Clinical Trials /

Alvocidib in Combination With Decitabine and Venetoclax in Patients With Relapsed or Refractory AML or as Frontline Therapy in Unfit Patients With AML

NCT04493099

Description:

This phase I/II trial investigates the side effects and best dose of alvocidib when given together with decitabine and venetoclax and to see how well it works in treating patients with acute myeloid leukemia that has come back (relapsed), has not responded to previous treatment (refractory), or as frontline treatment for patients unable to receive other therapies (unfit). Alvocidib, decitabine, and venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Alvocidib in Combination With Decitabine and Venetoclax in Patients With Relapsed or Refractory AML or as Frontline Therapy in Unfit Patients With AML
  • Official Title: A Phase 1/2 Study of Alvocidib in Combination With Decitabine and Venetoclax in Patients With Relapsed or Refractory AML or as Frontline Therapy in Unfit Patients With AML

Clinical Trial IDs

  • ORG STUDY ID: 2019-1053
  • SECONDARY ID: NCI-2020-05266
  • SECONDARY ID: 2019-1053
  • NCT ID: NCT04493099

Conditions

  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Alvocidib Hydrochloride4H-1-Benzopyran-4-one, 2-(2-chlorophenyl)-5, 7-dihydroxy-8-(3-hydroxy-1-methyl-4-piperidinyl)-, hydrochloride, (-)-cis-, Flavopiridol Hydrochloride, HL-275, HMR 1275, L-86-8275, L-868275, MDL 107,826A, MDL-107826ATreatment (decitabine, alvocidib hydrochloride, venetoclax)
Decitabine5-Aza-2''-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineTreatment (decitabine, alvocidib hydrochloride, venetoclax)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoTreatment (decitabine, alvocidib hydrochloride, venetoclax)

Purpose

This phase I/II trial investigates the side effects and best dose of alvocidib when given together with decitabine and venetoclax and to see how well it works in treating patients with acute myeloid leukemia that has come back (relapsed), has not responded to previous treatment (refractory), or as frontline treatment for patients unable to receive other therapies (unfit). Alvocidib, decitabine, and venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety of alvocidib hydrochloride (alvocidib) in combination with
      decitabine and venetoclax in relapsed or refractory patients with acute myeloid leukemia
      (AML) or as frontline therapy in unfit/frail patients with AML. (Phase I) II. To determine
      the efficacy alvocidib in combination with decitabine and venetoclax in relapsed or
      refractory patients with acute myeloid leukemia (AML) or as frontline therapy in unfit/frail
      patients with AML. (Phase II)

      SECONDARY OBJECTIVE:

      I. To determine the preliminary assessment of efficacy by response to revised International
      Working Group (IWG) criteria and time to response variables, including overall survival (OS),
      event-free survival (EFS) and duration of response (DOR) of patients treated with this
      combination.

      EXPLORATORY OBJECTIVES:

      I. To determine the minimal residual disease (MRD) after treatment with this combination and
      its impact in long-term outcome.

      II. To determine the effect of the level of pre-treatment expression of BCL-2 and MCL-1 (by
      BH3 profiling) with response to this combination.

      III. To determine the effect of this treatment combination on responding patients
      transitioning to hematopoietic stem cell transplantation (HSCT).

      OUTLINE: This is a phase I, dose-escalation study of alvocidib followed by a phase II study.

      INDUCTION: Patients receive decitabine intravenously (IV) over 1 hour on days 1-10, alvocidib
      hydrochloride IV over 1 hour on days 1-3, 1-5, 1-7, 1-10, or 1-14, and venetoclax orally (PO)
      once daily (QD) on days 1-14 in the absence of disease progression or unacceptable toxicity.

      CONSOLIDATION: Patients receive decitabine IV over 1 hour on days 1-5, alvocidib
      hydrochloride IV over 1 hour on days 1-3, 1-5, 1-7, 1-10 or 1-14, and venetoclax PO QD on
      days 1-10. Treatment repeats every 28 days for up to 24 cycles in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 4 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (decitabine, alvocidib hydrochloride, venetoclax)ExperimentalINDUCTION: Patients receive decitabine IV over 1 hour on days 1-10, alvocidib hydrochloride IV over 1 hour on days 1-3, 1-5, 1-7, 1-10, or 1-14, and venetoclax PO QD on days 1-14 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive decitabine IV over 1 hour on days 1-5, alvocidib hydrochloride IV over 1 hour on days 1-3, 1-5, 1-7, 1-10 or 1-14, and venetoclax PO QD on days 1-10. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
  • Alvocidib Hydrochloride
  • Decitabine
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of relapsed or refractory acute myeloid leukemia by World Health
             Organization (WHO) criteria. Unfit/frail patients with newly diagnosed AML are also
             eligible if not considered good candidates to receive a higher intensity therapy

               -  A patient is considered unfit or frail if has three or more of the five factor
                  below:

                    -  Unintentional weight loss of 10 pounds or more in a year

                    -  General feeling of exhaustion

                    -  Weakness as measured by grip strength

                    -  Slow walking speed

                    -  Low levels of physical activity

          -  Eastern Cooperative Oncology Group (ECOG) performance status score of =< 3

          -  Total serum bilirubin =< 2 x upper limit of normal (ULN). Patients with known
             Gilbert's syndrome may have a total bilirubin up to =< 3 x ULN

          -  Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) =< 3 x ULN; or
             =< 5 x ULN in case of suspected leukemic liver involvement

          -  Serum creatinine =< 2.0 mg/dl

          -  Females of childbearing potential must have a negative serum or urine beta human
             chorionic gonadotropin (B-HCG) pregnancy test result within 1 week (+/-3 days) prior
             to the first dose of study drugs and must agree to use one of the following effective
             contraception methods during the study and for 30 days following the last dose of
             study drug. Effective methods of birth control include:

               -  Birth control pills, shots, implants (placed under the skin by a health care
                  provider) or patches (placed on the skin)

               -  Intrauterine devices (IUDs)

               -  Condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide

               -  Abstinence

               -  Females of non-childbearing potential are those who are postmenopausal greater
                  than 1 year or who have had a bilateral tubal ligation, oophorectomy, and/or
                  hysterectomy

          -  Males who have partners of childbearing potential must agree to use an effective
             contraceptive method (such as condom used with spermicide or abstinence) during the
             study and for 30 days following the last dose of study drug

          -  Patients or their legally authorized representative must provide written informed
             consent

        Exclusion Criteria:

          -  Patients with t(15;17) karyotype abnormality or acute promyelocytic leukemia

          -  History of another primary invasive malignancy that has not been definitively treated
             and in remission. Patients with non-melanoma skin cancers or with carcinomas in situ
             are eligible regardless of the time from diagnosis (including concomitant diagnoses)

          -  Presence of clinically significant uncontrolled central nervous system (CNS) pathology
             such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain
             injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome,
             or psychosis

          -  Evidence of active cerebral/meningeal disease. Patients may have history of CNS
             leukemic involvement if definitively treated with prior therapy and no evidence of
             active disease at the time of consent with at least 2 consecutive spinal fluid
             negative assessments for residual leukemia and negative imaging (imaging required only
             if previously showing evidence of CNS leukemia not otherwise documented by spinal
             fluid assessment)

          -  Patients with active unstable angina, concomitant clinically significant active
             arrhythmias, myocardial infarction within 6 months, or congestive heart failure New
             York Heart Association class III-IV. Patients with a cardiac ejection fraction (as
             measured by either multigated acquisition scan [MUGA] or echocardiogram) < 45% are
             excluded

          -  Patients with uncontrolled, active infections (viral, bacterial, or fungal)

          -  Known active hepatitis B or C infection, or known seropositivity for human
             immunodeficiency virus (HIV)

          -  Patients with liver cirrhosis or other serious active liver disease or with suspected
             active alcohol abuse

          -  Allogeneic hematopoietic cell transplantation (HSCT) within 6 months before the start
             of protocol-specified therapy, or with active acute/chronic graft-versus-host disease
             (GvHD) requiring systemic treatment; or receiving immunosuppression for GvHD
             prophylaxis within 2 weeks from the start of study therapy

          -  Prior chemotherapy/radiotherapy/investigational therapy within 2 weeks before the
             start of study drugs with the following exception:

               -  To reduce tumor burden, leukocytosis (circulating blast count) or palliation:
                  Intravenous cytarabine and/or hydroxyurea. No washout is necessary for these
                  agents. Patients must have recovered from acute non hematologic toxicity (to =<
                  grade 1) of all previous therapy prior to enrollment

          -  Females who are pregnant or lactating

          -  Male or female subjects of childbearing potential, unwilling to use an approved,
             effective means of contraception in accordance with institution's standards

          -  Other severe, uncontrolled acute or chronic medical or psychiatric condition or
             laboratory abnormality that in the opinion of the investigator may increase the risk
             associated with study participation or investigational product administration or may
             interfere with the interpretation of study results and/or would make the patient
             inappropriate for enrollment into this study

          -  Prior treatment with alvocidib

               -  Prior use of venetoclax single agent or any venetoclax-based combination therapy
                  is allowed
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall incidence and severity of all adverse events (Phase I)
Time Frame:Up to 6 years
Safety Issue:
Description:Measured using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Secondary Outcome Measures

Measure:Duration of response
Time Frame:Up to 6 years
Safety Issue:
Description:The duration of response is defined as the number of days from the date of initial response (partial response [PR] or better) to the date of first documented disease progression/relapse or death, whichever occurs first.
Measure:Event free survival
Time Frame:Up to 6 years
Safety Issue:
Description:Event-free survival is defined as the number of days from the date of treatment initiation (e.g., cycle 1 day 1 [C1D1]) to the date of documented treatment failure, relapses from complete response (CR), or death from any cause, whichever occurs first, and will be calculated for all patients. Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Measure:Overall survival
Time Frame:From treatment start till death or last follow-up, assessed up to 6 years
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

July 27, 2020