Clinical Trials /

Uproleselan, Azacitidine, and Venetoclax for the Treatment of Treatment Naive Acute Myeloid Leukemia

NCT04964505

Description:

This phase I trial evaluates the side effects of uproleselan, azacitidine, and venetoclax in treating older or unfit patients with treatment naive acute myeloid leukemia. Uproleselan may help block the formation of growths that may become cancer. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving uproleselan with azacitidine and venetoclax may help kill more cancer cells.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Uproleselan, Azacitidine, and Venetoclax for the Treatment of Treatment Naive Acute Myeloid Leukemia
  • Official Title: A Phase I Study of Uproleselan Combined With Azacitidine and Venetoclax for the Treatment of Older or Unfit Patients With Treatment Naive Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: UCDCC#294
  • SECONDARY ID: NCI-2021-06216
  • SECONDARY ID: UCDCC#294
  • SECONDARY ID: P30CA093373
  • NCT ID: NCT04964505

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, Onureg, U-18496, VidazaTreatment (uproleselan, azacitidine, venetoclax)
UproleselanGMI-1271Treatment (uproleselan, azacitidine, venetoclax)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoTreatment (uproleselan, azacitidine, venetoclax)

Purpose

This phase I trial evaluates the side effects of uproleselan, azacitidine, and venetoclax in treating older or unfit patients with treatment naive acute myeloid leukemia. Uproleselan may help block the formation of growths that may become cancer. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving uproleselan with azacitidine and venetoclax may help kill more cancer cells.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To assess the safety and tolerability of uproleselan combined with azacitidine and
      venetoclax in older or unfit patients with treatment naive acute myeloid leukemia (AML).

      SECONDARY OBJECTIVE:

      I. To evaluate the preliminary efficacy of uproleselan combined with azacitidine and
      venetoclax in older or unfit patients with treatment naive AML.

      OUTLINE:

      Patients receive uproleselan intravenously (IV) over 1 hour every 12 hours (Q12H) on days
      1-7, azacitidine IV or subcutaneously (SC) once daily (QD) on days 1-7, and venetoclax orally
      (PO) QD on days 1-28. Beginning cycle 5, patients achieving morphologic leukemia-free state
      (MLFS) or better response, may receive azacitidine IV or SC QD and uproleselan IV over 1 hour
      QD on days 1-6 and 8 or days 1-5 and 8-9 or days 1-5. Treatment with uproleselan repeats
      every 28 days for up to 6 cycles in the absence of disease progression or unacceptable
      toxicity. Cycles with azacitidine and venetoclax repeat every 28 days in the absence of
      disease progression and unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, and then every 3
      months for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (uproleselan, azacitidine, venetoclax)ExperimentalPatients receive uproleselan IV over 1 hour Q12H on days 1-7, azacitidine IV or SC QD on days 1-7, and venetoclax PO QD on days 1-28. Beginning cycle 5, patients achieving MLFS or better response, may receive azacitidine IV or SC QD and uproleselan IV over 1 hour QD on days 1-6 and 8 or days 1-5 and 8-9 or days 1-5. Treatment with uproleselan repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Cycles with azacitidine and venetoclax repeat every 28 days in the absence of disease progression and unacceptable toxicity.
  • Azacitidine
  • Uproleselan
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Ability to understand and the willingness to sign a written informed consent

          -  Diagnosis of AML by World Health Organization (WHO) 2016 criteria (Arber 2016)

          -  Age >= 18 years

          -  Treatment naive and eligible for venetoclax plus hypomethylating agents (HMA)

               -  Age >= 75 OR

               -  Age 18-74 with at least one of the following co-morbidities:

                    -  Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3

                    -  Cardiac history of congestive heart failure (CHF) requiring treatment or
                       left ventricular ejection fraction (LVEF) =< 50% or chronic stable angina

                    -  Carbon monoxide diffusing capability test (DLCO) =< 65% or forced expiratory
                       volume in 1 second (FEV1) =< 65%

                    -  Any other situation that the investigator judges to be incompatible with
                       intensive chemotherapy must be reviewed with the study chair before study
                       enrollment

          -  ECOG performance status of:

               -  0 to 2 for subjects >= 75 years of age OR

               -  0 to 3 for subjects 18-74 years of age

          -  White blood cell (WBC) =< 25,000/mm^3 at the start of study therapy (leukapheresis and
             hydroxyurea are allowed to meet this criteria). No other hematologic parameters

          -  Total bilirubin =< 1.5 x institution's upper limit of normal (ULN) unless related to
             AML or Gilbert's syndrome

          -  Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and
             alanine aminotransferase (ALT)/serum pyruvic glutamic transaminase (SPGT) =< 3 x
             institutional ULN unless related to AML

          -  Creatinine clearance >= 45 mL/min (calculated by the Cockcroft Gault formula or
             measured by 24-hour urine collection)

               -  Note, if >= 65 years of age, creatinine clearance or serum creatinine can be used
                  for determining eligibility with creatinine clearance >= 45 mL/min (calculated by
                  the Cockcroft Gault formula or measured by 24-hour urine collection) or serum
                  creatinine =< institution's ULN considered eligible

          -  Women of child-bearing potential and men with partners of child-bearing potential must
             agree to use adequate contraception (non-estrogen hormonal or barrier method of birth
             control; abstinence) prior to study entry, for the duration of study participation,
             and for 90 days following completion of therapy. Should a woman or female partner of a
             male subject become pregnant or suspect she is pregnant while participating in this
             study, she should inform her treating physician immediately

               -  A woman of child-bearing potential is any female (regardless of sexual
                  orientation, having undergone a tubal ligation, or remaining celibate by choice)
                  who meets the following criteria:

                    -  Has not undergone a hysterectomy or bilateral oophorectomy; or

                    -  Has not been naturally postmenopausal for at least 12 consecutive months
                       (i.e., has had menses at any time in the preceding 12 consecutive months)

          -  Women of child-bearing potential has negative pregnancy test prior to initiating study
             drug dosing

          -  Able to swallow and retain oral medication

        Exclusion Criteria:

          -  Current or anticipated use of other investigational agents

          -  Diagnosis of acute promyelocytic leukemia

          -  Active central nervous system involvement by AML

          -  AML must be treatment naive. Prior treatment with hypomethylating agent (azacitidine
             or decitabine), venetoclax or uproleselan, including for antecedent hematologic
             disorders. Prior allogeneic hematopoietic transplant for antecedent hematologic
             disorder is allowed if done at least 3 months prior to enrollment and there is no
             evidence of active graft versus host disease (GVHD) or requirement for systemic immune
             suppression

          -  Anticancer therapies, including investigational therapy, chemotherapy, targeted small
             molecule agents, or radiotherapy within 14 days or 5 half-lives (whichever is shorter)
             prior to the first dose and throughout venetoclax administration. Biologic agents
             (e.g. monoclonal antibodies) given for anti-neoplastic intent within 30 days prior to
             the first dose and throughout venetoclax administration

          -  Known diagnosis of human immunodeficiency virus (HIV) infection or known active
             hepatitis A, B or C infection with the exception of those with an undetectable viral
             load within 3 months of starting study treatment

          -  Known strong and/or moderate CYP3A inducers within 7 days prior to the initiation of
             study treatment

          -  Subject has consumed grapefruit, grapefruit products, Seville oranges or Starfruit
             within 3 days prior to the initiation of study treatment

          -  Severe or uncontrolled medical disorder that would, in the investigator's opinion,
             impair ability to receive study treatment (i.e., uncontrolled diabetes, chronic renal
             disease, chronic pulmonary disease or active, uncontrolled infection, psychiatric
             illness/social situations that would limit compliance with study requirements)

          -  History of other malignancies, except for malignancy treated with curative intent with
             no known active disease present for >= 1 year; treated non-melanoma skin cancer; and
             localized, cured prostate and cervical cancer

          -  Evidence of uncontrolled active systemic infection requiring therapy (viral,
             bacterial, or fungal). Fever of unknown origin is not an exclusion criterion, as this
             may be disease related

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to agents used in study

          -  Subject has a malabsorption syndrome of other condition that precludes enteral route
             of administration

          -  Subjects with a cardiovascular disability status of New York Heart Association class
             greater than 2

          -  Pregnant or nursing. There is a potential for congenital abnormalities and for this
             regimen to harm nursing infants.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 30 days
Safety Issue:
Description:Defined and graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 toxicity criteria.

Secondary Outcome Measures

Measure:Rate of multiparameter flow cytometry (MFC) measurable/minimal residual disease (MRD) negative complete remission (CR) plus CR with incomplete count recovery (CRi)
Time Frame:Up to 3 years
Safety Issue:
Description:Will be summarized using means, medians, and percentiles for continuous variables and percentages for categorical variables and associated exact 95% confidence intervals will be constructed. Comparisons between subsets of study participants will be conducted using exact tests.
Measure:Rate of CR plus CR with partial count recovery (CRh)
Time Frame:Up to 3 years
Safety Issue:
Description:Will be summarized using means, medians, and percentiles for continuous variables and percentages for categorical variables and associated exact 95% confidence intervals will be constructed. Comparisons between subsets of study participants will be conducted using exact tests.
Measure:Overall response rate (ORR)
Time Frame:Up to 3 years
Safety Issue:
Description:Defined as the rate of CR plus CRi and rate of CR plus CR with partial count recovery (CRh). Will be summarized using means, medians, and percentiles for continuous variables and percentages for categorical variables and associated exact 95% confidence intervals will be constructed. Comparisons between subsets of study participants will be conducted using exact tests.
Measure:Rate of transfusion-independence (TI)
Time Frame:Up to 3 years
Safety Issue:
Description:Will be summarized using means, medians, and percentiles for continuous variables and percentages for categorical variables and associated exact 95% confidence intervals will be constructed. Comparisons between subsets of study participants will be conducted using exact tests.
Measure:Duration of CR/CRi and CR/CRh (DoR)
Time Frame:From the date of CR, CRi or CRh until the date of relapse or death, assessed up to 3 years
Safety Issue:
Description:Analysis of DOR will be performed using Cox Regression, and Kaplan-Meier plots will be provided.
Measure:Relapse-free survival (RFS)
Time Frame:From the date of CR, CRi or CRh until the date of relapse or death from any cause, assessed up to 3 years
Safety Issue:
Description:Analysis of RFS will be performed using Cox Regression, and Kaplan-Meier plots will be provided.
Measure:Event-free survival (EFS)
Time Frame:From the date of entry into study to the date of treatment failure, relapse, or death from any cause, assessed up to 3 years
Safety Issue:
Description:Analysis of EFS will be performed using Cox Regression, and Kaplan-Meier plots will be provided.
Measure:Overall survival (OS)
Time Frame:From the date of entry into study to the date of death from any cause, assessed up to 3 years
Safety Issue:
Description:Analysis of OS will be performed using Cox Regression, and Kaplan-Meier plots will be provided.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Brian Jonas

Last Updated

August 5, 2021