A Phase I Study in Patients with Solid or Hematologic Malignancies of the Dose Proportionality of Subcutaneous Azacitidine and Its Pharmacokinetics in Patients with Severe Renal Impairment

2013 ◽  
Vol 34 (5) ◽  
pp. 440-451 ◽  
Author(s):  
Eric Laille ◽  
Sanjay Goel ◽  
Alain C. Mita ◽  
Nashat Y. Gabrail ◽  
Kevin Kelly ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Phase I ◽  
Phase I Study ◽  
Severe Renal Impairment ◽  
Hematologic Malignancies ◽  
Dose Proportionality

scholarly journals A Phase I Study to Evaluate the Pharmacokinetics and Safety of Cabotegravir in Adults With Severe Renal Impairment and Healthy Matched Control Participants

2019 ◽  
Vol 8 (5) ◽  
pp. 674-681 ◽  
Author(s):  
Ridhi Parasrampuria ◽  
Susan L. Ford ◽  
Yu Lou ◽  
Caifeng Fu ◽  
Kalpana K. Bakshi ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Phase I ◽  
Phase I Study ◽  
Matched Control ◽  
Severe Renal Impairment

A 2-Part Phase I Study in Patients with Solid or Hematologic Malignancies: Dose Proportionality of Subcutaneous (SC) Azacitidine (AZA) and Pharmacokinetics of SC AZA in Patients with Severe Renal Impairment,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3480-3480
Author(s):  
Eric Laille ◽  
Alain C. Mita ◽  
Sanjay Goel ◽  
Nashat Y. Gabrail ◽  
Joseph Schwarz ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Severe Renal Impairment ◽  
Hematologic Malignancies ◽  
Dose Proportionality ◽  
Employment Equity ◽  
Post Dose ◽  
Equity Ownership ◽  
To Receive

Abstract Abstract 3480 Background: The recommended starting dose for all patients receiving SC AZA is 75 mg/m2 daily for 7 days in 28-day cycles. If no response is observed, the dose may be increased to 100 mg/m2. Conversely, if cytopenias do not adequately resolve between dosing cycles, AZA dose may be reduced. Similarly, because AZA and its metabolites are primarily excreted by the kidneys, patients with renal impairment may require monitoring for elevations of BUN or serum creatinine (cr), in which case the next AZA treatment cycle should be delayed until values return to baseline and the next AZA dose should be reduced by 50% (Vidaza® prescribing information, 2011). Currently, the pharmacokinetics (PK) of SC AZA in reduced (<75 mg/m2) or increased (100 mg/m2) doses, and AZA exposure at the recommended dose in patients with renal impairment, are unknown. Objectives: To assess the dose proportionality of AZA PK after single SC doses ranging from 25 to 100 mg/m2, and to determine the effect of renal impairment on AZA PK after single and multiple (5 days) SC doses of 75 mg/m2. Also, the safety and tolerability of AZA in patients with severe renal impairment were determined. Methods: This 2-part multicenter, randomized, open-label study included patients with solid or hematologic malignancies. Part 1 was a 4-treatment, parallel-group evaluation of the dose proportionality of SC AZA in patients with normal renal function (cr clearance [CLcr] >80 mL/min/1.73 m2, Cockcroft-Gault equation adjusted for body surface area). Patients were randomized to receive a single dose of 25-, 50-, 75-, or 100-mg/m2 SC AZA. Blood and urine samples were collected before dosing and at various time points up to 8 hours post-dose. The 75 mg/m2 dosing group in Part 1 received an additional 4 days of AZA treatment and blood and urine were collected from these patients on the same schedule on Day 5. For Part 2, patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) received SC AZA 75 mg/m2 for 5 consecutive days. PK parameters were determined using non-compartmental methods. Patients could continue to receive treatment with AZA (75 mg/m2/d SC x 7d q 28 days) in an extension phase for up to 6 cycles (patients were followed for safety only). Results: At the time of this analysis, 21 patients were enrolled and were included in safety evaluations, with PK data available for 18 patients. At baseline, median ages of patients with normal renal function (n=17) or severe renal impairment (n=4) were 61 years (range: 38–76) and 71 years (range: 54–90), respectively. Of patients with normal renal function, 12 (70%) had solid tumors, 4 had MDS (RAEB-t [n=2], RA, RARS), and 1 had multiple myeloma. Of patients with severe renal impairment, 2 (50%) had solid tumors, 1 had CMML, and 1 had MDS (RA). In Part 1, 14 patients were randomized to either 25 mg/m2 (n=4), 50 mg/m2 (n=4), 75 mg/m2 (n=3), or 100 mg/m2 (n=3). Mean [±SD] AUC0-∞ in the 25-, 50-, 75-, and 100 mg/m2 dose groups were 490 [146], 895 [300], 1270 [480], and 1410 [212] ng*hr/mL, respectively. Preliminary results show AZA is dose proportional across the 25–100 mg/m2dose range (Figure 1). In Part 2, on Days 1 and 5 of 5 consecutive days of SC AZA administration, AZA was rapidly absorbed by patients with severe renal impairment, reaching Cmax within 0.75 hours post-dose. AZA concentration decreased thereafter in a pseudobiphasic manner (Figure 2). Similar profiles were observed in patients with normal renal function who received the same dose. Mean [±SD] AUC0-∞ values after a 75 mg/m2 SC AZA dose on Day 1 were 1270 [480] ng*hr/mL in patients with normal renal function and 1630 [913] ng*hr/mL in patients with severely impaired renal function. On Day 5, mean AUC0-∞ values were 901 [92] and 1280 [728] ng*hr/mL, respectively. Similar observations were noted for Cmax. No accumulation of AZA was noted on Day 5 in either group. High inter-patient variability was noted in both groups (% coefficient of variation up to ∼82%). Patients with or without renal impairment did not show unusual or unexpected adverse events. Conclusions: AZA is dose-proportional over the 25–100 mg/m2 dosing range. PK parameters from patients with severe renal impairment treated with multiple doses of AZA 75 mg/m2 SC were comparable to those obtained from patients with normal renal function. Treatment with AZA 75 mg/m2 SC over multiple days was safe and well tolerated in this small group of patients with normal renal function or severe renal impairment. Disclosures: Laille: Celgene Corporation: Employment, Equity Ownership. Goel:Celgene: Research Funding. Schwarz:Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership.

A Phase I Study of the Metal Ionophore Clioquinol in Patients With Advanced Hematologic Malignancies

2012 ◽  
Vol 12 (5) ◽  
pp. 330-336 ◽  
Author(s):  
Aaron D. Schimmer ◽  
Yulia Jitkova ◽  
Marcela Gronda ◽  
Zezhou Wang ◽  
Joseph Brandwein ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Hematologic Malignancies

A phase I study of panobinostat in children with relapsed and refractory hematologic malignancies

2020 ◽  
Vol 37 (6) ◽  
pp. 465-474
Author(s):  
John Goldberg ◽  
Maria Luisa Sulis ◽  
Julia Bender ◽  
Sima Jeha ◽  
Rebecca Gardner ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Hematologic Malignancies

Phase I Study of XK469R (NSC 698215), a Quinoxaline Phenoxypropionic Acid Derivative, in Patients with Refractory Hematological Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1952-1952
Author(s):  
Wendy Stock ◽  
Samir D. Undevia ◽  
Stefan Faderl ◽  
Olotoyosi Odenike ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Phase I ◽  
Acid Derivative ◽  
Dose Level ◽  
Phase I Study ◽  
Plasma Concentrations ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Fixed Dose ◽  
Pharmacokinetic Analysis ◽  
Clinical Activity

Abstract XK469R is a quinoxaline phenoxypropionic acid derivative which possesses broad activity against murine and human tumors (including leukemia) and high activity against multidrug-resistant tumors. COMPARE analysis of cytotoxicity data from the NCI cell line screen suggested a unique mechanism. Phase I studies in patients with advanced solid tumors indicated that the dose-limiting toxicity (DLT) was myelosuppression, without other significant toxicities noted, at a fixed dose of 1400 mg/dose when given on a day 1,3,5 schedule every 21 days. Therefore, we conducted a phase I study to establish the DLT and maximally tolerated dose (MTD) of XK469R in patients with refractory hematologic malignancies, as well as to study the pharmacokinetics of XK469R in this patient population. XK469R was given as a straight dose as an IV infusion over 30 minutes-1 hour on days 1, 3, and 5 of a 21 day cycle. Because significant interpatient variability in drug clearance (associated with toxicity) was noted in prior studies, each dose cohort included a minimum of six patients. The dose levels studied were 1400 mg (n=6), 1750 mg (n=12), 2200 mg (n=14), and 2750mg (n=14). A total of 46 patients with relapsed/refractory leukemia have been treated and are evaluable for toxicity; 41 patients with AML, 4 ALL, and 1 CML-BC. The group consists of 26 males and 20 females with a median age of 53 (range 20–85). ECOG PS included 0 (n=19), 1 (n=21), and 2 (n=6). Median number of cycles received was 1; 10 patients received 2 cycles and 2 patients received 3 cycles. DLT was defined as any clinically significant grade 3 or 4 adverse nonhematologic toxicity other than prolonged myelosuppression, as defined by NCI criteria specific for leukemia. DLTs of colitis and mucositis were observed at the 2200 mg dose level, and mucositis and elevated bilirubin at the 2750 mg dose level. Other possibly related grade 1 and 2 toxicities noted were SGOT/PT elevations, nausea/vomiting, diarrhea, anorexia, indigestion, rash, and alopecia. The MTD, defined as the dose level at which <2/6 patients experience a DLT, was 2200 mg. Forty-two patients were evaluable for response and include CR (n=1, in 1750 mg cohort), HI (n=5), SD (n=21), and PD (n=15). Preliminary pharmacokinetic analysis revealed that plasma concentrations of XK469R decline in a biphasic manner. Half-life was long with a mean value of 48 h. Mean clearance was 206 ml/h with a coefficient of variation of 32%. Patients with lower clearance did not appear to be at greater risk of DLT. In conclusion, the recommended phase II dose of XK469R in patients with advanced leukemia is 1750 mg (day 1,3,5). Due to its novel mechanism of action, reasonable toxicity profile, and clinical activity in these high-risk patients, further exploration of XK469R, possibly in combination with other established agents, is warranted in patients with relapsed/refractory acute leukemia.

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.

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