Papers by Jonathan Shamash
Annals of Oncology, Sep 1, 2012
ABSTRACT Introduction Both dovitinib and everolimus are agents used, or under investigation in pa... more ABSTRACT Introduction Both dovitinib and everolimus are agents used, or under investigation in patients with renal cancer refractory to VEGF targeted therapy. It is potentially attractive to use these agents in combination in patients with VEGF TKI refractory disease. Together they target mTOR, VEGF and FGF-2. The purpose of this study is to establish a dose for this combination to take forward in randomised trials. Method This phase I study (EUDRACT 2010-021250-19) followed a classic dose escalation 3 + 3 designed. Sequential patients with metastatic clear cell renal cancer, who had previously failed VEGF tyrosine kinase inhibitors were included. Patients received fixed doses of drug in each escalating cohort (maximum n = 6) until dose limiting toxicity (DLT) was reached. DLT included grade 3 toxicity during the first 6 weeks of therapy. If 2 episodes of grade 3 or more toxicity occurred in a specific cohort the DLT cohort had been reached. The study has appropriate ethical approval. Assement of response and progression free survival was by RECIST v1.1 Results Patients were entered into 2 cohorts before DLT occurred (cohort 0: dovitinib 200 mg/everolimus 5mg [n = 6]; cohort 1: dovitinib 300 mg/everolimus 5mg [n = 3]) . DLT in cohort 1 included grade 3 fatigue (2/3) after 2 and 3 week of therapy. In cohort 0 the following toxicity was identified: Lethargy grade 2 3/6 and 3 1/6; Diarrhoea Grade 2 2/6 and 3 0/6 mucositis; grade 2 0/6 and 3 0/6; nausea/vomiting grade 2 0/6 and 3 1/6, pulmonary fibrosis grade 2 1/6 3 0/6 . Grade 3 toxicity after the first 6 weeks of therapy included pulmonary fibrosis 1/6, lipid abnormalities 2/6. Overall 1 patient (11%) had a partial response to therapy. Of the 5 patients who did not stop therapy during the first 6 weeks due to toxicity, 3 continued for 6 months or more without progression. Conclusion The maximum tolerable dose for this combination was dovitinib 200mg and everolimus 5mg. This dose is being taken forward in an expansion cohort which will explore efficacy. Disclosure T.B. Powles: Novarits Has supplied an educational grant for this project. Advisroy role for Novratis. S. Chowdhury: Advisory role. All other authors have declared no conflicts of interest.
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Lung Cancer, Aug 1, 2003
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Cancer, 2007
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Lung Cancer, 2009
Malignant pleural mesothelioma (MPM) is a rapidly progressive invariably lethal tumor. Treatment ... more Malignant pleural mesothelioma (MPM) is a rapidly progressive invariably lethal tumor. Treatment options remain limited and the outcome in relapsed disease is poor warranting new therapeutic options. Following our previous experience in the first-line setting, we conducted a phase 2 open-label non-comparative study to assess the safety and efficacy of weekly vinorelbine chemotherapy, each cycle consisting of 30 mg/m(2) for 6 weeks, in patients with previous exposure to chemotherapy. In 63 individuals with relapsed MPM who had not received previous vinorelbine, we observed an objective response rate of 16% and an overall survival of 9.6 months (95% confidence interval 7.3-11.8 months). The main grade III/IV toxicity observed was neutropenia and toxicity was similar to weekly vinorelbine when used in the first-line setting. Weekly vinorelbine appeared to have a reasonable response rate with an acceptable toxicity profile in the second-line treatment of MPM. Its use should be prospectively evaluated in a randomised trial in the first or second-line therapy of MPM.
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CCR Translation for This Article from Sequential FDG-PET/CT as a Biomarker of Response to Sunitin... more CCR Translation for This Article from Sequential FDG-PET/CT as a Biomarker of Response to Sunitinib in Metastatic Clear Cell Renal Cancer
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Lung Cancer, Aug 1, 2003
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International Journal of Urology, Apr 1, 2010
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British Journal of Cancer, Oct 1, 2002
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Journal of Clinical Oncology, May 20, 2016
e16602Background: Patients with early prostate cancer have a spectrum of treatment options, deliv... more e16602Background: Patients with early prostate cancer have a spectrum of treatment options, delivered by different healthcare professionals. To address this a multidisciplinary prostate cancer clinic (MDC) was started at Barts Cancer Centre in 2011, covering all treatment options in one appointment. Methods: Between 2011-15 all patients with early prostate cancer and fit enough for radical therapy were referred to the MDC from a catchment area of 1.2 million patients. Clinical data and treatment choice on the first 1000 patients was collected within this audit. Patient demographics and tumour characteristics were recorded. Only patients with confirmed prostate cancer were included in the analysis. This was either by histology from a biopsy specimen, or by the demonstration of metastatic disease on imaging and a PSA test > 100. Patients were separated into risk groups using the D’Amico classification. Results: 1069 male patients attended the clinic. 1000 patients had confirmed prostate cancer. Median age w...
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Journal of Clinical Oncology, May 20, 2013
4535 Background: Bleomycin is an integral part of combination chemotherapy in germ cell tumours. ... more 4535 Background: Bleomycin is an integral part of combination chemotherapy in germ cell tumours. Pulmonary symptoms often dictate drug cessation and death occurs in 1-2% of patients. Circumstantial evidence suggests that continuous infusion may be less toxic. Methods: We conducted a randomized phase 3 study to see whether infusional bleomycin was associated with less pulmonary toxicity. Patients were stratified for smoking, renal dysfunction and age and were randomized to receive either conventional BEP with weekly bleomycin (3,0000 units /week iv over 30min) or the same doses but administered as a 90,000 unit infusion on day 1 over 72 hours. The primary endpoint was CT proven lung toxicity, secondary endpoints included PFS and changes in lung function testing. CT scans and lung function testing were conducted after 1 cycle, end of treatment and 1 year post treatment. Sample size of 210 was calculated to detect a difference of 16% Bleomycin damage with 80% power at the 5% level of significance using 2-sided test. Results: The median follow-up was 2.5 years. At day 21 of the treatment, 52% patients in the infusional arm had grade 1 or above toxicity compared to 55% in the conventional. At the end of treatment the results were 84% vs. 60% and at one year it was 65% vs. 59%. Repeated measures mixed effects model shows no significant difference in percentage of grade 1 and above toxicity between the two arms (Difference=1.63, P=0.09, 95% CI: -0.28, 3.54). However, there was a significantly higher level of grade 2 and above toxicity in patients in the infusion arm (difference=0.8; 95% CI 0.11 to 1.49). Toxicity level was the highest at the end of treatment and in older patients (Age>30). Lung function testing between the two arms failed to show any differences. Two-years PFS rate was 93% in both arms (hazard ratio infusion vs conventional was 0.91; 95% CI 0.33 to 2.52). There was an association between toxicity after 1 cycle and subsequent toxicity at end of treatment and at 1 year (p=0.003). Conclusions: Infusional bleomycin has no advantage over standard administration of bleomycin. Clinical trial information: 08648791.
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Journal of Clinical Oncology, Mar 1, 2011
301 Background: The purpose of this study was to investigate sequential FDG PET-CT as a correlati... more 301 Background: The purpose of this study was to investigate sequential FDG PET-CT as a correlative marker in metastatic clear cell renal cancer (mRCC) patients treated with first line sunitinib. Three sequential scans were performed to determine the importance of the timing of scans. Methods: Forty-four untreated mRCC patients with MSKCC intermediate risk and poor risk disease were enrolled into a prospective study. FDG PET-CT scans were performed before (n=44), after 4 weeks (n=43) and 16 weeks (n=40) of sunitinib given at standard doses as the translational aspect of this trial ( NCT01024205 ). The primary endpoint was to determine whether 18F-FDG PET-CT response (defined as a 20% reduction in SUVmax) correlated with survival. Results: Forty-three (98%) patients had FDG PET-CT avid lesions at diagnosis (median SUVmax 6.8 range: <2.5–18.4). In multivariate analysis a high SUVmax and increased number of PET positive lesions correlated with worse overall survival (OS) (HR: 3.30 (95%CI: 1.36–8.45) and 3.67 (95%CI: 1.43–9.39) respectively[p<0.05]). After 4 weeks of sunitinib, metabolic responses occurred in 24 (57%) patients at 4 weeks, but this did not correlate with progression-free survival [PFS] (HR for responders= 0.87 [95%CI: 0.40–1.99]) or OS (HR for responders= 0.80 [95%CI: 0.34–1.85]) (p>0.05 for both). After 16 weeks of treatment, FDG PET-CT demonstrated disease progression in 28% (n=12) patients. At this time point, the FDG PET-CT correlated with both OS and PFS (HR 5.96 [95%CI: 2.43–19.02] and HR 12.13 [95%CI: 3.72–46.45] respectively). Conclusions: Baseline FDG PET prior to sunitinib yields prognostically significant data. FDG PET response at 16 weeks predicts outcome, which is not the case at 4 weeks. This subsets of patients with a poor prognosis at 16 weeks could be investigated within the context of a randomized clinical trial. [Table: see text]
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Springer eBooks, 2002
The results of BEP chemotherapy for all cases of metastatic germ cell tumours (GCTs) remains to b... more The results of BEP chemotherapy for all cases of metastatic germ cell tumours (GCTs) remains to be bettered in any multicenter randomised controlled trial. However, less than half of patients with poor prognosis disease can expect to be cured with it. For salvage therapy a cisplatin and ifosfamide based treatment will cure 25–30 per cent of cases; alternatively a weekly-based therapy (m-BOP) [1] may achieve similar results. High dose therapy may be able to improve on this, although its exact role remains to be determined. The recognition that actinomycin and methotrexate have a role in salvage [2] has encouraged us to investigate these drugs with cisplatin and etoposide in a new schedule (GAMEC) — cisplatin 100mg/m2 weeks 1,3,6,8 and 10 with 50mg/m2 on weeks 2 and 4. Etoposide 360mg/m2 over 4 days on weeks 1,3,6,8 and 10. Methotrexate with folinic acid rescue 10g/m2 on weeks 1, 3, 6, 8 and 10 (with linear dose reduction for creatinine clearance of < 120ml/min).Actinomycin-D lmg/m2 on weeks 1,3,6,8 and 10. Granulocyte colony-stimulating factor (GCSF) is given between courses. The proposed advantages of this therapy included the fact that it did not contain bleomycin and therefore would not be contra-indicated as a salvage regimen. It allowed the integration of high dose methotrexate and actinomycin, both active agents in GCTs, into a dose-dense high intensity cisplatin based regimen whilst maintaining the exposure to etoposide in a therapeutic dose without resorting to stem cell rescue.
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British Journal of Cancer, Dec 3, 2013
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International Journal of Cancer, 2007
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European Journal of Cancer, 2020
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European Urology Focus, 2021
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Prostate Cancer and Prostatic Diseases, 2020
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Clinical Genitourinary Cancer, 2019
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European Journal of Cancer, 2019
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Journal of Clinical Oncology, 2016
4545Background: Carboplatin montherapy for metastatic seminoma has not been pursued following two... more 4545Background: Carboplatin montherapy for metastatic seminoma has not been pursued following two studies showing reduced progression-free survival compared to combination therapy. The doses were i...
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Papers by Jonathan Shamash