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

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02575963
Recruitment Status : Active, not recruiting
First Posted : October 15, 2015
Last Update Posted : May 26, 2020
Sponsor:
Information provided by (Responsible Party):
Actinium Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE October 7, 2015
First Posted Date  ICMJE October 15, 2015
Last Update Posted Date May 26, 2020
Study Start Date  ICMJE October 2012
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 11, 2017)
  • Phase I: Maximum Tolerated Dose (MTD) of Lintuzumab-Ac225 [ Time Frame: 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.
  • Phase II: CR+CRp+CRi [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 13, 2015)
  • Phase I: Maximum Tolerated Dose (MTD) of Lintuzumab-Ac225 [ Time Frame: 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.
  • Phase II: CR+CRp [ Time Frame: Up to 22 weeks from enrollment ]
    The primary objective is to determine the antileukemic effects, including its ability to produce complete remissions, of Lintuzumab-Ac225.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 16, 2015)
  • Phase II: PFS [ Time Frame: 1 year ]
    Progression Free Survival
  • Phase II: LFS [ Time Frame: 1 year ]
    Leukemia Free Survival
  • Phase II: OS [ Time Frame: 1 year ]
    Overall Survival
  • Phase II: Toxicity Spectrum [ Time Frame: 1 year ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 13, 2015)
  • Phase II: Response Rate [ Time Frame: After 4, 28 day cycles ]
    Response criteria defined by Cheson et al. used. Patients assessed for response at the end of Cycle 4 (just prior to Cycle 5 LDAC administration). The response rate, complete remission plus complete remission with incomplete platelet count recovery (CR + CRp), is primary efficacy endpoint.
  • Phase II: PFS [ Time Frame: 1 year ]
    Progression Free Survival
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Lintuzumab-Ac225 in Older Acute Myeloid Leukemia (AML) Patients
Official Title  ICMJE A Phase I/II Study of Lintuzumab-Ac225 in Older Patients With Untreated Acute Myeloid Leukemia
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)
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE AML
Intervention  ICMJE
  • 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 Name: Lasix
  • Drug: Spironolactone
    25 mg by mouth daily, administered 10 days after second dose of 225Ac-HuM195 and continued for 12 months.
    Other Name: Aldactone
Study Arms  ICMJE 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.

Interventions:
  • Drug: Cytarabine (Phase 1 only)
  • Biological: Lintuzumab-Ac225
  • Drug: Furosemide (Phase 1 only)
  • Drug: Spironolactone
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: October 13, 2015)
72
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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:

    1. Are unwilling to receive intensive (e.g. 7+3) chemotherapy, or
    2. 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
    3. 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;
    4. Any patient age ≥ 70 years.
  3. Blast count ≥20%
  4. Greater than 25% of blasts must be CD33 positive.
  5. Adequate renal and hepatic function
  6. 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:

    1. 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
    2. 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
    3. 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02575963
Other Study ID Numbers  ICMJE API-01
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Actinium Pharmaceuticals
Study Sponsor  ICMJE Actinium Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Mark Berger, MD Actinium Pharmaceuticals Inc.
PRS Account Actinium Pharmaceuticals
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP