Cancer Research Center for Drug Development

Bodle Street, United Kingdom

Cancer Research Center for Drug Development

Bodle Street, United Kingdom

Time filter

Source Type

Rampling R.,University of Glasgow | Peoples S.,Western General Hospital | Mulholland P.J.,University College London | James A.,University of Glasgow | And 16 more authors.
Clinical Cancer Research | Year: 2016

Purpose: To perform a two-cohort, phase I safety and immunogenicity study of IMA950 in addition to standard chemoradiotherapy and adjuvant temozolomide in patients with newly diagnosed glioblastoma. IMA950 is a novel glioblastoma-specific therapeutic vaccine containing 11 tumor-associated peptides (TUMAP), identified on human leukocyte antigen (HLA) surface receptors in primary human glioblastoma tissue. Experimental Design: Patients were HLA-A-02-positive and had undergone tumor resection. Vaccination comprised 11 intradermal injections with IMA950 plus granulocyte macrophage colony-stimulating factor (GM-CSF) over a 24-week period, beginning 7 to 14 days prior to initiation of chemoradiotherapy (Cohort 1) or 7 days after chemoradiotherapy (Cohort 2). Safety was assessed according to NCI CTCAE Version 4.0 and TUMAP-specific T-cell immune responses determined. Secondary observations included progression-free survival (PFS), pretreatment regulatory T cell (Treg) levels, and the effect of steroids on T-cell responses. Results: Forty-five patients were recruited. Related adverse events included minor injection site reactions, rash, pruritus, fatigue, neutropenia and single cases of allergic reaction, anemia and anaphylaxis. Two patients experienced grade 3 doselimiting toxicity of fatigue and anaphylaxis. Of 40 evaluable patients, 36 were TUMAP responders and 20 were multi- TUMAP responders, with no important differences between cohorts. No effect of pretreatment Treg levels on IMA950 immunogenicity was observed, and steroids did not affect TUMAP responses. PFS rates were 74% at 6 months and 31% at 9 months. Conclusions: IMA950 plus GM-CSF was well-tolerated with the primary immunogenicity endpoint of observing multi- TUMAP responses in at least 30% of patients exceeded. Further development of IMA950 is encouraged. Clin Cancer Res; 22(19); 4776-85. © 2016 American Association for Cancer Research.


PubMed | Astex, Great Ormond Street Hospital for Children, University of Manchester, Cancer Research Center for Drug Development and 4 more.
Type: | Journal: Pediatric blood & cancer | Year: 2016

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.


PubMed | Addensbrookes Hospital, St James's Hospital, University of Manchester, Western General Hospital and 6 more.
Type: Journal Article | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

To perform a two-cohort, phase I safety and immunogenicity study of IMA950 in addition to standard chemoradiotherapy and adjuvant temozolomide in patients with newly diagnosed glioblastoma. IMA950 is a novel glioblastoma-specific therapeutic vaccine containing 11 tumor-associated peptides (TUMAP), identified on human leukocyte antigen (HLA) surface receptors in primary human glioblastoma tissue.Patients were HLA-A*02-positive and had undergone tumor resection. Vaccination comprised 11 intradermal injections with IMA950 plus granulocyte macrophage colony-stimulating factor (GM-CSF) over a 24-week period, beginning 7 to 14 days prior to initiation of chemoradiotherapy (Cohort 1) or 7 days after chemoradiotherapy (Cohort 2). Safety was assessed according to NCI CTCAE Version 4.0 and TUMAP-specific T-cell immune responses determined. Secondary observations included progression-free survival (PFS), pretreatment regulatory T cell (TForty-five patients were recruited. Related adverse events included minor injection site reactions, rash, pruritus, fatigue, neutropenia and single cases of allergic reaction, anemia and anaphylaxis. Two patients experienced grade 3 dose-limiting toxicity of fatigue and anaphylaxis. Of 40 evaluable patients, 36 were TUMAP responders and 20 were multi-TUMAP responders, with no important differences between cohorts. No effect of pretreatment Treg levels on IMA950 immunogenicity was observed, and steroids did not affect TUMAP responses. PFS rates were 74% at 6 months and 31% at 9 months.IMA950 plus GM-CSF was well-tolerated with the primary immunogenicity endpoint of observing multi-TUMAP responses in at least 30% of patients exceeded. Further development of IMA950 is encouraged. Clin Cancer Res; 22(19); 4776-85. 2016 AACRSee related commentary by Lowenstein and Castro, p. 4760.


McCann K.J.,University of Southampton | Mander A.,University of Southampton | Cazaly A.,University of Southampton | Chudley L.,University of Southampton | And 19 more authors.
Clinical Cancer Research | Year: 2016

Purpose: We have clinically evaluated a DNA fusion vaccine to target the HLA-A∗0201-binding peptide CAP-1 from carcinoembryonic antigen (CEA605-613) linked to an immunostimulatory domain (DOM) from fragment C of tetanus toxin. Experimental Design: Twenty-seven patients with CEA-expressing carcinomas were recruited: 15 patients with measurable disease (arm-I) and 12 patients without radiological evidence of disease (arm-II). Six intramuscular vaccinations of nakedDNA (1mg/dose) were administered up to week 12. Clinical and immunologic follow-up was up to week 64 or clinical/radiological disease. Results: DOM-specific immune responses demonstrated successful vaccine delivery. All patients without measurable disease compared with 60% with advanced disease responded immunologically, while 58% and 20% expanded anti-CAP-1 CD8+ T cells, respectively. CAP-1-specific T cells were only detectable in the blood postvaccination but could also be identified in previously resected cancer tissue. The gastrointestinal adverse event diarrhea was reported by 48% of patients and linked to more frequent decreases in CEA (P < 0.001) and improved global immunologic responses [anti-DOM responses of greater magnitude (P < 0.001), frequency (P = 0.004), and duration] compared with patients without diarrhea. In advanced disease patients, decreases in CEA were associated with better overall survival (HR = 0.14, P = 0.017). CAP-1 peptide was detectable on MHC class I of normal bowel mucosa and primary colorectal cancer tissue by mass spectrometry, offering a mechanistic explanation for diarrhea through CD8+ T-cell attack. Conclusions: Our data suggest that DNA vaccination is able to overcome peripheral tolerance in normal and tumor tissue and warrants testing in combination studies, for example, by vaccinating in parallel to treatment with an anti-PD1 antibody. Clin Cancer Res; 22(19); 4827-36. © 2016 American Association for Cancer Research.


PubMed | Johannes Gutenberg University Mainz, University of Bristol, Western General Hospital, Portsmouth Hospitals NHS Trust and 5 more.
Type: Journal Article | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

We have clinically evaluated a DNA fusion vaccine to target the HLA-A*0201-binding peptide CAP-1 from carcinoembryonic antigen (CEATwenty-seven patients with CEA-expressing carcinomas were recruited: 15 patients with measurable disease (arm-I) and 12 patients without radiological evidence of disease (arm-II). Six intramuscular vaccinations of naked DNA (1 mg/dose) were administered up to week 12. Clinical and immunologic follow-up was up to week 64 or clinical/radiological disease.DOM-specific immune responses demonstrated successful vaccine delivery. All patients without measurable disease compared with 60% with advanced disease responded immunologically, while 58% and 20% expanded anti-CAP-1 CD8Our data suggest that DNA vaccination is able to overcome peripheral tolerance in normal and tumor tissue and warrants testing in combination studies, for example, by vaccinating in parallel to treatment with an anti-PD1 antibody. Clin Cancer Res; 22(19); 4827-36. 2016 AACR.


PubMed | Cambridge University Hospitals Foundation Trust and Cancer Research Center for Drug Development
Type: | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2016

Phase I oncology trials have evolved over the years, and these changes could have implications for future studies and patients.Adult trials sponsored by Cancer Research UK Centre for Drug Development between 1995 and 2013 were analysed. Forty-nine trials were divided into two groups based on the starting date for recruitment: 1995-2003 (24 trials, n=603) and 2004-2013 (25 trials, n=750) for comparative purposes.From 1995-2003 to 2004-2013, there was a shift towards studying non-cytotoxic agents that are administered orally. In later trials, patients tended to have better performance status, were older, had greater disease burden, and were more likely to have received prior treatment. In 2004-2013, wider variety of dose escalation designs were used, and studies were more likely to be multicentre, target/disease specific, conducted in first-/any-line settingand to require tumour biopsy. The overall incidence of dose-limiting toxicities (DLTs) was unchanged (10.9%; risk of death 0.4%), but DLTs such as neuropathy, stomatitis and thrombocytopaenia were less frequent in the more recent trials, while elevated liver enzymes were more frequent. Non-classical DLTs emerged in the later trials, including hypertension, hypophosphataemia, cardiac and ophthalmic toxicities. Disease control rate (DCR) increased from 27.9% (1995-2003) to 36.0% (2004-2013; P=0.0033) due to higher rates of disease stabilisation.Changes in trial designs, therapeutic agents, patient characteristics and DLTs were observed. Although the nature of DLTs changed, the incidence was similar in the two time periods and DCR improved, suggesting that the benefit-risk balance for patients participating in early-phase trials remains acceptable.


Wong H.H.,Cancer Research Center for Drug Development | Wong H.H.,University of Cambridge | Barton C.,Cancer Research Center for Drug Development | Acton G.,Cancer Research Center for Drug Development | And 2 more authors.
European Journal of Cancer | Year: 2016

Introduction Phase I oncology trials have evolved over the years, and these changes could have implications for future studies and patients. Methods Adult trials sponsored by Cancer Research UK Centre for Drug Development between 1995 and 2013 were analysed. Forty-nine trials were divided into two groups based on the starting date for recruitment: 1995–2003 (24 trials, n = 603) and 2004–2013 (25 trials, n = 750) for comparative purposes. Results From 1995–2003 to 2004–2013, there was a shift towards studying non-cytotoxic agents that are administered orally. In later trials, patients tended to have better performance status, were older, had greater disease burden, and were more likely to have received prior treatment. In 2004–2013, wider variety of dose escalation designs were used, and studies were more likely to be multicentre, target/disease specific, conducted in first-/any-line setting and to require tumour biopsy. The overall incidence of dose-limiting toxicities (DLTs) was unchanged (10.9%; risk of death 0.4%), but DLTs such as neuropathy, stomatitis and thrombocytopaenia were less frequent in the more recent trials, while elevated liver enzymes were more frequent. Non-classical DLTs emerged in the later trials, including hypertension, hypophosphataemia, cardiac and ophthalmic toxicities. Disease control rate (DCR) increased from 27.9% (1995–2003) to 36.0% (2004–2013; P = 0.0033) due to higher rates of disease stabilisation. Conclusion Changes in trial designs, therapeutic agents, patient characteristics and DLTs were observed. Although the nature of DLTs changed, the incidence was similar in the two time periods and DCR improved, suggesting that the benefit-risk balance for patients participating in early-phase trials remains acceptable. © 2016 Elsevier Ltd

Loading Cancer Research Center for Drug Development collaborators
Loading Cancer Research Center for Drug Development collaborators