scholarly journals On the relationship between tumour growth rate and survival in non-small cell lung cancer

2017 ◽  
Author(s):  
Hitesh B. Mistry
Keyword(s):  
Growth Rate ◽  
Tumour Size ◽  
Phase Iii ◽  
End Points ◽  
Phase Iii Trial ◽  
New Treatment ◽  
Reverse Alignment ◽  
The Relationship ◽  
Tumour Growth Rate ◽  
Better Than

AbstractA recurrent question within oncology drug development is predicting phase III outcome for a new treatment using early clinical data. One approach to tackle this problem has been to derive metrics from mathematical models that describe tumour size dynamics termed re-growth rate and time to tumour re-growth. They have shown to be strong predictors of overall survival in numerous studies but there is debate about how these metrics are derived and if they are more predictive than empirical end-points. This work explores the issues raised in using model-derived metric as predictors for survival analyses. Re-growth rate and time to tumour re-growth were calculated for three large clinical studies by forward and reverse alignment. The latter involves re-aligning patients to their time of progression. Hence it accounts for the time taken to estimate re-growth rate and time to tumour re-growth but also assesses if these predictors correlate to survival from the time of progression. We found that neither re-growth rate nor time to tumour re-growth correlated to survival using reverse alignment. This suggests that the dynamics of tumours up until disease progression has no relationship to survival post progression. For prediction of a phase III trial we found the metrics performed no better than empirical end-points. These results highlight that care must be taken when relating dynamics of tumour imaging to survival and that bench-marking new approaches to existing ones is essential.

scholarly journals On the relationship between tumour growth rate and survival in non-small cell lung cancer

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e4111 ◽  
Author(s):  
Hitesh B. Mistry
Keyword(s):  
Growth Rate ◽  
Tumour Size ◽  
Phase Iii ◽  
End Points ◽  
Phase Iii Trial ◽  
New Treatment ◽  
Reverse Alignment ◽  
The Relationship ◽  
Tumour Growth Rate ◽  
Better Than

A recurrent question within oncology drug development is predicting phase III outcome for a new treatment using early clinical data. One approach to tackle this problem has been to derive metrics from mathematical models that describe tumour size dynamics termed re-growth rate and time to tumour re-growth. They have shown to be strong predictors of overall survival in numerous studies but there is debate about how these metrics are derived and if they are more predictive than empirical end-points. This work explores the issues raised in using model-derived metric as predictors for survival analyses. Re-growth rate and time to tumour re-growth were calculated for three large clinical studies by forward and reverse alignment. The latter involves re-aligning patients to their time of progression. Hence, it accounts for the time taken to estimate re-growth rate and time to tumour re-growth but also assesses if these predictors correlate to survival from the time of progression. I found that neither re-growth rate nor time to tumour re-growth correlated to survival using reverse alignment. This suggests that the dynamics of tumours up until disease progression has no relationship to survival post progression. For prediction of a phase III trial I found the metrics performed no better than empirical end-points. These results highlight that care must be taken when relating dynamics of tumour imaging to survival and that bench-marking new approaches to existing ones is essential.

scholarly journals When, why and how clonal diversity predicts future tumour growth

2019 ◽  
Author(s):  
Robert Noble ◽  
John T Burley ◽  
Cécile Le Sueur ◽  
Michael E Hochberg
Keyword(s):  
Growth Rate ◽  
Tumour Growth ◽  
Evolutionary Process ◽  
Clonal Diversity ◽  
Driver Mutations ◽  
Multiple Cancer ◽  
Intratumour Heterogeneity ◽  
Cancer Types ◽  
The Relationship ◽  
Tumour Growth Rate

AbstractIntratumour heterogeneity holds promise as a prognostic biomarker in multiple cancer types. However, the relationship between this marker and its clinical impact is mediated by an evolutionary process that is not well understood. Here we employ a spatial computational model of tumour evolution to assess when, why and how intratumour heterogeneity can be used to forecast tumour growth rate, an important predictor of clinical progression. We identify three conditions that can lead to a positive correlation between clonal diversity and subsequent growth rate: diversity is measured early in tumour development; selective sweeps are rare; and/or tumours vary in the rate at which they acquire driver mutations. Opposite conditions typically lead to negative correlation. Our results further suggest that prognosis can be better predicted on the basis of both clonal diversity and genomic instability than either factor alone. Nevertheless, we find that, for predicting tumour growth, clonal diversity is likely to perform worse than conventional measures of tumour stage and grade. We thus offer explanations – grounded in evolutionary theory – for empirical findings in various cancers. Our work informs the search for new prognostic biomarkers and contributes to the development of predictive oncology.

A randomized phase II multi-institutional trial of anlotinib plus docetaxel versus docetaxel in EGFR-wild-type non-small cell lung cancer (NSCLC) patients after progression on first-line platinum-base chemotherapy: ALTER-L018.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21703-e21703
Author(s):  
Lin Wu ◽  
Zhijun Wu ◽  
Zemin Xiao ◽  
Jie Weng ◽  
Zhongsha Ma ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Phase Iii ◽  
Wild Type ◽  
First Line ◽  
End Points ◽  
Phase Iii Trial ◽  
Platinum Based Chemotherapy ◽  
Group A ◽  
Group B ◽  
Nsclc Patients

e21703 Background: Anlotinib is an oral VEGFR, FGFR, PDGFR and c-Kit tyrosine kinase inhibitor, which can prolong both PFS and OS of refractory advanced NSCLC patients in phase III trial: ALTER0303. The combination of docetaxel and ramucirumab/nintedanib had been demonstrated activity in the second line therapy setting for NSCLC. We performed ALTER-L018 to assessed the safety and efficacy of anlotinib with docetaxel in EGFR-wild type refractory advanced NSCLC (NCT03624309). Methods: Patients (pts) with EGFR-wild type refractory advanced NSCLC, who failed to first-line platinum-based chemotherapy, were randomized to group A(anlotinib: 12mg QD from day 1 to 14 of a 21-day cycle +docetaxel: 75mg/m2 Q3W) and group B(docetaxel: 75mg/m2 Q3W). The primary end points is PFS, and secondary end points include OS, ORR, DCR and safety. Results: Between January and December 2019, 36 pts were enrolled at 10 institutions in Hunan China, with 31(15 in group A, 16 in group B) of these individuals being evaluable for treatment efficacy and safety. Pt characteristics(group A/ group B): median age: 55(39-70)/57(44-67); male: 73%/81%; non-squamous NSCLC: 86%/75%. Median PFS were 5.3 months (95%CI:2.76-7.85) in group A and 2.3 months (95%CI, 1.14-3.46) in group B (HR 0.42; 95% CI:0.16-1.13; p = 0.047); In group A and B, ORR and DCR were 26.67% versus 0%(p = 0.043), 60.00% versus 31.25%(p = 0.16), respectively. Among 31 pts, 89% of treatment-related AEs (TRAEs) were grade 1 or 2, and the most common TRAEs in group A were hand-foot syndrome, pruritus and insomnia of 13%(2/15) each; in group B were alopecia, constipation and anemia of 12%(1/16) each. Toxicities≥grade 3(TRAEs) included: neutropenia, leukopenia, diarrhea and hrombocytopenia, 6.6%(1/15) each in group A. There was 1 grade 5 AE in group A. Conclusions: This combination of anlotinib and docetaxel with significant difference PFS prolonging and manageable safety profile, is a viable option in relapsed NSCLC, should be considered following progression on platinum-based chemotherapy. It will be further explored in a randomized phase III trial. Clinical trial information: NCT03624309.

The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9064-9064 ◽  
Author(s):  
Rudolph M. Navari ◽  
Cindy K Nagy ◽  
Sarah E Gray
Keyword(s):  
Emetogenic Chemotherapy ◽  
Phase Iii ◽  
Highly Emetogenic Chemotherapy ◽  
Double Blind ◽  
Phase Iii Trial ◽  
Grade 3 ◽  
Ecog Ps ◽  
To Receive ◽  
Better Than ◽  
Observation Period

9064 Background: Olanzapine (OLN) has been shown to be a safe and effective agent for the prevention of CINV. OLN may also be an effective rescue medication for patients who develop breakthrough CINV despite having received guideline directed CINV prophylaxis. Methods: A double blind, randomized phase III trial was performed for the treatment of breakthrough CINV in chemotherapy naïve patients receiving highly emetogenic chemotherapy (HEC) (cisplatin, >70 mg/m2, or doxorubicin, >50 mg/m2 and cyclophosphamide, > 600mg/m2 ) comparing OLN to Metoclopramide (METO). Patients who developed breakthrough emesis or nausea despite prophylactic dexamethasone (12 mg IV), palonosetron (0.25 mg IV), and fosaprepitant (150 mg IV) pre chemotherapy and dexamethasone (8 mg p.o. daily, days 2-4) post chemotherapy were randomized to receive OLN, 10 mg orally daily for three days or METO, 10 mg orally TID for three days. Patients were monitored for emesis and nausea for the 72 hours after taking OLN or METO. Eighty patients (median age 56 yrs, range 38-79; 43 females; ECOG PS 0,1) consented to the protocol and all were evaluable. Results: During the 72 hour observation period, 30 of 42 (71%) patients receiving OLN had no emesis compared to 12 of 38 (32%) patients with no emesis for patients receiving METO (p<0.01). Patients without nausea (0, scale 0-10, M.D. Anderson Symptom Inventory) during the 72 hour observation period was: OLN: 67% (28 of 42); METO 24% (9 of 38) (p<0.01). There were no Grade 3 or 4 toxicities. Conclusions: OLN was significantly better than METO in the control of breakthrough emesis and nausea in patients receiving HEC.

scholarly journals Efficacy and Tolerability of First-Line Cetuximab Plus Leucovorin, Fluorouracil, and Oxaliplatin (FOLFOX-4) Versus FOLFOX-4 in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The Open-Label, Randomized, Phase III TAILOR Trial

2018 ◽  
Vol 36 (30) ◽  
pp. 3031-3039 ◽  
Author(s):  
Shukui Qin ◽  
Jin Li ◽  
Liwei Wang ◽  
Jianming Xu ◽  
Ying Cheng ◽  
...  
Keyword(s):  
Survival Time ◽  
Overall Response Rate ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
First Line ◽  
Open Label ◽  
End Points ◽  
Phase Iii Trial ◽  
Free Survival

Purpose Cetuximab in combination with chemotherapy is a standard-of-care first-line treatment regimen for patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC); however, the efficacy of cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX) has never before been proven in a controlled and randomized phase III trial. To our knowledge, the TAILOR trial ( ClinicalTrials.gov identifier: NCT01228734) is the first randomized, multicenter, phase III study of the addition of cetuximab to first-line FOLFOX prospectively choosing a RAS wt population and thus providing confirmative data for the efficacy and safety of cetuximab plus FOLFOX versus FOLFOX alone. Patients and Methods TAILOR is an open-label, randomized (1:1), multicenter, phase III trial in patients from China comparing FOLFOX-4 with or without cetuximab in RAS wt ( KRAS/ NRAS, exons 2 to 4) mCRC. The primary end point of TAILOR was progression-free survival time; secondary end points included overall survival time, overall response rate, and safety and tolerability. Results In the modified intent-to-treat population of 393 patients with RAS wt mCRC, adding cetuximab to FOLFOX-4 significantly improved the primary end point of progression-free survival time compared with FOLFOX-4 alone (hazard ratio, 0.69; 95% CI, 0.54 to 0.89; P = .004; median, 9.2 v 7.4 months, respectively), as well as the secondary end points of overall survival time (current assessment after 300 events: hazard ratio, 0.76; 95% CI, 0.61 to 0.96; P = .02; median, 20.7 v 17.8 months, respectively) and overall response rate (odds ratio, 2.41; 95% CI, 1.61 to 3.61; P < .001; 61.1% v 39.5%, respectively). Treatment was well tolerated, and there were no new or unexpected safety findings. Conclusion The TAILOR study met all of its objectives and relevant clinical end points, confirming cetuximab in combination with FOLFOX as an effective standard-of-care first-line treatment regimen for patients with RAS wt mCRC.

scholarly journals Testing many treatments within a single protocol over 10 years at MRC Clinical Trials Unit at UCL: Multi-arm, multi-stage platform, umbrella and basket protocols

2017 ◽  
Vol 14 (5) ◽  
pp. 451-461 ◽  
Author(s):  
Mahesh KB Parmar ◽  
Matthew R Sydes ◽  
Fay H Cafferty ◽  
Babak Choodari-Oskooei ◽  
Ruth E Langley ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Iii ◽  
Current Standard ◽  
New Methods ◽  
Multi Stage ◽  
Phase Iii Trials ◽  
Clinical Trials Unit ◽  
New Treatment ◽  
Better Than ◽  
Phase I And Ii

There is real need to change how we do some of our clinical trials, as currently the testing and development process is too slow, too costly and too failure-prone often we find that a new treatment is no better than the current standard. Much of the focus on the development and testing pathway has been in improving the design of phase I and II trials. In this article, we present examples of new methods for improving the design of phase III trials (and the necessary lead up to them) as they are the most time-consuming and expensive part of the pathway. Key to all these methods is the aim to test many treatments and/or pose many therapeutic questions within one protocol.

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