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

Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03441048
• Other study ID #: PRO00031633
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: May 22, 2018
• Est. completion date: October 2024

Study information

• Verified date: November 2023
• Source: Medical College of Wisconsin
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

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

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 26
• Est. completion date: October 2024
• Est. primary completion date: May 20, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age =18 years at the time of informed consent.

2. 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.

3. 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.

4. Eastern Cooperative Oncology Group (ECOG) performance score 0-2.

5. Greater than 25% of blasts must be CD33 positive on flow cytometry using Phycoerythrin (PE) labeled anti-CD33 antibody.

6. 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%

7. Female patients must agree to avoid becoming pregnant, and male patients should avoid impregnating a female partner.

Exclusion Criteria:

1. Acute Promyelocytic Leukemia.

2. Active severe infection not well controlled by antibacterial or antiviral therapy.

3. Known infection with human immunodeficiency virus.

4. 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.

5. Pregnant or breast feeding women.

6. Prior chemotherapy or radiotherapy within 14 days of study entry unless fully recovered from adverse effects due to treatment, at investigator's discretion.

7. 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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Biological:
• Lintuzumab-Ac-225 (Dose 1: 0.25 µCi/kg Ac-225 with 1.6 µg/kg lintuzumab)
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia. Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.

Drug:
• Cladribine
Cladribine 5mg/m^2/day IV over two hours on days 2-6.
• Cytarabine
Cytarabine 2 gm/m^2/day IV over four hours on days 2-6.
• Mitoxantrone
Mitoxantrone 10mg/m^2/day IV on days 2-4.
• G-CSF
G-CSF at a dose of 300 µg on days 1-6.

Biological:
• Lintuzumab-Ac-225 (Dose 2: 0.50 µCi/kg Ac-225 with 3.2 µg/kg lintuzumab)
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia. Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
• Lintuzumab-Ac-225 (Dose 3: 0.75 µCi/kg with 4.7µg/kg lintuzumab)
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia. Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
• Lintuzumab-Ac-225 (Dose 4: 1.00 µCi/kg with 6.4 µg/kg lintuzumab)
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia. Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
• Lintuzumab-Ac-225 (Dose 5: 1.25 µCi/kg with 8.0 µg/kg lintuzumab)
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia. Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
• Lintuzumab-Ac-225 (Recommended Phase 2 Dose)
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.

Locations

Country	Name	City	State
United States	Froedtert Hospital and the Medical College of Wisconsin	Milwaukee	Wisconsin

Sponsors (1)

Lead Sponsor	Collaborator
Medical College of Wisconsin

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Maximum-tolerated dose.	Defined as the dosage with the highest level at which no more than one subject experiences a DLT.	28 Days
Primary	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
Primary	Overall survival	The number of subjects alive at two years from the first day of salvage therapy.	2 years
Secondary	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.	Up to Day 60
Secondary	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.	Up to Day 60
Secondary	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.	Up to Day 60
Secondary	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).	Up to Day 60
Secondary	Progression-free Survival	The number of subjects, who from the first day of remission until one year, do not relapse or progress.	1 Year