UK ABC-03 Trial results published (NCT0939848)

Stock DZ
PCIB
06.07.2018 kl 12:41
1610

Dette er en arkivert tråd!
published 21/06/2018

Full study results link:

https://www.nature.com/articles/s41416-018-0132-8#Sec18

Introduction

Novel therapeutic options, based on an improved understanding of underlying biology and response to therapy, are urgently needed for patients presenting with advanced biliary tract cancer (ABC). Whilst uncommon in the developed world, biliary tract cancer (BTC including cholangiocarcinoma [CCA], gallbladder and ampullary carcinoma) represent a significant global problem due to areas of high incidence, for instance of liver fluke-associated cholangiocarcinoma in Northern Thailand1 and of gallbladder cancer in Chile and India.2

Surgery is the cornerstone of curative therapy for BTC the use of adjuvant therapy has historically been based on meta-analyses of non-randomised series and prospective studies.3 The recently presented phase III, randomised, BilCap study has demonstrated an overall survival (OS) benefit from the use of adjuvant use of oral capecitabine following surgery versus surgery alone.4 Unfortunately, most patients are present with advanced (non-resectable or metastatic) disease and their survival is 𕟫 months, with best supportive care alone.5 In the ABC-02 study,6 the combination chemotherapy with cisplatin and gemcitabine achieved a median survival of 11.7 months, compared to gemcitabine monotherapy (8.0 months HR =𔁚.64, 95% confidence interval (CI) 0.52–0.80 P𔁚.001), findings which were confirmed in the Japanese BT22 study.7 Although this is the international reference regimen,8 there is a pressing need to improve the efficacy, given these modest outcomes.

Angiogenesis is one of the hallmarks of neoplasia the expression of vascular endothelial growth factor (VEGF) is associated with adverse clinical features including the presence of liver metastases in intra-hepatic cholangiocarcinoma (iCCA)9 and increased microvessel density (MVD) in both gallbladder cancer10 and CCA.11 In patients undergoing curative resection, MVD has been identified as an independent prognostic risk factor for OS in lymph node-negative iCCA12 and gallbladder cancer,13 as well as for disease-free survival (DFS)13 and OS14 in patients with extrahepatic cholangiocarcinoma (eCCA). These clinical observations are consistent with the demonstration of receptors for VEGF (VEGFR1 and VEGFR2) in tumour proximal endothelial cells15 along with the frequent (40–75%) expression of VEGF (particularly VEGFA) in BTC 9-,11 particularly at the invasive edge of the tumour.13

Cediranib is an oral VEGFR1, VEGFR2 and VEGFR3 tyrosine kinase inhibitor (TKI), with additional activity against platelet-derived growth factor (PDGF) receptors and c-KIT.16 In the prospective randomised double blind placebo-controlled phase II ABC-03 study, the cisplatin and gemcitabine combination was evaluated with either cediranib or placebo. Although an improved response rate was observed (44% vs. 19% with placebo P =𔁚.0036) along with an improved 6-month progression-free survival (PFS, 70.5% vs. 61.3% P𔁚.05) in cediranib-treated patients, the magnitude of this effect did not reach the pre-defined level of statistical significance (hazard ratio [HR] for PFS: 0.93, 80% CI 0.74–1.19 P =𔁚.72) for the primary endpoint. This may have been due to lack of efficacy, or alternatively, underpowering of the statistical plan, or because cediranib was not well tolerated in this combination.17

Recognising the challenge of serial tumour biopsy, an exploratory translational endpoint of the ABC-03 study was the prospective longitudinal profiling of circulating biomarkers associated with angiogenes is. We now present the findings of this work, set the findings in context and evaluate the implications for future clinical trials.
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Flottesen
06.07.2018 kl 13:11
1006

Så her har de prøvd og feilet med tyrosine kinase inhibitorer. Disse har jo god effekt i f.eks lungekreft, men er utsatt for resistensutvikling. De har jo forbedret ORR og PFS, men ikke nok til å møte endepunktene.

Det blir spennende å se studieoppsettet for PCIB sin PF2.
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Stock DZ
08.07.2018 kl 15:09
829

Hi

Another thing the ABC study above tells us is the patients enrollment rate. The study recruited 124 patients in the course of 18 months with a patients median age of 65.1 years (between 05 April 2011 and 28 Sept 2012). with a total number of 15 clinical sites in the UK (only UK sites)

this gives an average of approx. 7 patients per month.

Now let refer to what Arctic analysis thinks about the recruitment rate:

" There is large variety in inclusion numbers for a (pivotal) trial within CCA, depending on i.e.
statistical powering related to the expected outcome. According to listed trials on clinicaltrials.gov,
the numbers range from some 40 to up to 400. We believe PCIB will be able to differentiate itself with regards to efficacy data and we therefore estimate 100-150 patients to be included in the two arm pivotal study, through engagement of some 30-50 sites. Due to the number of sites, the unmet need in CCA and the more accessible design of pivotal trials in general, we expect recruitment could be done rather quickly, some 9 to 15 months. We assume the time of follow-up to be similar to the
phase I expansion trial, in which patients, if eligible, are treated with Amphinex twice (second treatment some 4-5 months after the first). This would mean a minimum follow-up of 6 months per patient (after first treatment), with read-outs as late as at 18 months after study start"

Now if we consider worst and best case scenarios:

Worst case scenario:
*30 sites and 150 patients. now with double the # of site from the ABC-3 study we can assume an enrollment rate of 14 patients a month. Therefore the whole recruitment for the study can take approx 11 months

Best case sceranio:
*50 sites and 100 patients. now the # of site is 3.33 x. we can then assume an enrollment rate of approx 23 patients a months. resulting in only 6,5 months to complete the patient registration phase.

I believe Arctic analysis is conservative when it says the recruitment can take between 9-15 Months because based on the facts above from the ABC 3 study we can assume that this range is 6,5-11 months. so I think the enrollment phase can be finished super super fast. Here we have excluded any potential sites in geographical areas with high incidence rate such us Japan for example which will obviously speed up the process.




Redigert 08.07.2018 kl 15:10 Arkivert
SafeInvest
09.07.2018 kl 10:31
550

Nice find, StockDZ!
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Ydmykamatør
09.07.2018 kl 10:33
545

Finnes Artic analysen tilgjengelig noe sted?
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Snøffelen
09.07.2018 kl 11:08
515

Super-interessant link Stock DZ, og spennende tankerekke angående rekrutteringshastighet.

Mange er opptatt av biomarkører for å kunne skreddersy behandlingen, "desverre" ser det ut til at å bruke ressurser på det er dårlig payback i GGK, spesielt sammenlignet med å bare frese på med PCI.
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Kappa3278
09.07.2018 kl 13:02
396

Ser ikke bra ut for øyeblikket, stor overvekt av selgere, og ned over to prosent på en sterk børs.
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InfoLeecher
09.07.2018 kl 14:24
290

haha Kappa3278
Volumet er 3 sokker og en brukt bandasje.

En seriøs Kappa?? :p
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