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BACKGROUND: Constitutive activation of signal transducer and activator of transcription-3 (STAT3) was detected in blasts from approximately 50% of patients with acute myeloid leukemia (AML) and was correlated with an adverse outcome. In vitro treatment of AML blasts with arsenic trioxide (ATO) down-regulated STAT3 activity within 6 hours associated with a reduced viability within 48 hours. METHODS: A phase 1 clinical trial to evaluate the biologically effective dose and/or the maximally tolerated dose (MTD) of ATO in vivo in conjunction with high-dose cytarabine (Hidac) and idarubicin (Ida) in patients with AML aged

Heat shock protein 90 (Hsp90) is a molecular chaperone with many oncogenic client proteins. The small-molecule Hsp90 inhibitor alvespimycin, a geldanamycin derivative, is being developed for various malignancies. This phase 1 study examined the maximum-tolerated dose (MTD), safety and pharmacokinetic/pharmacodynamic profiles of alvespimycin in patients with advanced acute myeloid leukemia (AML). Patients with advanced AML received escalating doses of intravenous alvespimycin (8-32 mg/m(2)), twice weekly, for 2 of 3 weeks. Dose-limiting toxicities (DLTs) were assessed during cycle 1. A total of 24 enrolled patients were evaluable for toxicity. Alvespimycin was well tolerated; the MTD was 24 mg/m(2) twice weekly. Common toxicities included neutropenic fever, fatigue, nausea and diarrhea. Cardiac DLTs occurred at 32 mg/m(2) (elevated troponin and myocardial infarction). Pharmacokinetics revealed linear increases in C(max) and area under the curve (AUC) from 8 to 32 mg/m(2) and minor accumulation upon repeated doses. Pharmacodynamic analyses on day 15 revealed increased apoptosis and Hsp70 levels when compared with baseline within marrow blasts. Antileukemia activity occurred in 3 of 17 evaluable patients (complete remission with incomplete blood count recovery). The twice-weekly administered alvespimycin was well tolerated in patients with advanced AML, showing linear pharmacokinetics, target inhibition and signs of clinical activity. We determined a recommended phase 2 dose of 24 mg/m(2).

Patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) refractory to or in relapse following induction chemotherapy have a poor prognosis, and inducing an immune response to autologous AML or ALL cells following chemotherapy is an attractive approach to improving outcome. Immune responses to autologous leukemia cells may be stimulated by dendritic cell presentation of leukemia cell antigens, dendritic cells may be deficient in acute leukemia, and administration of the recombinant hematopoietic growth factors granulocyte-monocyte colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) following chemotherapy may increase dendritic cell numbers. We compared the effects of GM-CSF and G-CSF administered following high-dose chemotherapy. Adult relapsed and refractory AML and ALL patients received salvage chemotherapy consisting of high-dose cytarabine 3 g/m2 (1.5 g/m2 for age ≥50 years) over one hour every 12 hours × 12 doses and mitoxantrone 12 mg/m2 daily × 3 (HiDAC/Mx), and at completion of chemotherapy were randomized to receive GM-CSF 250 mcg/m2 or G-CSF 5 mcg/kg daily beginning 12 hours after the last chemotherapy dose, until absolute neutrophil count ≥5 × 109〈1 year) and late (≥1 year) first and subsequent relapse. Peripheral blood was collected when ANC reached 5 × 109/L for measurement of myeloid dendritic cell (lineage-negative, HLADr+, CD11c+) percentages by flow cytometry. Sixty patients were enrolled, ages 18 to 82 (median 66) years, 41 male and 19 female, 47 with AML and 13 with ALL, and 15 with primary refractory disease, 27 in early and 17 in late first relapse and one in subsequent relapse; 6 had relapsed following allogeneic transplantation. Overall, 22 of 60 patients (37%) achieved CR and 4 (7%) CR with incomplete count recovery (CRi), while 23 (38%) had resistant disease and 11 (18%) died. The regimen was generally well tolerated, the most frequent grade ≥4 toxicities pulmonary, infectious and cardiac, in 8, 7 and 6 patients, respectively, and 13 patients subsequently received transplant-based therapies (9 allogeneic, 4 autologous). 56 patients were randomized, as 4 died or stopped therapy before randomization, and randomization was to GM-CSF in 29 patients and G-CSF in 27. CR and CRi were achieved by 13 and 1 patients of 29 patients receiving GM-CSF and 9 and 3 of 27 receiving G-CSF (p NS, Fisher’s Exact Text). ANC ≥0.5 was achieved at 22 to 98 days (median 27) from start of chemotherapy in 25 GM-CSF patients and at 18 to 65 days (median 25) in 20 G-CSF patients (p=0.08, Wilcoxon Rank Sum Test). Toxicities did not differ significantly on the two arms. Only 17 patients (G-CSF: 7 and GM-CSF: 10) had blood samples submitted and successfully studied for myeloid dendritic cell percentages. Myeloid dendritic cell percentages were 0 to 40 (median 22), and the comparison by treatment group showed no evidence of a difference. In summary, HiDAC/Mx is an effective salvage regimen in this high-risk population and may serve as a bridge to transplant-based therapies or, possibly, a backbone for targeted therapies, myeloid dendritic cells are present at count recovery in patients receiving GM-CSF or G-CSF following HiDAC/Mx, and treatment outcome, toxicities, count recovery and myeloid dendritic cell percentages did not differ in patients receiving GM-CSF or G-CSF following HiDAC/Mx.

Background: Alvespimycin (KOS-1022), an Hsp90 inhibitor and a derivative of geldanamycin, is in phase 1 trials investigating a variety of intravenous and oral schedules. Compared to 17-AAG (the first Hsp90 inhibitor to enter clinical testing), KOS-1022 is ~3–5 fold more potent (comparing in vitro cytotoxicity or the MTD in toxicology studies); its formulation is water-soluble. The objectives of this trial were to establish the MTD and recommended phase 2 dose in patients with refractory hematologic malignancies; to assess the safety, to document responses and to characterize the PK and PD of KOS-1022. Methods: Escalating doses of KOS-1022 were given IV over 1 hour twice weekly for 2 out of 3 weeks; premedications were not given. Plasma KOS-1022 concentrations (1st and 4th infusion in Cycle 1) were quantitated by LC/MS/MS. Pre and on-study CD34+ bone marrow and peripheral blasts were analyzed by flow cytometry to quantify HSP70/90, pAKT/total AKT and markers of apoptosis and proliferation. Toxicity was assessed by CTCAE v 3.0; responses in AML pts were assessed using Cheson JCO 2003 criteria. Results: 24 pts were enrolled at doses of 8 (n=4), 16 (n=7), 24 (n=11) and 32mg/m2 (n=2). All were AML, except 1 CML pt; 3 pts had FLT3 mutations. Median age 72; median ECOG PS 1; most (n=21) patients had had 2 or 3 prior induction regimens. Cardiac DLT was noted in 2 patients treated at 32 mg/m2 (acute myocardial infarction and elevation of troponin; significant co-morbidity existed for both pts: prior myocardial infarction on post-mortem/CHF/ventricular hypertrophy and rapidly progressive AML with troponin elevation during induction chemotherapy 6 weeks prior to study). Cardiotoxicity was not notable at the three lower doses. Common drug-related toxicities (all Grade 1–2): fatigue 29%, nausea 19%, diarrhea 14%, arthralgias and dizziness 14%. Grade 3–4 non-hematological toxicity (except for the DLT noted above) was not observed. KOS-1022 PK: Cmax was roughly dose-proportional and clearance (CL) showed no clear dose- or time-dependency. The median Cmax, CL, and elimination half-life for the 24 mg/m2 cohort (n=8) were 291 ng/mL, 16.0 L/hr/m2, and 18.1 h, respectively, after dosing on Day 1. Comparing exposure on Day 1 and Day 11 at 24 mg/m2 (n=6), AUC values were 1951 and 2168 ng*hr/mL, respectively; pre-infusion drug levels at this dose on Day 11 were 8 ng/mL. In the six pts with matched pairs of bone marrow aspirates, increased apoptosis by mitochondrial potential was observed on Day 15, after four infusions; (p=0.027). Activity in AML: 3 pts with CRi; one patient remained stable on study x 9 cycles (three of these pts had wild-type FLT3 and one had unknown FLT3 status). Conclusions: Encouraging signs of antileukemia activity were observed in a refractory population. Using a twice weekly schedule, 24 mg/m2 was well tolerated in this population. KOS-1022 plasma PK are generally linear over this dose range. Apoptosis of bone marrow cells by flow cytometry was observed after 4 infusions.