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Targeted Atomic Nano-Generators (Actinium-225-Labeled Humanized Anti-CD33 Monoclonal Antibody HuM195) in Patients With Advanced Myeloid Malignancies

Primary Purpose

Leukemia, Myelodysplastic Syndrome

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

ACTINIUM-225-LABELED HUMANIZED ANTI-CD33 MONOCLONAL ANTIBODY HuM195

About this trial

This is an interventional treatment trial for Leukemia focused on measuring MAB HUM 195 ACTINIUM-225 LABELED, HEMATOPOIETIC SYSTEM, 02-017

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients must have one of the following pathologically confirmed diagnoses:
AML in relapse,
AML refractory to at least 2 courses of standard induction chemotherapy or one course of high-dose cytarabine-containing induction chemotherapy,
CML in accelerated phase or myeloid blast crisis that has progressed after treatment with imatinib and a second generation tyrosine kinase inhibitor (e.g., dasatinib or nilotinib)
RAEB with International Prognostic Scoring System (IPSS) score ≥ 2.5, or - CMMOL with IPSS score ≥ 2.5 refractory to or relapsed after a hypomethylating agent (e.g., azacitidine or decitabine) refractory to or relapsed after a hypomethylating agent (e.g., azacitidine or decitabine).
Greater than 25% of bone marrow blasts must be CD33 positive.
Patients must have a life expectancy of at least 6 weeks and a Karnofsky performance status of ≥ 60%.
Adequate renal function as demonstrated by a serum creatinine ≤ 1.5 mg/dl, a creatinine clearance > 60 ml/min, and < 1 gram urinary protein/24 hours.
Adequate hepatic function as demonstrated by a bilirubin ≤ 1.5 mg/dl (unless attributable to leukemia or Gilbert's disease) and alkaline phosphatase and AST ≤ 2.5 times the upper limit of normal.

Exclusion Criteria:

Untreated AML, regardless of prognostic features.
Treatment with chemotherapy or biologic therapy within 3 weeks of 225Ac- HuM195 administration. Hydroxyurea is permitted but must be discontinued prior to treatment on study. Patients must have recovered from the effects of previous treatment.
Treatment with radiation therapy within 6 weeks of 225Ac-HuM195 administration. Patients must have recovered from the effects of previous treatment.
Active serious infections not controlled by antibiotics.
Pregnant women or women who are breast-feeding.
Concurrent active malignancy requiring therapy.
Clinically significant cardiac disease (NY Heart Association Class III or IV)or pulmonary disease.
Patients with HLA-compatible donor bone marrow who are immediate candidates for bone marrow transplantation.
Patients who are candidates for alternative treatments of known effectiveness.
Patients eligible for protocols of higher priority.
Patients previously treated with any monoclonal antibody for any reason.
Active CNS leukemia
Other serious or life-threatening conditions deemed unacceptable by the principal investigator.

Sites / Locations

Memorial Sloan Kettering Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm Description

This is a phase I, dose-escalation trial. The starting dose level will be 0.5 μCi/kg of 225Ac-HuM195. Three to six patients will be treated at each dose level, and dose escalation will proceed if less than 33% of patients in a cohort experience dose limiting toxicity. Six patients will be treated at the maximum tolerated dose

Outcomes

Primary Outcome Measures

To determine the maximum tolerated dose of 225Ac-HuM195 that can be administered to patients with advanced myeloid leukemias.

Secondary Outcome Measures

To determine the pharmacokinetics and dosimetry of 225Ac-HuM195.

To determine the biological effects of 225Ac-HuM195, including its ability to produce complete remissions.

Full Information

NCT ID

NCT00672165

First Posted

May 2, 2008

Last Updated

February 24, 2015

Sponsor

Memorial Sloan Kettering Cancer Center

Collaborators

National Cancer Institute (NCI), Actinium Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT00672165

Brief Title

Targeted Atomic Nano-Generators (Actinium-225-Labeled Humanized Anti-CD33 Monoclonal Antibody HuM195) in Patients With Advanced Myeloid Malignancies

Official Title

Phase I Trial of Targeted Atomic Nano-Generators (Actinium-225-Labeled Humanized Anti-CD33 Monoclonal Antibody HuM195) in Patients With Advanced Myeloid Malignancies

Study Type

Interventional

2. Study Status

Record Verification Date

February 2015

Overall Recruitment Status

Completed

Study Start Date

July 2005 (undefined)

Primary Completion Date

February 2015 (Actual)

Study Completion Date

February 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Memorial Sloan Kettering Cancer Center

Collaborators

National Cancer Institute (NCI), Actinium Pharmaceuticals

4. Oversight

5. Study Description

Brief Summary

The purpose of this study is to find a safe dose of actinium-225 when it is labeled to HuM195. This will be done with a "phase I trial," in which a preset schedule of doses gets more powerful for each new group of patients as the trial progresses. If too many serious side effects are seen with a certain dose, no one will be treated with a higher dose, and some additional patients may be treated with a lower dose to make sure that this dose is safe. The starting dose of actinium-225 in this study is less than doses that are known to be safe in animals. Antibodies are proteins that are produced by the immune system and help the body to fight foreign substances, such as bacteria or viruses. HuM195 was made by putting human leukemia cells into mice. Most of the mouse parts of this antibody were replaced with human parts. Only the part of the antibody that binds to the leukemia cells was kept from the mouse. HuM195 attaches to leukemia cells but does not attach to most normal cells. It can kill small amounts of disease by identifying the leukemia cells as "foreign." HuM195 has worked less well against large amounts of leukemia since the normal immune cells needed to kill leukemia cells are lowered in most patients with leukemia.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Leukemia, Myelodysplastic Syndrome

Keywords

MAB HUM 195 ACTINIUM-225 LABELED, HEMATOPOIETIC SYSTEM, 02-017

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

23 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

ACTINIUM-225-LABELED HUMANIZED ANTI-CD33 MONOCLONAL ANTIBODY HuM195

Intervention Description

A single infusion of 225Ac-HuM195 will be administered at a starting dose of 0.5 μCi/kg. Additionally, 100 mCi of 213Bi-HuM195 have been administered with full dose cytarabine (200 mg/m2 daily for 5 days) without dose-limiting toxicity.Serial sampling of blood, urine, and bone marrow will be performed following treatment to determine the toxicity, pharmacokinetics, immunogenicity, and antileukemic effects. Three to six patients will be treated at each dose level. Dose escalation will proceed if less than 33% of patients in a cohort experience dose-limiting toxicity.Patients will be followed until completion of therapy as outlined in the study, loss to follow-up, death, or until the day the patient is removed from the study.

Primary Outcome Measure Information:

Title

To determine the maximum tolerated dose of 225Ac-HuM195 that can be administered to patients with advanced myeloid leukemias.

Time Frame

conclusion of study

Secondary Outcome Measure Information:

Title

To determine the pharmacokinetics and dosimetry of 225Ac-HuM195.

Time Frame

conclusion of the study

Title

To determine the biological effects of 225Ac-HuM195, including its ability to produce complete remissions.

Time Frame

conclusion of the study

10. Eligibility

Sex

All

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients must have one of the following pathologically confirmed diagnoses: AML in relapse, AML refractory to at least 2 courses of standard induction chemotherapy or one course of high-dose cytarabine-containing induction chemotherapy, CML in accelerated phase or myeloid blast crisis that has progressed after treatment with imatinib and a second generation tyrosine kinase inhibitor (e.g., dasatinib or nilotinib) RAEB with International Prognostic Scoring System (IPSS) score ≥ 2.5, or - CMMOL with IPSS score ≥ 2.5 refractory to or relapsed after a hypomethylating agent (e.g., azacitidine or decitabine) refractory to or relapsed after a hypomethylating agent (e.g., azacitidine or decitabine). Greater than 25% of bone marrow blasts must be CD33 positive. Patients must have a life expectancy of at least 6 weeks and a Karnofsky performance status of ≥ 60%. Adequate renal function as demonstrated by a serum creatinine ≤ 1.5 mg/dl, a creatinine clearance > 60 ml/min, and < 1 gram urinary protein/24 hours. Adequate hepatic function as demonstrated by a bilirubin ≤ 1.5 mg/dl (unless attributable to leukemia or Gilbert's disease) and alkaline phosphatase and AST ≤ 2.5 times the upper limit of normal. Exclusion Criteria: Untreated AML, regardless of prognostic features. Treatment with chemotherapy or biologic therapy within 3 weeks of 225Ac- HuM195 administration. Hydroxyurea is permitted but must be discontinued prior to treatment on study. Patients must have recovered from the effects of previous treatment. Treatment with radiation therapy within 6 weeks of 225Ac-HuM195 administration. Patients must have recovered from the effects of previous treatment. Active serious infections not controlled by antibiotics. Pregnant women or women who are breast-feeding. Concurrent active malignancy requiring therapy. Clinically significant cardiac disease (NY Heart Association Class III or IV)or pulmonary disease. Patients with HLA-compatible donor bone marrow who are immediate candidates for bone marrow transplantation. Patients who are candidates for alternative treatments of known effectiveness. Patients eligible for protocols of higher priority. Patients previously treated with any monoclonal antibody for any reason. Active CNS leukemia Other serious or life-threatening conditions deemed unacceptable by the principal investigator.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Dan Douer, MD

Organizational Affiliation

Memorial Sloan Kettering Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Memorial Sloan Kettering Cancer Center

City

New York

State/Province

New York

ZIP/Postal Code

10065

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

35357290

Citation

Nikitaki Z, Velalopoulou A, Zanni V, Tremi I, Havaki S, Kokkoris M, Gorgoulis VG, Koumenis C, Georgakilas AG. Key biological mechanisms involved in high-LET radiation therapies with a focus on DNA damage and repair. Expert Rev Mol Med. 2022 Mar 31;24:e15. doi: 10.1017/erm.2022.6.

Results Reference

derived

Links:

URL

http://www.mskcc.org

Description

Memorial Sloan Kettering Cancer Center

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Targeted Atomic Nano-Generators (Actinium-225-Labeled Humanized Anti-CD33 Monoclonal Antibody HuM195) in Patients With Advanced Myeloid Malignancies

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