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Acute Myeloid LeukemiaPhase 1/2NCT03634228

Milademetan Tosylate and Low-Dose Cytarabine With or Without Venetoclax in Treating Participants With Recurrent or Refractory Acute Myeloid Leukemia

A Phase 1/2 study testing Cytarabine, Milademetan Tosylate and Venetoclax in people with Acute Myeloid Leukemia and Recurrent Acute Myeloid Leukemia, run by M.D. Anderson Cancer Center at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This phase I/II trial studies the side effects and best dose of milademetan tosylate and to see how well it works with cytarabine with or without ventoclax in treating participants with acute myeloid leukemia that has come back (recurrent) or that does not respond to treatment (refractory). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Cytarabine, Milademetan Tosylate and Venetoclax
Could I receive a placebo?
No, everyone receives an active treatment
How many people
16 participants
Where
1 siteUnited States
Study dates
17 Dec 2018to 3 Apr 2022
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Diagnosis of acute myeloid leukemia (AML) by World Health Organization (WHO) 2016 criteria. Patients will be divided into 2 arms during the phase 2 portion:
  • Arm A: Subjects must have newly diagnosed AML
  • Arm B: Subjects must have refractory or relapsed AML
  • TP53 wild-type status on molecular testing performed within the last 3 months
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 3
  • Creatinine clearance >= 60 mL/min, as calculated using the modified Cockcroft-Gault equation OR creatinine =< 1.5 x upper limit of normal (ULN)
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  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN
  • Bilirubin =< 1.5 x ULN, unless resulting from hemolysis, Gilbert's disease or considered to be due to leukemic involvement
  • No gastrointestinal issues to interfere with oral medication absorption
  • No active uncontrolled infection or comorbidity that would interfere with therapy or place patient at increased risk
  • Subject (male and female) of childbearing/reproductive potential must agree to use double-barrier contraceptive measures or avoid intercourse during the study and for 90 days after the last dose of study drug
  • Subject must sign and date an Institutional Review Board-approved informed consent form (including Health Insurance Portability and Accountability Act authorization, if applicable) before performance of any study-specific procedures or tests
  • Able and willing to provide bone marrow biopsies/aspirates as requested by the protocol
  • Willing to undergo malignancy genotyping for TP53 mutation, insertion, or deletion at screening
  • Use of hydroxyurea is allowed prior to and during the first cycle of study treatment. 1-2 doses of cytarabine are also permitted if needed for cytoreduction prior to initiating study treatment

Who cannot join

  • Patient with t(15;17) karyotypic abnormality or a diagnosis of acute promyelocytic leukemia
  • Patient with other malignancy that contains a non-synonymous mutation, insertion, or deletion in the TP53 gene determined previously or at screening
  • Prior treatment with an MDM2 inhibitor
  • Presence of central nervous system involvement of leukemia. History of prior leptomeningeal leukemia/disease that has fully resolved is eligible
  • A second concurrent primary malignancy that has required systemic anti-neoplastic treatment within the previous 6 months, except for localized cancers that have apparently been cured, for example non-melanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast
  • Any condition that would preclude adequate absorption of DS-3032b, including refractory vomiting, malabsorption, biliary shunt, significant bowel resection, and/or graft-versus-host disease (GVHD) affecting the gut
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  • Any active uncontrolled infection, known human immunodeficiency virus infection, or active hepatitis B or C infection
  • Any concomitant medical condition that would in the opinion of the investigator increase the risk of toxicity
  • Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5, grade =< 1 or baseline. Subjects with chronic grade 2 toxicities may be eligible per discretion of the investigator and sponsor (e.g., grade 2 chemotherapy-induced neuropathy)
  • Patient having received hematopoietic stem cell transplantation (HSCT) within 60 days of the first dose of DS-3032b, is on immuno-suppressive therapy post-HSCT at the time of screening, or has clinically significant GVHD (use of topical steroids for ongoing skin GVHD will be permitted)
  • Prolongation of corrected QT interval using Fridericia's method (QTcF) at rest, where the mean QTcF interval is >= 450 ms for males or >= 470 ms for females based on electrocardiograms (ECGs). Patients with right bundle branch block (RBBB) will be eligible after discussion with principal investigator (PI)
  • Pregnant or breastfeeding
  • Substance abuse or medical, psychological, or social conditions that, in the opinion of the investigator, may interfere with the subject's participation in the clinical study or evaluation of the clinical study results

Trial locations and contacts

1 site in 1 country.

United States1 site

  • M D Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: A Phase I/II Study of the Oral MDM2 Inhibitor DS-3032b (Milademetan) in Combination With Low Dose Cytarabine (LDAC) in Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML)

This phase I/II trial studies the side effects and best dose of milademetan tosylate and to see how well it works with cytarabine with or without ventoclax in treating participants with acute myeloid leukemia that has come back (recurrent) or that does not respond to treatment (refractory). Milademetan tosylate and ventoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine, 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. It is not yet known if giving milademetan tosylate and low-dose cytarabine with or without ventoclax will work better in treating participants with recurrent or refractory acute myeloid leukemia.

Read the detailed description

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study.

If you are enrolled in Phase 1, the dose of DS-3032b you receive will depend on when you join this study.

If you are enrolled in Phase 2, you will receive DS-3032b at the highest dose that was tolerated in Phase 1.

All participants will receive LDAC at a fixed dose (meaning the dose will not change). If you are assigned to receive it, your dose of venetoclax will not change either. However, if needed because you have side effects, your dose may be adjusted.

Up to 58 participants will be enrolled in this study. All will take part at MD Anderson.

Being tested
Cytarabine, Milademetan Tosylate, Venetoclax
Medical subject headings
Leukemia, Myeloid, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CytarabineDrug

    Also called .beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone

    Given SC

  • Milademetan TosylateDrug

    Also called DS-3032 Tosylate, DS-3032b, DS-3032b Tosylate

    Given PO

  • VenetoclaxDrug

    Also called ABT-0199, ABT-199, ABT199, GDC-0199

    Given PO

Study groups in NCT03634228
Study groupRoleWhat they receive
Phase I (low dose cytarabine, MDM2 inhibitor DS-3032b)ExperimentalPatients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Cytarabine; Drug: Milademetan Tosylate
Phase II (low dose cytarabine, MDM2 inhibitor DS-3032b)ExperimentalPatients receive low dose cytarabine SC BID on days 1-10, milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17, and venetoclax PO QD on days 1-14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Cytarabine; Drug: Milademetan Tosylate; Drug: Venetoclax

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum Tolerated Dose (MTD) (Phase I)

    As determined by dose limiting toxicity (DLT). MTD is defined the highest dose at which no more than one patient out of 6 patients experience DLTs in the first cycle. A 3+3 algorithm will be applied for dose escalation or dose de-escalation.

    Measured: Up to 28 days

  2. Participants With a Response

    Response is Complete Response (CR) + Complete Response with Incomplete Blood Count Recovery (CRi) + Partial Response (PR) + Morphologic Leukemia -Free State (MLFS: CR is Bone marrow blasts < 5%; absence of circulating blasts and blasts with Auer rods; absence of extra-medullary disease; ANC >/= 1.0 x 10^9/L; platelet count >/= 100 x 10^9/L. CRi is CR except for ANC < 1.0 x 10^9 or platelet count , 100 x 10^9/L. PR is decreased bone marrow blast % by at least 50% to a value of 5% to 25% and ANC >/= 1.0 x 10^9/L; platelet count >/= 100 x 10^9/L. MLFS is Bone marrow blasts < 5%; abcence of blasts with Auer rods; absence of extra-medullary disease; no hematologic recovery required.

    Measured: Up to 3 years, 4 months

Secondary outcomes (2)

  1. Overall Survival

    Time from date of treatment start until date of death due to any cause or last Follow-up.

    Measured: Up to 3 years, 4 months

  2. Event Free Survival (EFS)

    Time from date of treatment start until the date of first objective documentation of disease-relapse.

    Measured: Up to 3 years, 4 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Aug 2018
  2. Study start17 Dec 2018
  3. Primary completion3 Apr 2022
  4. Study completion3 Apr 2022

Why it stopped: This study was terminated early due to lack of adequate response, and did not move to the Phase II portion of the study

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
16 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03634228
Sponsor's protocol ID
2018-0333
Other IDs
NCI-2018-01612, 2018-0333
Status last verified
May 2023
First submitted
9 Aug 2018
Last updated
15 Jun 2023
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Senapati J, Muftuoglu M, Ishizawa J, Abbas HA, Loghavi S, Borthakur G, Yilmaz M, Issa GC, Dara SI, Basyal M, Li L, Naqvi K, Pourebrahim R, Jabbour EJ, Kornblau SM, Short NJ, Pemmaraju N, Garcia-Manero G, Ravandi F, Khoury J, Daver N, Kantarjian HM, Andreeff M, DiNardo CD. A Phase I study of Milademetan (DS3032b) in combination with low dose cytarabine with or without venetoclax in acute myeloid leukemia: Clinical safety, efficacy, and correlative analysis. Blood Cancer J. 2023 Jun 29;13(1):101. doi: 10.1038/s41408-023-00871-1.

    PubMed 37386016

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Cytarabine, Milademetan Tosylate and Venetoclax in people with Acute Myeloid Leukemia and Recurrent Acute Myeloid Leukemia, run by M.D. Anderson Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 15 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 15 Jun 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose (MTD) (Phase I) (time frame: Up to 28 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03634228, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jun 2023.

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Clinical Trial NCT03634228 | AzTrials