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

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.

• Cytarabine (Phase 1 only) (Drug), also known as Low dose Ara-C, LDAC: 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.
• Lintuzumab-Ac225 (Biological), also known as HuM195-Ac225, Actimab-A: 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.
• Furosemide (Phase 1 only) (Drug), also known as Lasix: 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.
• Spironolactone (Drug), also known as Aldactone: 25 mg by mouth daily, administered 10 days after second dose of 225Ac-HuM195 and continued for 12 months.

Primary outcomes

• 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.
• 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 outcomes

• Phase II: PFS [1 year]: Progression Free Survival
• Phase II: LFS [1 year]: Leukemia Free Survival
• Phase II: OS [1 year]: Overall Survival
• Phase II: Toxicity Spectrum [1 year]: Safety Data

Sex: All, ages: 60 Years to any

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

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• Avinash Desai, MD, Study chair, Actinium Pharmaceuticals Inc.