A Phase I Trial of Lenalidomide in Combination with Intermediate Dose Cytarabine (IDC) in Relapsed or Refractory Acute Myeloid Leukemia (AML) Patients

Abstracts Context: Lintuzumab, a humanized anti-CD33 antibody, has modest activity against AML. To increase the antibody's potency yet avoid nonspecific cytotoxicity seen with b-emitting isotopes, 225 Ac (t1/2 ¼10 days), which yields 4 a-emitting isotopes, was conjugated to lintuzumab. Objectives: We sought to determine the MTD, toxicity, pharmacokinetics, and antileukemic activity of 225 Ac-lintuzumab. Design: We conducted a first-in-man, phase I, 3+3, dose-escalation trial from 2006-2012. Setting: This was a single-institution study performed at a tertiary cancer center. Patients: Eighteen patients (median age, 64 yrs; range, 45-80 yrs) with relapsed (n¼11) or refractory (n¼7) AML were treated. Intervention: Patients received a single infusion of 225Ac-lintuzumab at doses of 0.5 (n¼3), 1 (n¼4), 2 (n¼3), 3 (n¼6) or 4 (n¼2) mCi/kg. Main Outcome Measure: MTD was defined as the highest dose for which the incidence of DLT was < 33%. Results: DLT's included myelosuppression lasting > 35 days in 1 patient receiving 4 mCi/kg and death from sepsis in 2 patients receiving 3 and 4 mCi/kg. The MTD was 3 mCi/kg. Myelosuppression was the most common toxicity. Median time to resolution of grade 4 leukopenia was 27 days (range, 0-71 days). Significant extramedullary toxicities were limited to transient grade 3 liver function abnormalities in 3 patients. We analyzed plasma pharmacokinetics by gamma counting at energy windows for 2 daughters of 225Ac, francium-221 and bismuth-213. Two-phase elimination kinetics were seen with mean plasma t1/2 -a and t1/2 -b of 1.9 and 38 hours, respectively, similar to other lintuzumab constructs containing long-lived radionuclides. Peripheral blasts were eliminated in 10 of 16 evaluable patients (63%), but only at doses of  1 mCi/kg. Marrow blast reductions were seen in 10 of 15 evaluable patients (67%) at 4 weeks, including 8 patients (53%) who had blast reductions of  50%. Three patients receiving 1, 3, and 4 mCi/kg achieved marrow blasts of  5%. Conclusions: This is the first study to show that therapy with a targeted a-particle generator is feasible in humans. 225Ac-lintuzumab had antileukemic activity across all dose levels and is now being investigated in a multicenter phase I/II trial in combination with low-dose cytarabine for older AML patients.

516 A Phase I Trial of Lenalidomide in Combination with Intermediate Dose Cytarabine (IDC) in Relapsed or Refractory Acute Myeloid Leukemia (AML) Patients Carlos E. Vigil,1 Elizabeth A. Griffiths,1 James E. Thompson,1 William E. Brady,2 Noelle M. Dickey,3 Laurie Ann Ford,1 Eunice S. Wang,1 Meir Wetzler1 1

Leukemia Section, Roswell Park Cancer Institute ,Buffalo, NY;

2

Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, NY;

3

Research Coordinator Services, Roswell Park Cancer Institute, Buffalo,

NY

aberrations achieved cytogenetic complete response. Dose escalations to 50 mg daily for 21 days were safe and active with relatively minimal toxicity (Blum et al, JCO 2010). Low single-agent CR rates, prompt the question of whether combining lenalidomide with chemotherapy might improve outcomes. IDC induces CR in approximately 17% of relapsed/refractory AML pts (Faderl et al, JCO 2012), thus we performed a phase I study to assess the safety and preliminary activity of IDC followed by lenalidomide in this patient population. Objectives: -To determine the maximum tolerated dose (MTD) of lenalidomide following IDC therapy in relapsed/refractory AML patients in the dose finding phase. To evaluate the safety and preliminary anti-leukemic activity of this combination in the dose expansion phase. Methods: The study has two phases: A dose finding and a dose expansion phase. IDC was administered at 1.5 gm/m2/day on days 1-5 of a 28 day cycle followed by lenalidomide given days 6-10 (6-10d) or days 6-26 (6-26d).The lenalidomide doses were 25mg, 15mg and 10mg. A maximum of two such inductions were allowed if only a partial response was observed. Upon achievement of CR, lenalidomide maintenance was given daily for 28 days until disease progression. Results: Twenty patients have been enrolled in the dose finding arm of this study. The median age is 70. Two patients have insufficient follow-up to report treatment results and adverse events. Thirteen pts (72%) have received more than two prior therapies. The number of pts with dose limiting toxicities (DLTs) at each dose level (DL) was: 0/4 pts in DL 1 (25 mg/d; 6-10d), 4/6 (all grade 3 non-blistering macularpapular rash) in DL 2 (25 mg/d; 6-26d), 3/7 pts (grade 3 AST, grade 3 anorexia, grade 3 bilirubin) in DL 3 (15 mg/d; 6-26d), and 0/3 pts in DL 4 with no DLT at present time and 2 pts with no information available (10 mg/d; 6-26d). Severe (grade 35) adverse events (SAEs) were observed in 17 of 18 pts. The most frequent hematological SAEs were thrombocytopenia (89%). anemia (83%) and neutropenia (61%). The most frequent non-hematological SAEs included nausea and vomiting (61%), skin rash (39%) and fatigue (33%). Two patients achieved CR and 1 patient demonstrated CR without platelet recovery (CRp) for an overall CR/CRp rate of 17% (3/18 evaluable patients). Three patients had stable disease. Conclusions: IDC and lenalidomide can be safely administered to refractory/relapsed AML pts. The dose expansion phase is ongoing at lenalidomide 10mg daily.

**517 Comparison of Outcome in Erythroleukemia Patients Treated with Standard Chemotherapy Regimens or Hypomethylating Agents Carlos E. Vigil ,1 Wei Tan,2 Gregory Wilding,2 Guillermo Garcia-Manero,3 Eunice S. Wang,1 Meir Wetzler,1 Alan F. List4 1

Leukemia Section, Department of Medicine, Roswell Park Cancer

Background: Lenalidomide, an oral immunomodulator, has been studied as a single agent in the treatment of relapsed/refractory AML. In a recent study, five (16%) of 31 patients (pts) achieved complete remission (CR), and all three pts with karyotype

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Clinical Lymphoma, Myeloma & Leukemia September 2013

Institute, Buffalo,NY; 2Department of Biostatistics, Roswell Park Cancer Institute, Buffalo,NY; 3Department of Leukemia, MD Anderson Cancer Center, Houston, TX; 4Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL