A Phase I Study of Lintuzumab-Ac225 in Patients With Refractory Multiple Myeloma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02998047
Recruitment Status : Recruiting
First Posted : December 20, 2016
Last Update Posted : October 20, 2017
Information provided by (Responsible Party):
Actinium Pharmaceuticals

Brief Summary:
  1. Establish the MTD of fractionated doses of Lintuzumab-Ac225 as monotherapy
  2. Establish overall response rate (ORR) where ORR = CR + sCR+ VGPR+PR)
  3. Confirm the safety profile of the treatment regimen
  4. Determine changes in plasmocyte, T-cell and MDSC cell populations
  5. Estimate progression-free survival (PFS) and overall survival

Condition or disease Intervention/treatment Phase
Refractory Multiple Myeloma Drug: Lintuzumab AC 225 Phase 1

Detailed Description:

The study is a multicenter, open label Phase I trial. Phase 1, dose-escalation : This study uses a 3+3 design to estimate the maximum tolerated dose (MTD).

There will be 2 escalating dose levels in the trial (0.5 μCi/kg and 1 μCi/kg,). Each dose can be administered in up to 4-8 cycles providing that the total dose received per patient does not exceed 4 μCi/kg.

De-escalation (decrease dose level to 0.25 μCi/kg) is planned if at the first dose level of 0.5 μCi/kg, after expanding the cohort to a maximum of 6 patients, ≥1/3 patients have M protein decrease >10% AND ≥2 patient have DLTs. At the dose level of 0.25 μCi/kg, if eligible to continue receiving additional doses of the study drug, patients will receive up to 8 doses in total, with the total administered activity being 2 μCi/kg.

The starting dose level will be 0.5 μCi/kg of 225Ac-Lintuzumab administered on day 1 of each cycle. If this dose level is safe, the second dose level of 1 μCi/kg will be explored. If the starting dose level results in DLTs in ≥2 patients and ≥1/3 patients have M protein decrease >10%, the dose level of 0.25 μCi/kg will be explored.

Subjects will receive the investigational drug as a single infusion at the prescribed dose level.

Intra cohort dose escalation/ decrease is not allowed.

Minimum three to maximum six patients will be treated at each dose level, and dose escalation will proceed as follows:

  1. if 1/3 patients have M protein decrease >10% on Day 42 AND no patients have DLTs, redose at the same dose level by Day 60 if ANC and PLT counts allow;
  2. if 1 patient at the given dose level has DLTs, expand the cohort by adding 3 more patients at that dose level.
  3. if 1/3 of patients in the expanded cohort exhibit DLTs, proceed to the next dose level.
  4. if at the first dose level,after expanding the cohort to a maximum of 6 patients .1/3 patients have M protein decrease >10% AND .2 patient has DLTs, decrease dose level to 0.25 uCi/kg
  5. if no patients at the reduced dose level of 0.25 uCi/kg have M protein decrease >10% AND 1 patient has DLTs terminate trial
  6. if none of the patients have DLTs at the given dose level, escalate to the next dose level.
  7. if 2 or more patient exhibit DLTs at any given dose level, the previous dose level will be considered MTD.
  8. if 2/3 patients respond with PR or better and <1/3 patients have DLTs, complete Phase 1 portion at that dose level (no further dose escalation).
  9. if patients who have at least stable disease are eligible to receive an additional cycle of treatment by Day 60 and their response status remains worse than CR, they will continue receiving repeated doses of study drug every 60 days after cycle 2 until they have received a cumulative dose of up to 4 ìCi/kg or until they achieve CR, whichever is sooner.

All patients will receive GCSF support starting on Day 9 and continuing until ANC>1,000.

After the dose escalation portion is completed, treat 3 additional patients at the highest established dose level to confirm MTD and establish that dose level as MTD.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Lintuzumab-Ac225 in Patients With Refractory Multiple Myeloma
Study Start Date : December 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : January 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
Experimental: IV infusion of Lintuzumab AC225
Starting dose - 0.5 μCi/Kg IV infusion of Lintuzumab AC225 on Day 1 of each cycle with dose escalation 1 μCi/Kg or de-escalation to 0.25 μCi/Kg. 1 cycle = 42 days, up to 8 cycles. Re-dosing is done no sooner than 60 days.
Drug: Lintuzumab AC 225
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of multiple myeloma.
Other Name: HuM195-Ac225

Primary Outcome Measures :
  1. Maximum Tolerated dose of Lintuzumab-AC225 [ Time Frame: Through study completion, an average of 2.5 year ]
  2. Adverse events- Treatment Emergent [ Time Frame: Through study completion, an average of 2.5 year ]

Secondary Outcome Measures :
  1. Response rates (objective response rate, complete response rate, stringent complete response rate, very good partial response rate and partial response rate) [ Time Frame: Through study completion, an average of 2.5 year ]
  2. Progression free survival [ Time Frame: Through study completion, an average of 2.5 year ]
  3. Overall survival [ Time Frame: Through study completion, an average of 2.5 year ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria-

  • Confirmed diagnosis of multiple myeloma with measurable disease, as defined by the presence of M immunoglobulin protein in serum electrophoresis of at least 1 g/dL for IgG or 0.5 g/dL for IgA or urinary excretion of at least 200 mg monoclonal light chain per 24 hours.
  • Clinical diagnosis of multiple myeloma requiring treatment that has relapsed after or proven refractory to at least three prior treatment regimens, and must not be candidates for any regimen known to provide clinical benefit.
  • No multiple myeloma treatment (ie, chemotherapy, biological, immunotherapy or investigational agent [therapeutic or diagnostic]) within three weeks prior to treatment initiation.
  • No bone marrow transplant within 3 months prior to treatment initiation.
  • All acute toxicities from any prior therapy (radiotherapy, chemotherapy, or surgical procedures) resolved to Grade ≤ 2, NCI CTCAE.
  • Serum potassium and magnesium levels within institutional normal limits. Total serum calcium or ionized calcium level must be greater than or equal to the lower limit of normal.
  • Greater than 25% of myeloma plasmocytes from bone marrow must be CD33 positive.
  • Required baseline laboratory data including: White blood cell count, Absolute neutrophil count (ANC), Platelets, Hemoglobin, Serum creatinine, AST, Creatinine clearance, Bilirubin , AST and ALT , FEV1/FVC
  • Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2

Exclusion Criteria-

  • Sex and Reproductive Status

    • Women of child bearing potential (WOCBP) who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least one month (4 weeks) before and for at least six months (6 months) after the last dose of study medication.
    • Women who are pregnant or breastfeeding
    • Women with a positive pregnancy test on enrollment or prior to investigational product administration.
    • Men whose sexual partners are WOCBP, who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least six months (6 months) after completion of study medication.
  • Target Disease Exceptions

    • Concurrent therapy with any other investigational agent.
    • Concomitant therapy with bisphosphonates.
    • Pathological fracture within 3 months prior to treatment;
    • Symptomatic spinal cord compression;
  • Medical History and Concurrent Diseases

    • Treatment with chemotherapy or biological therapy 3 weeks prior to enrollment;
    • Presence of HAHA on screening
    • Prior treatment with radiation to cumulative maximum tolerated dose
    • Clinically significant cardiac disease (NYHA Class III or IV) including preexisting arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or "Torsade de Pointes")
    • Myocardial infarction, uncontrolled angina within 6 months, congestive heart failure, or cardiomyopathy.
    • Abnormal QTc interval prolonged (> 450 msec) after electrolytes have been corrected on baseline ECG.
    • Clinically significant pleural effusion in the previous 12 months or current ascites.
    • Clinically-significant coagulation or platelet function disorder (eg, known von Willebrand's disease).
    • Prior or concurrent malignancy, except for the following:

      i) Adequately treated basal cell or squamous cell skin cancer ii) Cervical carcinoma in situ iii) Adequately treated Stage I or II cancer from which the subject is currently in complete remission iv) Or any other cancer from which the subject has been disease-free for 3 years.

  • Physical and Laboratory Test Findings

    o Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality, serious uncontrolled medical disorder or active infection that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for this study.

  • Allergies and Adverse Drug Reactions

    o Intolerance to humanized monoclonal antibodies

  • Other Exclusion Criteria

    • Prisoners or subjects who are involuntarily incarcerated.
    • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
  • Treatment with chemotherapy or biologic therapy within 3 weeks
  • Treatment with radiation within 6 weeks
  • Active serious infections uncontrolled by antibiotics
  • Clinically significant pulmonary disease

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02998047

Contact: Actinium Pharmaceuticals,Inc (Director of Clinical Operations)

United States, Texas
Baylor Scott and White Research Institute, Charles A. Sammons Cancer Center Recruiting
Dallas, Texas, United States, 75246
Sponsors and Collaborators
Actinium Pharmaceuticals
Study Director: Mark Berger, MD Actinium Pharmaceuticals

Responsible Party: Actinium Pharmaceuticals Identifier: NCT02998047     History of Changes
Other Study ID Numbers: Lin-AC225-MM01
First Posted: December 20, 2016    Key Record Dates
Last Update Posted: October 20, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: This is not yet decided. We will update this section as and when the information become available prior to the end of the study

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs