Phase I Trial of Targeted Alpha-Particle Therapy with Actinium-225 (225Ac)-Lintuzumab and Low-Dose Cytarabine (LDAC) in Patients Age 60 or Older with Untreated Acute Myeloid Leukemia (AML)
Author:
Jurcic Joseph G.1, Levy Moshe Yair2, Park Jae H.3, Ravandi Farhad4, Perl Alexander E.5, Pagel John M.6, Smith B. Douglas7, Estey Elihu H.8, Kantarjian Hagop4, Cicic Dragan9, Scheinberg David A.10
Affiliation:
1. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 2. Charles A Sammons Cancer Center, Texas Oncology-Baylor, Dallas, TX 3. Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 4. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 5. Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 6. Swedish Medical Center, Seattle, WA 7. Department of Oncology, Division of Hematological Malignancies, Sidney Kimmel Comprehensive Cancer Center at John Hopkins, Baltimore, MD 8. Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA 9. Actinium Pharmaceuticals, Inc., New York, NY 10. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY
Abstract
Abstract
Background: 225Ac-lintuzumab is a radioimmunoconjugate composed of 225Ac (t½=10 days), which emits 4 α-particles, linked to a humanized anti-CD33 monoclonal antibody. Short-ranged (50-80 µm), high-energy (~100 keV/µm) α particle-emitting isotopes such as 225Ac may result in more specific tumor cell kill and less damage to normal tissues than β-emitters. An initial phase I trial in 20 patients with relapsed/refractory AML showed that a single infusion of 225Ac-lintuzumab is safe at doses ≤ 3 µCi/kg and has anti-leukemic activity (Jurcic et al. ASH, 2011). We conducted a multicenter, phase I dose-escalation trial to determine the maximum tolerated dose (MTD), toxicity, and biological activity of fractionated-dose 225Ac-lintuzumab in combination with LDAC.
Patients and Methods: Patients ≥ 60 years with untreated AML not candidates for standard induction therapy (e.g., antecedent hematologic disorder, poor-risk cytogenetic or molecular features, and significant comorbidities) were eligible. Patients received LDAC 20 mg twice a day for 10 days every 4-6 weeks for up to 12 cycles. During Cycle 1, 2 fractions of 225Ac-lintuzumab were given 1 week apart, beginning 4-7 days following completion of LDAC. To prevent radiation-induced nephrotoxicity, patients were given furosemide while receiving 225Ac-lintuzumab then spironolactone for 1 year afterward. Four dose levels of 225Ac-lintuzumab were studied using a 3+3 design. Dose escalation proceeded if < 33% of patients in a cohort experienced dose-limiting toxicity (DLT).
Results: Eighteen patients (median age, 77 years; range, 68-87 years) completed therapy. Twelve (67%) had prior myelodysplastic syndrome (MDS), for which 10 (83%) received therapy with hypomethylating agents (n=9) or allogeneic hematopoietic cell transplantation (n=1). One patient (6%) had chronic myeloid leukemia in molecular remission prior to developing AML. Eleven patients (61%) had intermediate-risk and 7 (39%) had poor-risk disease by NCCN criteria. Median CD33 expression was 81% (range, 30-100%). 225Ac-lintuzumab was given at 0.5 (n=3), 1 (n=6), 1.5 (n=3), or 2 (n=6) μCi/kg/fraction. Up to 4 cycles of LDAC were administered. Two patients experienced DLT (grade 4 thrombocytopenia with marrow aplasia for > 6 weeks following therapy), one each in the 1 and 2 µCi/kg/fraction cohorts. Although the MTD was not reached, 2 µCi/kg/fraction was chosen as the phase II dose to limit prolonged myelosuppression. Hematologic toxicities included grade 4 neutropenia (n=5) and thrombocytopenia (n=9). Grade 3/4 non-hematologic toxicities included febrile neutropenia (n=6), pneumonia (n=5), other infections (n=3), atrial fibrillation/syncope (n=1), transient creatinine increase (n=1), generalized fatigue (n=1), hypokalemia (n=1), mucositis (n=1), and rectal hemorrhage (n=1). Thirty- and 60-day mortality rates were 0% and 17%, respectively. Eleven of 14 patients (79%) evaluated after Cycle 1 had bone marrow blast reductions (mean reduction, 66%; range, 19-100%). Objective responses (2 CR, 1 CRp, 2 CRi) were seen in 5 of the 18 patients (28%), but only at doses ≥ 1 µCi/kg/fraction (Table 1). One of the responders received 15 cycles of azacitidine for prior MDS. All responses occurred after 1 cycle of therapy, in contrast to historical data with LDAC alone, where the median time to response was 3 cycles. Median progression-free survival (PFS) for all patients was 2.7 months (range, 1.0-31.8+ months). Median overall survival (OS) was 5.6 months (range, 1.6-32+ months). Median response duration was 5.6 months (range, 4.9-32+ months). Peripheral blood blast counts were a strong predictor of response. Among 38 patients treated in the current and initial phase I trials, responses were seen in 8 of 19 patients (42%) with blast counts < 200/µL, compared with 0 of 17 patients with blast counts ≥ 200/µL (P=0.002). This difference is likely due to decreased marrow targeting in patients with higher circulating blast counts when the subsaturating antibody doses used in this trial are given.
Conclusions: Fractionated-dose 225Ac-linutuzmab can be safely combined with LDAC and induce remission in older patients with untreated AML. A phase II trial of 225Ac-lintuzumab monotherapy at 2 µCi/kg/fraction using hydroxyurea, if needed, to lower peripheral blast counts prior toadministration will be undertaken to determine response rate, PFS, and OS in this patient population.
Disclosures
Jurcic: Forma Therapeutics: Research Funding; Seattle Genetics: Research Funding; Kura Oncology: Research Funding; Celgene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Alexion Pharmaceuticals: Consultancy; Merck & Co.: Consultancy; Astellas: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding; Daiichi-Sankyo: Research Funding. Levy:Janssen: Speakers Bureau; Actinium Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Research Funding; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau. Park:Amgen: Consultancy; Genentech/Roche: Research Funding; Juno Therapeutics: Consultancy, Research Funding. Ravandi:Actinium Pharmaceuticals, Inc.: Research Funding. Perl:Actinium Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Consultancy. Smith:Actinium Pharmaceuticals, Inc.: Research Funding. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Scheinberg:Actinium Pharmaceuticals, Inc.: Equity Ownership, Patents & Royalties: Ac-225-Lintuzumab.
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
Cited by
43 articles.
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