Dose Escalation Studies of Cytarabine, Daunorubicin, and Etoposide With and Without Multidrug Resistance Modulation With PSC-833 in Untreated Adults With Acute Myeloid Leukemia Younger Than 60 Years: Final Induction Results of Cancer and Leukemia Group B Study 9621

2004 ◽  
Vol 22 (21) ◽  
pp. 4290-4301 ◽  
Author(s):  
Jonathan E. Kolitz ◽  
Stephen L. George ◽  
Richard K. Dodge ◽  
David D. Hurd ◽  
Bayard L. Powell ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Phase Iii ◽  
Fixed Dose ◽  
Dose Escalation Study ◽  
Data Set ◽  
Psc 833 ◽  
Group B ◽  
Acute Myeloid

Purpose P-glycoprotein (Pgp) is strongly inhibited by PSC-833. A chemotherapy dose-escalation study was performed with PSC-833 in patients younger than 60 years with untreated acute myeloid leukemia. Clinical rather than pharmacokinetic end points were used to develop two induction therapies containing drugs susceptible to Pgp-mediated efflux and associated with comparable toxicities at the maximum-tolerated doses. Patients and Methods A total of 410 patients were enrolled. Fifteen induction regimens containing variable doses of daunorubicin (DNR) and etoposide (ETOP) and fixed doses of cytarabine were evaluated with (ADEP) or without (ADE) a fixed dose of PSC-833. Results Doses selected for phase III testing were DNR 90 mg/m2 and ETOP 100 mg/m2 in ADE, and DNR and ETOP each 40 mg/m2 in ADEP. Intolerable mucosal toxicity occurred at higher doses of ADEP. Although the design of this study precludes direct comparisons, there was an apparent advantage for receiving ADEP with respect to disease-free and overall survival in patients ≤ 45 years old, despite the significantly lower doses of DNR and ETOP given in ADEP compared with ADE. Conclusion A large clinical data set was used to develop induction regimens containing two drugs susceptible to Pgp-mediated efflux, with and without an inhibitor of Pgp function. The chosen doses have comparable antileukemia activity and toxicity, making them suitable for use in a phase III comparative study of induction chemotherapy for patients with acute myeloid leukemia younger than 60 years. That trial will also clarify whether patients ≤ 45 years old are especially likely to benefit from Pgp inhibition during induction therapy.

Parallel Phase I Studies of Daunorubicin Given With Cytarabine and Etoposide With or Without the Multidrug Resistance Modulator PSC-833 in Previously Untreated Patients 60 Years of Age or Older With Acute Myeloid Leukemia: Results of Cancer and Leukemia Group B Study 9420

1999 ◽  
Vol 17 (9) ◽  
pp. 2831-2831 ◽  
Author(s):  
Edward J. Lee ◽  
Stephen L. George ◽  
Michael Caligiuri ◽  
Ted P. Szatrowski ◽  
Bayard L. Powell ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Phase I ◽  
Continuous Infusion ◽  
Myeloid Leukemia ◽  
Phase Iii ◽  
Psc 833 ◽  
Group B ◽  
Leukemia Group ◽  
Acute Myeloid

PURPOSE: The Cancer and Leukemia Group B conducted parallel phase I trials of cytarabine, daunorubicin, and etoposide (ADE) with or without PSC-833 (P), a modulator of p-glycoprotein–mediated multidrug resistance.PATIENTS AND METHODS: One hundred ten newly diagnosed patients ≥ 60 years of age with de novo acute myeloid leukemia (AML) were treated. All patients received cytarabine by continuous infusion for 7 days at 100 mg/m2/d. The starting dose of daunorubicin was 30 mg/m2/d for 3 days. Etoposide was administered at a dose of 100 mg/m2/d for 3 days, except in the last cohort administered ADEP, who received 60 mg/m2. PSC-833 was given intravenously with a loading dose of 1.5 mg/kg over 2 hours and a simultaneous continuous infusion of 10 mg/kg/d continued until 24 hours after the last dose of daunorubicin or etoposide.RESULTS: There was no toxicity attributed to the PSC-833. Dose-limiting toxicity was primarily gastrointestinal (diarrhea, mucositis in the ADEP group). The estimated maximum-tolerated doses, calculated using a logistic regression model, were daunorubicin 40 mg/m2/d for 3 days with etoposide 60 mg/m2for 3 days in the ADEP group and daunorubicin 60 mg/m2/d for 3 days and etoposide 100 mg/m2/d for 3 days in the ADE group. Twenty-one (48%) of 44 patients achieved complete remission with ADE, compared with 29 (44%) of 66 patients treated with ADEP.CONCLUSION: It is necessary to decrease the doses of daunorubicin and etoposide when they are administered with PSC-833, presumably because of the effect of the modulator on the pharmacokinetics of these agents. A phase III trial comparing the regimens derived from this phase I trial has recently begun.

Results of a Phase 1/2a dose–escalation study of FF-10501-01, an IMPDH inhibitor, in patients with acute myeloid leukemia or myelodysplastic syndromes

2020 ◽  
Vol 61 (8) ◽  
pp. 1943-1953 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Naveen Pemmaraju ◽  
Yesid Alvarado ◽  
Kiran Naqvi ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Escalation ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Dose Escalation Study ◽  
Acute Myeloid

scholarly journals Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome

2020 ◽  
Vol 4 (9) ◽  
pp. 2032-2043 ◽  
Author(s):  
Je-Hwan Lee ◽  
Stefan Faderl ◽  
John M. Pagel ◽  
Chul Won Jung ◽  
Sung-Soo Yoon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Acute Myeloid

Abstract CWP232291 (CWP291) is a small-molecule inhibitor of Wnt signaling that causes degradation of β-catenin via apoptosis induction through endoplasmic reticulum stress activation. This first-in-human, open-label, dose-escalation study to evaluate the safety, maximum tolerated dose (MTD), and preliminary efficacy of CWP291 enrolled 69 patients with hematologic malignancies (acute myeloid leukemia [AML], n = 64; myelodysplastic syndrome, n = 5) in 15 dose-escalation cohorts of 4 to 334 mg/m2 using a modified 3+3 design and 1 dose-expansion cohort. CWP291 was administered IV daily for 7 days every 21 days. The most common treatment-emergent adverse events (TEAEs) were nausea (n = 44, 64%), vomiting (n = 32, 46%), diarrhea (n = 25, 36%), and infusion-related reactions (n = 20, 29%). Grade ≥3 TEAEs in >3 patients (5%) were pneumonia (n = 8, 12%); hypophosphatemia (n = 6, 8%); leukocytosis, nausea, cellulitis, sepsis, and hypokalemia (n = 5 each, 7% each); and hypertension (n = 4, 6%). Dose-limiting toxicities included nausea (n = 3) and abdominal pain, anaphylactic reaction, myalgia, and rash (n = 1, each); the MTD was defined at 257 mg/m2. CWP232204, the active metabolite of CWP291, showed pharmacokinetic linearity on both days 1 and 7, and a terminal half-life of ∼12 hours. Among 54 response-evaluable AML patients, there was one complete response at a dose of 153 mg/m2 and one partial response at 198 mg/m2; bone marrow blast percentage reduced from a median of 58.3% to 3.5% and 15.0% to 4.2%, respectively. Future studies will explore CWP291, with a mechanism of action aimed at eradication of earlier progenitors via Wnt pathway blockade, as combination therapy. This trial was registered at www.clinicaltrials.gov as #NCT01398462.

scholarly journals Safety and Pharmacokinetics of Isavuconazole as Antifungal Prophylaxis in Acute Myeloid Leukemia Patients with Neutropenia: Results of a Phase 2, Dose Escalation Study

2015 ◽  
Vol 59 (4) ◽  
pp. 2078-2085 ◽  
Author(s):  
Oliver A. Cornely ◽  
Angelika Böhme ◽  
Anne Schmitt-Hoffmann ◽  
Andrew J. Ullmann
Keyword(s):  
Acute Myeloid Leukemia ◽  
Adverse Events ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
High Dose ◽  
Dose Escalation Study ◽  
Once Daily ◽  
Dose Cohort ◽  
Acute Myeloid

ABSTRACTIsavuconazole is a novel broad-spectrum triazole antifungal agent. This open-label dose escalation study assessed the safety and pharmacokinetics of intravenous isavuconazole prophylaxis in patients with acute myeloid leukemia who had undergone chemotherapy and had preexisting/expected neutropenia. Twenty-four patients were enrolled, and 20 patients completed the study. The patients in the low-dose cohort (n= 11) received isavuconazole loading doses on day 1 (400/200/200 mg, 6 h apart) and day 2 (200/200 mg, 12 h apart), followed by once-daily maintenance dosing (200 mg) on days 3 to 28. The loading and maintenance doses were doubled in the high-dose cohort (n= 12). The mean ± standard deviation plasma isavuconazole areas under the concentration-time curves for the dosing period on day 7 were 60.1 ± 22.3 μg · h/ml and 113.1 ± 19.6 μg · h/ml for the patients in the low-dose and high-dose cohorts, respectively. The adverse events in five patients in the low-dose cohort and in eight patients in the high-dose cohort were considered to be drug related. Most were mild to moderate in severity, and the most common adverse events were headache and rash (n= 3 each). One patient in the high-dose cohort experienced a serious adverse event (unrelated to isavuconazole treatment), and two patients each in the low-dose and high-dose cohorts discontinued the study due to adverse events. Of the 20 patients who completed the study, 18 were classified as a treatment success. In summary, the results of this analysis support the safety and tolerability of isavuconazole administered at 200 mg and 400 mg once-daily as prophylaxis in immunosuppressed patients at high risk of fungal infections. (This study is registered at ClinicalTrials.gov under registration number NCT00413439.)

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