scholarly journals NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Patrick J. Mansky ◽  
Dawn B. Wallerstedt ◽  
Timothy S. Sannes ◽  
Jamie Stagl ◽  
Laura Lee Johnson ◽  
...  
Keyword(s):  
Clinical Response ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Stage Iv ◽  
Dosage Level ◽  
Maximum Tolerated Dose ◽  
Stage I ◽  
Fixed Dose ◽  
Mistletoe Lectin ◽  
Mistletoe Extract

Purpose.European Mistletoe (Viscum albumL.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM.Methods.Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery.Results.DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1380 mg/m2and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high.Conclusion.GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone.

RP101 improves the efficacy of gemcitabine in treating pancreatic carcinoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14075-14075
Author(s):  
M. Haenel ◽  
D. Quietzsch ◽  
V. Heinemann ◽  
S. Boeck ◽  
R. M. Schmid ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Median Survival ◽  
Phase 1 ◽  
Advanced Pancreatic Cancer ◽  
Stage Iv ◽  
Underlying Disease ◽  
Fixed Dose ◽  
Survival Status ◽  
Phase 2 Study ◽  
One Year

14075 Background: (E)-5-(2-bromovinyl)-2’-deoxyuridine (BVDU, RP101), was initially tested in a phase 1 pilot study in pancreatic cancer. Patients (n=13) received gemcitabine (1000 mg/m2), cisplatin (50 mg/m2) and RP101 (500 mg/day). The median survival was 447 days and the TTP was 280 days. Ten of the 13 pts lived longer than one year, 4 nearly two years. Based on these promising results a phase 2 study was initiated to explore varying doses of RP101 used with a fixed dose of GEM. Methods: Pts with advanced pancreatic adenocarcinoma were eligible for treatment in this single arm study. 22 pts (16 stage IV and 5 stage III) received GEM 1000 mg/m2 on days 1, 8 and 15 of a 28-day schedule. RP101 treatment, at doses of 500, 625, 750, 875 or 1000 mg/day, was on the same day and for three days after chemotherapy. The mean age was 60 years and 73% of pts were males. Results: The results are based on interim data from an ongoing study and patients at the 2 highest dose groups are still being treated. All RP101 dose groups were combined for analyses, which included all enrolled pts. The data on the 6-month survival status show that 41% are alive; 23% dead; and 36% followed less than 6 months. The median survival (95% CI) is 7.1 months (5.9, not calculated) and 14/22 pts (64%) are still alive. The 6 month survival rate (95% CI) is 0.69 (0.52, 0.85). This compares very favorably with a large recent randomized trial in which pts who received GEM alone had a median survival (95%CI) of 5.9 months (5.1–6.7). PFS and TTP continue to be assessed in this ongoing trial. There appears to be a dose dependent increase in peak GEM levels as a function of the dose of RP101. To date, adverse events are consistent with those observed with GEM or the underlying disease. Conclusion: RP101 may improve treatment of advanced pancreatic cancer when used with gemcitabine. Updated data on survival, PFS, and safety will be presented based on available data. [Table: see text]

Phase I dose-escalation study of pasireotide LAR in patients with advanced neuroendocrine tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15126-e15126 ◽  
Author(s):  
Alexandria T. Phan ◽  
Edward M. Wolin ◽  
Jennifer A. Chan ◽  
Jerry M. Huang ◽  
Michelle Hudson ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Somatostatin Receptor ◽  
Plasma Concentrations ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Best Response ◽  
Long Acting

e15126 Background: Somastatin analogs (SSA), including octreotide and lanreotide, bind predominantly to somatostatin receptor (SSTR) 2 and form the foundation of treatment for symptomatic neuroendocrine tumors (NET). Pasireotide, a novel SSA with a broad binding affinity (SSTR 1-3 and 5), is being explored for treatment of NET. A phase 1 dose-escalation study (NCT01364415) of pasireotide long-acting release (LAR; starting dose of 80 mg) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) and to characterize safety, tolerability, pharmacokinetics, and efficacy in pts with advanced NET. Methods: Pts with advanced, well- or moderately differentiated NET received pasireotide LAR beginning at a dose of 80 mg q28d. Successive cohorts will receive doses (up to 220 mg) guided by a Bayesian logistic regression model until MTD/RP2D is reached. Results: To date, 15 pts have been treated at 80 mg (n=6) and 120 mg (n=9). Median age is 59 (44-76) years. Primary tumor sites include small intestine (40%), pancreas (20%), and lung (13.3%). All pts received prior antineoplastic therapy; 93% received prior SSA. Median number of cycles of pasireotide was 6.68 (2-14) (1 cycle=28 days). 10 (67%) pts remain on treatment: 3 on 80 mg and 7 on 120 mg. 5 (33%) have discontinued (disease progression, 2 pts; withdrew consent, 2 pts; adverse event [AE], 1 pt). Median plasma concentrations of pasireotide increased with dose. No dose-limiting toxicities have been reported. Most frequent AEs were similar in both dose groups and included hyperglycemia (87%), diarrhea (53%), abdominal pain (47%), nausea (40%), anemia (33%), and fatigue (33%). Most AEs were mild/moderate. 2 pts (1 in each group) had grade 3 hyperglycemia. 4 (27%) and 2 (13%) pts had HbA1C increase from <6.5% at baseline to 6.5-<8% and ≥8%, respectively. 13 (87%) pts had radiographically stable disease as best response. More pts at 120 mg (50%) vs 80 mg (33%) achieved ≥50% reduction in chromogranin A. Conclusions: Pasireotide LAR up to 120 mg appears to be well tolerated in patients with advanced NET. The study is ongoing. Pasireotide represents a promising therapy for pts with NET. Clinical trial information: NCT01364415.

Phase 1 study of MK-4166, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) antibody, as monotherapy or with pembrolizumab (pembro) in patients (pts) with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9509-9509 ◽  
Author(s):  
Kyriakos P. Papadopoulos ◽  
Karen A. Autio ◽  
Talia Golan ◽  
Konstantin Dobrenkov ◽  
Elliot Chartash ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Drug Disposition ◽  
Phase 1 ◽  
Objective Response ◽  
Study Drug ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Phase 1 Study

9509 Background: Ligation of GITR on immune cells decreases Treg-mediated suppression and enhances T cell proliferation. MK-4166 is a humanized IgG1 agonist monoclonal antibody targeting GITR. Data from the first-in-human phase 1 study (NCT02132754) of MK-4166 as monotherapy (mono) or in combination with pembro (combo) are presented. Methods: MK-4166 was tested alone (0.0015 mg IV-900 mg Q3W ×4 doses) or with pembro (fixed dose 200 mg IV Q3W up to 35 doses) in the absence of toxicity or progression. Study included a dose escalation/confirmation cohort (metastatic solid tumors) and an expansion cohort (treatment-naive and pretreated melanoma). A T cell–inflamed gene expression profile (GEP) was assessed using RNA from baseline tumor samples. End points – primary: safety/tolerability, maximum tolerated dose (MTD) of MK-4166; secondary: pharmacokinetics (PK), pharmacodynamics (PD); exploratory: objective response rate (ORR) per irRECIST1.1. Results: Of 113 pts, 48 received mono and 65 combo; 20 were in the melanoma expansion. Common AEs ( > 20%) were fatigue, infusion-related reaction, nausea, abdominal pain, and pruritus; 43 pts had grade ≥3 AEs (38.1%); 6 (5.3%) were treatment-related. One dose-limiting toxicity (bladder perforation in a urothelial pt with a neobladder) possibly related to study drug was observed with mono. MTD was not reached. No treatment-related deaths were observed. MK-4166 PK/PD showed target-mediated drug disposition concomitant with decreased GITR availability on T cells in blood with increasing doses. Four objective responses (4/45; ORR, 9%) were seen with combo in dose escalation. For ICI-naive melanoma pts (n = 13) in expansion, ORR was 69% (95% CI, 38-91), including 4 CRs and 5 PRs. No response was observed in 7 pts previously treated with ICI. High ORRs were observed in noninflamed and inflamed ICI-naive melanoma pts. Conclusions: MK-4166 at a dose up to 900 mg as monotherapy and in combination with pembro was well tolerated, with dose-related evidence of target engagement. Responses were observed with MK-4166 900 mg plus pembro, particularly in pts with melanoma naive to ICIs. Clinical trial information: NCT02132754.

Phase I-II open label multicenter study of PD0332991 in BRAFV600mut metastatic melanoma patients harboring CDKN2A loss and RB1 expression and treated with vemurafenib.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9545-9545
Author(s):  
Baptiste Louveau ◽  
Matthieu Resche-Rigon ◽  
Thierry Lesimple ◽  
Marc Pracht ◽  
Barouyr Baroudjian ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Phase I ◽  
Clinical Response ◽  
Metastatic Melanoma ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Open Label ◽  
Melanoma Patients ◽  
Group 2 ◽  
Group 1

9545 Background: Among mechanisms of resistance to BRAF inhibitors (BRAFi), cell cycle effectors including CDK4 have been involved in ERK reactivation. In this phase I-II open label study, we aimed to establish the Maximum Tolerated Dose (MTD) of PD0332991, an inhibitor of CDK4/6, when added to vemurafenib (VM) in metastatic melanoma patients. Methods: Patients with BRAFV600E/K mutated metastatic melanoma harbouring CDKN2A loss and RB1 expression were included. Patients were treated with a 14 days followed by 7 days rest daily dosing schedule of PD0332991 + continuous BID dosing of VM, and stratified into 2 groups according to previous BRAFi treatment (no group 1, yes group 2). Dose levels (PD0332991 (mg/QD)/VM (mg/BID) ranged from 25/720 to 200/960. The primary endpoint was the occurrence of a DLT within the first 2 cycles of therapy. Secondary endpoints included best response (RECIST), OS, PFS, pharmacokinetics parameters, tumour molecular profiling on baseline lesions using transcriptomic and NGS analysis. Results: Nineteen patients were enrolled, among them 16 (84%) in group 2, with 18.5 months median follow-up. Characteristics at baseline were: male 11 (58%), median age 54.4 years, unresectable stage IIIC 2 (11%), stage IV 17 (89%), M1C 12 (67%), high LDH 9 (47%), median time from advanced melanoma diagnosis to inclusion 26.8 months, ≥ 2 lines therapy 13 (68%). A DLT was observed for 1 and 5 patients in group 1 and 2 respectively, defining the MTD at PD0332991 25mg and VM 960mg in group 2. No significant evidence for drug-drug interaction between PD0332991 and VM was highlighted. In group 2, ORR was estimated to 4 (25%), SD to 8 (50%), median PFS to 9.3 months and median OS to 13.2 months. Baseline transcriptomic analysis revealed high alteration rate associated with clinical response and enrichment in genes related to MAPK, cell cycle and apoptosis pathways. Conclusions: While combination of fixed dose of PD0332991 + VM did not allow us to increase PD0332991 dosage above 25mg, significant clinical benefit was achieved in heavily pretreated patients; baseline molecular analysis revealed an association between transcriptomic data and clinical response. Clinical trial information: NCT02202200.

Safety and antitumor activity of AMG 706 in patients (pts) with thyroid cancer (TC): A subset analysis from a phase 1 dose-finding study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3030-3030 ◽  
Author(s):  
D. Boughton ◽  
L. Rosen ◽  
A. Van Vugt ◽  
R. Kurzrock ◽  
M. Eschenberg ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Stage Iv ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Finding Study ◽  
Stage Iv Disease ◽  
Modified Recist ◽  
Dose Finding Study

3030 Background: AMG 706 is an investigational, oral, small molecule multi-kinase inhibitor with both antiangiogenic and direct antitumor activity that selectively targets VEGF, PDGF, and Kit receptors. From a phase 1 study (Rosen ASCO 2005; Herbst EORTC 2005), encouraging antitumor activity was seen in pts with TC. In this analysis, we report on the TC subset from the study. Methods: Pts with refractory solid tumors received oral AMG 706 QD (50, 100, 125, 175 mg) or BID (25 mg) intermittently or continuously for 28-day cycles. Study objectives were to assess safety, establish the maximum tolerated dose (MTD), and generate pharmacokinetic profiles of AMG 706 in these pts. Tumor response (modified RECIST) was evaluated at wk 8 and Q12W thereafter. Data from Oct 2005 were analyzed. Results: In this study, 7 of 71 pts enrolled had TC. Baseline demographics for this subset were 4 W/3 M, median (range) age of 58 (41, 78) yrs, ECOG 1 (71%), and all had stage IV disease. Histologies were papillary (3: PTC), follicular (1; FTC), Hürthle cell (1), anaplastic (1), and medullary TC (1; MTC). All pts received prior external radiotherapy, radioiodine, chemotherapy, and/or surgery. Initial doses of AMG 706 were 125 mg and 175 QD and 25 mg BID. The MTD for the study was 125 mg QD. Median (range) time on treatment for the TC pts was 141 (14, 564) days. Treatment-related adverse events are summarized ( table ). Best objective responses were 3 pts with partial response (PR), 3 with stable disease (SD), and 1 with progressive disease. PR was seen in pts with MTC, PTC and FTC. Two pts with PR did not have confirmation of response (1 had a PR during the last assessment). The 3 pts with PR received AMG 706 for 338, 366, and 564 days; 2 pts are still receiving AMG 706. Time to response for these 3 pts were 210, 217, and 304 days. Conclusion: In patients with TC, AMG 706 appears to be relatively well tolerated and displays promising antitumor activity for some pts. Based on these favorable findings, a phase 2 study of AMG 706 for the treatment of advanced TC is ongoing. [Table: see text] [Table: see text]

Anti-tumor activity of recombinant human Interleukin-21 (rIL-21): Preliminary data from a phase 2a study in patients with stage IV malignant melanoma (MM) without prior treatment

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3055-3055
Author(s):  
I. D. Davis ◽  
B. Brady ◽  
M. Millward ◽  
B. K. Skrumsager ◽  
U. Mouritzen ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Performance Status ◽  
Stage Iv ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Two Stage ◽  
Two Phase ◽  
Study Results

3055 Background: rIL-21 is a pleiotropic class I cytokine that activates CD8+ T cells and NK cells. The safety and pharmacologic profile of rIL-21 was characterized in two phase 1 dose escalation studies including patients with MM, performed in Australia and the US, respectively. Two dosing schedules were tested: “5+9” (5 days of dosing followed by 9 days of rest) and “3/wk” (dosing 3 times per week for 6 weeks). The maximum tolerated dose (MTD) was determined to be 30 μg/kg for both dosing regimens and two complete remissions (at the 30 μg/kg dose level) were observed in the MM patients. A phase 2a study was initiated to estimate the preliminary efficacy of rIL-21 in patients with advanced MM. Methods: The phase 2a study design is an open-label, two-stage trial. Primary objective: antitumor efficacy as determined by response rate. Secondary objectives: safety, effects on blood biomarkers, and measurement of anti-rIL-21 antibodies. Eligible patients had unresectable MM with measurable disease, no prior systemic therapy (adjuvant interferon was permitted), adequate major organ function, good performance status, no brain metastases, and no evidence of significant autoimmune disease. rIL-21 was administered by i.v. bolus injection using the “5+9” regimen for 6 weeks (= three cycles) at 30 μg/kg dose level. Results: At the time of writing (January 2007), all 14 patients have entered the first stage of the phase 2a study and currently seven patients are evaluable for response after completion of 3 treatment cycles (6 weeks). One patient had a complete remission, five patients had stable disease, and one patient had progressive disease. So far, six patients have gone on to receive further treatment with rIL-21. Similar to the phase 1 experience, treatment with rIL-21demonstrated an acceptable safety profile. Updated interim study results, including response data, will be presented. Conclusions: rIL-21 administered at 30 μg/kg/day using the “5+9” regimen is well tolerated by patients with MM. Preliminary evidence of clinical response has been observed and the second stage of the two-stage phase 2a study has opened for accrual. [Table: see text]

Interleukin-21 (IL-21): Tolerability and anti-tumor activity following two 5-day cycles in patients with stage IV melanoma (MM) or renal cell carcinoma (RCC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2505-2505 ◽  
Author(s):  
J. A. Thompson ◽  
B. D. Curti ◽  
B. G. Redman ◽  
J. S. Weber ◽  
S. S. Agarwala ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Nk Cell ◽  
Phase 1 ◽  
Cell Activity ◽  
Stage Iv ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Study Results ◽  
Initiation Of Therapy ◽  
Anti Tumor Activity

2505 Background: IL-21 enhances NK cell activity and the proliferation and activation of CD8+ T cells. A Phase 1 outpatient dose-escalation trial of IL-21 in patients with MM or RCC established a maximum tolerated dose and demonstrated biologic effects as measured by increased soluble CD25 levels and decreased lymphocyte counts. Partial responses (PR) were observed in 2 patients with RCC (J Immunother. 2005; 28:641–642). Methods: IL-21 was administered by intravenous push at 30 μg/kg/day for two 5-day cycles separated by a 9- or 16-day rest to a total of 34 patients (18 MM and 16 RCC) to further characterize safety and evaluate preliminary signs of anti-tumor activity. Results: All patients received 2 cycles of treatment with the exception of one patient who discontinued secondary to pleural effusion. Common drug-related Grade 1–2 adverse events (AEs) included pyrexia (n=27), fatigue (n=25), chills (n=18), headache (n=18), and rash (n=16). Related Grade 3 AEs included pleural effusion, abdominal pain, hypophosphatemia, and thrombocytopenia (n=1 each). Laboratory abnormalities commonly observed were decreased lymphocytes (n=31), platelets (n=31), albumin (n=29), and hemoglobin (n=27); increased triglycerides (n=27) and ALT (n=26). Except for lymphopenia (an expected pharmacodynamic response), most toxicities were Grade 1–2. AEs and laboratory abnormalities were generally transient. Final study results, including response data, will be presented. To date, of 28 patients evaluable for response (i.e., those who received at least 8 of 10 doses and have had a final evaluation), one PR has been confirmed in a patient with MM and 18 patients have stable disease two months following initiation of therapy. Conclusions: Two 5-day outpatient cycles of IL-21 at 30 μg/kg/day have been reasonably well tolerated and have demonstrated preliminary evidence of anti-tumor activity in patients with advanced MM or RCC. [Table: see text]

A phase 1 dose finding study of CHR-2797, an inhibitor of M1 aminopeptidases, in patients with advanced solid tumours

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3053-3053
Author(s):  
A. Reid ◽  
A. Protheroe ◽  
G. Attard ◽  
C. Cowsill ◽  
J. Spicer ◽  
...  
Keyword(s):  
Phase 1 ◽  
Plasma Concentrations ◽  
Dose Finding ◽  
Fixed Dose ◽  
10Mg Dose ◽  
Finding Study ◽  
Orally Bioavailable ◽  
Two Phases ◽  
Ecog Ps

3053 Background: CHR-2797 is a novel, orally bioavailable inhibitor of the M1 family of aminopeptidases, in particular PuSA, and LTA4 hydrolase. Exposure of cancer cells to CHR-2797 results in the generation of the active metabolite CHR-79888 which is poorly membrane-permeable, resulting in intracellular accumulation. CHR-2797 has shown anti-proliferative activity in syngeneic (rat) and xenograft (mouse) cancer models, and is anti-angiogenic in vitro. Methods: Patients (pts) (ECOG PS ≤ 2) with histologically confirmed advanced solid tumors resistant or refractory to standard therapy were eligible. The accelerated titration design of the trial involved two phases for evaluation of schedule and dose: 1) fixed dose with increasing duration, and 2) dose escalation over a fixed duration (28 days). Results: 16 pts (median age: 64.5 years [range 48.8–80.1], 13M/3F)were treated with once daily doses ranging from 10mg to 130mg. The first four patients received a 10mg dose for 7, 14, 21 or 28 days respectively. Five subsequent cohorts received 28 days continuous dosing, with dose doubling in single patient cohorts until drug-related toxicity ≥ Grade 2. Thereafter dose was escalated in ≤ 40% increments in 3-patient cohorts. The most frequent adverse events were: gr 1–2 thrombocytopenia (44%), gr 1 diarrhea (25%), gr 1–2 transaminitis (19%), gr 1–2 fatigue (13%), gr 1 hot flushes (13%), and gr 1 lightheadedness (13%). There were no DLTs. Five patients continued therapy after 28 days; stable disease has been achieved in 1 pt for 6 months with granulosa cell carcinoma of ovary, who was progressing prior to study entry. CHR-2797 and CHR-79888 demonstrate dose proportional increases in AUC and Cmax. The terminal half-life for CHR-2797 is around 1–2 hours, whereas it is between 9 and 11 hours for CHR-79888. Intracellular (packed blood cells) exposure to both CHR-2797 and CHR-79888 is good, with CHR-79888 accumulating over 28 days, such that by day 28 the intracellular levels are comparable to plasma. Conclusions: CHR-2797 is well tolerated and can be safely administered at doses that reach plasma concentrations associated with activity in pre-clinical models. Accrual into the study continues. No significant financial relationships to disclose.

Neuroleptic Plasma Concentrations and Clinical Response: In Search of a Therapeutic Window

1988 ◽  
Vol 22 (5) ◽  
pp. 373-380 ◽  
Author(s):  
John J. Sramek ◽  
Steven G. Potkin ◽  
Rhoda Hahn
Keyword(s):  
Side Effects ◽  
Clinical Response ◽  
Study Design ◽  
Therapeutic Response ◽  
Plasma Concentrations ◽  
Therapeutic Window ◽  
Fixed Dose ◽  
The Relationship

There is much interest in finding a therapeutic window for commonly used neuroleptics so that dosage can be individualized and side effects minimized. The authors review specific requirements of good study design and survey the literature that has investigated the relationship between therapeutic response and plasma concentrations of neuroleptics. The evidence from a number of fixed-dose haloperidol studies suggests, but does not yet prove, the existence of a therapeutic window for this compound.

scholarly journals A Phase 1 Trial and Pharmacokinetic Study of Cediranib, an Orally Bioavailable Pan–Vascular Endothelial Growth Factor Receptor Inhibitor, in Children and Adolescents With Refractory Solid Tumors

2010 ◽  
Vol 28 (35) ◽  
pp. 5174-5181 ◽  
Author(s):  
Elizabeth Fox ◽  
Richard Aplenc ◽  
Rochelle Bagatell ◽  
Meredith K. Chuk ◽  
Eva Dombi ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Solid Tumors ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Thyroid Stimulating Hormone ◽  
Left Ventricular ◽  
Fixed Dose ◽  
Time Curve ◽  
Once Daily ◽  
Grade 3

Purpose To determine the toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of cediranib administered orally, once daily, continuously in children and adolescents with solid tumors. Patients and Methods Children and adolescents with refractory solid tumors, excluding primary brain tumors, were eligible. DLT at the starting dose of 12 mg/m2/d resulted in de-escalation to 8 mg/m2/d and subsequent re-escalation to 12 and 17 mg/m2/d. Pharmacokinetic and pharmacodynamic studies were performed during cycle 1. Response was evaluated using WHO criteria. Results Sixteen patients (median age, 15 years; range, 8 to 18 years) were evaluable for toxicity. DLTs (grade 3 nausea, vomiting, fatigue in one; hypertension and prolonged corrected QT interval in another) occurred in patients initially enrolled at 12 mg/m2/d. Subsequently, 8 mg/m2/d was well tolerated in three patients. An additional seven patients were enrolled at 12 mg/m2/d; one had DLT (grade 3 diarrhea). At 17 mg/m2/d, two of four patients had DLTs (grade 3 nausea; intolerable grade 2 fatigue). Non–dose-limiting toxicities included left ventricular dysfunction, elevated thyroid stimulating hormone, palmar-plantar erythrodysesthesia, weight loss, and headache. The MTD of cediranib was 12 mg/m2/d (adult fixed dose equivalent, 20 mg). At 12 mg/m2/d, the median area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) was 900 ng·h/mL, which is similar to adults receiving 20 mg. Objective responses were observed in patients with Ewing sarcoma, synovial sarcoma, and osteosarcoma. Conclusion The recommended monotherapy dose of cediranib for children with extracranial solid tumors is 12 mg/m2/d administered orally, once daily, continuously. A phase II study is in development.

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