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

Conditions:Blood Cancer, Hematology, Hematology
Therapuetic Areas:Hematology, Oncology
Age Range:18 - Any
Start Date:December 2016
End Date:January 2020
Contact:Actinium Pharmaceuticals,Inc (Director of Clinical Operations)

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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

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

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

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

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.

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

- 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

- 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
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Los Angeles, California 90095
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3901 Rainbow Blvd
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