Clinical Trials /

Magrolimab, Azacitidine, and Venetoclax for the Treatment of Acute Myeloid Leukemia

NCT04435691

Description:

This phase Ib/II trial studies the side effects and best dose of magrolimab and venetoclax when given together with azacitidine and to see how well they work in treating patients with acute myeloid leukemia. Chemotherapy drugs, such as venetoclax and 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. Magrolimab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving magrolimab, azacitidine, and venetoclax may help to control the disease.

Related Conditions:
  • Acute Myeloid Leukemia
  • Acute Myeloid Leukemia Arising from Previous Myelodysplastic Syndrome
  • Therapy-Related Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Magrolimab, Azacitidine, and Venetoclax for the Treatment of Acute Myeloid Leukemia
  • Official Title: An Open-Label Phase IB/II Study of Magrolimab in Combination With Azacitidine and Venetoclax for the Treatment of Patients With Acute Myeloid Leukemia (AML)

Clinical Trial IDs

  • ORG STUDY ID: 2020-0027
  • SECONDARY ID: NCI-2020-04163
  • SECONDARY ID: 2020-0027
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04435691

Conditions

  • Acute Myeloid Leukemia
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (azacitidine, venetoclax, magrolimab)
MagrolimabHu5F9-G4Treatment (azacitidine, venetoclax, magrolimab)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoTreatment (azacitidine, venetoclax, magrolimab)

Purpose

This phase Ib/II trial studies the side effects and best dose of magrolimab and venetoclax when given together with azacitidine and to see how well they work in treating patients with acute myeloid leukemia. Chemotherapy drugs, such as venetoclax and 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. Magrolimab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving magrolimab, azacitidine, and venetoclax may help to control the disease.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and maximum tolerable dose (MTD) of this combination in patients
      with acute myeloid leukemia (AML).

      II. To determine the response rate (RR) including CR (complete remission) + CRi (complete
      remission with incomplete count recovery) within 3 months of treatment initiation of this
      combination in patients with AML.

      SECONDARY OBJECTIVES:

      I. To assess the CR + complete remission with partial hematological recovery (CRh) rate and
      morphologic leukemia free (MLF) rate within 3 months of treatment initiation of this
      combination in patients with AML.

      II. To determine the duration of response (DOR), event-free survival (EFS), overall survival
      (OS), MRD status at response and best MRD response attained by flow-cytometry, 4- and 8-week
      mortality, and number of patients bridged to hematopoetic stem cell transplant (HSCT) and
      median duration to HSCT from the initiation of the combination.

      III. To investigate correlations of response to this combination with a pre- therapy,
      on-therapy, and progression 81-gene panel of gene mutations in AML.

      EXPLORATORY OBJECTIVES:

      I. To investigate possible relationships between response and non-response to the combination
      with pretherapy, on-therapy, and progression gene expression signatures.

      II. To investigate the characterization of genetic heterogeneity in tumor cell populations,
      by performing targeted single-cell sequencing on longitudinally collected AML tumor
      populations from patients using a novel microfluidic approach that barcodes amplified genomic
      deoxyribonucleic acid (DNA) from thousands of individual leukemia cells confined to droplets
      (single cell sequencing).

      III. To identify individual cell populations (AML blasts, T-cells - both bulk and T-cell
      subsets and coreceptor/ligand expression, macrophages and their coreceptor/ligands) and how
      their signaling state in disease relates to clinical outcomes.

      IV. To store and/or analyze surplus blood or tissue including bone marrow, if available, for
      potential future exploratory research into factors that may influence development of AML
      and/or response to the combination (where response is defined broadly to include efficacy,
      tolerability or safety).

      OUTLINE: This is a phase Ib, dose-escalation study of venetoclax and magrolimab followed by a
      phase II study.

      Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 30-60 minutes on
      days 1-7, venetoclax orally (PO) once daily (QD) on days 1-21 of cycle 1 (may be reduced to
      days 1-14 for subsequent cycles after principal investigator approval), and magrolimab IV
      over 2-3 hours on days 1, 4, 8, 11, 15, and 22 of cycle 1, days 1, 8, 15, and 22 of cycle 2,
      and days 1 and 15 of cycle 3 and subsequent cycles. Treatment repeats every 28 days for up to
      12 cycles in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 and 100 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (azacitidine, venetoclax, magrolimab)ExperimentalPatients receive azacitidine SC or IV over 30-60 minutes on days 1-7, venetoclax PO QD on days 1-21 of cycle 1 (may be reduced to days 1-14 for subsequent cycles after principal investigator approval), and magrolimab IV over 2-3 hours on days 1, 4, 8, 11, 15, and 22 of cycle 1, days 1, 8, 15, and 22 of cycle 2, and days 1 and 15 of cycle 3 and subsequent cycles. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
  • Azacitidine
  • Magrolimab
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of 1) Pathology diagnosis of AML (World Health Organization [WHO]
             classification definition of >= 20% blasts in bone marrow or peripheral blood,
             excluding acute promyelocytic leukemia [APL])

          -  Phase Ib dose finding cohort: Patients aged >= 18 years old with relapsed/refractory
             AML are eligible if they are not eligible for potentially curative therapy such as
             effective salvage therapy or hematopoietic stem cell transplantation or who refuse
             these options at the time of enrollment. Patients must have received at least one
             prior therapy for AML

          -  Phase Ib dose finding cohort: Patients may have received up to 4 prior salvages for
             AML (i.e. up to salvage 3 status)

          -  Phase Ib dose finding cohort: Eastern Cooperative Oncology Group (ECOG) performance
             status =< 2

          -  Phase II (frontline cohort): Patients aged >= 60 years old with newly diagnosed AML
             who are chemonaive who are not candidates for intensive induction therapy and agree to
             receive the proposed combination therapy will be enrolled: Not considered candidates
             for intensive remission induction chemotherapy at time of enrollment based on EITHER:

               -  >= 75 years of age OR

               -  < 75 years of age with at least 1 of the following:

                    -  Poor performance status (ECOG) score of 2.

                    -  Clinically significant heart or lung comorbidities, as reflected by at least
                       1 of:

                         -  Left ventricular ejection fraction (LVEF) =< 50%.

                         -  Lung diffusing capacity for carbon monoxide (DLCO) =< 65% of expected.

                         -  Forced expiratory volume in 1 second (FEV1) =< 65% of expected.

                         -  Chronic stable angina or congestive heart failure controlled with
                            medication.

                    -  Other contraindication(s) to anthracycline therapy (must be documented).

                    -  Other comorbidity the investigator judges incompatible with intensive
                       remission induction chemotherapy, which must be documented and approved by
                       the principal investigator (PI)

          -  Phase II (frontline cohort): For patients with prior MDS or chronic myelomonocytic
             leukemia (CMML) or MPN who transformed to AML, therapy received for MDS, CMML, or MPN
             is NOT considered as prior therapy for AML. Patients with MDS or CMML treated with
             hypomethylating agent (HMA) therapies who progress to AML, and have no available
             therapies or are not candidates for available therapies, will be eligible at the time
             of progression to AML. Temporary prior measures such as apheresis, ATRA, steroids
             while diagnostic work-up of AML is being performed are allowed and not counted as a
             prior salvage

          -  Patients with newly diagnosed AML with poor risk karyotype or complex karyotype and/or
             TP53 deletions/mutations equal or younger than 60 year old will be eligible for the
             Phase II (frontline cohort)

          -  For Phase II (frontline cohort): Patients must be chemonaive, i.e., not have received
             any chemotherapy (except hydrea or 1-2 doses of ara-C for transient control of
             hyperleukocytosis) for AML. They may have received transfusions, hematopoietic growth
             factors or vitamins for an antecedent hematological disorder (AHD) or for AML.
             Temporary prior measures such as apheresis, ATRA, steroids or hydrea while diagnostic
             work-up is being performed are allowed and not counted as a prior salvage. Supportive
             care therapy for MDS (growth factors, transfusions) will not be considered as prior
             therapy for MDS/AML and these patients will be enrolled to the frontline cohort of the
             study if they are otherwise eligible

          -  In the absence of rapidly progressing disease, the interval from prior treatment to
             time of initiation of protocol therapy will be at least 2 weeks or at least 5
             half-lives (whichever is shorter). The half-life for the therapy in question will be
             based on published pharmacokinetic literature (abstracts, manuscripts, investigator
             brochure's, or drug-administration manuals) and will be documented in the protocol
             eligibility document. The toxicity from prior therapy should have resolved to grade =<
             1, however alopecia and sensory neuropathy grade =< 2 not constituting a safety risk
             based on investigators judgement is acceptable. The use of chemotherapeutic or
             anti-leukemic agents is not permitted during the study with the following exceptions:
             (1) intrathecal (IT) therapy for patients with controlled central nervous system (CNS)
             leukemia at the discretion of the PI. (2) Use of 1-2 doses of cytarabine (up to 2
             g/m^2 each dose) for patients with rapidly proliferative disease is allowed before the
             start of study therapy and for the first four weeks on therapy. Since the effect of
             most immuno-oncology (IO)-agents, HMA-therapies, venetoclax may be delayed, use of
             hydroxyurea for patients with rapidly proliferative disease is allowed on study and
             before the start of study therapy and will not require a washout. These medications
             will be recorded in the case-report form

          -  Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled CNS
             disease is permitted. Patients with a known history of CNS disease or leukemic brain
             metastasis must have been treated locally, have at least 2 consecutive LPs with no
             evidence of CNS leukemia, and must be clinically stable for at least 4 weeks prior to
             enrollment and have no ongoing neurological symptoms that in the opinion of the
             treating physician are related to the CNS disease (sequelae that are a consequence of
             the treatment of the CNS disease are acceptable)

          -  Creatinine < 2.0 mg/dl, or a calculated glomerular filtration rate of >=40 mL/min/1.73
             m^2

          -  Total bilirubin < 2.5 mg/dL unless considered due to Gilbert's syndrome

          -  Aspartate aminotransferase or alanine aminotransferase =< 2.5 x ULN (aspartate
             aminotransferase or alanine aminotransferase =< 5.0 x ULN if deemed related to
             leukemia by the treating physician)

          -  White blood cell count < 15 x 10^9/L. Patients must have a white blood cell (WBC)
             count < 15 x 10^9/L prior to each dose of magrolimab in cycle 1. Hydroxyurea may be
             used to reduce the WBC count to =< 15 x 10^9/L

          -  Ability to understand and provide signed informed consent

          -  Females must be surgically or biologically sterile or postmenopausal (amenorrheic for
             at least 12 months) or if of childbearing potential, must have a negative serum or
             urine pregnancy test within 72 hours before the start of the treatment

          -  Women of childbearing potential must agree to use an adequate method of contraception
             during the study and until 4 months after the last treatment. Males must be surgically
             or biologically sterile or agree to use an adequate method of contraception during the
             study until 3 months after the last treatment. Adequate methods of contraception
             include:

               -  Total abstinence when this is in line with the preferred and usual lifestyle of
                  the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
                  post-ovulation methods) and withdrawal are not acceptable methods of
                  contraception.

               -  Female sterilization (have had surgical bilateral oophorectomy with or without
                  hysterectomy) or tubal ligation at least six weeks before taking study treatment.
                  In case of oophorectomy alone, only when the reproductive status of the woman has
                  been confirmed by follow up hormone level assessment

               -  Male sterilization (at least 6 months prior to screening). For female patients on
                  the study, the vasectomized male partner should be the sole partner for that
                  patient

               -  Combination of any of the two following (a+b or a+c or b+c)

                    1. Use of oral, injected or implanted hormonal methods of contraception or
                       other forms of hormonal contraception that have comparable efficacy (failure
                       rate <1%), for example hormone vaginal ring or transdermal hormone
                       contraception

                    2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

                    3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
                       cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal
                       suppository

               -  In case of use of oral contraception, women should have been stable on the same
                  pill before taking study treatment

               -  Note: Oral contraceptives are allowed but should be used in conjunction with a
                  barrier method of contraception due to unknown effect of drug-drug interaction.

               -  Women are considered post-menopausal and not of child bearing potential if they
                  have had 12 months of natural (spontaneous) amenorrhea with an appropriate
                  clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have
                  had surgical bilateral oophorectomy (with or without hysterectomy) or tubal
                  ligation at least six weeks ago. In the case of oophorectomy alone, only when the
                  reproductive status of the woman has been confirmed by follow up hormone level
                  assessment is she considered not of child bearing potential.

               -  Male patients who are sexually active with a WOCBP and who have not had
                  vasectomies must be willing to use a barrier method of contraception during the
                  study and for 3 months after the last dose of magrolimab, venetoclax or
                  azacitidine, whichever ends later.

               -  Women who are pregnant or breastfeeding will not be eligible

        Exclusion Criteria:

          -  Patients with known allergy or hypersensitivity to magrolimab, venetoclax, azacitidine
             or any of their components

          -  Patients with any other known concurrent severe and/or uncontrolled medical condition
             including but not limited to diabetes, cardiovascular disease including hypertension,
             renal disease, or active uncontrolled infection, which could compromise participation
             in the study. Patients on active antineoplastic or radiation therapy for a concurrent
             malignancy at the time of screening. Maintenance therapy, hormonal therapy, or steroid
             therapy for well-controlled malignancy is allowed

          -  Prior organ transplantation including allogenic stem-cell transplantation within 3
             months prior to planned enrollment, active graft versus host disease (GVHD) > grade 1,
             or requiring transplant-related immunosuppression

          -  Known inherited or acquired bleeding disorders

          -  Prior treatment with a CD47 or SIRPalpha targeting agent

          -  Patients with symptomatic CNS leukemia or patients with poorly controlled CNS leukemia

          -  Patients with a known human immunodeficiency virus (HIV) infection that is not well
             controlled (i.e. any detectable circulating viral load) at the time of enrollment

          -  Patients with known positive hepatitis B or C infection by serology, with the
             exception of those with an undetectable viral load within 3 months (hepatitis B or C
             testing is not required prior to study entry). Subjects with serologic evidence of
             prior vaccination to hepatitis B virus (HBV) [i.e., hepatitis B surface antigen
             (HBsAg)-, and anti-HBs+] may participate

          -  Patients who have consumed grapefruit, grapefruit products, Seville oranges (including
             marmalade containing Seville oranges) or starfruit within 3 days prior to the
             initiation of study treatment

          -  Patients who have had any major surgical procedure within 14 days of day 1

          -  Other severe acute or chronic medical conditions that is active and not well
             controlled including colitis, inflammatory bowel disease, or psychiatric conditions
             including recent (within the past year) or active suicidal ideation or behavior; or
             laboratory abnormalities that may increase the risk associated with study
             participation or study treatment administration or may interfere with the
             interpretation of study results and, in the judgment of the investigator, would make
             the patient inappropriate for entry into this study

          -  Active and uncontrolled disease (active infection requiring systemic therapy or fever
             likely secondary to infection within prior 48 hours): prophylactic antibiotics or
             prolonged course of IV antibiotics for controlled infection are allowed, uncontrolled
             hypertension despite adequate medical therapy, active and uncontrolled congestive
             heart failure New York Heart Association (NYHA) class III/IV, clinically significant
             and uncontrolled arrhythmia) as judged by the treating physician

          -  Patients unwilling or unable to comply with the protocol
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of the combination drugs (phase Ib)
Time Frame:28 days
Safety Issue:
Description:Will be monitored simultaneously. Will be estimated along with 95% credible intervals. Chi-square tests or Fisher's exact test will be used to evaluate the association between patient's prognostic factor and response.

Secondary Outcome Measures

Measure:Change in gene expression (phase II)
Time Frame:Baseline up to 100 days
Safety Issue:
Description:Paired t-tests will be used.
Measure:Change in clinical variables (phase II)
Time Frame:Baseline up to 100 days
Safety Issue:
Description:Paired t-tests will be used.

Details

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

Last Updated

July 2, 2020