Acute Myeloid Leukemia, Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia
Conditions
Brief summary
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.
Detailed 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.
Interventions
Given IV
DRUGVenetoclax
Given PO
Sponsors
City of Hope Medical Center
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events (AEs) | Up to 1 year | Toxicities will be graded using the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events version 5.0. |
| Dose limiting toxicity (DLT) | Up to 1 cycle (Each cycle is 28 days) | Toxicities will be graded using the NCI-Common Terminology Criteria for Adverse Events version 5.0. DLT will be assessed after cycle one. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to response | Up to 1 year | Defined by European LeukemiaNet (ELN) criteria 2017 in response-evaluable participants that achieve a best response of either complete remission (CR), complete remission with incomplete hematologic recovery (CRi), or partial response (PR) at the end of study therapy. Will be estimated using the product-limit method of Kaplan and Meier. |
| Duration of response (DOR) | From the first achievement of PR, CR, or CRi to time of disease progression, assessed up to 1 year | Patients will be considered evaluable for response if they are eligible, have baseline disease assessments, and receive 2 cycles of protocol treatment, or achieve a CR/CRi after 1 cycle of protocol treatment, or progressed. Patients will have their response classified according to the European Leukemia Network (ELN) 2017 criteria. Will be estimated using the product-limit method of Kaplan and Meier. |
| Overall survival (OS) | From start of protocol treatment to time of death due to any cause, or until last follow-up, assessed up to 1 year | Patients will be considered evaluable for response if they are eligible, have baseline disease assessments, and receive 2 cycles of protocol treatment, or achieve a CR/CRi after 1 cycle of protocol treatment, or progressed. Patients will have their response classified according to the European Leukemia Network (ELN) 2017 criteria. Will be estimated using the product-limit method of Kaplan and Meier. |
| Event-free survival (EFS) | From start of protocol treatment to time of disease relapse/progression or death due to any cause, whichever occurs earlier; or until last follow-up, assessed up to 1 year | Patients will be considered evaluable for response if they are eligible, have baseline disease assessments, and receive 2 cycles of protocol treatment, or achieve a CR/CRi after 1 cycle of protocol treatment, or progressed. Patients will have their response classified according to the European Leukemia Network (ELN) 2017 criteria. Will be estimated using the product-limit method of Kaplan and Meier. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORVinod Pullarkat
City of Hope Medical Center
Outcome results
None listed