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

NCT03441048 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: PRO00031633
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief 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. This study uses a 3+3 design with a five-patient cohort at the recommended phase 2 dose.

Conditions

Acute Myeloid Leukemia

Keywords

Acute myeloid leukemia; Relapsed/refractory acute myeloid leukemia; CLAG-M; Lintuzumab

Outcome Measures

Primary Outcomes (4)

• 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.

  28 Days

• Maximum-tolerated dose.

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

  28 Days

• 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.

  60 days

• Overall survival

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

  2 years

Secondary Outcomes (5)

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

  Up to Day 60

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

  Up to Day 60

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

  Up to Day 60

• The number of subjects experiencing partial remission.

  Up to Day 60

• Progression-free Survival

  1 Year

Study Arms (6)

Lintuzumab Ac225 (Dose 1 - 0.25 μCi/kg Ac-225 with 1.6 μg/kg lintuzumab)

EXPERIMENTAL

Dose 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.

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)

EXPERIMENTAL

Dose 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.

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)

EXPERIMENTAL

Dose 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.

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)

EXPERIMENTAL

Dose 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.

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)

EXPERIMENTAL

Dose 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.

Biological: Lintuzumab-Ac-225; Drug: Cladribine; Drug: Cytarabine; Drug: Mitoxantrone; Drug: G-CSF

Lintuzumab Ac225 Recommended Phase 2 Dose (RP2D)

EXPERIMENTAL

The 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.

Biological: Lintuzumab-Ac-225; Drug: Cladribine; Drug: Cytarabine; Drug: Mitoxantrone; Drug: G-CSF

Interventions

Lintuzumab-Ac-225 BIOLOGICAL

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

Also known as: HuM195-Ac225, Actimab-A

Lintuzumab Ac225 (Dose 1 - 0.25 μCi/kg Ac-225 with 1.6 μg/kg lintuzumab); Lintuzumab Ac225 (Dose 2 - 0.50 μCi/kg Ac-225 with 3.2 μg/kg lintuzumab); Lintuzumab Ac225 (Dose 3 - 0.75 μCi/kg Ac-225 with 4.7μg/kg lintuzumab); Lintuzumab Ac225 (Dose 4 - 1.00 μCi/kg Ac-225 with 6.4 μg/kg lintuzumab); Lintuzumab Ac225 (Dose 5 - 1.25 μCi/kg Ac-225 with 8.0 μg/kg lintuzumab); Lintuzumab Ac225 Recommended Phase 2 Dose (RP2D)

Cladribine DRUG

Cladribine is a purine antimetabolite.

Also known as: Leustatin, Mavenclad

Lintuzumab Ac225 (Dose 1 - 0.25 μCi/kg Ac-225 with 1.6 μg/kg lintuzumab); Lintuzumab Ac225 (Dose 2 - 0.50 μCi/kg Ac-225 with 3.2 μg/kg lintuzumab); Lintuzumab Ac225 (Dose 3 - 0.75 μCi/kg Ac-225 with 4.7μg/kg lintuzumab); Lintuzumab Ac225 (Dose 4 - 1.00 μCi/kg Ac-225 with 6.4 μg/kg lintuzumab); Lintuzumab Ac225 (Dose 5 - 1.25 μCi/kg Ac-225 with 8.0 μg/kg lintuzumab); Lintuzumab Ac225 Recommended Phase 2 Dose (RP2D)

Cytarabine DRUG

Cytarabine is an antineoplastic anti-metabolite.

Also known as: Cytosar-U, Depocyt, cytosine arabinoside (ara-C)

Lintuzumab Ac225 (Dose 1 - 0.25 μCi/kg Ac-225 with 1.6 μg/kg lintuzumab); Lintuzumab Ac225 (Dose 2 - 0.50 μCi/kg Ac-225 with 3.2 μg/kg lintuzumab); Lintuzumab Ac225 (Dose 3 - 0.75 μCi/kg Ac-225 with 4.7μg/kg lintuzumab); Lintuzumab Ac225 (Dose 4 - 1.00 μCi/kg Ac-225 with 6.4 μg/kg lintuzumab); Lintuzumab Ac225 (Dose 5 - 1.25 μCi/kg Ac-225 with 8.0 μg/kg lintuzumab); Lintuzumab Ac225 Recommended Phase 2 Dose (RP2D)

Mitoxantrone DRUG

Mitoxantrone is an anthracenedione antineoplastic agent.

Also known as: Mitozantrone, Novantrone

Lintuzumab Ac225 (Dose 1 - 0.25 μCi/kg Ac-225 with 1.6 μg/kg lintuzumab); Lintuzumab Ac225 (Dose 2 - 0.50 μCi/kg Ac-225 with 3.2 μg/kg lintuzumab); Lintuzumab Ac225 (Dose 3 - 0.75 μCi/kg Ac-225 with 4.7μg/kg lintuzumab); Lintuzumab Ac225 (Dose 4 - 1.00 μCi/kg Ac-225 with 6.4 μg/kg lintuzumab); Lintuzumab Ac225 (Dose 5 - 1.25 μCi/kg Ac-225 with 8.0 μg/kg lintuzumab); Lintuzumab Ac225 Recommended Phase 2 Dose (RP2D)

G-CSF DRUG

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

Also known as: colony-stimulating factor 3 (CSF 3)

Lintuzumab Ac225 (Dose 1 - 0.25 μCi/kg Ac-225 with 1.6 μg/kg lintuzumab); Lintuzumab Ac225 (Dose 2 - 0.50 μCi/kg Ac-225 with 3.2 μg/kg lintuzumab); Lintuzumab Ac225 (Dose 3 - 0.75 μCi/kg Ac-225 with 4.7μg/kg lintuzumab); Lintuzumab Ac225 (Dose 4 - 1.00 μCi/kg Ac-225 with 6.4 μg/kg lintuzumab); Lintuzumab Ac225 (Dose 5 - 1.25 μCi/kg Ac-225 with 8.0 μg/kg lintuzumab); Lintuzumab Ac225 Recommended Phase 2 Dose (RP2D)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Medical College of Wisconsin: lead

Study Sites (1)

Froedtert Hospital and the Medical College of Wisconsin

Milwuakee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Cladribine; Cytarabine; Mitoxantrone; Granulocyte Colony-Stimulating Factor

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Quinones; Polycyclic Compounds; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Sameem Abedin, MD

  Medical College of Wisconsin

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: February 15, 2018
• First Posted: February 22, 2018
• Study Start: May 22, 2018
• Primary Completion: May 22, 2024
• Study Completion: May 22, 2024
• Last Updated: October 8, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)