Clinical Trials /

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

NCT02998047

Description:

1. Establish the MTD 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. Estimate progression-free survival (PFS) and overall survival

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase I Study of Lintuzumab-Ac225 in Patients With Refractory Multiple Myeloma
  • Official Title: A Phase I Study of Lintuzumab-Ac225 in Patients With Refractory Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: Lin-AC225-MM01
  • NCT ID: NCT02998047

Conditions

  • Refractory Multiple Myeloma

Interventions

DrugSynonymsArms
Lintuzumab AC 225HuM195-Ac225IV infusion of Lintuzumab AC225

Purpose

1. Establish the MTD 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. Estimate progression-free survival (PFS) and overall survival

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 3 escalating dose levels in the trial (0.5 μCi/kg, 1 μCi/kg, and 1.5 μCi/kg).
      Each dose can be administered in up to 3-8 cycles providing that the total dose received per
      patient does not exceed 4.5 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, ≥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, 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. Rules for dose escalation are:

             1. If 0 of 3 patients have a DLT, escalate to the next dose level (Unless enrolling
                patients at the 0.25 µCi/kg dose level)

             2. If 1 of 3 patients has a DLT, expand the cohort to 6 patients

             3. If ≤1 of 6 patients has a DLT, escalate to the next dose level (Unless enrolling
                patients at the 0.25 µCi/kg dose level)

             4. If ≥2 of 3 or ≥2 of 6 patients have a DLT, then the previous dose is the MTD
                (Unless enrolling patients at the 0.25 µCi/kg level, in which case the trial is
                terminated)

             5. Three patients will start at the 0.50 uCi/kg dose. The next dose level will be 1.0
                µCi/kg and the final dose level will be 1.5 µCi/kg. Dose de-escalation to 0.25
                µCi/kg will occur if, at the 0.5 µCi/kg dose, there are ≥2 of 3 or ≥2 of 6 patients
                with a DLT.

        2. If a patient has not progressed nor had CR by the end of a cycle, the patient can
           continue treatment for a maximum of three (1.5 µCi/kg), four (1.0 µCi/kg), or eight
           cycles (0.25 µCi/kg and 0.50 µCi/kg).

      All patients may receive GCSF support starting on Day 9 if clinically indicated 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.
    

Trial Arms

NameTypeDescriptionInterventions
IV infusion of Lintuzumab AC225ExperimentalStarting dose - 0.5 μCi/Kg IV infusion of Lintuzumab AC225 on Day 1 of each cycle with dose escalation 1 μCi/Kg and 1.5 μCi/Kg or de-escalation to 0.25 μCi/Kg. 1 cycle = 28 days, up to 3 to 8 cycles (depending on the cohort).
  • Lintuzumab AC 225

Eligibility Criteria

        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 0.5 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 in the opinion of
             the investigator must not be candidates for any FDA approved drug known to provide
             clinical benefit.

          -  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

               -  No bone marrow transplant within 3 months prior to treatment initiation

               -  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 radiation within 6 weeks

          -  Active serious infections uncontrolled by antibiotics

          -  Clinically significant pulmonary disease
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:Accepts Healthy Volunteers

Primary Outcome Measures

Measure:Maximum Tolerated dose of Lintuzumab-AC225
Time Frame:Through study completion, an average of 2.5 year
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:
Measure:Progression free survival
Time Frame:Through study completion, an average of 2.5 year
Safety Issue:
Description:
Measure:Overall survival
Time Frame:Through study completion, an average of 2.5 year
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Actinium Pharmaceuticals

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