8-chloroadenosine in combination with venetoclax for the treatment of patients with relapsed/refractory acute myeloid leukemia

Conditions: Acute Myeloid Leukemia; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

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.

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.

Eligibility criteria:
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).