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Lintuzumab-Ac225 in Older Acute Myeloid Leukemia (AML) Patients

Sponsor
Actinium Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT02575963
Collaborator
(none)
40
Enrollment
17
Locations
1
Arm
91
Duration (Months)
2.4
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study is a multicenter, open label Phase I/II trial.

  1. Establish the MTD of fractionated doses of Lintuzumab-Ac225 in combination with low dose cytosine arabinoside (Low Dose Ara-C, LDAC) (Phase 1 portion)

  2. Determine the response rate (CR + CRp + CRi) to fractionated doses of Lintuzumab-Ac225 alone (Phase 2 portion)

Condition or Disease Intervention/Treatment Phase
  • Drug: Cytarabine (Phase 1 only)
  • Biological: Lintuzumab-Ac225
  • Drug: Furosemide (Phase 1 only)
  • Drug: Spironolactone
 Phase 1/Phase 2

Detailed Description

The study is a multicenter, open label Phase I/II trial. Phase I, dose-escalation: This portion of the overall study uses a 3+3 design to estimate the maximum tolerated dose (MTD). The starting dose level will be 1.0 μCi/Kg of Lintuzumab-Ac225 and 15 μg/Kg unlabeled HuM195 divided into 2 equal fractionated doses (0.5 μCi/Kg and 7.5 μg /Kg + 0.5 μCi/Kg and 7.5 μg /Kg) with the first fraction administered approximately 4 - 7 days after 1 cycle of LDAC (20 mg subQ every 12 h x 10 days administered for cytoreduction) and the second fraction administered 4-7 days after the first fraction. Subjects will then go on to receive up to 11 additional cycles of LDAC or until progression of disease. 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.

Phase II, efficacy component. The study was designed as a 2- stage minimax design. Patients will be given two infusions of Lintuzumab-Ac225, 4-8 days apart (Day 5-Day 9), initially at the dose level determined to be the MTD in the Phase I portion. The second dose of Lintuzumab-Ac225 may be delayed up to 14 days after the first dose for clinical or scheduling reasons. Response will be initially assessed on or around days 28-42 after the final study drug administration. The primary endpoint (CR+CRp + CRi) will be determined on day 42. Best response will be evaluated from Day 1, Dose 1 until the end of the study.

Study Design

Study Type:
Interventional
Actual Enrollment :
40 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I/II Study of Lintuzumab-Ac225 in Older Patients With Untreated Acute Myeloid Leukemia
Study Start Date :
Oct 1, 2012
Actual Primary Completion Date :
Nov 1, 2018
Actual Study Completion Date :
May 1, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Phase 1 (Completed)

Cytarabine + Lintuzumab-Ac225 Cytarabine days 1 to 10 of each cycle. Doses were divided into 2 equal fractions with the first fraction given approx. 4-7 days after 1 cycle of low dose cytarabine and the second fraction given 4-7 days after the first fraction, followed by up to 11 more cycles. Furosemide (Phase 1 only) and Spironolactone were administered after Lintuzumab-Ac225. Experimental: Phase 2 Experimental: Lintuzumab-Ac225 The Phase II dose determined during the Phase I dose escalation was 4.0 μCi/Kg Lintuzumab-Ac225 and 25 μg/Kg unlabeled HuM195 divided into 2 equal fractions with the first fraction given on Day 1 and the second fraction given on Day 5-8. Spironolactone is administered after Lintuzumab-Ac225.

Drug: Cytarabine (Phase 1 only)
Low dose cytarabine administered at 20 mg subcutaneously every 12 hours for the first 10 days (Days 1 to 10) of every cycle. Cycle 1 can last up to 52 days (depending on the schedule of study drug dosing) in order to allow for recovery from Lintuzumab-Ac225. Cycles 2-12 will last 28 days each.
Other Names:
  • Low dose Ara-C
  • LDAC

    • Biological: Lintuzumab-Ac225
    In Phase 1 the starting dose level was 1.0 μCi/Kg of Lintuzumab-Ac225 and 15 μg/Kg unlabeled HuM195 divided into 2 equal fractionated doses (0.5 μCi/Kg and 7.5 μg /Kg + 0.5 μCi/Kg and 7.5 μg /Kg) with the first fraction administered approximately 4-7 days after 1 cycle of low dose cytarabine and the second fraction administered 4-7 days after the first fraction, followed by up to 11 more cycles. In Phase 2 the dose will be 4.0 μCi/Kg Lintuzumab-Ac225 and 25 μg/Kg unlabeled HuM195 divided into 2 equal fractions with the first fraction given on Day 1 and the second fraction given on Day 5-8.
    Other Names:
  • HuM195-Ac225
  • Actimab-A

    • Drug: Furosemide (Phase 1 only)
    40 mg by mouth daily one day prior to treatment with Lintuzumab-Ac225 and continuing for 10 days following administration of the 2nd divided dose.
    Other Names:
  • Lasix

    • Drug: Spironolactone
    25 mg by mouth daily, administered 10 days after second dose of 225Ac-HuM195 and continued for 12 months.
    Other Names:
  • Aldactone

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Phase I: Maximum Tolerated Dose (MTD) of Lintuzumab-Ac225 [Cycle 1, up to 52 days]

      If two or more patients in a cohort experience dose limiting toxicity (DLT), then maximum tolerated dose (MTD) will have been exceeded, and no further dose escalation will occur. If only three patients were treated at a dose level under consideration as the MTD, then up to three additional patients will be accrued. If no more than one of the six patients at that dose level experiences DLT, then that dose level will be confirmed as the MTD.

    2. Phase II: CR+CRp+CRi [First evaluation at 42 days after treatment]

      The primary objective is to determine the antileukemic effects, including its ability to produce complete remissions, of Lintuzumab-Ac225.

    Secondary Outcome Measures

    1. Phase II: PFS [1 year]

      Progression Free Survival

    2. Phase II: LFS [1 year]

      Leukemia Free Survival

    3. Phase II: OS [1 year]

      Overall Survival

    4. Phase II: Toxicity Spectrum [1 year]

      Safety Data

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    60 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Phase 1 Major Inclusion Criteria:

    1. Untreated AML, including patients with an antecedent hematologic disorder or secondary disease. Patients with prior MDS may have received therapy with immunomodulatory agents or hypomethylating agents for this diagnosis. Patients with other prior cancer diagnoses are allowed as long as they have no measurable disease, are not undergoing active therapy, and have a life expectancy of ≥ 4 months.

    2. Patients age ≥60 years who:

    3. Are unwilling to receive intensive (e.g. 7+3) chemotherapy, or

    4. Have poor-risk prognostic factors defined as antecedent hematologic disorder, prior chemotherapy or XRT, abnormal karyotype other than t(8;21), inv16, or t(16;16), any karyotype with FLT3-ITD, or presenting WBC>100K, or

    5. Have significant comorbidities, that in the judgment of the investigator makes the subject unsuitable for standard dose induction chemotherapy (e.g. anthracycline and infusional cytarabine given as 7+3), or;

    6. Any patient age ≥ 70 years.

    7. Blast count ≥20%

    8. Greater than 25% of blasts must be CD33 positive.

    9. Adequate renal and hepatic function

    10. ECOG ≤ 3

    Phase 2 Inclusion Criteria:

    1. Untreated AML, including patients with an antecedent hematologic disorder or secondary disease. Patients with prior MDS may have received therapy with immunomodulatory agents for this diagnosis.

    2. Patients age ≥60 years who:

    3. Patients ≥60 years unfit to receive intensive (e.g., 7+3) chemotherapy who have:

    • Congestive heart failure or documented cardiomyopathy with an EF ≤50%, provided that EF ≥35% or,

    • Documented pulmonary disease with DLCO ≤65% or FEV1 ≤65%, provided that patients do not require more than 2 L of oxygen per minute or,

    • Documented liver disease with marked elevation of transaminases >3 x ULN or,

    • Serum creatinine >1.2 mg/dL

    1. Have significant comorbidities, that in the judgment of the investigator makes the subject unsuitable for standard dose induction chemotherapy (e.g., anthracycline and infusional cytarabine given as 7+3); or

    2. Any patient age ≥ 75 years.

    3. Blast count ≥ 20% (WHO criteria)

    4. Greater than 25% of blasts must be CD33 positive.

    5. Have a circulating blast count of less than 200/mm3 (control with hydroxyurea or similar agent is allowed);

    6. Creatinine < 2.0 mg/dl

    7. Estimated creatinine clearance ≥ 50ml/min

    8. Bilirubin ≤ 2.0 mg/dl; AST and ALT < 5.0 times the ULN

    9. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2

    Exclusion Criteria:

    1. Patients with acute promyelocytic leukemia

    2. Treatment with chemotherapy or biologic therapy within 3 weeks, except for hydroxyurea, which must be discontinued prior to treatment on study

    3. Treatment with radiation within 6 weeks

    4. Active serious infections uncontrolled by antibiotics

    5. Active malignancy within 2 years of entry, except previously treated non-melanoma skin cancer, carcinoma in situ or cervical intraepithelial neoplasia, and organ confined prostate cancer with no evidence of progressive disease based on PSA levels and are not on active therapy.

    6. Clinically significant cardiac or pulmonary disease

    7. Patients with liver cirrhosis

    8. Active CNS leukemia. Patients with symptoms of CNS involvement, particularly those with M4 or M5 subtypes, should undergo lumbar puncture prior to treatment on study to exclude CNS disease. Symptoms include cranial neuropathies, other neurologic deficits, and headache.

    9. Psychiatric disorder that would preclude study participation

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 UCLA Medical Center, Division of Hematology/Oncology Los Angeles California United States 90095
    2 University of Kentucky, Markey Cancer Center Lexington Kentucky United States 40536
    3 University of Louisville, James Graham Brown Cancer Center Louisville Kentucky United States 40202
    4 Ochsner Medical Center, The Gayle and Tom Benson Cancer Center New Orleans Louisiana United States 70121
    5 Mayo Clinic Rochester Minnesota United States 55905
    6 Weill Medical College of Cornell University New York New York United States 10021
    7 Columbia University Medical, Herbert Irving Comprehensive Cancer Center New York New York United States 10032
    8 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    9 Duke Cancer Center Durham North Carolina United States 27705
    10 University of Pennsylvania, Perelman Center for Advanced Medicine Philadelphia Pennsylvania United States 19104
    11 St. Francis Cancer Center Greenville South Carolina United States 29607
    12 Baylor Scott and White Research Institute, Charles A. Sammons Cancer Center Dallas Texas United States 75246
    13 Swedish Cancer Institute, Center for Blood Disorders and Stem Cell Transplantation Seattle Washington United States 98104
    14 Fred Hutchinson Cancer Research Center Seattle Washington United States 98109
    15 West Virginia University, Mary Babb Randolph Cancer Center Morgantown West Virginia United States 26506
    16 Medical College of Wisconsin Cancer Center Milwaukee Wisconsin United States 53226
    17 VA Caribbean Healthcare System San Juan Puerto Rico 00921

    Sponsors and Collaborators

    • Actinium Pharmaceuticals

    Investigators

    • Study Chair: Avinash Desai, MD, Actinium Pharmaceuticals Inc.

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Actinium Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT02575963
    Other Study ID Numbers:
    • API-01
    • NCT01756677
    First Posted:
    Oct 15, 2015
    Last Update Posted:
    Mar 9, 2022
    Last Verified:
    Feb 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Additional relevant MeSH terms:
    Leukemia, Myeloid, Acute
    Cytarabine
    Lintuzumab
    Furosemide
    Spironolactone

    Study Results

    No Results Posted as of Mar 9, 2022