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Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); MLLT3-MLLPhase 1/2NCT03701295

Pinometostat and Azacitidine in Treating Patients With Relapsed, Refractory, or Newly Diagnosed Acute Myeloid Leukemia With 11q23 Rearrangement

A Phase 1/2 study testing Azacitidine and Pinometostat in people with Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); MLLT3-MLL and Leukemia Cutis, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This phase Ib/II trial studies the side effects and best dose of pinometostat when given together with azacitidine and to see how well it works in treating patients with acute myeloid leukemia that has come back (relapsed), does not respond to treatment (refractory), or is newly diagnosed, with an 11q23 rearrangement. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Azacitidine and Pinometostat
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1 participants
Where
1 siteUnited States
Study dates
6 Mar 2020to 12 Jan 2021
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

  • Patients must have histologically or cytologically confirmed acute myeloid leukemia
  • Patients must have an 11q23 translocation or partial tandem duplication, confirmed by cytogenetics, fluorescence in situ hybridization (FISH), or myeloid panel. Both de novo and therapy-related acute myeloid leukemia (AML) with an 11q23 rearrangement or partial tandem duplication (PTD) are considered eligible
  • Patients may not have any other targetable mutations (such as FLT3, IDH1, and IDH2) identified on myeloid mutational panel testing or must refuse treatment with a targeted agent if such a mutation is detected
  • Eastern Cooperative Oncology Group (ECOG) performance status < 3 (Karnofsky > 60%)
  • Prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 1.5 x upper limit of normal (ULN)
  • Total bilirubin < 2 times the upper limit of institutional normal (ULN) unless due to Gilbert's disease
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  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
  • Creatinine =< 2 times the upper limit of institutional normal (ULN) OR creatinine clearance glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2
  • Patients treated in the up-front setting must decline standard-of-care therapy
  • Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity with a close legal guardian/caregiver may be considered
  • Patients must have measurable disease, defined as abnormal blasts detectable in the peripheral blood or bone marrow or the presence of extramedullary disease, including leukemia cutis. Patients with extramedullary disease but no bone marrow disease are still considered eligible
  • Patients may have had previous treatment with standard-of-care or experimental agents. Patients who have previously undergone bone marrow transplantation may also be included
  • Patients who are human immunodeficiency virus (HIV) positive (+), hepatitis B virus (HBV)+, and/or hepatitis C virus (HCV)+ may be eligible as follows:
  • Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial. The antiretroviral therapy should not strongly induce or inhibit CYP3A4
  • If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated
  • If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load
  • The effects of pinometostat on the developing human fetus are unknown. For this reason and because histone methyltransferase inhibitors as well as hypomethylating agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, and for the duration of study participation and for 4 weeks after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 90 days after completion of pinometostat and azacitidine administration

Who cannot join

  • Patients who are receiving any other investigational agents
  • Patients with active central nervous system (CNS) disease are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with a prior history of CNS disease will not be excluded
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to pinometostat or azacitidine
  • Patients receiving any medications or substances that are inhibitors or inducers of the CYP3A4 or CYP450 system should have their medications reviewed and adjusted for interactions as appropriate for local institutional practice. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
  • Patients receiving any medications or substances that are inhibitors or inducers of MATE1 and MATE2-K transporters should have their medications reviewed and adjusted for interactions as appropriate for local institutional practice. Pinometostat has been demonstrated to be an inhibitor of MATE1 and MATE2-K transporters in vitro, although the clinical significance of this is unclear. Drug interactions may occur between pinometostat and other therapies that are MATE substrates, including metformin. Consultation with a frequently updated medical reference and/or pharmacist should be sought to guide necessary changes in the patient's other medications
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled or clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients with these conditions that are medically well controlled may be considered for enrollment
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  • Pregnant women are excluded from this study because pinometostat is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pinometostat, breastfeeding should be discontinued if the mother is treated with pinometostat. These potential risks may also apply to other agents used in this study
  • HIV-positive patients on combination antiretroviral therapy should have their regimen reviewed for potential pharmacokinetic interactions with pinometostat and azacitidine. In the event of a potential interaction, alternative therapies may be considered in consultation with the patient's primary HIV physician
  • Absence of an 11q23 rearrangement or absence of an 11q23 partial tandem duplication
  • Patients with an active bleeding diathesis
  • Patients at increased risk of QT prolongation (e.g. from known long-QT syndrome) or who have a corrected QT interval that is persistently longer than 450 ms despite adjustments to other medications
  • Patients who are eligible for or willing to receive intensive induction therapy for de novo AML

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Memorial Sloan Kettering Cancer Center

    New York, New York, 10065

Other trials in United States

About this study

Official title: A Phase Ib/II Study of the Histone Methyltransferase Inhibitor Pinometostat in Combination With Azacitidine in Patients With 11q23-Rearranged Acute Myeloid Leukemia

This phase Ib/II trial studies the side effects and best dose of pinometostat when given together with azacitidine and to see how well it works in treating patients with acute myeloid leukemia that has come back (relapsed), does not respond to treatment (refractory), or is newly diagnosed, with an 11q23 rearrangement. Pinometostat and azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine if the combination of pinometostat, at a dose of 54 or 90 mg/m^2/day, and azacitidine, at a dose of 75 mg/m^2 daily for 7 days, is safe and tolerable in patients with MLL-rearranged acute myeloid leukemia, either in the relapsed/ refractory setting or in those who choose not to undergo standard induction therapy in the previously untreated setting. (Phase Ib) II. To determine the preliminary efficacy, as determined by overall response rate (complete response [CR], complete response with incomplete bone marrow recovery [CRi], partial response [PR], and morphologic leukemia-free state [MLFS]), of pinometostat administered at the maximum tolerated dose from the phase 1b, combined with azacitidine administered at 75 mg/m^2 daily for 7 days, in patients with MLL-rearranged acute myeloid leukemia, either in the relapsed/refractory setting or in those who choose not to undergo standard induction therapy in the previously untreated setting. (Phase II)

SECONDARY OBJECTIVES:

  1. Perform correlative studies to evaluate for on-target effects, cellular differentiation, and decreased leukemia cell proliferation in these patients. (Phase Ib and II) II. To observe and record anti-tumor activity. (Phase Ib)

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

Patients receive pinometostat intravenously (IV) continuously on days 1-28 and azacitidine IV over 10-40 minutes or subcutaneously (SC) for 7 of the first 10 days of the cycle. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 month.

Being tested
Azacitidine, Pinometostat
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.

  • AzacitidineDrug

    Also called 5 AZC, 5-AC, 5-Azacytidine, 5-AZC

    Given IV or SC

  • PinometostatDrug

    Also called DOT1L Inhibitor EPZ-5676, EPZ-5676

    Given IV

Study groups in NCT03701295
Study groupRoleWhat they receive
Treatment (pinometostat, azacitidine)ExperimentalPatients receive pinometostat IV continuously on days 1-28 and azacitidine IV over 10-40 minutes or SC for 7 of the first 10 days of the cycle. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Azacitidine; Drug: Pinometostat

What is being measured

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

  1. Incidence of Dose-limiting Toxicities (DLTs) (Phase Ib)

    Safety and tolerability will be assessed by evaluating the number of patients out of 6 who experience a DLT defined as a significant suspected adverse reaction or clinically significant abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications.

    Measured: Up to day 42

  2. Response Rate (Phase II)

    Will be defined by the 2017 European Leukemia Network guidelines and as the number of patients who achieve a complete response (CR), complete response with incomplete bone marrow recovery (CRi), partial response (PR), or morphologic leukemia-free state (MLFS), with or without minimal residual disease (MRD), at any time point.

    Measured: Up to the time of count recovery after 6 cycles of combination therapy

Secondary outcomes (11)

  1. Number of Patients Who Experience a DLT (Phase Ib)

    Measured: Up to day 42

  2. Change in H3K79 Methylation (Phase Ib)

    Will compare quantitative methylation and methylation valence (e.g. if H3K27 has been methylated once, twice, or three times) from baseline and subsequent bone marrow samples using descriptive statistics and graphical displays. A Wilcoxon signed rank test will be used to assess post-treatment differences as compared to baseline.

    Measured: Baseline up to day 28

  3. Change in Expression Levels of HOXA9 and Meis1 (Phase Ib)

    Will compare expression level by quantitative polymerase chain reaction (qPCR) of HOXA9 and Meis1 levels from baseline and subsequent bone marrow samples using descriptive statistics and graphical displays. A Wilcoxon signed rank test will be used to assess post-treatment differences as compared to baseline.

    Measured: Baseline up to day 28

  4. Fraction of Cells With 11q23 Rearrangements (Phase Ib)

    Samples will be banked, and cytogenetic and fluorescence in situ hybridization (FISH) analysis of these cells will be performed to evaluate for the presence of MLL-rearrangement in patients who respond to therapy.

    Measured: Up to day 28

  5. Change in Absolute Neutrophil/Absolute Monocyte Count (Phase Ib)

    Will evaluate differentiation by performing a differential on the bone marrow biopsy and peripheral blood samples at baseline and from subsequent time points and assessing percentage of monocytes / neutrophils, bands, and myeloid forms present.

    Measured: Baseline up to day 28

  6. Number of Patients Who Experience a DLT (Phase II)

    Measured: Up to 1 month post-treatment

  7. Response Rate Based on Relapsed / Refractory or Previously Untreated Status (Phase II)

    Patients will be stratified based on treatment for relapsed / refractory or previously untreated disease. The response of each stratum to combination therapy, defined as CR, CRi, MLFS, or PR, with or without MRD, on bone marrow biopsy as defined by the 2017 European Leukemia Network guidelines, will be described. Kaplan-Meier estimates will be calculated and compared for each stratum. A report will be generated to look at all patients, all eligible patients who were enrolled, and all evaluable patients.

    Measured: Up to 1 month post-treatment

  8. Change in H3K79 Methylation (Phase II)

    Will compare quantitative methylation and methylation valence (e.g. if H3K27 has been methylated once, twice, or three times) from baseline and subsequent bone marrow samples using descriptive statistics and graphical displays. A Wilcoxon signed rank test will be used to assess post-treatment differences as compared to baseline.

    Measured: Baseline up to 1 month post-treatment

  9. Change in Expression Levels of HOXA9 and Meis1 (Phase II)

    Will compare expression level by qPCR of HOXA9 and Meis1 levels from baseline and subsequent bone marrow samples using descriptive statistics and graphical displays. A Wilcoxon signed rank test will be used to assess post-treatment differences as compared to baseline.

    Measured: Baseline up to 1 month post-treatment

  10. Fraction of Cells With 11q23 Rearrangements (Phase II)

    Samples will be banked, and cytogenetic and FISH analysis of these cells will be performed to evaluate for the presence of MLL-rearrangement in patients who respond to therapy.

    Measured: Up to 1 month post-treatment

  11. Change in Absolute Neutrophil / Absolute Monocyte Count (Phase II)

    Will evaluate differentiation by performing a differential on the bone marrow biopsy and peripheral blood samples at baseline and from subsequent time points and assessing percentage of monocytes / neutrophils, bands, and myeloid forms present.

    Measured: Baseline up to the end of course 1

Timeline

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

  1. First posted10 Oct 2018
  2. Study start6 Mar 2020
  3. Primary completion8 Dec 2020
  4. Study completion12 Jan 2021

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
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
1 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03701295
Sponsor's protocol ID
NCI-2018-02128
Other IDs
NCI-2018-02128, 10200, 10200, UM1CA186691
Status last verified
Sep 2023
First submitted
8 Oct 2018
Last updated
18 Oct 2023
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Azacitidine and Pinometostat in people with Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); MLLT3-MLL and Leukemia Cutis, run by National Cancer Institute (NCI) 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 17 inclusion and 12 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: finished, as of the sponsor's last update on 18 Oct 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 9 Sep 2021). 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?

Incidence of Dose-limiting Toxicities (DLTs) (Phase Ib) (time frame: Up to day 42). 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 NCT03701295.

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 18 Oct 2023.

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