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

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ClinicalTrials.gov Identifier: NCT04435691
Recruitment Status : Recruiting
First Posted : June 17, 2020
Last Update Posted : August 26, 2020
Sponsor:
Collaborators:
Genentech, Inc.
Forty-Seven/Gilead
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Drug: Azacitidine Biological: Magrolimab Drug: Venetoclax Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : July 28, 2020
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021


Arm Intervention/treatment
Experimental: Treatment (azacitidine, venetoclax, magrolimab)
Patients 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.
Drug: Azacitidine
Given SC or IV
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • U-18496
  • Vidaza

Biological: Magrolimab
Given IV
Other Name: Hu5F9-G4

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto




Primary Outcome Measures :
  1. Maximum tolerated dose of the combination drugs (phase Ib) [ Time Frame: 28 days ]
  2. Response rate (complete remission + complete remission with incomplete count recovery) (phase II) [ Time Frame: Within 3 months of treatment initiation ]
    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.

  3. Incidence of adverse events (phase II) [ Time Frame: Within 3 months of treatment initiation ]
    Toxicities are defined as drug-related non-hematological grade >= 3 adverse events.

  4. Event-free survival (phase II) [ Time Frame: Time duration from the start of treatment to disease progression/death or censored at last follow-up while on the drug, assessed up to 100 days ]
    Kaplan-Meier method will be used.

  5. Duration of response (phase II) [ Time Frame: Up to 100 days ]
    Kaplan-Meier method will be used.

  6. Overall survival (phase II) [ Time Frame: Up to 100 days ]
    Kaplan-Meier method will be used.


Secondary Outcome Measures :
  1. Change in gene expression (phase II) [ Time Frame: Baseline up to 100 days ]
    Paired t-tests will be used.

  2. Change in clinical variables (phase II) [ Time Frame: Baseline up to 100 days ]
    Paired t-tests will be used.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04435691


Contacts
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Contact: Naval G Daver 713-794-4392 ndaver@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Naval G. Daver    713-794-4392      
Principal Investigator: Naval G. Daver         
Sponsors and Collaborators
M.D. Anderson Cancer Center
Genentech, Inc.
Forty-Seven/Gilead
Investigators
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Principal Investigator: Naval G Daver M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT04435691    
Other Study ID Numbers: 2020-0027
NCI-2020-04163 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2020-0027 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: June 17, 2020    Key Record Dates
Last Update Posted: August 26, 2020
Last Verified: August 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Azacitidine
Venetoclax
Hu5F9-G4
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Antineoplastic Agents, Immunological