Model-based estimates of tumor growth inhibition (TGI) metrics to predict for overall survival (OS) in first-line non-small cell lung cancer (NSCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19049-e19049 ◽  
Author(s):  
Laurent Claret ◽  
Pierre Mancini ◽  
Bernard Sebastien ◽  
Christine Veyrat-Follet ◽  
Rene Bruno
Keyword(s):  
Tumor Growth ◽  
Phase Ii ◽  
Tumor Size ◽  
Univariate Analysis ◽  
External Validation ◽  
Phase Iii ◽  
Parameter Estimates ◽  
Ratio Test ◽  
Phase Ii Studies ◽  
Phase Iii Study

e19049 Background: A survival model using change in tumor size at week 8 from baseline (CTS) (Clin Pharmacol Ther 86:167-174, 2009) was used to predict OS of the motesanib phase III study in NSCLC (Clin Pharmacol Ther 92:631-634, 2012). However CTS may not fully capture treatment effect on OS. We investigated other TGI metrics to predict OS using historical phase III data. Methods: Various TGI metrics, CTS, time to growth (TTG), and tumor growth rate (G), were estimated using two longitudinal tumor size models (Clin Cancer Res 17:907-917, 2011, PAGE 21 [www.page-meeting.org/?abstract=2328], 2012, JCO in press, 2013) developed from phase III data (1218 1st-line patients with NSCLC treated with doxetaxel (D) plus cisplatin (Cs) or carboplatin (Cb) or vinorelbine (V) plus Cs) (J Clin Oncol, 21:2016-3024, 2003). TGI metrics and baseline prognostic factors were assessed in univariate Cox and multivariate parametric survival models. Alternative models were qualified by simulating OS distributions in 1000 replicates of the phase III study and checking that observed OS distribution belongs to the 95% prediction intervals. Results: In a univariate analysis all TS metrics were strong predictors of OS (p<0.0001). TTG and G were similar and much better than CTS (likelihood ratio test). OS was best described by a log-normal distribution and the influence of the covariates was assessed based on linear regression of the logarithm of OS (days). Parameter estimates of the best multivariate model are shown in the Table. The model was qualified in predicting OS distributions in the 3 arms (D+Cs, D+Cb, V+Cs). Conclusions: With further external validation, this model could be used to analyze longitudinal NSCLC tumor size data and their relationship to OS, in phase II studies of new agents and support end-of-phase-II decisions. [Table: see text]

Exploratory modeling and simulation to support development of motesanib in Asian patients with non-small cell lung cancer (NSCLC) based on MONET1 study results.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19103-e19103
Author(s):  
Rene Bruno ◽  
Cheng-Pang Hsu ◽  
Laurent Claret ◽  
Jianfeng Lu ◽  
Yu-Nien Sun
Keyword(s):  
Prognostic Factors ◽  
Treatment Effect ◽  
Tumor Size ◽  
Phase Iii ◽  
Smoking History ◽  
Tumor Growth Inhibition ◽  
Parameter Estimates ◽  
Asian Patients ◽  
Study Results ◽  
Phase Iii Study

e19103 Background: Motesanib failed to improve overall survival (OS) in the MONET1 phase III study when combined to carboplatin/paclitaxel (CP) vs. CP in first-line NSCLC cancer patients (JCO 30:2829-2836, 2011). However, outcome of the study was favorable in a sub-population of Asian patients. We performed exploratory modeling and simulations based on the MONET1 data in order to support further development of motesanib in Asians. Methods: We developed 1) a longitudinal tumor growth inhibition model to estimate time to tumor regrowth (TTG)) using data from 934 out of 1,090 (86%) included in MONET1 and 2) a multivariate parametric model for OS including baseline prognostic factors and tumor size metrics to capture treatment effect. OS model was assessed in simulating OS distribution and hazard ratios (HR) in multiple replicates of MONET1 and comparing 95% predictive distribution (PI) with observed data. Multiple replicates of virtual phase III studies in Asian patients were simulated to assess probability of success of alternative designs. Results: Baseline tumor size (TS) and smoking history (former and current smokers vs. never smokers) were significant independent prognostic factors for OS with Asian ethnicity and log (TTG). Logarithm of OS (in days) was defined by a linear model. Parameter estimates of the OS model are given below (Table). The model successfully predicted OS distributions and HR in the full populations and in Asian patients. Simulations suggested that a 500 patient phase III study would exceed 80% power to demonstrate motesanib combination OS superiority in Asian with an expected HR of 0.74. Conclusions: A model-based estimate of TTG captured treatment effect in Asian and simulations suggested superiority of motesanib combination in these patients. The OS model could be used to simulate expected OS based on longitudinal NSCLC tumor size data with new investigational agents and support development decisions and study design. [Table: see text]

Comparison of Outcomes of Phase II Studies and Subsequent Randomized Control Studies Using Identical Chemotherapeutic Regimens

2005 ◽  
Vol 23 (28) ◽  
pp. 6982-6991 ◽  
Author(s):  
Mohammad I. Zia ◽  
Lillian L. Siu ◽  
Greg R. Pond ◽  
Eric X. Chen
Keyword(s):  
Phase Ii ◽  
English Language ◽  
Response Rates ◽  
Phase Iii ◽  
Positive Phase ◽  
Phase Ii Studies ◽  
Solid Malignancies ◽  
Study Characteristics ◽  
Phase Iii Study ◽  
Phase Iii Studies

Purpose To determine whether promising results from phase II studies could be reproduced in phase III studies, and to examine which characteristics of phase II studies might be of predictive value for subsequent phase III studies. Methods We searched for all phase III studies of chemotherapy in advanced solid malignancies, published in the English language literature from July 1998 to June 2003. Each phase III study was reviewed to identify preceding phase II studies. Phase II and phase III studies included in this analysis must have used identical regimens. Data were extracted from both phase II and phase III studies. Results Of 181 phase III studies identified, 43 used therapeutic regimens identical to those in 49 preceding phase II studies. Twelve phase III studies (28%) were “positive.” The vast majority (81%) of phase III studies have lower response rates than preceding phase II studies, with a mean difference of 12.9% among all studies analyzed. None of the phase II study characteristics evaluated significantly predicted for “positive” phase III studies, but the sample size of phase II studies demonstrated a trend toward being predictive (P = .083). Conclusion Promising results from phase II studies frequently do not translate into “positive” phase III studies. Response rates in most phase III studies are lower than those in preceding phase II studies.

Model-Based Prediction of Phase III Overall Survival in Colorectal Cancer on the Basis of Phase II Tumor Dynamics

2009 ◽  
Vol 27 (25) ◽  
pp. 4103-4108 ◽  
Author(s):  
Laurent Claret ◽  
Pascal Girard ◽  
Paulo M. Hoff ◽  
Eric Van Cutsem ◽  
Klaas P. Zuideveld ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Survival Time ◽  
Phase Ii ◽  
Tumor Size ◽  
Prediction Interval ◽  
Phase Iii ◽  
Antitumor Response ◽  
Phase Iii Study ◽  
Phase Iii Studies ◽  
Size Data

PurposeWe developed a drug-disease simulation model to predict antitumor response and overall survival in phase III studies from longitudinal tumor size data in phase II trials.MethodsWe developed a longitudinal exposure-response tumor-growth inhibition (TGI) model of drug effect (and resistance) using phase II data of capecitabine (n = 34) and historical phase III data of fluorouracil (FU; n = 252) in colorectal cancer (CRC); and we developed a parametric survival model that related change in tumor size and patient characteristics to survival time using historical phase III data (n = 245). The models were validated in simulation of antitumor response and survival in an independent phase III study (n = 1,000 replicates) of capecitabine versus FU in CRC.ResultsThe TGI model provided a good fit of longitudinal tumor size data. A lognormal distribution best described the survival time, and baseline tumor size and change in tumor size from baseline at week 7 were predictors (P < .00001). Predicted change of tumor size and survival time distributions in the phase III study for both capecitabine and FU were consistent with observed values, for example, 431 days (90% prediction interval, 362 to 514 days) versus 401 days observed for survival in the capecitabine arm. A modest survival improvement of 39 days (90% prediction interval, −21 to 110 days) versus 35 days observed was predicted for capecitabine.ConclusionThe modeling framework successfully predicted survival in a phase III trial on the basis of capecitabine phase II data in CRC. It is a useful tool to support end-of-phase II decisions and design of phase III studies.

Phase II testing of melphalan in children with newly diagnosed rhabdomyosarcoma: a model for anticancer drug development.

1988 ◽  
Vol 6 (2) ◽  
pp. 308-314 ◽  
Author(s):  
M E Horowitz ◽  
E Etcubanas ◽  
M L Christensen ◽  
J A Houghton ◽  
S L George ◽  
...  
Keyword(s):  
Phase Ii ◽  
Drug Disposition ◽  
Clinical Performance ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Heavily Pretreated ◽  
Phase Iii Study ◽  
Successful Testing ◽  
Previously Treated Patients ◽  
Pretreated Patients

We describe events that led to successful testing of melphalan, one of the nitrogen mustard compounds, in children with newly diagnosed, poor-risk rhabdomyosarcoma (RMS). Preclinical studies with xenografts of human RMS, growing in the flanks of immune-deprived mice, had indicated superior oncolytic activity by melphalan compared with other agents commonly used to treat this tumor. However, in a conventional phase II trial, melphalan failed to produce partial responses in 12 of 13 heavily pretreated patients with recurrent tumors. Subsequent comparison of the drug's pharmacokinetics in mice and patients indicated that its poor clinical performance was not the result of interspecies differences in drug disposition. Therefore, we elected to retest melphalan in untreated patients, before they were enrolled in a phase III study. Of 13 children who received the drug for 6 weeks, ten had partial responses, confirming the significant antitumor activity seen in the xenograft system. These findings illustrate the inherent limitations of phase II drug trials in previously treated patients and suggest a useful paradigm for the development of antineoplastic drugs.

Randomized Multicenter Phase II Trial of a Biweekly Regimen of Fluorouracil and Leucovorin (LV5FU2), LV5FU2 Plus Cisplatin, or LV5FU2 Plus Irinotecan in Patients With Previously Untreated Metastatic Gastric Cancer: A Fédération Francophone de Cancérologie Digestive Group Study—FFCD 9803

2004 ◽  
Vol 22 (21) ◽  
pp. 4319-4328 ◽  
Author(s):  
Olivier Bouché ◽  
Jean Luc Raoul ◽  
Franck Bonnetain ◽  
Marc Giovannini ◽  
Pierre Luc Etienne ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Phase Iii ◽  
Survival Times ◽  
Multicenter Phase ◽  
Independent Expert ◽  
Phase Iii Study ◽  
Cancérologie Digestive

Purpose To determine the efficacy and safety of a biweekly regimen of leucovorin (LV) plus fluorouracil (FU) alone or in combination with cisplatin or irinotecan in patients with previously untreated metastatic gastric adenocarcinoma and to select the best arm for a phase III study. Patients and Methods One hundred thirty-six patients (two were ineligible) were enrolled onto the randomized multicenter phase II trial. Patients received LV 200 mg/m2 (2-hour infusion) followed by FU 400 mg/m2 (bolus) and FU 600 mg/m2 (22-hour continuous infusion) on days 1 and 2 every 14 days (LV5FU2; arm A), LV5FU2 plus cisplatin 50 mg/m2 (1-hour infusion) on day 1 or 2 (arm B), or LV5FU2 plus irinotecan 180 mg/m2 (2-hour infusion) on day 1 (arm C). Results The overall response rates, which were confirmed by an independent expert panel, were 13% (95% CI, 3.4% to 23.3%), 27% (95% CI, 14.1% to 40.4%), and 40% (95% CI, 25.7% to 54.3%) for arms A, B, and C, respectively. Median progression-free survival and overall survival times were 3.2 months (95% CI, 1.8 to 4.6 months) and 6.8 months (95% CI, 2.6 to 11.1 months) with LV5FU2, respectively; 4.9 months (95% CI, 3.5 to 6.3 months) and 9.5 months (95% CI, 6.9 to 12.2 months) with LV5FU2-cisplatin, respectively; and 6.9 months (95% CI, 5.5 to 8.3 months) and 11.3 months (95% CI, 9.3 to 13.3 months) with LV5FU2-irinotecan, respectively. Conclusion Of the three regimens tested, the combination of LV5FU2-irinotecan is the most promising and will be assessed in a phase III trial.

scholarly journals A Review of Docetaxel: Its Use in the Treatment of Gastric Cancer

2010 ◽  
Vol 2 ◽  
pp. CMT.S5191
Author(s):  
Alessandro Inno ◽  
Michele Basso ◽  
Alessandra Cassano ◽  
Carlo Barone
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Poor Performance ◽  
Phase Iii ◽  
Poor Performance Status ◽  
Phase Ii Studies ◽  
Combination Regimens

Docetaxel, a member of the taxane family, promotes cell death by binding β-tubulin and has demonstrated activity against several human malignancies, both as a single agent and in combination therapy. It has been approved in Europe and the US as front-line treatment for advanced gastric cancer in combination with cisplatin and fluorouracil (DCF regimen). This approval was based on the results of a pivotal study (V325) which demonstrated that the addition of docetaxel to the reference regimen of cisplatin and fluorouracil improves overall survival and progression-free survival with a better quality of life despite increased toxicity (mainly haematological). Modifications of DCF regimen have been successfully investigated as a means of making the treatment more tolerable and suitable also for elderly patients or patients with poor performance status. Emerging data from several phase II studies suggest that other docetaxel-based combination regimens with anthracyclines or irinotecan have interesting activity with acceptable toxicity profiles, but the true efficacy of these regimens needs to be assessed in large randomized phase III studies. Thus, the best docetaxel-containing regimen has yet to be identified. Docetaxel also represents a good candidate for combination with novel molecular target agents. In light of the high response rates observed in phase II-III studies, a docetaxel-based chemotherapy regimen might also be considered a treatment option as perioperative or adjuvant therapy in potentially curable gastric cancer and further studies with or without biological agents are eagerly awaited in this setting.

scholarly journals MICS-Asia III: Overview of model inter-comparison and evaluation of acid deposition over Asia

2019 ◽  
Author(s):  
Syuichi Itahashi ◽  
Baozhu Ge ◽  
Keiichi Sato ◽  
Joshua S. Fu ◽  
Xuemei Wang ◽  
...  
Keyword(s):  
Acid Deposition ◽  
Phase Ii ◽  
Wet Deposition ◽  
Lessons Learned ◽  
Phase Iii ◽  
Anthropogenic Emissions ◽  
Observation Data ◽  
Total Deposition ◽  
North Asia ◽  
Phase Iii Study

Abstract. The Model Inter-Comparison Study for Asia (MICS-Asia) Phase III was conducted to promote understanding of regional air quality and climate change in Asia, which have received growing attention due to the huge amount of anthropogenic emissions worldwide. This study provides an overview of acid depositions. Specifically, dry and wet depositions of the following species were analyzed: S (sulfate aerosol, sulfur dioxide (SO2), and sulfuric acid (H2SO4)), N (nitrate aerosol, nitrogen monoxide (NO), nitrogen dioxide (NO2), and nitric acid (HNO3)), and A (ammonium aerosol and ammonia (NH3)). The wet deposition simulated by a total of nine models was analyzed and evaluated using ground observation data from the Acid Deposition Monitoring Network in East Asia (EANET). In this Phase III study, the number of observation sites was increased to 54 from 37 in the Phase II study, and Southeast Asian countries were newly added. Additionally, whereas the analysis period was limited to representative months of each season in MICS-Asia Phase II, this Phase III study analyzed the full year of 2010. The scope of this overview mainly focuses on the annual accumulated depositions. In general, models can capture the observed wet depositions over Asia but underestimate the wet deposition of S and A and show large differences in the wet deposition of N. Furthermore, the ratio of wet deposition to the total deposition (the sum of dry and wet deposition) was investigated in order to understand the role of important processes in the total deposition. The general dominance of wet deposition over Asia and attributions from dry deposition over land were consistently found in all models. Then, total deposition maps over 13 countries participating in EANET were produced, and the balance between deposition and anthropogenic emissions was calculated. Excesses of deposition, rather than of anthropogenic emissions, were found over Japan, North Asia, and Southeast Asia, indicating the possibility of long-range transport within and outside Asia, as well as other emission sources. To improve the ability of models to capture the observed wet deposition, two approaches were attempted, namely, ensemble and precipitation adjustment. The ensemble approach was effective at modulating the differences in performance among models, and the precipitation-adjusted approach demonstrated that the model performance for precipitation played a key role in better simulating wet deposition. Finally, the lessons learned from this Phase III study and future perspectives for Phase IV are summarized.

OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC). A GERCOR study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3504-3504 ◽  
Author(s):  
F. Maindrault-Goebel ◽  
G. Lledo ◽  
B. Chibaudel ◽  
L. Mineur ◽  
T. Andre ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Phase Ii ◽  
Median Duration ◽  
Phase Ii Study ◽  
Phase Iii ◽  
Randomized Phase Ii ◽  
Phase Iii Study ◽  
Large Phase ◽  
Duration Of Disease

3504 Background: The OPTIMOX1 study (JCO 2006) has shown that the strategy of 6 cycles of FOLFOX7 followed by maintenance therapy and FOLFOX reintroduction was as active and better tolerated than FOLFOX4 until progression. The aim of the OPTIMOX2 study was to evaluate a complete stop of chemotherapy after 6 bimonthly cycles of FOLFOX. Methods: Initially planned as a phase III study, OPTIMOX2 was downgraded to a large phase II study since the availability of bevacizumab. Patients (pts) were randomized between an OPTIMOX1 arm: 6 cycles of FOLFOX7 followed by LV5FU until progression and reintroduction of FOLFOX7, and the OPTIMOX2 arm: 6 cycles of FOLFOX7, complete stop of chemotherapy and reintroduction of FOLFOX7 before the tumor progression reached the baseline measures. Results: 187/200 planned pts were included between Feb 2004 and Nov 2005. Response rates were (OPTIMOX1 arm/OPTIMOX2 arm): CR 2%/2%, PR 54%/51%, stable 24%/33%, progression 11%/7%, non assessable 9%/7%. Median PFS were (OPTIMOX1 arm/OPTIMOX2 arm) 36/28 weeks (p=.01), PFS in responders 41/30 weeks (p=.001), PFS in stable patients 34/26 weeks (p=.23). Median duration of disease control (DDC), addition of PFS of first FOLFOX7 administration plus PFS of FOLFOX reintroduction if no progression at first evaluation, was 41 weeks in the OPTIMOX1 arm and 36 in the OPTIMOX2 arm, p=.17. Median duration of chemotherapy-free interval in the OPTIMOX2 arm was 25 weeks (5.7 months). Conclusions: Maintenance LV5FU therapy prolongs PFS. The quality of life of almost 6 months CFI can balance a small advantage in DDC for maintenance therapy. Our next goal is to evaluate maintenance therapy with targeted agents alone. [Table: see text]

Randomised phase II study evaluating weekly docetaxel in combination with cisplatin and 5FU or capecitabine in metastatic oesophago-gastric cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4067-4067 ◽  
Author(s):  
N. Tebbutt ◽  
V. Gebski ◽  
A. Strickland ◽  
D. Gibbs ◽  
E. Walpole ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Haematological Toxicity ◽  
Phase Iii ◽  
Stage Design ◽  
Weekly Docetaxel ◽  
Phase Iii Study ◽  
Recent Phase ◽  
Combination Regimens

4067 Background: Docetaxel (T), cisplatin (C) and 5FU (F) are active agents in oesophago-gastric cancer. A recent phase III study using TCF achieved a survival advantage but was associated with high rates of haematological toxicity (30% incidence of febrile neutropenia/neutropenic infection) as well as non-haematological side effects (Moiseyenko et al, 2005 Pr ASCO abstr 4002). Weekly docetaxel is associated with a lower incidence of haematological toxicity. This randomised phase II study aimed to test weekly docetaxel based combination chemotherapy regimens with the aim of maintaining the activity of docetaxel based combination regimens but reducing toxicity. Methods: Eligibility included; histologically confirmed, metastatic oesophageal or gastric (OG) carcinoma, measurable disease, PS0–2, adequate organ function, no prior treatment, informed consent. Pts were randomised to receive weekly (w) T 30 mg/m2 d1, 8 C 60 mg/m2 d1 F 200 mg/m2/d continuously q 3w or wT 30 mg/m2 d1, d8 and capecitabine (×)1600 mg/m2/d d1–14 q3w. The primary endpoint is confirmed response rate (RR), with each arm analysed independently. Simon’s 2 stage design was used, with 5/21 responses required in the first stage to allow continuation to 48 pts per arm. Results: 79 pts enrolled to date. Protocol specified interim analysis of efficacy after 21 pts per arm and of toxicity after 25 pts per arm ( Table ). In the first 21 pts per arm; 12 responses (11 confirmed) in wTCF arm, 6 responses (5 confirmed) in wTX arm. Trial continues accrual to target of 48 pts per arm. Complete accrual expected by April 2006. Updated data will be presented at the meeting. Conclusions: wTCF and wTX have encouraging activity and and a more favourable toxicity profile than TCF administered 3-weekly. [Table: see text] [Table: see text]

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