Clinical trial NCT02575963: Lintuzumab-Ac225 in Older Acute Myeloid Leukemia (AML) Patients
Official title: A Phase I/II Study of Lintuzumab-Ac225 in Older Patients With Untreated Acute Myeloid Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: AML
Lead sponsor: Actinium Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2015-10-15
Enrollment: 40
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Phase I: Maximum Tolerated Dose (MTD) of Lintuzumab-Ac225
timeFrame: Cycle 1, up to 52 days
measure: Phase II: CR+CRp+CRi
timeFrame: First evaluation at 42 days after treatment
Secondary outcomes:
measure: Phase II: PFS
timeFrame: 1 year
measure: Phase II: LFS
timeFrame: 1 year
measure: Phase II: OS
timeFrame: 1 year
measure: Phase II: Toxicity Spectrum
timeFrame: 1 year
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Medical Center, Division of Hematology/Oncology
state: California
city: Lexington
country: United States
facility: University of Kentucky, Markey Cancer Center
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville, James Graham Brown Cancer Center
state: Kentucky
city: New Orleans
country: United States
facility: Ochsner Medical Center, The Gayle and Tom Benson Cancer Center
state: Louisiana
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: New York
country: United States
facility: Columbia University Medical, Herbert Irving Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke Cancer Center
state: North Carolina
city: Philadelphia
country: United States
facility: University of Pennsylvania, Perelman Center for Advanced Medicine
state: Pennsylvania
city: Greenville
country: United States
facility: St. Francis Cancer Center
state: South Carolina
city: Dallas
country: United States
facility: Baylor Scott and White Research Institute, Charles A. Sammons Cancer Center
state: Texas
city: Seattle
country: United States
facility: Swedish Cancer Institute, Center for Blood Disorders and Stem Cell Transplantation
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Morgantown
country: United States
facility: West Virginia University, Mary Babb Randolph Cancer Center
state: West Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin Cancer Center
state: Wisconsin
city: San Juan
country: Puerto Rico
facility: VA Caribbean Healthcare System
Study officials:
affiliation: Actinium Pharmaceuticals Inc.
name: Avinash Desai, MD
role: STUDY_CHAIR
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