Phase I Study of S-trans, Trans-farnesylthiosalicylic Acid (FTS), a Novel Oral Ras Inhibitor, in Patients with Refractory Hematologic Malignancies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1600-1600 ◽  
Author(s):  
Gautam Borthakur ◽  
Farhad Ravandi ◽  
Susan O’Brien ◽  
Miloslav Beran ◽  
Betsy Williams ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Hematologic Malignancies ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Hematologic Toxicity ◽  
Pharmacokinetic Data ◽  
Farnesyl Transferase ◽  
Acute Myelogenous ◽  
American Society

Abstract Background: Ras activation (mutational or non-mutational) is a key pathway for survival and proliferative advantage of leukemic cells. Farnesyl transferase inhibitors (FTI) that are thought to alter lipid modification of Ras and thereby alter its membrane targeting, are in clinical trial in hematologic malignancies but their target may not be specific for Ras. Toxicities of FTIs include diarrhea, skin rash and hepatic toxicity. FTS is an oral Ras inhibitor that causes dislocation of Ras from its membrane location by competing directly with farnesylated Ras to bind to its putative membrane binding proteins. FTS does not inhibit farnesyl transferase enzyme. Methods: We report on an ongoing phase I study of FTS in patients with relapsed/refractory hematologic malignancies in which FTS is administered orally twice daily on days 1–21 of a 28 day cycle in a “3+3” dose escalation design. Results: To date, 18 patients (pts) have been enrolled, with 17 pts treated (1 cycle=2, 2 cycles=8, 4 cycles=2, 5 cycles=1, 6 cycles=2, 8 cycles=1 and 9 cycles=1). Four pts were enrolled at dose level (DL) of 100 mg, 3 pts at each DL of 200, 400, 600 and 800 mg and 2 pts at DL of 900 mg. One pt enrolled at 100 mg DL was never treated. Median age was 72 years (range, 35 to 85 years), median ECOG status 1 (range 0–2) and median no. of prior therapies 2 (range, 0–7). Diagnoses included: Acute myelogenous leukemia (AML) = 9 pts, myelodysplastic syndrome (MDS) = 5 pts, chronic myelomonocytic leukemia (CMML) = 2 pts, chronic myelogenous leukemia (CML) = 1 pt. and Myeloproliferative Disorder = 1 pt. Preliminary analysis of pharmacokinetic data indicates that both Cmax and AUC increase with dose, but less than dose proportionately. Detailed PK data will be available for presentation at the American Society of Hematology 2007 Annual Meeting. Of 17 pts evaluable for response, 7 pts (41%) (4 MDS, 1 CMML, 1 CML, 1 AML) had hematological improvement (HI) (1 in three lineages, 6 in one lineage) without any complete remission. These responses lasted for a median of 9 weeks (range, 4 to 26 weeks). Currently, 2 patients are continuing on study with improvement in cytopenia and stable disease for over 20 weeks each. Grade 1–2 diarrhea has been the only non-hematologic toxicity seen, observed in 14 of 17 (82%) pts evaluable for toxicity and is completely correctable with oral antidiarrheals. Conclusion: FTS shows promising activity in refractory hematologic malignancies and to date has minimal toxicity.

Phase I study of s-trans, trans-farnesylthiosalicylic acid (FTS), a novel oral Ras inhibitor, in patients with refractory hematologic malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7071-7071 ◽  
Author(s):  
G. Borthakur ◽  
F. Ravandi ◽  
S. O'Brien ◽  
B. Williams ◽  
F. Giles
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Hematologic Malignancies ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Hematologic Toxicity ◽  
Farnesyl Transferase ◽  
Ras Activation ◽  
Acute Myelogenous ◽  
Myelomonocytic Leukemia

7071 Background: Ras activation (mutational or non-mutational) is a key pathway for survival and proliferative advantage of leukemic cells. Farnesyl transferase inhibitors (FTI) that are thought to alter lipid modification of Ras and thereby alter its membrane targeting, are in clinical trial in hematologic malignancies but their target may not be specific for Ras. Toxicities of FTIs include diarrhea, skin rash and hepatic toxicity. FTS is an oral Ras inhibitor that causes dislocation of Ras from its membrane location by competing directly with farnesylated Ras to bind to its putative membrane binding proteins. FTS does not inhibit farnesyl transferase enzyme. Methods: We report on an ongoing phase I study of FTS in patients with relapsed/refractory hematologic malignancies in which FTS is administered orally twice daily on days 1–21 of a 28 day cycle in a “3+3” dose escalation design. Results: To date, 12 patients (pts) have been enrolled, with 11 pts treated (1 cycle=3, 2 cycles=5, 4cycles=1, 2= too early). Four pts were enrolled at dose level (DL) of 100 mg , 3 pts at each DL of 200 and 400 mg and 2 pts at DL of 600 mg. One pt enrolled at 100 mg DL was never treated. Median age was 74 years (range, 57 to 85 years), median ECOG status 1 (range, 0–2) and median no. of prior therapies 2 (range, 0–7). Diagnoses included: Acute myelogenous leukemia (AML) = 6 pts, myelodysplastic syndrome (MDS) = 4 pts, chronic myelomonocytic leukemia (CMML) = 1 pt and chronic myelogenous leukemia (CML) = 1 pt. Of 9 pts evaluable for response, 6 pts (3 MDS, 1 CMML, 2 AML) had hematological improvement (HI) (3 in two lineages, 3 in one lineage). Grade 1 diarrhea has been the only non-hematologic toxicity seen, observed in 8 of 10 (80%) pts evaluable for toxicity and is completely correctable with oral antidiarrheals. Conclusions: FTS shows promising activity in refractory hematologic malignancies and to date has minimal toxicity. No significant financial relationships to disclose.

Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia.

1997 ◽  
Vol 15 (5) ◽  
pp. 1796-1802 ◽  
Author(s):  
S M Kornblau ◽  
E Estey ◽  
T Madden ◽  
H T Tran ◽  
S Zhao ◽  
...  
Keyword(s):  
Phase I ◽  
Acute Myelogenous Leukemia ◽  
Phase I Study ◽  
Quantitative Polymerase Chain Reaction ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Psc 833 ◽  
Mdr1 Expression ◽  
Acute Myelogenous ◽  
Sdz Psc 833

PURPOSE Expression of the multidrug resistance gene (MDR1) p170 protein is frequent in leukemic blasts from patients with relapsed acute myelogenous leukemia (AML). A phase I study using the nonimmunosuppressive MDR1 blocker SDZ PSC-833 (PSC) in combination with mitoxantrone (MITO) and etoposide (VP) was performed. PATIENTS AND METHODS Starting doses (LVL0) of MITO (3.25 mg/m2/d on days 1 and 3 to 6) and VP (210 mg/m2/d on days 1 and 3 to 5) were 40% of the maximal-tolerated dose (MTD) from a prior study. A 1.5-mg/kg loading dose of PSC was followed by a 120-hour continuous infusion of 10 mg/kg/d on days 2 to 6. Blood samples for PSC, MITO, and VP pharmacokinetics (PK) were taken on days 1 and 3, and samples for MDR1 expression were taken on day 0. RESULTS Severe mucositis developed in all patients at LVL0; therefore, MITO and VP doses were reduced to 2.5 and 170 mg/m2 (LVL-1) for the next seven patients, and this dose proved to be MTD. All LVL0 and three LVL-1 patients had transient elevations in the serum bilirubin level to > or = 4 mg/dL. Serum creatinine level increased to greater than 2 mg/dL in one case. There were no other grade 3 or 4 nonhematologic toxicities observed. The peripheral blood was cleared of leukemia in three LVL0 and four LVL-1 patients. The marrow was cleared of leukemic cells in one LVL0 and five LVL-1 patients, and a significant reduction in marrow leukemic infiltrate was observed in eight of 10. No patient achieved complete remission (CR), and all died of progressive disease (n = 8) or infection (n = 2). MDR1 expression was detected by fluorescent-activated cell sorter (FACS) analysis in five of seven cases. An elevated MDR1 mRNA level was detected by quantitative polymerase chain reaction (Q-PCR) in six of eight cases studied. Clearing of leukemia cells from the marrow occurred in four of six MDR1-positive and one of three MDR1-negative patients. Despite the fact that LVL0 doses had to be reduced due to toxicity, coadministration of PSC did not produce a consistent effect on MITO PK; however, it did repeatedly lead to increased levels of VP in the serum. CONCLUSION We conclude that PSC-MITO-VP is a tolerable regimen with antileukemic activity. Addition of PSC necessitated a 66% reduction in MITO and VP doses from a prior study without PSC.

Phase I Study of Triciribine Phosphate Monohydrate, a Specific Inhibitor of AKt Phosphorylation, in Adult Patients with Advanced Hematologic Malignancies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 913-913
Author(s):  
Farhad Ravandi ◽  
Jeffrey Lancet ◽  
Francis Giles ◽  
William Plunkett ◽  
Betsy Williams ◽  
...  
Keyword(s):  
Platelet Count ◽  
Phase I ◽  
Phase I Study ◽  
Specific Inhibitor ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Pharmacokinetic Data ◽  
Akt Phosphorylation ◽  
Akt Activation ◽  
Prior Therapy

Abstract Activation of Akt, a serine/thronine protein kinase downstream of PI3 kinase, promotes cell survival through phosphorylation of Bad as well as activation of IKKa-NFkB pathway. Aberrant activation of Akt, by its amplification and overexpression, as well as through the loss of the upstream tumor suppressor PTEN, has been reported in many human cancers and is associated with poor prognosis, resistance to chemotherapy and shortened survival; disruption of Akt pathways inhibits tumor cell growth, angiogenesis and metastasis, and induces apoptosis. Through high through put screening of a library of small molecules, it has been determined that Triciribine Phosphate Monohydrate (TCN-PM), a nucleoside analog, is an inhibitor of Akt activation, and inhibition of Akt activation may be one of its antiproliferative mechanisms. We have conducted a phase I study of TCN-PM in patients with advanced hematological malignancies. Cohorts of 3 patients receive escalating doses of TCN-PM at 15, 25, 35, and 45 mg/m2 administered IV on days 1, 8, and 15 of a 28 day cycle. Twenty four (19M, 5F) patients have been enrolled in 2 institutions and have received a median of 1 cycle (range, 1 – 3) of TCN-PM including 4 in cohort I, 4 in cohort II and 16 in cohort III. Median age of the patients is 60 (range, 30 – 79). Twenty two patients had AML, 1 CLL, and 1 MDS. Median number of prior therapy before inclusion in the study was 3 (range, 1 – 7). Ten patients were inevaluable including 1 in cohort I, 1 in cohort II, and 8 in cohort III due to disease progression (in 7) and other (in 3). Dose limiting toxicity of mucositis was observed in a patient on the third cohort resulting in expansion of that cohort. No further incidences of mucositis were seen in the expanded cohort. No other severe adverse events related to treatment have been observed. 2 patients have achieved major improvements in platelet count lasting 7 and 36 days. One patient achieved a minor improvement in platelet count. Four patients have achieved major improvements in neutrophil count lasting a median of 19 (range, 8 – 40) days while on therapy. Cell death, measured by annexin-5 staining was examined in pre and post treatment samples in 14 patients; in 2 patients there was a significant increase in apoptosis to 25% and 27% after TCN-PM but this did not correlate with response. Pharmacodynamic studies evaluating inhibition of Akt phosphorylation as well as pharmacokinetic data will be presented. Accrual to higher dose levels is continuing.

scholarly journals Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia

Blood ◽  
1993 ◽  
Vol 81 (5) ◽  
pp. 1146-1151
Author(s):  
HM Kantarjian ◽  
M Beran ◽  
A Ellis ◽  
L Zwelling ◽  
S O'Brien ◽  
...  
Keyword(s):  
Partial Response ◽  
Acute Leukemia ◽  
Phase I ◽  
Continuous Infusion ◽  
Phase I Study ◽  
Topoisomerase I ◽  
Myelogenous Leukemia ◽  
Acute Myelogenous ◽  
Dose Limiting Toxicity ◽  
Severe Mucositis

The purpose of this study was to define, in a phase I study in leukemia, the maximally tolerated dose (MTD), major toxicities, and possible antitumor activity of Topotecan, a new topoisomerase I (topo I) inhibitor. Topotecan was delivered by a 5-day continuous infusion every 3 to 4 weeks to patients with refractory or relapsed acute leukemia, at doses ranging from 3.5 mg/m2 to 18 mg/m2 per course. Twenty-seven patients were treated, including 17 patients with acute myelogenous or undifferentiated leukemia, 7 with acute lymphocytic leukemia, and 3 with chronic myelogenous leukemia in blastic phase. Severe mucositis was the dose-limiting toxicity occurring in two of five patients treated with Topotecan 11.8 mg/m2 per course; a third patient had prolonged myelosuppression. At the MTD of 10 mg/m2 per course, 1 of 12 patients had severe mucositis and 5 had mild-to- moderate mucositis. Nausea, vomiting, diarrhea, and prolonged myelosuppression were uncommon. Three patients (11%) achieved a complete response, two (7%) had a partial response, and one (4%) had a hematologic improvement. The overall complete plus partial response rate was 19%, and 24% in acute myelogenous or undifferentiated leukemia. A novel in vitro assay that quantifies Topotecan-stabilized topo I-DNA complexes in patient samples was used, which demonstrated heterogeneity in the ability of Topotecan to interact with topo I, the intracellular target of Topotecan. This phase I study defined the MTD of Topotecan to be 10 mg/m2 by continuous infusion over 5 days every 3 to 4 weeks in patients with refractory or relapsed acute leukemia. Severe mucositis was the dose-limiting toxicity. Future studies will define the precise activity of Topotecan in different leukemia subsets, its efficacy in combination with other antileukemic drugs, and correlations between Topotecan-induced topo I-DNA complex formation and individual patient response to Topotecan.

A phase I study of flavopiridol using an alternative schedule in patients (pts) with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2580-2580
Author(s):  
B. Ramaswamy ◽  
M. Phelps ◽  
R. Baiocchi ◽  
T. Bekaii-Saab ◽  
D. Wilkins ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Alternative Schedule

2580 Background: A phase I study of flavopiridol, a cyclin-dependent kinase inhibitor, using an alternative schedule was conducted in pts with solid tumors given its promising activity in pts with chronic lymphocytic leukemia (CLL). Methods: Using standard 3x3 ph I dose escalation design, NCI-sponsored trial was performed to determine the safety and dose-limiting toxicity (DLT) of flavopiridol given as a 30-min IV loading dose followed by a 4-hr infusion weekly for 4 wks repeated every 6 wks. DLT was defined as Gr 4 hematologic toxicity (HT) for > 7 days, > Gr 3 non-HT except Gr 3 fatigue or diarrhea resolving <4 days and cytokine release syndrome (CRS) > Gr 3 despite steroids. Blood samples were obtained at pre-dose and 0.5, 1, 3, 4.5, 6, 8, 24, and 48-hr after start of first bolus dose for pharmacokinetics (PK). Results: 26 pts with advanced solid tumors with a median age of 63 (44–75) yrs were enrolled. Median no. of doses was 7.5 (1–24). Table 1 outlines the PK parameters, DLTs and CRS. Due to a grade 5 CRS/death in cohort 3, the protocol was amended to include 20 mg IV dexamethasone prior to flavopiridol to prevent CRS (cohorts 2B, 1B). Of the 20 evaluable pts, 35% had stable- and 65% had progressive-disease. Results of serum cytokines (IL-2, IL-4, IL-6, TNF-a, IFN-g, IL-10) levels will be presented. Conclusions: There was a higher frequency of CRS, despite prophylactic steroids seen our pts with solid tumors compared to previous studies with CLL and this correlated with AUC. PK and toxicity profile in our pt population differs from pts with hematologic malignancies administered flavopiridol on the same schedule. Protein binding and serum albumin levels are under evaluation as potential contributors. This work is supported by NCI U01-CA76576. [Table: see text] [Table: see text]

scholarly journals Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia

Blood ◽  
1993 ◽  
Vol 81 (5) ◽  
pp. 1146-1151 ◽  
Author(s):  
HM Kantarjian ◽  
M Beran ◽  
A Ellis ◽  
L Zwelling ◽  
S O'Brien ◽  
...  
Keyword(s):  
Partial Response ◽  
Acute Leukemia ◽  
Phase I ◽  
Continuous Infusion ◽  
Phase I Study ◽  
Topoisomerase I ◽  
Myelogenous Leukemia ◽  
Acute Myelogenous ◽  
Dose Limiting Toxicity ◽  
Severe Mucositis

Abstract The purpose of this study was to define, in a phase I study in leukemia, the maximally tolerated dose (MTD), major toxicities, and possible antitumor activity of Topotecan, a new topoisomerase I (topo I) inhibitor. Topotecan was delivered by a 5-day continuous infusion every 3 to 4 weeks to patients with refractory or relapsed acute leukemia, at doses ranging from 3.5 mg/m2 to 18 mg/m2 per course. Twenty-seven patients were treated, including 17 patients with acute myelogenous or undifferentiated leukemia, 7 with acute lymphocytic leukemia, and 3 with chronic myelogenous leukemia in blastic phase. Severe mucositis was the dose-limiting toxicity occurring in two of five patients treated with Topotecan 11.8 mg/m2 per course; a third patient had prolonged myelosuppression. At the MTD of 10 mg/m2 per course, 1 of 12 patients had severe mucositis and 5 had mild-to- moderate mucositis. Nausea, vomiting, diarrhea, and prolonged myelosuppression were uncommon. Three patients (11%) achieved a complete response, two (7%) had a partial response, and one (4%) had a hematologic improvement. The overall complete plus partial response rate was 19%, and 24% in acute myelogenous or undifferentiated leukemia. A novel in vitro assay that quantifies Topotecan-stabilized topo I-DNA complexes in patient samples was used, which demonstrated heterogeneity in the ability of Topotecan to interact with topo I, the intracellular target of Topotecan. This phase I study defined the MTD of Topotecan to be 10 mg/m2 by continuous infusion over 5 days every 3 to 4 weeks in patients with refractory or relapsed acute leukemia. Severe mucositis was the dose-limiting toxicity. Future studies will define the precise activity of Topotecan in different leukemia subsets, its efficacy in combination with other antileukemic drugs, and correlations between Topotecan-induced topo I-DNA complex formation and individual patient response to Topotecan.

Phase I Study of Decitabine and Rapamycin in Relapsed/Refractory Acute Myelogenous Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3549-3549
Author(s):  
Jane L. Liesveld ◽  
Kristen O'Dwyer ◽  
Michael W. Becker ◽  
Deborah Mulford ◽  
Alison Walker ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase I ◽  
Phase I Study ◽  
Stem Cell Transplant ◽  
Single Agent ◽  
Myelogenous Leukemia ◽  
Akt Pathway ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant ◽  
Acute Myelogenous

Abstract Abstract 3549 Introduction: Decitabine (5-aza-2'-deoxyctiidine) has demonstrated single agent activity in newly diagnosed acute myelogenous leukemia (AML). Complete response rates are low, however, and this agent has not been extensively studied in settings of relapsed or refractory disease where treatment responses are generally short in the absence of allogeneic stem cell transplantation. Most AML cases have activation of the mTOR pathway as evidenced by expression of phosphorylated p70S6 kinase or phopho-4EBP1. Since inhibitors of the mTOR pathway such as the tuberous sclerosis genes (TSC1 and TSC2) are hypermethylated in some cases of AML and there is evidence that decitabine may inhibit the PI3K/Akt pathway often activated after mTOR inhibition, we conducted a phase I study utilizing decitabine (DAC) followed by the mTOR inhibitor rapamycin in patients with relapsed/refractory AML to assess safety and feasibility. Methods: Patients ≥ 18 years of age with non-M3 AML with relapsed or refractory disease were eligible for this protocol. Patients who had relapsed after allogeneic stem cell transplant were eligible if they did not have active graft vs. host disease >grade 1 of skin. Patients received DAC 20 mg/m2 intravenously daily for 5 days followed by rapamycin from day 6 to 25 at doses of 2mg, 4mg, and 6 mg/day in a 3+3 dose escalation design. Cycles were 28 days in duration, and in the absence of overt progression of disease, patients could receive up to 6 cycles of therapy. A marrow aspirate was performed at day 5 to assess effects of single agent decitabine on mTOR and Akt pathway mediators. Bone marrow responses were assessed after cycles 1 and 3. Results: Thirteen patients were treated, and 12 are available for safety evaluation. The median age of patients is 64 years (range 46–78). Median marrow blast percentage at enrollment was 35% (range 6–83%). In the 2 mg dose cohort, 1 patient had disease progression before completion of cycle 1 and another patient in the first cohort had a history of prolonged neutropenia at the time of enrollment and experienced reversible grade 3 mucositis, which was deemed a DLT. Three more patients enrolled at this dose, and no further DLTs were observed, allowing dose escalation to the 4 mg and 6 mg cohorts. The MTD has not yet been reached. Reversible grade 2–3 mucositis occurred in 7 patients, but no other recurrent non-hematologic toxicities were seen. On the 2 mg cohort, all patients achieved therapeutic rapamycin levels (5–15 ng/ml) during the first cycle, and in 5/7 patients, the therapeutic level was achieved within 4 days of beginning rapamycin. In the 2 mg cohort, no cumulative increase in rapamycin levels occurred over subsequent cycles (4/7 completed >1 cycle). In the 4 mg cohort, one patient had an elevated level at day 9, and one patient on concomitant voriconazole had supra-therapeutic levels at day 16 and day 23. At the end of one cycle, 4 patients demonstrated disease progression, 5 had stable marrow blasts, and 4 demonstrated a decline in marrow blast percentage. Median survival to date is 6 months (range 1 to 15+ months). Two patients proceeded to allogeneic stem cell transplant, and one patient who relapsed shortly after stem cell transplant survived 4 months and demonstrated stable donor chimerism during that time. As assessed by Western blotting in 9 patients with evaluable samples at baseline, 87% of these cases expressed phospho (p)-4EBP1 at diagnosis, 56% p70S6K, 67% peIF4E, and 44% pAKT. In the 7 patients with Western blot samples evaluable at the end of cycle 1, 3 had decreases in p4EBP1 after the first cycle, and 4 had increased expression. Of the 7 evaluable patients, only 3 expressed baseline p70S6K, and this decreased in 2 and was unchanged in 1 patient. Conclusion: The combination of decitabine and rapamycin can be safely administered to patients with relapsed/refractory AML. Based on this phase I data, a phase II cohort to define efficacy can be conducted at the 2 mg rapamycin dosing given the therapeutic rapamycin levels demonstrated at this dose. Effects on mTOR mediators and on AKT can be serially assessed and are variable. Correlation with clinical response will require a phase II study. This trial is registered at clinical trials.gov as NCT00861874. Disclosures: Liesveld: Eisai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Ariad: Honoraria. Off Label Use: This is a phase 1 study to see if rapamycin is safe in AML.

Phase I/II study of idarubicin given with continuous infusion fludarabine followed by continuous infusion cytarabine in children with acute leukemia: a report from the Children's Cancer Group.

1997 ◽  
Vol 15 (8) ◽  
pp. 2780-2785 ◽  
Author(s):  
P A Dinndorf ◽  
V I Avramis ◽  
S Wiersma ◽  
M D Krailo ◽  
W Liu-Mares ◽  
...  
Keyword(s):  
Phase I ◽  
Continuous Infusion ◽  
Phase Ii ◽  
Phase I Study ◽  
Lymphoblastic Leukemia ◽  
Myelogenous Leukemia ◽  
Cancer Group ◽  
Major Toxicity ◽  
Acute Myelogenous ◽  
Refractory Aml

PURPOSE The Children's Cancer Group (CCG) undertook a phase I study (CCG-0922) to determine a tolerable dose of idarubicin given with fludarabine and cytarabine in children with relapsed or refractory leukemia. The phase I study was extended to a limited phase II study to assess the activity of this combination in children with acute myelogenous leukemia (AML). PATIENTS AND METHODS This was a multiinstitutional study within the CCG. Eleven patients were entered onto the phase I study: seven with AML, three with acute lymphoblastic leukemia (ALL), and one with chronic myelogenous leukemia (CML). The maximal-tolerated dose (MTD) of fludarabine and cytarabine determined in a previous study was a fludarabine loading dose (LD) of 10.5 mg/m2 followed by a continuous infusion (CI) of 30.5 mg/m2/24 hours for 48 hours, followed by cytarabine LD 390 mg/m2, then CI 101 mg/m2/h for 72 hours. Idarubicin was given at three dose levels: 6, 9, and 12 mg/m2 intravenously (I.V.) on days 0, 1, and 2. The phase II portion of the trial included 10 additional patients with relapsed or refractory AML. RESULTS A dose of idarubicin 12 mg/m2/d for 3 days given in combination with fludarabine and cytarabine was tolerated. The major toxicity encountered was hematologic. Nonhematologic toxicities included transaminase elevations, hyperbilirubinemia, and infections. Eight of 10 patients with AML in the phase II portion (12 mg/m2 idarubicin) achieved a complete remission (CR). CONCLUSION This combination is active in patients with relapsed or refractory AML. The major toxicity encountered is hematologic. This regimen may be useful therapy for AML and should be compared with standard induction therapy in children with newly diagnosed AML.

A Phase I Study of Temozolomide (Temodar®) in Pediatric Patients with Relapsed or Refractory Leukemia—A Children’s Oncology Group Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4455-4455
Author(s):  
Terzah M. Horton ◽  
Eileen Dolan ◽  
Madhuri Hegde ◽  
Stacey L. Berg ◽  
Peter Adamson ◽  
...  
Keyword(s):  
Phase I ◽  
Microsatellite Instability ◽  
Phase I Study ◽  
Sampling Strategy ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Methyl Transferase ◽  
Starting Dose ◽  
Acute Myelogenous ◽  
Dose Limiting Toxicity

Abstract A phase I study of oral temozolomide, administered daily for 5 days every 28 days, was performed in children with relapsed or primary refractory leukemias. The starting dose was 200 mg/m2/day with subsequent dose escalation to 260 mg/m2/day. Ten patients (5 male, 5 female), median age 9 years (range: 1–18 years), with leukemia (6 with acute lymphocytic leukemia [ALL], 4 with acute myelogenous leukemia [AML]) received a total of 14 cycles of temozolomide. Serum pharmacokinetic (PK) samples were obtained in 6 patients using a limited pharmacokinetic sampling strategy. Samples were also obtained from 8 patients for correlative biology studies, including analysis of methyl-guanine methyl transferase (MGMT) activity and microsatellite instability (MSI). MGMT activity was measured in 7 patients; all 3 patients with ALL tested for MGMT had elevated MGMT activity, with a median MGMT activity of 1240 fmol/mg protein (range: 356–1756). In contrast, 3 out of 4 patients with AML had MGMT activity below the limits of detection. Eight patients were tested for microsatellite instability by multiplex PCR using a panel of 13 MSI loci. Two patients (one with ALL and one with AML) demonstrated probable MSI instability. Temozolomide has been well tolerated, with no patients developing dose-limiting toxicity to date. One patient with AML, undetectable MGMT activity and no microsatellite instability had a partial response (PR) lasting 4 cycles (<10% myeloblasts in bone marrow). Further analysis is underway to determine the frequency of elevated MGMT activity in ALL and AML patients at diagnosis and following relapse.

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