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Acute Myeloid LeukemiaPhase 1NCT03441048

Lintuzumab-Ac225 in Combination with Cladribine + Cytarabine + Filgastrim + Mitoxantrone (CLAG-M) for Relapsed/Refractory Acute Myeloid Leukemia

A Phase 1 study testing Lintuzumab-Ac-225, Cladribine and Cytarabine in people with Acute Myeloid Leukemia, run by Medical College of Wisconsin 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 is a prospective, single-center phase I clinical study aimed at determining the maximum-tolerated dose, recommended phase 2 dose and safety of Lintuzumab-Ac225 in combination with CLAG-M chemotherapy in the management of relapsed/refractory acute myeloid leukemia. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Acute Myeloid Leukemia
What is being tested?
Lintuzumab-Ac-225, Cladribine and Cytarabine
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
26 participants
Where
1 siteUnited States
Study dates
22 May 2018to 22 May 2024
Phase
Phase 1
Are there results?
None posted in the registry

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

  • Age ≥18 years at the time of informed consent.
  • Morphologically documented primary AML or secondary AML [from prior conditions such as Myelodysplastic Syndrome (MDS), myeloproliferative neoplasm (MPN)] or therapy related AML (t-AML), as defined by World Health Organization (WHO) criteria.
  • In first or subsequent relapse or refractory status after prior therapy, with or without prior hematopoietic stem cell transplant (HSCT). Patients with MDS and progression to AML on hypomethylating agents will also be included.
  • Eastern Cooperative Oncology Group (ECOG) performance score 0-2.
  • Greater than 25% of blasts must be CD33 positive on flow cytometry using Phycoerythrin (PE) labeled anti-CD33 antibody.
  • Patients must meet the following clinical laboratory criteria:
Show all 11Show fewer
  • Total bilirubin ≤ 2 x the upper limit of the normal range (ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x ULN.
  • Calculated creatinine clearance ≥ 50 mL/min
  • Resting left ventricular ejection fraction (LVEF) > 40%
  • Female patients must agree to avoid becoming pregnant, and male patients should avoid impregnating a female partner.

Who cannot join

  • Acute Promyelocytic Leukemia.
  • Active severe infection not well controlled by antibacterial or antiviral therapy.
  • Known infection with human immunodeficiency virus.
  • Patients with documented pulmonary disease, with a diffusing capacity of the lungs for carbon monoxide (DLCO) and/or forced expiratory volume in one second (FEV1) <65%, or history of dyspnea at rest, or requiring oxygen.
  • Pregnant or breast feeding women.
  • Prior chemotherapy or radiotherapy within 14 days of study entry unless fully recovered from adverse effects due to treatment, at investigator's discretion.
  • Active malignancy within 2 years of entry, except previously treated melanoma grade 2 or less, non-melanoma skin cancer, carcinoma in situ, or cervical intraepithelial neoplasia, and organ confined prostate cancer with no evidence of progressive disease based on prostate-specific antigen (PSA) levels and are not on active therapy. Active malignancy is malignancy receiving treatment.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Froedtert Hospital and the Medical College of Wisconsin

    Milwuakee, Wisconsin, 53226

Other trials in United States

About this study

Official title: A Phase I Study of Lintuzumab-Ac225 in Combination with CLAG-M Chemotherapy in Patients with Relapsed/Refractory Acute Myeloid Leukemia

This is a prospective, single-center phase I clinical study aimed at determining the maximum-tolerated dose, recommended phase 2 dose and safety of Lintuzumab-Ac225 in combination with CLAG-M chemotherapy in the management of relapsed/refractory acute myeloid leukemia. This study uses a 3+3 design with a five-patient cohort at the recommended phase 2 dose.

Read the detailed description

Relapsed/refractory acute myeloid leukemia (RR-AML) in adults is an important therapeutic challenge. Nearly 60% of AML patients ultimately relapse or have refractory disease, and failure to achieve remission in this population is almost universally fatal. Therefore, a critical need exists for the development of novel therapies.

Currently, for RR-AML, many institutions utilize the chemotherapy regimen of CLAG-M (cladribine, cytarabine, G-CSF, mitoxantrone) based on a reported morphological complete remission (CR) rate of 58% in prospective clinical trials. Because of this, and its favorable performance when compared with outcomes reported for other regimens utilized in RR-AML, we believe enhancing the efficacy of CLAG-M is a rational approach to improve therapy in RR-AML.

A promising approach that could enhance the clearance of leukemic blasts when added to CLAG-M chemotherapy is a monoclonal antibody radioconjugate directed against markers expressed in leukemic cells. Radiation has known cytotoxic properties in chemo-resistant AML. The benefit of an antibody radioconjugate would be leukemic specific delivery of potent radiotherapy with potentially minimal systemic off-target side-effects. One such antibody radioconjugate is Lintuzumab-Ac225, a highly cytotoxic alpha radiation emitter that targets the cluster of differentiation 33 (CD33) cell surface antigen, which is expressed on leukemic cells.

In this novel study, we aim to add the radioconjugated antibody Lintuzumab-Ac225 to salvage CLAG-M chemotherapy in order to improve the treatment response for patients with RR-AML.

Being tested
Lintuzumab-Ac-225, Cladribine, Cytarabine, Mitoxantrone, G-CSF
Keywords
Acute myeloid leukemia, Relapsed/refractory acute myeloid leukemia, CLAG-M, Lintuzumab
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.

  • Lintuzumab-Ac-225Biological

    Also called HuM195-Ac225, Actimab-A

    Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia.

  • CladribineDrug

    Also called Leustatin, Mavenclad

    Cladribine is a purine antimetabolite.

  • CytarabineDrug

    Also called Cytosar-U, Depocyt, cytosine arabinoside (ara-C)

    Cytarabine is an antineoplastic anti-metabolite.

  • MitoxantroneDrug

    Also called Mitozantrone, Novantrone

    Mitoxantrone is an anthracenedione antineoplastic agent.

  • G-CSFDrug

    Also called colony-stimulating factor 3 (CSF 3)

    G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells.

Study groups in NCT03441048
Study groupRoleWhat they receive
Lintuzumab Ac225 (Dose 1 - 0.25 μCi/kg Ac-225 with 1.6 μg/kg lintuzumab)ExperimentalDose escalation for lintuzumab-Ac225 will be conducted according to a 3+3 design. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m^2/day IV over two hours on days 2-6; cytarabine 2 gm/m^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Receives: Biological: Lintuzumab-Ac-225; Drug: Cladribine; Drug: Cytarabine; Drug: Mitoxantrone; Drug: G-CSF
Lintuzumab Ac225 (Dose 2 - 0.50 μCi/kg Ac-225 with 3.2 μg/kg lintuzumab)ExperimentalDose escalation for lintuzumab-Ac225 will be conducted according to a 3+3 design. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m^2/day IV over two hours on days 2-6; cytarabine 2 gm/m^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Receives: Biological: Lintuzumab-Ac-225; Drug: Cladribine; Drug: Cytarabine; Drug: Mitoxantrone; Drug: G-CSF
Lintuzumab Ac225 (Dose 3 - 0.75 μCi/kg Ac-225 with 4.7μg/kg lintuzumab)ExperimentalDose escalation for lintuzumab-Ac225 will be conducted according to a 3+3 design. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m^2/day IV over two hours on days 2-6; cytarabine 2 gm/m^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Receives: Biological: Lintuzumab-Ac-225; Drug: Cladribine; Drug: Cytarabine; Drug: Mitoxantrone; Drug: G-CSF
Lintuzumab Ac225 (Dose 4 - 1.00 μCi/kg Ac-225 with 6.4 μg/kg lintuzumab)ExperimentalDose escalation for lintuzumab-Ac225 will be conducted according to a 3+3 design. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m^2/day IV over two hours on days 2-6; cytarabine 2 gm/m^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Receives: Biological: Lintuzumab-Ac-225; Drug: Cladribine; Drug: Cytarabine; Drug: Mitoxantrone; Drug: G-CSF
Lintuzumab Ac225 (Dose 5 - 1.25 μCi/kg Ac-225 with 8.0 μg/kg lintuzumab)ExperimentalDose escalation for lintuzumab-Ac225 will be conducted according to a 3+3 design. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m^2/day IV over two hours on days 2-6; cytarabine 2 gm/m^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Receives: Biological: Lintuzumab-Ac-225; Drug: Cladribine; Drug: Cytarabine; Drug: Mitoxantrone; Drug: G-CSF
Lintuzumab Ac225 Recommended Phase 2 Dose (RP2D)ExperimentalThe maximum-tolerated dose for lintuzumab-Ac225 is defined as the highest level at which no more than one patient experiences a dose-limiting toxicity. The RP2D is defined as the dose level below the dose where two or more dose-limiting toxicities were observed. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m^2/day IV over two hours on days 2-6; cytarabine 2 gm/m^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Receives: Biological: Lintuzumab-Ac-225; Drug: Cladribine; Drug: Cytarabine; Drug: Mitoxantrone; Drug: G-CSF

What is being measured

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

  1. The number of subjects with dose-limiting toxicities.

    Dose-escalation will be conducted according to a 3+3 design with a five-patient expansion cohort at the recommended phase 2 dose. The initial dose of Lintuzumab-Ac225 will be 0.25 micro-Curie (μCi)/kg (Dose level 1), and the highest dose administered will be 1.25 μCi/kg.

    • if 0/3 pts have no dose-limiting toxicity (DLT), new patients enter next dose level.
    • if 1/3 pts has DLT, 3 pts treated at same dose level.
    • if 0/3 pts at that dose level has DLT, new pts enter higher level.
    • if 1 or more of the additional 3 pts has a DLT, no further pts started at dose level, preceding dose is the MTD.
    • if 2/3 of initially dosed patients have a DLT on first dose, study terminated.
    • if 0/3 have DLT at highest dose, additional 3 enrolled.

    Measured: 28 Days

  2. Maximum-tolerated dose.

    Defined as the dosage with the highest level at which no more than one subject experiences a DLT.

    Measured: 28 Days

  3. The number of subjects who have at least one serious adverse event related to the study.

    All subjects who receive study drug will be closely monitored for serious adverse events (SAEs). The NCI's CTCAE (Common Toxicity Criteria for Adverse Effects) v4.03 will be used.

    Measured: 60 days

  4. Overall survival

    The number of subjects alive at two years from the first day of salvage therapy.

    Measured: 2 years

Secondary outcomes (5)

  1. The number of subjects with a complete response (CR).

    A complete response will be defined as bone marrow blasts <5% with absolute neutrophil count ≥1000/μL and platelet ≥100,000/μL.

    Measured: Up to Day 60

  2. The number of subjects with CR with incomplete hematologic recovery (CRi)

    CRi is defined as CR without platelet recovery or neutrophil recovery. This will be defined as bone marrow blasts <5% with absolute neutrophil count <1000/L and platelet <100,000/L.

    Measured: Up to Day 60

  3. The number of subjects in a morphologic leukemia-free state (MLFS).

    MLFS is bone marrow blasts <5% with absolute neutrophil count <1000/μL AND platelet <100,000/μL.

    Measured: Up to Day 60

  4. The number of subjects experiencing partial remission.

    Partial remission (PR) is defined by a decrease of at 50% or more in the percentage of blasts to less than 25% in the bone marrow. and normalized blood counts ( ANC>1000, Platelets>100,000/ml).

    Measured: Up to Day 60

  5. Progression-free Survival

    The number of subjects, who from the first day of remission until one year, do not relapse or progress.

    Measured: 1 Year

Timeline

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

  1. First posted22 Feb 2018
  2. Study start22 May 2018
  3. Primary completion22 May 2024
  4. Study completion22 May 2024

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
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
26 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03441048
Sponsor's protocol ID
PRO00031633
Status last verified
Sep 2024
First submitted
15 Feb 2018
Last updated
8 Oct 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Lintuzumab-Ac-225, Cladribine and Cytarabine in people with Acute Myeloid Leukemia, run by Medical College of Wisconsin 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 11 inclusion and 7 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 8 Oct 2024. 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 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.

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

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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?

The number of subjects with dose-limiting toxicities. (time frame: 28 Days). The study lists 4 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 NCT03441048.

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 8 Oct 2024.

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