8-Chloroadenosine in Combination With Venetoclax for the Treatment of Patients With Relapsed/Refractory Acute Myeloid Leukemia
Status and phase
Conditions
Treatments
Study type
Funder types
Identifiers
Details and patient eligibility
About
This phase I trial tests the safety, side effects, and best dose of a new 8-chloroadenosine in combination with venetoclax in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). 8-Chloroadenosine may help block the formation of growths that may become cancer. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving 8-chloroadenosine in combination with venetoclax may help prevent the disease from coming back in patients with acute myeloid leukemia.
Full description
PRIMARY OBJECTIVES:
I. Evaluate the safety and tolerability of a regimen combining 8-chloro-adenosine (8-Cl-Ado) and venetoclax in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML), including type, frequency, severity, attribution, and duration of the toxicity.
II. Establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of 8-Cl-Ado when given in combination with venetoclax.
SECONDARY OBJECTIVES:
I. Obtain preliminary estimates of the anti-leukemia activity of the 8-Cl-Ado/venetoclax regimen by assessing the overall response rate (Complete remission[CR]+ complete remission with incomplete hematologic recovery [CRi]+ partial response [PR]) and complete remission rate (CR+CRi).
II. Obtain preliminary estimates of duration of remission (DOR), overall survival (OS), and event-free survival (EFS).
III. Determine the pharmacokinetics (PK) of plasma 8-Cl-Ado and metabolites when 8-Cl-Ado is given in combination with venetoclax.
EXPLORATORY OBJECTIVES:
I. Evaluate PK and pharmacodynamics (PD) of VEN/8-Cl-Ado combination therapy to identify biomarkers of clinical response and resistance.
II. Identify genes and pathways associated with response to VEN/8-Cl-Ado. III. Determine the metabolic consequences of VEN/8 Cl-Ado treatment on leukemia stem cells (LSCs).
OUTLINE:
Patients receive 8-Cl-Ado intravenously (IV) over 4 hours daily on days 1-5 and venetoclax orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 28 days for up to 1 year.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
-
Documented informed consent of the participant and/or legally authorized representative.
-
Age: >= 18 years.
-
Eastern Cooperative Oncology Group (ECOG) =< 2.
-
Life expectancy > 3 months.
-
Patients with histologically confirmed acute myeloid leukemia (AML), according to World Health Organization (WHO) criteria, with relapsed/refractory disease.
-
Patients must have any one of the following treatment history criteria:
-
Relapsed AML
- Failed at least 1 line of salvage therapy or
- Untreated relapse and are not candidates for allogeneic hematopoietic stem cell transplantation (alloHCT)
-
De novo AML
- have not achieved complete response (CR) after 2 lines of therapy or
- refractory to frontline therapy and not eligible for alloHCT
-
AML evolving from myelodysplastic syndrome (MDS) or myeloproliferative disorder who have failed hypomethylating agents (HMA) or induction chemotherapy
-
Patients who have relapsed after allo-HCT are eligible if they are at least 3 months after HCT, do not have active graft versus host disease (GVHD) and are off immunosuppression except for maintenance dose of steroids (prednisone 10 mg/day or less).
-
-
Male subjects must agree to not donate sperm while taking protocol therapy through at least 90 days after the last dose.
-
White blood cell (WBC) =< 25 x 10^9/L prior to initiation of venetoclax. Cytoreduction with hydroxyurea prior to treatment and/or during cycle 1 may be required.
-
Total bilirubin =< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease).
-
Aspartate aminotransferase (AST) =< 2.5 x ULN.
-
Alanine aminotransferase (ALT) =< 2.5 x ULN.
-
Creatinine clearance of >= 50 mL/min per 24 hour urine test or the Cockcroft-Gault formula.
-
QTc =< 480 ms.
-
Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
-
Agreement by females and males of childbearing potential* to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months (females) and 3 months (males) after the last dose of protocol therapy.
- Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only).
Exclusion criteria
-
Current or planned use of other investigational agents, antineoplastic, biological, chemotherapy, or radiation therapy during the study treatment period, or within 2 weeks prior to day 1 of protocol therapy, with the following exception:
- Hydroxyurea which may be continued through cycle 1.
-
Expected to undergo HCT within 120 days of enrollment.
-
Current or planned use of agents that prolong or suspected to prolong QTc.
-
Received strong or moderate CYP3A inducers or St. John's Wort within 7 days prior to day 1 of protocol therapy.
-
Received strong or moderate CYP3A inhibitors, or consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to day 1 of protocol therapy.
-
P-glycoprotein (P-gp) inhibitors within 7 days prior to day 1 of protocol therapy.
-
Narrow therapeutic index P-gp substrates within 7 days prior to day 1 of protocol therapy.
-
Acute promyelocytic leukemia.
-
Active central nervous system (CNS) leukemia.
-
Active fungal infection or bacterial sepsis.
-
Class III/IV cardiovascular disability according to the New York Heart Association classification.
-
Participants with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of enrollment. Subjects with controlled, asymptomatic atrial fibrillation can enroll.
-
History of acute cardiovascular ischemic event, i.e., myocardial infarction or unstable angina within 6 months of enrollment.
-
History of unexplained syncope, significant histories of CAD (requiring revascularization by percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]), cardiomyopathy (ejection fraction [EF] < 50%).
-
Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy).
-
Unable to swallow capsules, has a partial or small bowel obstruction, or has a gastrointestinal condition resulting in a malabsorptive syndrome (e.g. small bowel resection with malabsorption).
-
Active peptic ulcer disease.
-
Other active malignancy except for localized skin cancer, bladder, prostate, breast or cervical carcinoma in situ.
-
Females only: Pregnant or breastfeeding.
-
Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures.
-
Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).
Trial design
Primary purpose
Allocation
Interventional model
Masking
30 participants in 1 patient group
Trial contacts and locations
Loading...
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal