8-Chloroadenosine in Combination With Venetoclax for the Treatment of Patients With Relapsed/Refractory Acute Myeloid Leukemia

Sponsor
City of Hope Medical Center (Other)
Overall Status
Recruiting
CT.gov ID
NCT05263284
Collaborator
National Cancer Institute (NCI) (NIH)
30
1
1
14
2.1

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.

Detailed Description

PRIMARY OBJECTIVES:
  1. 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.

  2. Establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of 8-Cl-Ado when given in combination with venetoclax.

SECONDARY OBJECTIVES:
  1. 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).

  2. Obtain preliminary estimates of duration of remission (DOR), overall survival (OS), and event-free survival (EFS).

  3. Determine the pharmacokinetics (PK) of plasma 8-Cl-Ado and metabolites when 8-Cl-Ado is given in combination with venetoclax.

EXPLORATORY OBJECTIVES:
  1. Evaluate PK and pharmacodynamics (PD) of VEN/8-Cl-Ado combination therapy to identify biomarkers of clinical response and resistance.

  2. 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

Study Type:
Interventional
Anticipated Enrollment :
30 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1 Trial of 8-Chloro-Adenosine in Combination With Venetoclax in Patients With Relapsed/Refractory Acute Myeloid Leukemia
Actual Study Start Date :
Jul 25, 2022
Anticipated Primary Completion Date :
Sep 24, 2023
Anticipated Study Completion Date :
Sep 24, 2023

Arms and Interventions

Arm Intervention/Treatment
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:
  • 8-Chloro-adenosine
  • 8-Cl-adenosine
  • 8-Cl-Ado
  • Drug: Venetoclax
    Given PO
    Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto
  • Outcome Measures

    Primary Outcome Measures

    1. 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.

    2. 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

    1. 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.

    2. 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.

    3. 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.

    4. 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

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts 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).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    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.
    Responsible Party:
    City of Hope Medical Center
    ClinicalTrials.gov Identifier:
    NCT05263284
    Other Study ID Numbers:
    • 21380
    • NCI-2022-00234
    • 21380
    • P30CA033572
    First Posted:
    Mar 2, 2022
    Last Update Posted:
    Aug 17, 2022
    Last Verified:
    Aug 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Aug 17, 2022