Phase I Study to Evaluate the Pharmacokinetics of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants

15058 Background: Imexon for inj. (Amplimexon®, AMP) is an aziridine-containing iminopyrrolidone which causes G2 arrest, accumulation of reactive oxygen species, and induction of apoptosis in pancreatic cancer cells. AMP demonstrated synergy with gemcitabine (GEM) in preclinical pancreatic cancer models. This phase I study of AMP plus GEM was undertaken to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Secondary endpoints were pharmacokinetics for both agents (PK) and tumor response. Methods: Patients (pts) with previously untreated advanced pancreatic adenocarcinoma received one of two dosing regimens. The first 19 received 30 minute AMP IV days 1–5 and 15–19 followed by 30 minute GEM IV days 1, 8 and 15 Q4 wks (Regimen A). Dosing was modified after 19 pts to administer both AMP and GEM over 30 minutes days 1, 8 and 15 every 4 weeks (Regimen B). Dose levels (AMP/GEM, in mg/m2) for Regimen A: 200/800, 280/800, 200/1000, and 280/1000, and for Regimen B: 280/1000, 335/1000, 390/1000, 540/1000, and 750/1000. The current cohort is 1000/1000. Pts were assessed for response after cycles 2, 5 and 8. PK and pharmacodynamic (plasma thiol depletion) measurements were obtained during cycle one. Results: Forty-six pts have been treated to date, with 36 having complete toxicity data and evaluable. Pt characteristics: M/F (24/12), Age (mean 60.4 years, range 43–75), ECOG PS 0/1 (56%, 44%), metastatic/locally advanced (91%, 9%). The 36 pts have completed 122.5 cycles of therapy (median 2, range 0.5–12). Common toxicities: anemia (77%), fatigue (71%), nausea (60%), fever (54%), and leukopenia (54%). DLT were 1/6 at 280/1000 (Regimen A - febrile neutropenia), 1/6 at 280/1000 (Regimen B - gr 3 hypotension, gr 4 renal failure), and 1/9 at 390/1000 (gr 3 hyperbilirubinemia). Accrual continues at 1000/1000. Of 36 pts, 4 have had partial responses and 14 stable disease. PK and plasma thiol analysis are ongoing. Conclusions: Imexon can be administered safely with full dose gemcitabine. Accrual continues to define the combination MTD. The response rate in this phase I study compares favorably with historical gemcitabine monotherapy, and further phase II evaluation of this combination in advanced pancreatic cancer is warranted. No significant financial relationships to disclose.

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Phase I study of gadolinium texaphyrin in newly diagnosed glioblastoma

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.2064 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 2064-2064

Author(s):

E. G. Shaw ◽

S. A. Grossman ◽

K. A. Carson ◽

J. D. Fisher ◽

L. Kleinberg

Keyword(s):

Phase I ◽

Initial Dose ◽

Phase I Study ◽

Radiation Treatment ◽

Tumor Therapy ◽

Maximum Tolerated Dose ◽

Cellular Respiration ◽

Newly Diagnosed ◽

Dosing Regimens ◽

Newly Diagnosed Glioblastoma

2064 Background: Gadolinium texaphyrin (Gad Tex) is a putative radiosensitizer which inhibits cellular respiration resulting in the production of reactive oxygen species and induces apoptosis (Drugs R D. 2004; 5(1):52–7). Methods: The New Approaches to Brain Tumor Therapy (NABTT) consortium conducted a prospective phase I dose-escalation trial to determine the maximum tolerated dose of Gad Tex along with brain radiation therapy (RT) in newly diagnosed glioblastoma multiforme with KPS > 60. RT was 60 Gy in 30 fractions, 5 days per week over 6 weeks, to localized treatment fields. Two different dosing regimens of Gad Tex were utilized. In regimen A, the initial dose was 2.5 mg/kg with each daily fraction of RT whereas in regimen B it was 5.5 mg/kg with every fraction of RT. Gad Tex was administered 2–5 hours before each radiation treatment. Results: The initial dose in both regimen A and B was found not to be tolerable. Of three patients treated at 2.5 mg/kg/dose on regimen A (daily dosing), one completed planned therapy (30 doses of Gad Tex), one had treatment stopped after 16 doses of Gad Tex when diffuse pulmonary infiltrates with shortness of breath developed and returned after rechallenge with an additional dose of Gad Tex, and one patient developed an allergic reaction after 15 doses of Gad Tex which returned on rechallenge. Of three patients treated at 5.5 mg/kg/dose (qod dosing) on regimen B, one completed planned therapy (15 doses of Gad Tex) after a dose reduction related for skin blisters, and the other two patients discontinued treatment after 9 doses of Gad Tex for debilitating skin blisters. Conclusions: Gad Tex was poorly tolerated as administered in this small phase I study as 4 of 6 patients experienced dose limiting toxicities. As such, NABTT elected not to pursue this drug in subsequent clinical trials. However, similar or more intensive regimens utilizing Gad Tex in combination with brain RT have been successfully administered in patients with newly diagnosed glioblastoma and brain metastases. No significant financial relationships to disclose.

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Abstract 4433: A Phase I study of two dosing regimens of oral AS703569, an inhibitor of aurora kinase and other kinases, in patients with hematologic malignancies

10.1158/1538-7445.am10-4433 ◽

2010 ◽

Author(s):

Carlos Graux ◽

Anne Sonet ◽

Johan Maertens ◽

Justus Duyster ◽

Jochen Greiner ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

Aurora Kinase ◽

Hematologic Malignancies ◽

Dosing Regimens

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Phase I Study To Evaluate the Pharmacokinetics, Safety, and Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00464-18 ◽

2018 ◽

Vol 62 (8) ◽

Cited By ~ 9

Author(s):

Eric Wenzler ◽

Susan C. Bleasdale ◽

Monica Sikka ◽

Kristen L. Bunnell ◽

Matthew Finnemeyer ◽

...

Keyword(s):

Phase I ◽

Healthy Adult ◽

Apparent Volume ◽

Volume Of Distribution ◽

Open Label ◽

Time Curve ◽

Elimination Half ◽

Apparent Clearance ◽

Dosing Regimens ◽

Repeated Dosing

ABSTRACTThe pharmacokinetics (PK), safety, and tolerability of two repeated dosing regimens of oral fosfomycin tromethamine were evaluated in 18 healthy adult subjects. Subjects received 3 g every other day (QOD) for 3 doses and then every day (QD) for 7 doses, or vice versa, in a phase I, randomized, open-label, two-period-crossover study. Serial blood (n= 11) and urine (n= 4 collection intervals) samples were collected before and up to 24 h after dosing on days 1 and 5, along with predose concentrations on days 3 and 7. PK parameters were similar between days 1 and 5 within and between dosing regimens. The mean (± standard deviation [SD]) PK parameters for fosfomycin in plasma on day 5 during the respective QOD and QD dosing regimens were as follows: maximum concentration of drug in serum (Cmax) = 24.4 ± 6.2 versus 23.8 ± 5.6 μg/ml, time toCmax(Tmax) = 2.2 ± 0.7 versus 2.0 ± 0.4 h, apparent volume of distribution (V/F) = 141 ± 67.9 versus 147 ± 67.6 liters, apparent clearance (CL/F) = 21.4 ± 8.0 versus 20.4 ± 5.3 liters/h, renal clearance (CLR) = 7.5 ± 4.1 versus 7.3 ± 3.5 liters/h, area under the concentration-time curve from 0 to 24 h (AUC0–24) = 151.6 ± 35.6 versus 156.6 ± 42.5 μg · h/ml, and elimination half-life (t1/2) = 4.5 ± 1.1 versus 5.0 ± 1.7 h. Urine concentrations peaked at approximately 600 μg/ml through the 0- to 8-h urine collection intervals but displayed significant interindividual variability. Roughly 35 to 40% of the 3-g dose was excreted in the urine by 24 h postdose. No new safety concerns were identified during this study. The proportion of diarrhea-free days during the study was significantly lower with the QD regimen than with the QOD regimen (61% versus 77%;P< 0.0001). Further studies to establish the clinical benefit/risk ratio for repeated dosing regimens of oral fosfomycin tromethamine are warranted. (This trial is registered at ClinicalTrials.gov under registration no. NCT02570074.)

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A Phase I Study of TACI-antibody Fusion Protein Injection (RC18) in Healthy Adult Chinese Subjects

Case Medical Research ◽

10.31525/ct1-nct04235933 ◽

2020 ◽

Author(s):

Keyword(s):

Fusion Protein ◽

Phase I ◽

Phase I Study ◽

Healthy Adult ◽

Antibody Fusion Protein ◽

Chinese Subjects

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Abstract C195: Phase I study of 2 dosing regimens of AS703569, an oral Aurora kinase inhibitor, in patients with solid tumors

10.1158/1535-7163.targ-09-c195 ◽

2009 ◽

Cited By ~ 1

Author(s):

Monica Mita ◽

Michael Gordon ◽

Athos Gianella‐Borradori ◽

Blandine Longerey ◽

Narmyn Rejeb ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Phase I Study ◽

Kinase Inhibitor ◽

Aurora Kinase ◽

Aurora Kinase Inhibitor ◽

Dosing Regimens

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Phase I study utilizing an intravenous busulfan test dose to prospectively target and determine the maximum tolerated systemic exposure (MTSE) of a continuous intravenous infusion

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.16502 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 16502-16502

Author(s):

C. M. Walko ◽

T. C. Shea ◽

K. Rao ◽

D. Gabriel ◽

J. Serody ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

Systemic Exposure ◽

Test Dose ◽

High Dose ◽

Systemic Clearance ◽

Blood Concentrations ◽

Dosing Regimens ◽

Matched Sibling ◽

Grade 3

16502 Background: Busulfan systemic concentration has correlated with toxicity and efficacy. We previously demonstrated that administration of intravenous high-dose busulfan (HD-Bu) as a 90 hour continuous infusion (CIV) has efficacy, safety, and mean daily area under the concentration curves (AUC) comparable to intermittent dosing regimens and that it is possible to use a test dose of busulfan to predict the systemic exposure with less than 10% variability. The objective of this study is to identify the MTSE of CIV HD-Bu utilizing a test dose for AUC targeting. Methods: Prior to HD-Bu, patients received a single test dose of Bu (0.8 mg/kg) by two hour infusion with blood concentrations obtained at 0, 2.5, 4, 5, and 6 hours. Serum concentrations were analyzed using GC-MS. Non-compartmental PK analysis was used to determine clearance using WIN-NONLIN software. The systemic clearance (dose/AUC) of the test dose was used to predict the 90 hour CIV dose of Bu needed to achieve the desired AUC. On days -7 to -3, the treatment dose was administered and blood samples were collected at 0, 12, 16, 18, 48, 60, 72, and 89.5 hours to verify that the desired AUC was reached. Dose adjustments were made after 18 hours if necessary. A blood sample was obtained for evaluation of polymorphisms in genes associated with busulfan metabolism and transport. Results: Five patients (4 MUD, 1 matched-sibling donor) were enrolled at the 24 hour Bu target AUC of 4800 uM*min ± 15%. One patient was not able to be evaluated due to errors in PK acquisition. 3 of the 4 patients required CIV doses different than that based on weight alone (i.e. 12.8 mg/kg). All 4 patients had AUCs within the desired range (mean 24 hour busulfan AUC of 4708 uM*min) with a mean bias and precision of −1.9% and 8.7%, respectively. No adjustments were required after 18 hours. No grade 3 or greater chemotherapy related toxicity has been identified. Conclusions: The systemic clearance determined by a busulfan test dose may be used to prospectively target the desired AUC of a 90 hour CIV. Enrollment on this Phase I study will continue beyond the first dose level which is at the upper limit of the normal range (4800 uM*min). No significant financial relationships to disclose.

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