Randomized phase II study comparing dose-escalated weekly paclitaxel (wPTX) versus standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC).

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 64-64 ◽  
Author(s):  
Daisuke Takahari ◽  
Kohei Shitara ◽  
Satoshi Yuki ◽  
Michio Nakamura ◽  
Chihiro Kondo ◽  
...  
Keyword(s):  
Phase Ii ◽  
Dose Escalation ◽  
Standard Dose ◽  
Sensory Neuropathy ◽  
Weekly Paclitaxel ◽  
Severe Toxicity ◽  
Randomized Phase Ii ◽  
Significant Difference ◽  
Previously Treated ◽  
Grade 3

64 Background: wPTX is one of the standard second-line chemotherapies for AGC. Meanwhile, retrospective analysis of neutropenia during wPTX showed better overall survival (OS) among patients with neutropenia compared to patients without neutropenia. Therefore, we conducted randomized phase II trial comparing dose-escalated wPTX with dose adjustments determined by degree of neutropenia versus standard-dose wPTX for patients with previously treated AGC. Methods: Patients with AGC that progressed during 1 or more previous chemotherapy regimens were randomized to a standard dose of weekly paclitaxel (80 mg/m2, standard dose arm) or an escalated dose of weekly paclitaxel (80 mg/m2 on day 1, 100 mg/m2 on day 8, and 120 mg/m2on day 15 unless severe toxicity nor neutropenia<1500 is observed, escalated dose arm). The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) and safety Results: From September 2010 to November 2011, a total of 90 patients were randomised. Number of previous line of chemotherapy was 1 in 55% and 2 or more in other 45%. Among the 44 patients of dose escalated arm, the dose of wPTX was escalated to 100 mg/m2 in 41 patients (93.2%) and then to 120 mg/m2in 29 patients (65.9%). Median PFS was significantly longer in dose escalated arm than standard dose (4.3 months. vs. 2.5 months, HR, 0.61; 95% CI, 0.39-0.95; p=0.03). ORR was 30.3% with dose escalation and 17.1% with standard dose (p=0.2). DCR was significantly higher with dose escalation (78.8% vs. 48.6%, p=0.009). Frequency of neutropenia (grade 1-4) was significantly higher with dose escalation (88.7% vs. 60.0%, p=0.002), but no significant difference was observed in grade 3/4 (40.9% vs.31.1%, p=0.34). Grade 3 peripheral sensory neuropathy was relatively common in dose escalated arm (13.6% vs. 6.7%, p=0.27). Conclusions: Dose escalated wPTX was associated with significantly longer PFS and higher DCR in patients with previously treated AGC in comparison with standard dose. The result of OS will be presented at the meeting Clinical trial information: UMIN000004055.

Randomized phase II study comparing dose-escalated weekly paclitaxel versus standard dose weekly paclitaxel for patients with previously treated advanced gastric cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4076-4076
Author(s):  
Kohei Shitara ◽  
Satoshi Yuki ◽  
Daisuke Takahari ◽  
Michio Nakamura ◽  
Chihiro Kondo ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Phase Ii ◽  
Dose Escalation ◽  
Standard Dose ◽  
Phase Iii ◽  
Weekly Paclitaxel ◽  
Subset Analysis ◽  
Randomized Phase Ii ◽  
Previously Treated

4076 Background: Retrospective analyses of neutropenia during chemotherapy of weekly paclitaxel (wPTX) suggested better overall survival (OS) among patients with neutropenia. We conducted a randomized phase II trial comparing dose-escalated wPTX with dose adjustments determined by degree of neutropenia versus standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC). Methods: Ninety-patients with AGC that progressed during one or more previous chemotherapy regimens were randomized to a standard dose of wPTX (80 mg/m2, standard dose arm) or an escalated dose of wPTX (80 mg/m2 on day 1, 100 mg/m2 on day 8, and 120 mg/m2 on day 15 unless severe toxicity nor neutropenia<1.5 x 109/L is observed, escalated dose arm) to assess superiority with a one-sided alpha of 0.3 and a power of 0.8. Results: The primary endpoint of median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs. 9.6 months; hazard ratio [HR], 0.75; 95% CI, 0.45-1.22; one-sided P=0.12). Median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs. 2.5 months, HR, 0.55; 95% CI, 0.34-0.90; P=0.017). Objective response rate was 30.3% with dose-escalation and 17.1% with standard dose (P=0.2). The disease control rate (DCR) was significantly higher with dose-escalation (78.8% vs. 48.6%, P=0.009). Subset-analysis according to stratification factors including ECOG PS, presence of measurable lesions and lines of previous chemotherapy indicated that OS benefit of the dose escalation is more prominent in PS 0-1 patients (N=81, median 13.6 vs. 9.8 months, HR 0.68, 95% CI 0.41-1.11) than PS2 patients with significant interaction (p=0.01) Conclusions: Dose escalated wPTX was associated with sufficiently longer OS in patients with pretreated AGC. In addition, significant longer PFS and higher DCR associated with dose-escalation and subset analysis according PS warrant further investigations in phase III trials, especially in patients with favorable PS patients. Clinical trial information: UMIN000004055.

A phase II study of high-dose cetuximab plus irinotecan in colorectal cancer patients with KRAS-wild type tumors who progressed on prior standard dose cetuximab and irinotecan.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3582-3582
Author(s):  
Ahmad Ali Fora ◽  
Jeanne A McMahon ◽  
Greg Wilding ◽  
Adrienne E. Groman ◽  
Wen Wee Ma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Dose Escalation ◽  
Standard Dose ◽  
Dose Schedule ◽  
High Dose ◽  
Grade 3 ◽  
Colorectal Cancer Patients

3582 Background: Prior clinical data suggest a dose-related response to cetuximab (cmab) when combined with irinotecan in patients (pts) with KRAS WT tumors who do not develop grade ≥ 2 rash with standard cmab dosing. However, the investigation of higher doses of cmab in the setting of acquired or innate resistance to standard dose cmab has not been previously investigated. We conducted a phase II clinical trial of high-dose cmab plus irinotecan in KRAS WT pts who progressed on standard-dose cmab plus irinotecan. Methods: Pts who progressed within 4 weeks from receiving a minimum of 6 weeks of standard dose cmab plus irinotecan were included in this study. Cmab was administered at 500 mg/m2/week and irinotecan was administered at the same dose/schedule on which each individual patient previously progressed. All pts received doxycyline 100 mg PO bid starting day 1 of treatment. 12-week PFS rate was the primary endpoint. The regimen was considered interesting if 7/36 patients had stable disease or response at 12 weeks. The study was closed early after meeting its primary endpoint. Results: 20 pts were treated on study: median age 65.5 yrs (44-84), 14 pts were males. 8 pts had grade ≥ 2 hypomagnesaemia (3 grade 3 and 2 grade 4), 6 pts had grade ≥ 2 skin rash (1 grade 3, 0 grade 4), and 4 pts had grade ≥ 2 diarrhea (1 grade 3, 0 grade 4). 1 pt had a confirmed PR and 12 pts had a SD (at 6 weeks). In 9 pts, SD was confirmed at 12 weeks (3 pts> 24 weeks). Median PFS and OS were 2.8 and 6.6 months, respectively. The 1-year survival was 25%. Conclusions: High-dose cmab plus irinotecan is well tolerated with an acceptable rate of diarrhea and skin toxicities but with an increased rate of grade 3-4 hypomagnesemia. The prolonged disease stabilization and single response suggest that resistance to standard dose cmab plus irinotecan can be overcome by cmab dose escalation. The identification of predictive markers of response from dose escalation will be necessary to implement this strategy selectively in KRAS WT colorectal cancer patients.

Rituximab +/− Bevacizumab for Patients with Previously Treated Follicular Non-Hodgkins Lymphoma: A Randomized Phase II Trial of the Sarah Cannon Research Institute.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2749-2749
Author(s):  
John D. Hainsworth ◽  
Dana S. Thompson ◽  
F. Anthony Greco ◽  
Eric Raefsky ◽  
Scott Lunin ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Off Label ◽  
Overall Response ◽  
Randomized Phase Ii ◽  
Previously Treated ◽  
Grade 3 ◽  
Tumor Types

Abstract Abstract 2749 Background: Single-agent rituximab produces an overall response rate of approximately 50% and a median PFS of 9 months in patients with previously treated follicular NHL. Since resistance to rituximab eventually develops in nearly all patients, a number of novel agents are currently being evaluated in combination with rituximab to improve treatment efficacy. Vascular endothelial growth factor (VEGF) promotes angiogenesis and is increased in many tumor types. In NHL, high levels of VEGF are correlated with disease progression. Bevacizumab, a monoclonal antibody inhibiting VEGF, has extended PFS in several solid tumor types when added to combination chemotherapy. In this randomized phase II trial, we compared the efficacy and toxicity of bevacizumab + rituximab versus single-agent rituximab, in patients with previously treated follicular NHL. Methods: Eligible patients had follicular NHL (grade 1 or 2); NHL progression after either 1 or 2 prior chemotherapy regimens; measurable or evaluable disease; and ECOG PS 0–2. Prior rituximab treatment was allowed as long as progression occurred > 6 months following completion of treatment. Patients were randomized to receive single-agent rituximab (Regimen A) or rituximab plus bevacizumab (Regimen B). All patients received 375 mg/m2IV of rituximab weekly for 4 weeks. Regimen B patients also received bevacizumab 10 mg/kg IV on days 3 and 15 during the 4-week course of rituximab. Response evaluations were performed at weeks 6 and 12 as well as 4 weeks after the completion of all therapy. Patients with objective response or stable disease at week 12 received 4 additional doses of rituximab administered at months 3 (week 12), 5, 7, and 9; in addition, regimen B patients received bevacizumab 10 mg/kg IV every 2 weeks for a total of 16 doses (also beginning week 12). Addition of bevacizumab was hypothesized to improve the median PFS from 15 months to 20 months. Accrual of 90 patients (45/arm) was initially planned; the study was stopped early due to slow accrual. Results: Between 8/2005 and 3/2012, 60 patients were enrolled (Regimen A, 30; Regimen B, 29). Key clinical characteristics including age, performance status, FLIPI score, and previous treatment were comparable in the 2 treatment groups. 95% of patients had received 2 previous regimens, and 78% had received previous rituximab. After a median followup of 36 months, 92% of patients have either completed (40%) or discontinued treatment (lymphoma progression 30%, toxicity 12%, patient/physician decision 8%). The overall response rates were 42% in Regimen A (CR rate 10%) and 45% in Regimen B (CR rate 17%). The median progression-free survivals for Regimens A and B were 10.4 and 18.4 months, respectively (HR 0.33, p=0.0090). Median OS has not been reached for either group; at 3 years, the estimated OS rates are 54% (Regimen A) and 81% (Regimen B) (p=0.12). Grade 3/4 hematologic toxicity was uncommon, with no grade 4 neutropenia or thrombycytopenia, and 1 episode of febrile neutropenia (Regimen B). No grade 4 non-hematologic toxicity occurred; grade 3 non-hematologic toxicity occurred in 3 patients (10%) on Regimen A (infusion reaction 1, hyperglycemia 1, pneumonia 1) and 7 patients (24%) on Regimen B (hypertension 3, epistaxis 1, abdominal wall hematoma 1, wound dehiscence 1, confusion 1). All 7 patients who discontinued treatment due to toxicity (3 during the first 12 weeks) were on regimen B; 5 had bevacizumab-related toxicity. There were no treatment-related deaths. Conclusion: The addition of bevacizumab to rituximab was feasible with a modest increase in toxicity in this group of patients with previously-treated follicular NHL. The toxicities observed were consistent with the known profiles of each agent. While response rates were similar between regimens, the addition of bevacizumab lengthened the progression-free survival when compared to rituximab alone (median 18.4 vs. 10.4 months). Although results of this study must be interpreted with caution due to its small size, further study of VEGF- targeted therapies in NHL may be warranted. Disclosures: Off Label Use: Off-label bevacizumab use for treatment of follicular non-Hodgkin's lymphoma. Reeves:Celgene: Equity Ownership.

scholarly journals Randomized, Phase II Study Prospectively Evaluating Treatment of Metastatic Esophageal, Gastric, or Gastroesophageal Cancer by Gene Expression of ERCC1: SWOG S1201

2020 ◽  
Vol 38 (5) ◽  
pp. 472-479 ◽  
Author(s):  
Syma Iqbal ◽  
Shannon McDonough ◽  
Heinz-Josef Lenz ◽  
David Ilson ◽  
Barbara Burtness ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Interactive Effects ◽  
Randomized Phase Ii ◽  
Esophagogastric Cancer ◽  
Significant Difference ◽  
Grade 3 ◽  
Ercc1 Expression

PURPOSE Platinum-based therapy is the standard of care in patients who have HER2-negative, advanced esophagogastric cancer (AEGC). Retrospective data suggest that intratumoral ERCC1 levels may determine platinum sensitivity. A randomized, phase II study was performed in patients with AEGC to explore whether the efficacy of a platinum-based therapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) versus a non–platinum-containing regimen of irinotecan and docetaxel (IT) differed according to ERCC1 levels. PATIENTS AND METHODS Overall, 202 untreated patients with HER2-negative AEGC and a Zubrod performance status of 0-1 were evaluated prospectively for mRNA expression of ERCC1 level and then randomly assigned to FOLFOX or IT, stratified by the intratumoral statuses of ERCC1 low (< 1.7) or high (≥ 1.7). Objectives were to assess progression-free survival (PFS) and overall survival (OS) in all patients treated with FOLFOX compared with IT, stratified by low and high ERCC1 levels, and to assess for interactive effects between ERCC1 expression and treatment arm. RESULTS Eighty-six percent of patients had ERCC1 values < 1.7. Thus, evaluation of the ERCC1-high subgroup was limited. Grade ≥ 3 anemia, dehydration, diarrhea, and fatigue were greater in patients with IT. Occurrences of grade ≥ 3 neuropathy and decreased neutrophils were greater in patients with FOLFOX. In all patients, FOLFOX had a statistically superior median PFS compared with IT (5.7 v 2.9 months; hazard ratio, 0.68; P = .02). In patients with ERCC1 levels < 1.7 receiving FOLFOX, PFS and response rate were statistically superior to IT, with no significant difference in OS. CONCLUSION The evaluation of ERCC1 in patients with upper GI tumors was thwarted by an overwhelming predominance of low ERCC1 mRNA expression. Nonetheless, distribution of treatment effects on PFS did not vary with expression. For all patients and for those with low ERCC1 expression, FOLFOX was superior in efficacy to IT.

Randomized phase II trial of three dosing schedules of nanoparticle albumin-bound paclitaxel with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer: An initial interim safety report

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1104-1104 ◽  
Author(s):  
A. K. Conlin ◽  
A. D. Seidman ◽  
M. E. Moynahan ◽  
T. Traina ◽  
J. R. Mace ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Safety Data ◽  
Metastatic Breast ◽  
Sensory Neuropathy ◽  
Safety Analysis ◽  
Proc Asco ◽  
Line Therapy ◽  
Randomized Phase Ii ◽  
Grade 3

1104 Background: Nanoparticle paclitaxel (NP) at 260mg/m2 every 3 weeks (q3wk) is more effective than standard paclitaxel (P) (Gradishar et al, JCO 2005). Weekly, uninterrupted administration of P is superior to q3wk P in MBC (Seidman et al, Proc ASCO 2004). When added to weekly P as 1st-line therapy for MBC, bevacizumab (B) improves response rate and progression-free survival (Miller et al, Proc ASCO 2005). We initiated a randomized phase II trial of NP given at 260mg/m2 q3wk (arm A) vs. 260mg/m2 q2wk with filgrastim (arm B) vs. 130mg/m2 weekly, all with B, as 1st-line therapy for patients (pts) with HER2- MBC. Methods: 66 of planned 225 pts have enrolled. After 31 pts had been randomized and treated, investigators concerned about possible differential neurotoxicity requested this early interim safety analysis. Median age is 54 (range 40–78). 83% are post-menopausal and 100% have visceral dominant disease. 68% had prior adjuvant or neo-adjuvant chemotherapy; 35% with taxanes. Results: With 170 cycles delivered (median: 4, range 1–15) 10 dose reductions have been necessary for NP (1 in A, 5 in B, 4 in C). No hypersensitivity reactions or dose interruptions have occurred for NP; 3 doses of B have been held due to hypertension. Significant preliminary antitumor activity has been noted in all arms. One grade 4 toxicity occurred in arm C, hyperglycemia. 15 grade 3 toxicities have been reported across all arms. Pts on arm A have experienced 3 grade 3 toxicities (30%): fatigue, neutropenia, and arthralgia with no grade 3 neurotoxicity. Pts on arm B have had 7 grade 3 toxicities (58%) with 3 pts experiencing grade 3 sensory neuropathy (25%) and others experiencing fatigue, neutropenia, anemia, esophagitis, dyspnea, and ataxia. 5 arm C pts experienced grade 3 toxicities (56%) including diarrhea, dehydration, mucositis, neutropenia, hypokalemia; 2 pts have had grade 3 sensory neuropathy (22%). Conclusions: This early safety analysis does not detect any statistically or clinically significant differences in grade 3 toxicity and all arms continue to accrue. The next protocol-specified safety analysis is expected in early 2007, with mature safety data for 60 pts. Updated results will be presented. [Table: see text]

A randomized phase II trial comparing docetaxel plus cyclophosphamide with epirubicin plus cyclophosphamide followed by docetaxel as neoadjuvant chemotherapy for hormone receptor-negative breast cancer: Kanagawa Breast Oncology Croup (KBOG) 1101 study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1047-1047
Author(s):  
Takashi Ishikawa ◽  
Daisuke Shimizu ◽  
Mikiko Tanabe ◽  
Mari S.Oba ◽  
Takeshi Sasaki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Phase Ii ◽  
Statistical Significance ◽  
Disease Free Survival ◽  
Her2 Status ◽  
Ki 67 ◽  
Randomized Phase Ii ◽  
Significant Difference ◽  
Grade 3

1047 Background: Taxane-based regimens have been widely used to treat breast cancer. Accordingly, it has become important to identify subgroups in which anthracyclines are indispensable. Thus, we initiated a randomized phase II neoadjuvant chemotherapy (NAC) study to compare taxane with and without anthracycline in hormone-negative subtypes. Methods: Eligibility criteria were hormone-negative, an age younger than 80 years and ECOG PS0-1. According to HER2 status, patients were randomly assigned to TC (75/600 mg/m2) q3wks ×6 or FEC (500/100/500 mg/m2) q3wks ×3 followed by D (100 mg/m2) q3wks ×3. The primary endpoint was the rate of pathological complete response (pCR; Grade 3 and Quasi-pCR; Grade 3+2b). Secondary endpoints were safety, breast-conserving surgery ratio, disease-free survival, overall survival, and predictive factors (HER2, Ki-67, P-53, CK5/6, EGFR, and TOP2A by IHC and TOP2A by FISH) for each regimen. Results: 97 out of 103 patients were successfully analyzed (47 for TC6 and 50 for FEC-D). Severe adverse events (Grade ≥2) were frequently observed in FEC-D-treated patients with statistical significance (poor appetite, nausea/vomiting: p<0.001; febrile neutropenia: p=0.016). The pCR rate tended to be higher in FEC-D-treated patients compared with that of TC6-treated patients (pCR: 36.0 vs. 25.5%, n.s.; Quasi-pCR: 46.0 vs. 40.4%, n.s.). There was no significant difference of pCR rates in the HER2 and triple negative (TN) subtypes between each regimen. Among predictors, only positive markers CK5/6 and EGFR predicted the superiority of the FEC-D treatment (p=0.05). Conclusions: TC6 was safe and relatively active even in HER2 subtype patients. Therefore, the concurrent use of trastuzumab with TC could be a reasonable option for NAC in HER2 subtype patients. However, anthracyclines are required to treat basal-type TN cancer. Clinical trial information: UMIN000002215.

Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)–An ACCRU Network study.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 611-611 ◽  
Author(s):  
Tanios S. Bekaii-Saab ◽  
Fang-Shu Ou ◽  
Daniel M. Anderson ◽  
Daniel H. Ahn ◽  
Patrick McKay Boland ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Dose Escalation ◽  
Standard Dose ◽  
Demographic Data ◽  
Progression Free Survival ◽  
P Value ◽  
Weekly Dose ◽  
Multikinase Inhibitor ◽  
Randomized Phase Ii

611 Background: Regorafenib is an oral multikinase inhibitor with survival benefit in refractory mCRC patients (pts). Toxicities such as Palmar-plantar erythrodysesthesia syndrome (PPES), fatigue and hypertension (HTN) have limited its use. Despite absence of supportive data, various dosing or interval scheduling have been implemented into clinical practice. Methods: A randomized phase II study of regorafenib dose-escalation (Arm A: 80 mg/day, weekly dose escalation if no significant drug-related toxicities, up to 160 mg/day) vs. standard dose (Arm B: 160 mg/day) in pts with mCRC for 21 days of a 28-day cycle. Pts were randomized 1:1:1:1 to arms A1 and B1 (Pre-emptive Clobetasol for PPES); A2 and B2 (Reactive Clobetasol). The primary endpoint was the proportion of patients who completed 2 cycles of treatment and initiated the 3rd in Arm A (Pooled A1 + A2) vs. Arm B (Pooled B1 + B2). Superiority for Arm A was to be declared if the one-sided p-value calculated using Fisher’s exact method was less than 0.2. Results: From June 2015 to June 2017, 123 pts were randomized with 116 (A = 54, B = 62) evaluable for the primary endpoint. Demographic data were well balanced with overall median age of 61yrs (range: 29-81), M/F (61/39%) and ECOG PS 0/1 (37/63%) and KRAS MT/WT/UNK (47/44/9%).The study met its primary endpoint with 43% of pts on Arm A initiating the 3rd vs. only 25% of pts Arm B [one-sided p-value 0.028]. Median Overall Survival (OS) was improved in Arm A vs. Arm B (9.0 mos vs. 5.9 mos; p = 0.094). Median Progression Free Survival (PFS) was 2.5 mos for Arm A vs. 2.0 mos for Arm B (p=0.553). Overall rates of grade 3/4 toxicity were more favorable for Arm A vs. Arm B (% PPES 15 vs. 16, HTN 7 vs. 15 and fatigue 13 vs. 18, respectively). Multiple QOL parameters were improved in A vs. B primarily at week 2 of the first cycle. Conclusion: A strategy with weekly dose escalation of regorafenib from 80 mg to 160 mg/day was found to be superior to a starting dose of 160 mg/day. These results establish a new standard for optimizing regorafenib dosing. Further data on outcomes of preemptive vs. reactive clobetasol strategies are undergoing analysis and will be presented later. Clinical trial information: NCT02368886.

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