Impact of gender on multikinase inhibitors (MKIs) toxicity in patients (pts) with advanced pancreatic and gastrointestinal neuroendocrine tumors (NETs): A pooled analysis of two phase II trials with pazopanib and lenvatinib.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4109-4109
Author(s):  
Jorge Hernando-Cubero ◽  
Enrique Grande ◽  
Daniel E. Castellano ◽  
Toni Ibrahim ◽  
Nicola Fazio ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Phase Ii ◽  
Liver Toxicity ◽  
Task Force ◽  
Pooled Analysis ◽  
Phase Ii Trials ◽  
Open Label ◽  
Two Phase ◽  
Phase Ii Studies ◽  
Grade 3

4109 Background: Retrospective data in some cancer types suggested a possible different toxicity profile with chemotherapy and targeted therapies according to gender. However, data from prospective studies are still very limited, especially in infrequent tumors such as NETs. Methods: Pts with advanced pancreatic and gastrointestinal NETs treated with pazopanib or lenvatinib in the multicenter open-label phase II studies PAZONET and TALENT respectively, were included in the analysis. Both studies were performed by Spanish Task Force Group for Neuroendocrine Tumors (GETNE). All toxicity grades with an incidence higher than 5% were considered for univariate review. Additionally, all grade 3-4 toxicities were analyzed separately. Results: 155 pts (47.7% female) with 1213 adverse events (AEs) (20% G3-4) divided in 121 categories were included. In female patients, liver toxicity, headache, pyrexia, nausea/vomiting, hair/skin disorders and dizziness were significantly more common (table). The only toxicity with higher incidence in men was dysphonia (OR 0.42, 95% CI 0.2-0.9, p 0.02). There were no gender differences in grade 3-4 toxicities. Conclusions: We observed significant differences in toxicity AEs by gender in two prospective phase II studies with MKIs in NETs patients. Potential different approach to manage toxicity may be adopted based on gender. [Table: see text]

Phase II Trials of Clofarabine in Relapsed or Refractory Pediatric Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 684-684 ◽  
Author(s):  
Sima Jeha ◽  
Bassem I. Razzouk ◽  
Michael E. Rytting ◽  
Paul S. Gaynon ◽  
Richard Kadota ◽  
...  
Keyword(s):  
Median Survival ◽  
Phase Ii ◽  
Median Duration ◽  
Single Agent ◽  
Median Number ◽  
Phase Ii Trials ◽  
Open Label ◽  
Two Phase ◽  
Pediatric Leukemia ◽  
Phase Ii Studies

Abstract Background: Clofarabine, a next generation nucleoside analogue, was well tolerated and demonstrated activity in adult and pediatric Phase I trials conducted in heavily pretreated leukemia patients. Multicenter Phase II studies in pediatric leukemia have completed accrual in the US and are reported here. Methods: Two Phase 2, multicenter, open-label studies were conducted with clofarabine in children with refractory or relapsed ALL or AML. Clofarabine was administered intravenously over 2 hours at 52 mg/m2/day for 5 consecutive days. Cycles were repeated every 2 to 6 weeks based on response and toxicity. Results: The studies enrolled 100 patients (60 ALL and 40 AML). Currently, data are available for 84 patients (49 ALL, 35 AML). Median age is 12 years (range 1 to 22 years) and median number of prior regimens is 3 (range 1 to 6). Thirty-nine percent had received prior bone marrow transplant (BMT). As determined by independent review, preliminary data indicate overall response rates of 31% in ALL (6 CR, 4 CRp, and 5 PR) and 26% in AML (1 CRp and 8 PR). Median duration of remission for ALL is 9.7 weeks (range 1.0 to 28.6) and for AML is 16.2 weeks (range 1.7 to 56.6+). Thirteen of 24 responding patients (54%) proceeded to BMT. Median survival was 42 weeks (range 7.0 to 63.1+) for responding ALL patients (CR+CRp+PR) and 39 weeks (range 7.7 to 93.6+) for responding AML patients (CRp+PR). Patients who failed treatment or were non-evaluable had shorter median survival; 7.4 weeks (range 0.9 to 40.1+) and 12.4 weeks (range 1.6 to 84.9+) for ALL and AML, respectively. Among the patients who were refractory to the last prior chemotherapy, 7/30 (23%) with ALL and 4/22 (18%) with AML achieved a response with clofarabine. Median duration of remission in these patients is 4.6 weeks (range 2.3 to 24.4+) for ALL and 20 weeks (range 1.7 to 56.6+) for AML. Most drug-related adverse events were transient including febrile neutropenia, diarrhea, nausea/vomiting, fever, skin rash, headache, elevation in liver enzymes and bilirubin, and infusion-related flushing and anxiety. Conclusions: Clofarabine is active as a single agent in pediatric ALL and AML that are refractory to intensive salvage regimens. The overall safety profile is similar to that reported in other pediatric salvage studies. Clofarabine in combination with standard chemotherapy is currently under investigation in children.

Three-year outcomes of two phase II studies of adjuvant chemotherapy with S-1 plus oxaliplatin or capecitabine plus oxaliplatin in patients with stage III gastric cancer after D2 gastrectomy.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 94-94 ◽  
Author(s):  
Yoshiaki Nakamura ◽  
Takeharu Yamanaka ◽  
Keisho Chin ◽  
Haruhiko Cho ◽  
Hitoshi Katai ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Adjuvant Chemotherapy ◽  
Phase Ii ◽  
Pooled Analysis ◽  
Stage Iii ◽  
Phase Ii Trials ◽  
Two Phase ◽  
D2 Gastrectomy ◽  
Phase Ii Studies

94 Background: Two phase II trials of oxaliplatin-based adjuvant chemotherapy for patients (pts) with gastric cancer (GC) after D2 gastrectomy have been conducted in Japan; the J-CLASSIC study of capecitabine plus oxaliplatin (CAPOX) and the SOXaGC study of S-1 plus oxaliplatin (SOX). In the current study, we evaluated survival outcomes of the two trials. Methods: The J-CLASSIC, enrolling stage II and III pts from 12 centers between July 2012 and July 2013, evaluated eight cycles of CAPOX. The SOXaGC, enrolling stage III pts from 11 centers between July 2013 and February 2014, evaluated seven cycles of SOX after one cycle of S-1 monotherapy. The two studies were conducted sequentially and most centers (9 centers) participated in both trials. In this pooled analysis, we updated relapse-free survival (RFS) and overall survival (OS) information. The median follow-up time was 49 months in the J-CLASSIC and 39 months in the SOXaGC. Results: Fifty-nine stage III pts treated with CAPOX and 62 stage III pts treated with SOX were analyzed. The 3-year RFS and OS rates of SOX were 70.9% (57.8-80.5%) and 75.7% (63.0-84.6%), respectively, whereas the 3-year RFS and OS rates of CAPOX were 67.8% (54.3-78.1%) and 79.3% (66.5-87.7%), respectively. The hazard ratio (HR) of SOX in comparison to CAPOX was 0.925 (0.498-1.720) for RFS, suggesting the efficacy of the two treatments was similar. Trend of a different efficacy was observed in some particular subgroups; the HR for RFS was 1.732 (0.506-5.927) in the intestinal type and 0.735 (0.353-1.528) in the diffuse type, while that was 2.008 (0.447-9.016) in stage IIIA, 0.872 (0.266-2.857) in stage IIIB, and 0.597 (0.258-1.383) in stage IIIC. Conclusions: This is the first report of survival follow-up in Japanese GC pts with oxaliplatin-based adjuvant chemotherapy, which suggests comparable outcomes in both treatments for stage III GC. Different trend in the treatment effect by histologic type or stage warrants further evaluation in a larger cohort. Clinical trial information: UMIN000026883.

Combination of Oxaliplatin Plus Irinotecan in Patients With Gastrointestinal Tumors: Results of Two Independent Phase I Studies With Pharmacokinetics

1999 ◽  
Vol 17 (6) ◽  
pp. 1751-1751 ◽  
Author(s):  
Ernesto Wasserman ◽  
Caroline Cuvier ◽  
François Lokiec ◽  
François Goldwasser ◽  
Salima Kalla ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Two Phase ◽  
Phase I Studies ◽  
Phase Ii Studies ◽  
Minute Period ◽  
Grade 3 ◽  
Febrile Episodes

PURPOSE: Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen. PATIENTS AND METHODS: Patients with a performance status (PS) of ≤2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks. Dose levels that were explored ranged from 85 to 110 mg/m2 for oxaliplatin and 150 to 250 mg/m2 for irinotecan. Plasma pharmacokinetics of total and ultrafiltrable platinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined. RESULTS: Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-tolerated dose was oxaliplatin 110 mg/m2 plus irinotecan 200 mg/m2 in one study and oxaliplatin 110 mg/m2 plus irinotecan 250 mg/m2 in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2. At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syndrome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients. CONCLUSION: This combination is feasible, with activity in 5-FU–resistant CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing.

scholarly journals MA07.01 Updated Pooled Analysis of CNS Endpoints in Two Phase II Studies of Alectinib in ALK+ NSCLC

2017 ◽  
Vol 12 (1) ◽  
pp. S377
Author(s):  
Sai-Hong Ignatius Ou ◽  
Leena Gandhi ◽  
Alice Shaw ◽  
Ramaswamy Govindan ◽  
Mark Socinski ◽  
...  
Keyword(s):  
Phase Ii ◽  
Pooled Analysis ◽  
Two Phase ◽  
Phase Ii Studies

Preliminary results from two phase II studies of lenalidomide monotherapy in relapsed/refractory non-Hodgkin’s Lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17569-17569 ◽  
Author(s):  
P. H. Wiernik ◽  
I. S. Lossos ◽  
G. Justice ◽  
J. B. Zeldis ◽  
K. Takeshita ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Phase Ii ◽  
Prior Treatment ◽  
Hodgkin's Lymphoma ◽  
Two Phase ◽  
Preliminary Results ◽  
Phase Ii Studies ◽  
Non Hodgkin's Lymphoma ◽  
Grade 3

17569 Background: Lenalidomide is an immunomodulatory drug of the IMiD class that has activity in multiple myeloma, myelodysplastic syndromes and chronic lymphocytic leukemia. We report preliminary results of two Phase II studies assessing the safety and efficacy of lenalidomide monotherapy in subjects with relapsed/refractory indolent or aggressive non-Hodgkin’s lymphoma (NHL). Methods: Subjects with indolent (study NHL-001) or aggressive (study NHL-002) relapsed/refractory NHL following ≥ 1 prior treatment regimen with measurable disease are eligible. Subjects receive 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continue therapy for 52 weeks as tolerated until disease progression. Response and progression are evaluated using cross sectional imaging by the NCI criteria. Results: 10 subjects (2 indolent (I), 8 aggressive (A)) of a planned 80 (40 in each study) have enrolled thus far. Median age is 66 (45–80) and 7 subjects are female. Indolent histology is follicular center lymphoma grade 1, 2 (n = 2) and aggressive histology diffuse large cell lymphoma (n = 7) and follicular center lymphoma grade 3 (n = 1). Median time from diagnosis to lenalidomide monotherapy is 2.9 years (1.1–10) and median number of prior treatment regimens per subject is 3 (1–6). Median duration of follow-up is 2 months. Of eight subjects (2 I, 6 A) evaluable for response at two months, three demonstrated a decrease in their tumor burden by 72% (I), 68% (A) and 52% (A), two subjects (2 A) exhibited stable disease and three subjects (1 I, 2 A) had disease progression. Six of the ten subjects (2 I, 4 A) demonstrated no Grade 3 or 4 adverse events. Grade 3 or 4 hematological adverse events (neutropenia, thrombocytopenia) occurred in four subjects including one febrile neutropenia and one of these four subjects also exhibited Grade 3 cellulitis. No tumor flare or tumor lysis has been observed to date. Conclusions: Preliminary data of lenalidomide monotherapy in relapsed and refractory NHL are encouraging. [Table: see text]

Trabectedin (T) in relapsed advanced ovarian cancer (ROC): A pooled analysis of three phase II studies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5579-5579 ◽  
Author(s):  
S. McMeekin ◽  
J. M. del Campo ◽  
N. Colombo ◽  
C. Krasner ◽  
A. Roszak ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Advanced Ovarian Cancer ◽  
Dose Intensity ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Clinical Activity ◽  
Weekly Schedule ◽  
Phase Ii Trials ◽  
Phase Ii Studies

5579 Introduction: Trabectedin is a DNA minor groove binding drug with a distinct MoA under development in sarcoma, prostate, breast and ROC. We have performed a pooled analysis of efficacy and tolerability of all phase II trials with T as 2nd - 3rd line in ROC. Methods: Three Trabectedin schedules were investigated: two every 3weeks (q3w; A: 1.3 mg/m2 3-h or B: 1.5 mg/m2 24-h) and one weekly (C: 0.58 mg/m2 3-h ×3 q4w). Endpoints were response rate (RR), time to progression (TTP), response duration (RD) and safety. 294 patients from 3 phase II (one randomized A vs B) trials were included: 108 were resistant (R) and 186 sensitive (S) to last platinum, based on progression-free interval <6 months or longer.Results: Overall RR and median TTP were 8% and 2.1mo in R and 34% and 5.8 mo in S patients. Median RD was 5.8 m. Schedules A & B q3w showed significant better RR (33% vs 16%, p=<0.0001) and median TTP (5.8 vs 2.8 m, p=0.0001) than the weekly schedule C. No efficacy difference was seen between 3-h and 24-h q3wk. In patients with = 2 prior platinum-based regimens, RR (R:7% and S:37%) and median TTP (R: 2.5 m and S:6.3 m) were similar than patients with only 1 prior platinum [RR (R:9%; S:33%) and TTP (R: 2 m; S: 5.5 m)]. 1,404 cycles were delivered [median A: 5(1–23), B: 5(1–19), C: 3(1–22)], with similar dose intensity (mg/m2/wk) across regimens (0.38, 0.42, 0.39). Most common drug-related AEs of any grade by cycle were (A, B, C) fatigue: 38, 35, 63% and vomiting: 16, 27, 21%. Grade 3/4 lab abnormalities were non-cumulative neutropenia: 21, 28, 1% and ALT increase: 32, 26, 3%. Low incidence of febrile neutropenia, neurotoxicity, stomatitis and alopecia was seen regardless of schedule. Conclusions: Trabectedin as single agent has shown clinical activity in both R and, particularly in S ROC. Activity was fully retained in patients with =2 prior platinum lines. Trabectedin q3w schedules (with no difference between 3 and 24-h) showed higher efficacy than T weekly. Toxicities were manageable and non-cumulative. Trabectedin is a promising new drug for the treatment of ROC and is under evaluation in a phase III trial. No significant financial relationships to disclose.

Biomodulation of capecitabine by weekly paclitaxel and carboplatin in patients with advanced solid tumor malignancies: A dose-escalating phase I study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2569-2569
Author(s):  
M. B. Lustberg ◽  
J. Nuovo ◽  
J. P. Thomas ◽  
P. J. Monk ◽  
S. Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Dihydropyrimidine Dehydrogenase ◽  
Weekly Paclitaxel ◽  
Unknown Primary ◽  
Cancer Tissue ◽  
Phase Ii Trials ◽  
Two Phase ◽  
Phase Ii Studies

2569 Background: A principal determinant of the therapeutic index with capecitabine-based treatment is the grade of thymidine phosphorylase (TP) activity in malignant tissue. The beneficial interactions of paclitaxel and carboplatin in upregulation of TP promise to make capecitabine more tumor specific and to provide the expected synergy. On the basis of the time-dependency and transiency for this upregulation we performed a phase I study of capecitabine in combination with weekly paclitaxel and carboplatin (CTX). Methods: Patients with advanced solid tumors received carboplatin on day 1, paclitaxel on days 1, 8, 15 and capecitabine orally twice a day on days 8–21, every 4 weeks. There were 5 planned dose levels (DL 1–5). Paclitaxel was escalated from 60 mg/m2 to 80 mg/m2 (DL 4) then 100 mg/m2 (DL 5). Capecitabine from 500 mg/m2 bid to 750 mg/2 bid (DL 2) then 1000 mg/m2 bid (DL 3–5). Carboplatin dose was fixed at AUC 6. Paraffin-embedded tissue was evaluated for expression of TP, thymidylate synthase and dihydropyrimidine dehydrogenase by immunohistochemistry. Results: 32 patients from Ohio State University (OSU) were enrolled. 84% had prior therapy. The most common grade 3/4 toxicities were neutropenia (59%), leukopenia (56%), and fatigue (16%). DLTs included neutropenic fever (1), prolonged neutropenia or thrombocytopenia (2) and diarrhea (1). The MTD was at DL 2. There were 10 confirmed responses [4 CR (esophagus, stomach, unknown primary and ampullary); 6 PRs (Pancreas (3), unknown primary, anal and esophagus] and stabilization of disease > 3 months in 12 patients. In normal tissue, there was no difference in expression levels of both TS and TP. On the other hand, in cancer tissue, TP levels seem to correlate with response whereas TS did not. Conclusions: CTX demonstrates acceptable tolerability. The recommended doses for phase II studies are capecitabine 750 mg/m2 bid, paclitaxel 60 mg/m2/week and carboplatin AUC=6. The acceptable toxicity profile in this dose schedule, and the promising antitumor activity observed warrant further evaluation of this regimen. Two phase II trials are already underway at OSU using this regimen for patients with pancreatic cancer and adenocarcinomas of unknown primary, the latter already actively enrolling patients. Pretreatment tumoral TP levels may help predict patients that are more likely to respond to CTX. Correlation of IHC data with responses will be presented at the meeting. [Table: see text]

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