8-Chloroadenosine in Combination With Venetoclax for the Treatment of Patients With Relapsed/Refractory Acute Myeloid Leukemia
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1 |
Detailed Description
PRIMARY OBJECTIVES:
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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.
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Establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of 8-Cl-Ado when given in combination with venetoclax.
SECONDARY OBJECTIVES:
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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).
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Obtain preliminary estimates of duration of remission (DOR), overall survival (OS), and event-free survival (EFS).
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Determine the pharmacokinetics (PK) of plasma 8-Cl-Ado and metabolites when 8-Cl-Ado is given in combination with venetoclax.
EXPLORATORY OBJECTIVES:
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Evaluate PK and pharmacodynamics (PD) of VEN/8-Cl-Ado combination therapy to identify biomarkers of clinical response and resistance.
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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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Treatment (8-chloroadenosine, venetoclax) Patients receive 8-Cl-Ado IV over 4 hours daily on days 1-5 and venetoclax PO QD on days 1-28. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. |
Drug: 8-Chloroadenosine
Given IV
Other Names:
Drug: Venetoclax
Given PO
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Documented informed consent of the participant and/or legally authorized representative.
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Age: >= 18 years.
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Eastern Cooperative Oncology Group (ECOG) =< 2.
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Life expectancy > 3 months.
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Patients with histologically confirmed acute myeloid leukemia (AML), according to World Health Organization (WHO) criteria, with relapsed/refractory disease.
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Patients must have any one of the following treatment history criteria:
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Relapsed AML
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Failed at least 1 line of salvage therapy or
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Untreated relapse and are not candidates for allogeneic hematopoietic stem cell transplantation (alloHCT)
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De novo AML
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have not achieved complete response (CR) after 2 lines of therapy or
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refractory to frontline therapy and not eligible for alloHCT
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AML evolving from myelodysplastic syndrome (MDS) or myeloproliferative disorder who have failed hypomethylating agents (HMA) or induction chemotherapy
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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).
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Male subjects must agree to not donate sperm while taking protocol therapy through at least 90 days after the last dose.
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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.
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Total bilirubin =< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease).
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Aspartate aminotransferase (AST) =< 2.5 x ULN.
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Alanine aminotransferase (ALT) =< 2.5 x ULN.
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Creatinine clearance of >= 50 mL/min per 24 hour urine test or the Cockcroft-Gault formula.
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QTc =< 480 ms.
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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.
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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.
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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:
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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:
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Hydroxyurea which may be continued through cycle 1.
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Expected to undergo HCT within 120 days of enrollment.
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Current or planned use of agents that prolong or suspected to prolong QTc.
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Received strong or moderate CYP3A inducers or St. John's Wort within 7 days prior to day 1 of protocol therapy.
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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.
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P-glycoprotein (P-gp) inhibitors within 7 days prior to day 1 of protocol therapy.
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Narrow therapeutic index P-gp substrates within 7 days prior to day 1 of protocol therapy.
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Acute promyelocytic leukemia.
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Active central nervous system (CNS) leukemia.
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Active fungal infection or bacterial sepsis.
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Class III/IV cardiovascular disability according to the New York Heart Association classification.
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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.
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History of acute cardiovascular ischemic event, i.e., myocardial infarction or unstable angina within 6 months of enrollment.
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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%).
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Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy).
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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).
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Active peptic ulcer disease.
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Other active malignancy except for localized skin cancer, bladder, prostate, breast or cervical carcinoma in situ.
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Females only: Pregnant or breastfeeding.
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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.
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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).
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | City of Hope Medical Center | Duarte | California | United States | 91010 |
Sponsors and Collaborators
- City of Hope Medical Center
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Vinod Pullarkat, City of Hope Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 21380
- NCI-2022-00234
- 21380
- P30CA033572