scholarly journals Pharmacodynamic-Guided Modified Continuous Reassessment Method–Based, Dose-Finding Study of Rapamycin in Adult Patients With Solid Tumors

2008 ◽  
Vol 26 (25) ◽  
pp. 4172-4179 ◽  
Author(s):  
Antonio Jimeno ◽  
Michelle A. Rudek ◽  
Peter Kulesza ◽  
Wen Wee Ma ◽  
Jenna Wheelhouse ◽  
...  
Keyword(s):  
Real Time ◽  
Solid Tumors ◽  
Mononuclear Cells ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Pharmacodynamic Effect ◽  
Dose Selection ◽  
Peripheral Blood Mononuclear ◽  
End Point ◽  
Dose Levels

Purpose Pharmacodynamic studies are frequently incorporated into phase I trials, but it is uncommon that they guide dose selection. We conducted a dose selection study with daily rapamycin (sirolimus) in patients with solid tumors employing a modified continuous reassessment method (mCRM) using real-time pharmacodynamic data as primary dose-estimation parameter. Patients and Methods We adapted the mCRM logit function from its classic toxicity-based input data to a pharmacodynamic-based input. The pharmacodynamic end point was skin phospho-P70 change after 28 days. Pharmacodynamic effect was defined as at least 80% inhibition from baseline. The first two dose levels (2 and 3 mg) were evaluated before implementing the mCRM, and the data used to estimate the next dose level based on statistical modeling. Toxicity-based boundaries limited the escalation steps. Other correlates analyzed were positron emission tomography (PET) and computed tomography, pharmacokinetics, phospho-P70 in peripheral-blood mononuclear cells, and tumor biopsies in patients at the maximum-tolerated dose (MTD). Results Twenty-one patients were enrolled at doses between 2 and 9 mg. Pharmacodynamic effect occurred across dose levels, and toxicity boundaries ultimately drove dose selection. The MTD of daily oral rapamycin was 6 mg. Toxicities in at least 20% were hyperglycemia, hyperlipidemia, elevated transaminases, anemia, leucopenia, neutropenia, and mucositis. Pharmacokinetics were consistent with prior data, and exposure increased with dose. No objective responses occurred, but five previously progressing patients received at least 12 cycles. PET showed generalized stable or decreased glucose uptake unrelated to antitumor effect. Conclusion mCRM-based dose escalation using real-time pharmacodynamic assessment was feasible. However, the selected pharmacodynamic end point did not correlate with dose. Toxicity ultimately drove dose selection. Rapamycin is a well-tolerated and active oral anticancer agent.

Phase 1/2 study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with solid tumor malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3161-TPS3161
Author(s):  
Ecaterina Elena Dumbrava ◽  
Amit Mahipal ◽  
Xin Gao ◽  
Geoffrey Shapiro ◽  
Jason S. Starr ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Tumor Growth Inhibition ◽  
Advanced Solid Tumors ◽  
Peripheral Blood Mononuclear

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.

Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer.

1998 ◽  
Vol 16 (4) ◽  
pp. 1450-1457 ◽  
Author(s):  
R L Schilsky ◽  
J Hohneker ◽  
M J Ratain ◽  
L Janisch ◽  
L Smetzer ◽  
...  
Keyword(s):  
Washout Period ◽  
Mononuclear Cells ◽  
Dihydropyrimidine Dehydrogenase ◽  
Maximum Tolerated Dose ◽  
Peripheral Blood Mononuclear ◽  
Period 2 ◽  
Daily Schedule ◽  
Starting Dose ◽  
Dose Levels

PURPOSE To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85. PATIENTS AND METHODS Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (i.v.) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU i.v. bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5-FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. RESULTS Sixty-five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose-limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with i.v. 5-FU 25 mg/m2/d; 776C85 10 mg/d with i.v. 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d. CONCLUSION 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmacokinetics.

Pharmacodynamic-guided, modified continuous reassessment method (mCRM)-based, dose finding study of rapamycin in adult patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3020-3020 ◽  
Author(s):  
A. Jimeno ◽  
P. Kulesza ◽  
G. Cusatis ◽  
A. Howard ◽  
Y. Khan ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Dose Finding ◽  
Phase I Trials ◽  
Dose Selection ◽  
Normal Tissues ◽  
Tumor Biopsies ◽  
Dose Levels

3020 Background: Pharmacodynamic (PD) studies, using either surrogate or tumor tissues, are frequently incorporated in Phase I trials. However, it has been less common to base dose selection, the primary endpoint in Phase I trials, in PD effects. We conducted a PD-based dose selection study with rapamycin (Rap). Methods: We used the modified continuous reassessment method (mCRM), a computer-based dose escalation algorithm, and adapted the logit function from its classic toxicity-based input data to a PD-based input. We coupled this design to a Phase I trial of Rap with 2 parts: a dose estimation phase where PD endpoints are measured in normal tissues and a confirmation phase where tumor tissue is assessed. Patients (pts) had solid tumors refractory to standard therapy. Rap was given starting at 2 mg/day continuously in 3-pt cohorts. The PD endpoint was pP70S6K in skin and tumor. Biopsies were done on days 0 and 28 of cycle 1, and a PD effect was defined as ≥ 80% inhibition from baseline. The first 2 dose levels (2 and 3 mgs) were evaluated before implementing the mCRM. The data was then fed to the computer that based on the PD effect calculated the next dose level. The mCRM was set so escalation continued until a dose level elicited a PD effect and the mCRM assigned the same dose to 8 consecutive pts, at which point the effect of that dose will be confirmed in tumor biopsies. Other correlates were PET-CT and pharmacokinetics. Results: Ten pts were enrolled at doses of 2 mg (n = 4), 3 mg (n = 3) and 6 mg (n = 3). Toxicity was anemia (4 G1, 1 G2), leucopenia (1 G1, 2 G2), low ANC (2 G2), hyperglycemia (2 G1, 1 G2), hyperlipidemia (4 G1), and mucositis (1 G1, 1 G2). PD responses were seen in 2 and 1 pt at 2 and 3 mg dose levels. Input of data to the mCRM selected a dose of 6 mg for the third cohort, where PD effect was seen in 1 pt, and thus a fourth dose around 9 mg will be tested. No responses by RECIST occurred, but 2 pts had a response by PET. The PK was consistent with prior data (t1/2 24.6 ± 10.2 h, CL 31.4 ± 12.0 L/h, vol of distribution 235 ± 65 L), and exposure increased with dose. Steady-state concentration were in the 5–20 nM range. Conclusions: mCRM-based dose escalation based on real-time PD assessment is feasible and permits the exploitation of PD effects for dose selection in a rational manner. No significant financial relationships to disclose.

scholarly journals Pediatric Phase I Trial and Pharmacokinetic Study of Vorinostat: A Children's Oncology Group Phase I Consortium Report

2010 ◽  
Vol 28 (22) ◽  
pp. 3623-3629 ◽  
Author(s):  
Maryam Fouladi ◽  
Julie R. Park ◽  
Clinton F. Stewart ◽  
Richard J. Gilbertson ◽  
Paula Schaiquevich ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Mononuclear Cells ◽  
Drug Disposition ◽  
Single Agent ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
Peripheral Blood Mononuclear ◽  
Higher Doses

Purpose The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children. Patients and Methods Vorinostat was administered orally daily starting at 180 mg/m2/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC). Results Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m2/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m2/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m2/d 4 times per week and 13cRA 80 mg/m2/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m2/d for the capsule (range, 1,415 to 9,291 ng/mL × hr) and oral suspension (range, 1,186 to 4,780 ng/mL × hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination. Conclusion In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m2/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.

Phase I Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients With Advanced Cancer

2005 ◽  
Vol 23 (6) ◽  
pp. 1078-1087 ◽  
Author(s):  
Matthew P. Goetz ◽  
David Toft ◽  
Joel Reid ◽  
Matthew Ames ◽  
Bridget Stensgard ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
Advanced Solid Tumor ◽  
Hsp 70 ◽  
Tumor Patients ◽  
Peripheral Blood Mononuclear ◽  
Client Proteins ◽  
Grade 3 ◽  
Dose Levels

Purpose We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity. Patients and Methods An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity. Results Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m2 were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t1/2) of 17-AAG were 11.6 L/h/m2 and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t1/2 of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance. Conclusion The MTD of weekly 17-AAG is 308 mg/m2. 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.

Phase I Study of Everolimus in Pediatric Patients With Refractory Solid Tumors

2007 ◽  
Vol 25 (30) ◽  
pp. 4806-4812 ◽  
Author(s):  
Maryam Fouladi ◽  
Fred Laningham ◽  
Jianrong Wu ◽  
Melinda A. O'Shaughnessy ◽  
Kristen Molina ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mononuclear Cells ◽  
Mammalian Target Of Rapamycin ◽  
Area Under The Curve ◽  
Dosage Level ◽  
Maximum Tolerated Dose ◽  
Significant Inhibition ◽  
Peripheral Blood Mononuclear ◽  
Pharmacokinetic Properties ◽  
Recommended Phase Ii Dose

Purpose To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic and pharmacodynamic properties of the mammalian target of rapamycin (mTOR) inhibitor, everolimus, in children with refractory or recurrent solid tumors. Patients and Methods Everolimus was administered orally at a daily dose of 2.1, 3, 5, or 6.5 mg/m2 in cohorts of three to six patients per dosage level. Pharmacokinetic and pharmacodynamic studies were performed during the first course. The phosphorylation status of various components of the mTOR signal pathway was assessed in peripheral-blood mononuclear cells (PBMCs) isolated from treated patients. Results There were 26 patients enrolled; 18 were assessable. DLTs included diarrhea (n = 1), mucositis (n = 1), and elevation of ALT (n = 1) at 6.5 mg/m2. At the MTD of 5 mg/m2, the median everolimus clearance was 15.2 L/h/m2, with a plasma everolimus concentration-time area under the curve (AUC) from 0 to infinity of 239.6 ng/mL·h. Significant inhibition of mTOR pathway signaling was observed in PBMCs from patients achieving AUCs ≥ 200 ng/mL·h, equivalent to dosages of 3 to 5 mg/m2 of everolimus. No objective tumor responses were observed. Conclusion Continuous, orally administered everolimus is well tolerated in children with recurrent or refractory solid tumors and demonstrates similar pharmacokinetic properties to those observed in adults. Everolimus significantly inhibits the mTOR signaling pathway in children at the MTD. The recommended phase II dose in children with solid tumors is 5 mg/m2.

Phase I Study of Depsipeptide in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Report

2006 ◽  
Vol 24 (22) ◽  
pp. 3678-3685 ◽  
Author(s):  
Maryam Fouladi ◽  
Wayne L. Furman ◽  
Thomas Chin ◽  
Burgess B. Freeman ◽  
Lorina Dudkin ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Histone Deacetylase ◽  
Mononuclear Cells ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Independent Manner ◽  
Time Curve ◽  
Peripheral Blood Mononuclear ◽  
Deacetylase Inhibitor ◽  
Recommended Phase Ii Dose

Purpose To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the histone deacetylase inhibitor, depsipeptide, in children with refractory or recurrent solid tumors. Patients and Methods Depsipeptide was administered as a 4-hour infusion weekly for 3 consecutive weeks every 28 days at dose levels of 10 mg/m2, 13 mg/m2, 17 mg/m2, and 22 mg/m2. Pharmacokinetics and histone acetylation studies were performed in the first course. The levels of H3 histone and acetyl-H3 histone were evaluated in peripheral blood mononuclear cells (PBMC) using immunofluorescence techniques. Results There were 24 patients, and 18 who were assessable were enrolled. DLTs included reversible, asymptomatic T-wave inversions, without any associated changes in troponin levels or evidence of ventricular dysfunction, in the inferior leads in two patients at 22 mg/m2 and in the lateral leads in one patient at 13 mg/m2 (n = 1), and transient asymptomatic sick sinus syndrome and hypocalcemia in one patient at 17 mg/m2. At the MTD (17 mg/m2), the median depsipeptide clearance was 6.8 L/h/m2 with an area under the plasma depsipeptide concentration-time curve from 0 to infinity of 2,414 ng/mL/h, similar to adults. Accumulation of acetylated H3 histones was seen in all patients in a dose independent manner, with maximal accumulation at a median of 4 hours, (range, 0 hours to 20 hours) after the end of the infusion. No objective tumor responses were observed. Conclusion Depsipeptide is well tolerated in children with recurrent or refractory solid tumors when administered weekly for 3 consecutive weeks every 28 days and inhibits histone deacetylase activity in PBMC in a dose-independent manner. The recommended phase II dose in children with solid tumors is 17 mg/m2.

A first-in-human phase I study of 4SC-201, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3530-3530 ◽  
Author(s):  
A. T. Brunetto ◽  
J. E. Ang ◽  
R. Lal ◽  
D. Olmos ◽  
S. Frentzas ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Hdac Inhibitor ◽  
Maximum Tolerated Dose ◽  
Individual Variability ◽  
Functional Assay ◽  
Histone H4 ◽  
Peripheral Blood Mononuclear ◽  
Histone H4 Acetylation ◽  
Grade 3 ◽  
Dose Levels

3530 Background: 4SC-201 (former code BYK408740) is a specific, potent, pan-HDAC inhibitor with improved ADME properties. Methods: Patients (pts) with advanced refractory solid tumors were dosed once daily (QD) d1–5 in a 14-day cycle in sequential cohorts of 3–6 pts with 50 or 100% dose increments. Primary objectives were to determine safety, tolerability, pharmacokinetics (PK) and maximum tolerated dose (MTD) of 4SC-201. Pharmacodynamic assessment (histone acetylation and HDAC enzyme activity) and anti-tumor efficacy were secondary objectives. Blood samples for PK and PD were taken on days 1, 5 and 47 of treatment. Results: 18 pts (9M/9F) with a median age of 58.5 yrs (range 40–70) were treated at five dose levels: 3 pts each at 100mg, 200mg, 400mg and 600mg and 6 pts at 800mg. All pts were evaluable for toxicity and received at least 2 treatment cycles. Grade 3 DLT of nausea and vomiting occurred in 1 pt dosed at 800mg. Most common adverse events included nausea, vomiting and fatigue. 8 of 9 pts treated in the 600mg and 800mg cohorts had stable disease during the main phase of the study (4 treatment cycles). A patient with liposarcoma and another with thymoma (marginal response) continued treatment beyond 6 months. PK parameters were dose-proportional with a low inter-individual variability and indicated good bioavailability. The apparent t1/2 of oral 4SC-201 ranged from 2.3 to 4.4 hours. The degree of HDAC inhibition measured in a peripheral blood mononuclear cell functional assay was dose- dependent and increased from 50 to 100 %, although histone H4 acetylation accumulation after dosing did not differ significantly between dose levels. Conclusions: Oral 4SC-201 has favorable disposition and can be safely administered; 600mg QD d1–5 in a 14-day cycle is recommended for phase II evaluation. Safely administered doses modulate target with antitumor activity. [Table: see text]

Phase I and Pharmacokinetic Study of MS-275, a Histone Deacetylase Inhibitor, in Patients With Advanced and Refractory Solid Tumors or Lymphoma

2005 ◽  
Vol 23 (17) ◽  
pp. 3912-3922 ◽  
Author(s):  
Qin C. Ryan ◽  
Donna Headlee ◽  
Milin Acharya ◽  
Alex Sparreboom ◽  
Jane B. Trepel ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Histone Deacetylase ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Maximum Tolerated Dose ◽  
Peripheral Blood Mononuclear ◽  
Histone Deacetylase Inhibition ◽  
Daily Schedule ◽  
Blood Mononuclear Cells

PurposeThe objective of this study was to define the maximum-tolerated dose (MTD), the recommended phase II dose, the dose-limiting toxicity, and determine the pharmacokinetic (PK) and pharmacodynamic profiles of MS-275.Patients and MethodsPatients with advanced solid tumors or lymphoma were treated with MS-275 orally initially on a once daily × 28 every 6 weeks (daily) and later on once every-14-days (q14-day) schedules. The starting dose was 2 mg/m2and the dose was escalated in three- to six-patient cohorts based on toxicity assessments.ResultsWith the daily schedule, the MTD was exceeded at the first dose level. Preliminary PK analysis suggested the half-life of MS-275 in humans was 39 to 80 hours, substantially longer than predicted by preclinical studies. With the q14-day schedule, 28 patients were treated. The MTD was 10 mg/m2and dose-limiting toxicities were nausea, vomiting, anorexia, and fatigue. Exposure to MS-275 was dose dependent, suggesting linear PK. Increased histone H3 acetylation in peripheral-blood mononuclear-cells was apparent at all dose levels by immunofluorescence analysis. Ten of 29 patients remained on treatment for ≥ 3 months.ConclusionThe MS-275 oral formulation on the daily schedule was intolerable at a dose and schedule explored. The q14-day schedule is reasonably well tolerated. Histone deacetylase inhibition was observed in peripheral-blood mononuclear-cells. Based on PK data from the q14-day schedule, a more frequent dosing schedule, weekly × 4, repeated every 6 weeks is presently being evaluated.

Phase I Trial of G3139, a bcl-2 Antisense Oligonucleotide, Combined With Doxorubicin and Cyclophosphamide in Children With Relapsed Solid Tumors: A Children's Oncology Group Study

2007 ◽  
Vol 25 (12) ◽  
pp. 1512-1518 ◽  
Author(s):  
Susan R. Rheingold ◽  
Michael D. Hogarty ◽  
Susan M. Blaney ◽  
James A. Zwiebel ◽  
Calies Sauk-Schubert ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Solid Tumors ◽  
Mononuclear Cells ◽  
Maximum Tolerated Dose ◽  
Average Standard Deviation ◽  
Peripheral Blood Mononuclear ◽  
Biologic Effects ◽  
Recommended Phase Ii Dose ◽  
Stimulating Factor ◽  
Time Point

Purpose To determine the maximum-tolerated dose, toxicity, pharmacokinetics, and biologic effects of G3139 when administered with doxorubicin and cyclophosphamide to children with relapsed solid tumors. Patients and Methods Patients received a 7-day continuous infusion of 3, 5, or 7 mg/kg/d of G3139 every 21 days. Doxorubicin, cyclophosphamide, and dexrazoxane were administered on days 5 and 6 of the infusion. Pharmacokinetics and biology studies were performed during the first course. Results Thirty-seven patients, median age 14 years (range, 1 to 19 years), were enrolled, of whom 29 were fully assessable for toxicity. Because of dose-limiting neutropenia, doses of doxorubicin 30 mg/m2/d for 2 days, dexrazoxane 300 mg/m2/d for 2 days, and cyclophosphamide 500 mg/m2/d for 2 days were reduced initially, but with the addition of granulocyte colony-stimulating factor (GCSF), could be re-escalated to starting doses. At the 7 mg/kg/d dose level, only one of six patients experienced DLT (neutropenia > 7 days). At this dose, the average (± standard deviation) steady-state G3139 concentration was 2.04 ± 1 μg/mL, a concentration associated with biologic activity. Eleven of 15 patients had reduced bcl-2 expression in peripheral-blood mononuclear cells at the first assessable time point of G3139 exposure, and in eight of 14 patients with serial specimens this reduction persisted through day 6. Conclusion The recommended phase II dose of G3139 is 7 mg/kg/d as a 7-day continuous infusion, with cyclophosphamide 500 mg/m2/d and doxorubicin 30 mg/m2/d on days 5 and 6, followed by GCSF. G3139 may accentuate the myelosuppressive effects of doxorubicin and cyclophosphamide. Evidence for biologic effects of G3139 was demonstrated.

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