL24 in patients with AML. At the end of PArt 1 an RD of SEL24 will be selected to further evaluation in Part 2. In Part 2 the safety and anti-leukemic activity of SEL24 will be further assessed in patients who are unfit to receive intensive chemotherapy.
Objectives:
Part 1
Primary:
- To estimate the MTD or MAD and determine the RD of SEL24 for Part 2
Secondary:
- To assess the safety and tolerability of SEL24
- To assess anti-leukemic activity of SEL24
- To evalute the PK profile of SEL24 and its metabolites as appropriate
Exploratory:
- To assess the PD activity of SEL24
Part 2
Primary:
- To further characterize the safety profile of single agent SEL24
Secondary:
- To assess anti-leukemic activity of single agent SEL24
- To evaluate the PK profile of SEL24 and its metabolites, as appropriate
Exploratory:
- To assess the PD activity of SEL24
Inclusion Criteria
1. Patient with diagnosis of AML (i.e. ≥20% blasts in bone marrow or peripheral blood) harboring IDH1 or IDH2 mutation (as per local assessment).
2. Provide written informed consent prior to Screening.
3. Male or female patients, age ≥18 years old.
4. Patient has no standard therapeutic options available (including IDH inhibitors where approved) and has:
a) Relapsed AML unsuitable for intensive chemotherapy;
b) Primary refractory AML unsuitable for intensive chemotherapy;
Clarification note: Patients naïve to IDH inhibitors are eligible ONLY if no IDH inhibitors are approved/available in the country/site where they are enrolled.
5. ECOG Performance Status 0, 1 or 2.
6. Adequate organ function at Screening, including:
e) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5X the upper limit of normal (ULN);
f) Total bilirubin ≤2X ULN;
g) Creatinine clearance ≥40 mL/min (Cockcroft-Gault formula) (see Appendix B);
h) Left ventricular ejection fracture (LVEF) ≥40% as per local assessment practice.
7. A female of childbearing potential, defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or is not postmenopausal (i.e. has serum follicle stimulating hormone level ≥30 IU/L in the absence of hormone replacement therapy, or complete absence of menses for at least 12 consecutive months which is not due to medication), must have a negative pregnancy test within 7 days prior to receiving study drug.
8. Sexually active male or female patients of childbearing potentialare eligible providing that:
Female:
- Agrees to use an effective method of birth control as applicable per local law that both results in a Pearl index < 1 and is considered highly effective as defined by the Clinical Trial Facilitation Group (e.g. combined estrogen and progestogen containing hormonal contraception, progestogen-only hormonal contraception, intrauterine device, intrauterine hormone-releasing system, vasectomized partner, total sexual abstinence or bilateral tubal occlusion)*.
- Undergoes a pregnancy test at Day 1 of each treatment cycle and after the end of relevant systemic exposure (30 days from the last study drug administration).
Male:
- Agrees to use an effective contraceptive method (condom) during treatment and until the end of relevant systemic exposure. Females of childbearing potential that are partners of male study participants have to observe the same birth control indications that apply to female participants.
Exclusion Criteria
- Received anti-cancer treatments (including cytotoxic chemotherapy, radiotherapy, hormonal therapy, biologic, immunotherapy or investigational drugs) within 14 days or 5 half-lives for targeted therapies (whichever is shorter) before first dose of study drug.
- Prior treatment with PIM inhibitor.
- Hyperleukocytosis (leukocytes > 30 x109/L) immediately prior to the first dose of study drug and/or clinical concerns of leukostasis. Note: Patients may undergo leukapheresis according to routine practice before the first dose of study drug; where hydroxyurea is used prior to receiving study drug, it may be continued up to Cycle 1, Day 21, although Investigators are asked to stop treatment prior to the first dose of study drug or before Day 7, wherever possible.
- Clinically significant active central nervous system (CNS) leukemia. Note: Previously treated and controlled CNS leukemia and ongoing standard CNS prophylaxis (e.g. with intrathecal cytarabine) is acceptable.
- Patients who have undergone major surgery within 1 month prior to first dose of study drug.
- Hematopoietic stem cell transplant within 4 months of first dose of study drug.
- Requires systemic immune-modulating therapy (regardless of dose) for the prophylaxis or treatment of GVHD.
- Evidence of ongoing and uncontrolled systemic bacterial, fungal, or viral infection, with the exception of patients with documented infections who are receiving therapy with evidence of improvement or without evidenec of worsening infection.
- Known positive serology for human immunodeficiency virus (HIV).
- Ongoing drug-induced liver injury, known chronic active hepatitis C (HCV) infection, known chronic active hepatitis B (HBV) infection, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction cause by cholelithiasis, cirrhosis or the liver, or portal hypertension.
- Ongoing drug-induced pneumonitis.
- Ongoing inflammatory bowel disease.
- Pregnancy or breastfeeding.
- Concurrent participation in another therapeutic clinical trial.
- Ongoing toxicity from any prior anti-cancer therapy that has not resolved to Grade 1 or less prior to the first dose of study drug.
- Received an agent known to be a sensitive CYP2D6 subtrate or a CYP2D6 substrate with a narrow therapeutic range, a strong or moderate CYP2D6 inhibitor, or a BCRP inhibitor within 7 days, or a period corresponding to 4-5 half-lives of the agent, prior to the first dose of study drug.
- Cardiac dysfunction defined as myocardial infarction within 6 months of study entry, NYHA Class III or IV heart failure, uncontrolled dyrhythmias or poorly controlled angina.
- Is receiving any active treatment for thrombosis.
- History or serious ventricular arrhythmia (e.g., VT or VF, ≥ 3 beats in a row), or QTc ≥ 480 ms. Note: QTc values up to 500 ms will be acceptable where patient's medical history e.g., bundle branch block, is known to cause mild QTc prolongation and the condition is well controlled.
- Any disease, syndrome or condition which may affect significantly drug intake via oral route.
- Any other prior or current medical condition, intercurrent illness, surgical history, physical or ECG findings, laboratory abnormalities, or extenuating circumstances (e.g., alcohol or drug addiction) that, in the investigator's opinion, could jeopardize patient safety or interfere with the objetives of the study.
