A5021787511- Ovarian cancer diagnosis and treatment
- Colorectal Cancer Treatments and Studies
- Pancreatic and Hepatic Oncology Research
- Growth Hormone and Insulin-like Growth Factors
- Gastric Cancer Management and Outcomes
- PI3K/AKT/mTOR signaling in cancer
- Lung Cancer Treatments and Mutations
- Cancer Genomics and Diagnostics
- Cancer Immunotherapy and Biomarkers
- Advanced Breast Cancer Therapies
- Melanoma and MAPK Pathways
- Cancer Mechanisms and Therapy
- PARP inhibition in cancer therapy
- Multiple Myeloma Research and Treatments
- Cancer Treatment and Pharmacology
- Chronic Lymphocytic Leukemia Research
- Pharmacological Effects and Assays
- Asthma and respiratory diseases
- Lower Extremity Biomechanics and Pathologies
- Cancer-related Molecular Pathways
- Health Systems, Economic Evaluations, Quality of Life
- BRCA gene mutations in cancer
- Sports Performance and Training
- Sports injuries and prevention
- RNA Interference and Gene Delivery
Institute of Cancer Research
2015-2024
Royal Marsden NHS Foundation Trust
2014-2023
Royal Marsden Hospital
2015-2020
University of Cape Town
2004
St George's, University of London
1997
Aberystwyth University
1995
The University of Sydney
1981-1987
Abstract Inflammation is a hallmark of cancer 1 . In patients with cancer, peripheral blood myeloid expansion, indicated by high neutrophil-to-lymphocyte ratio, associates shorter survival and treatment resistance across malignancies therapeutic modalities 2–5 Whether inflammation drives progression prostate in humans remain unclear. Here we show that inhibition chemotaxis can reduce tumour-elicited reverse therapy subset metastatic castration-resistant (CRPC). We higher ratio reflects...
Abstract Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 BRCA2 (BRCA1/2)–deficient BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP 64 patients advanced solid Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage...
Background Data suggest that immunomodulation induced by DNA hypomethylating agents can sensitize tumors to immune checkpoint inhibitors. We conducted a phase 1 dose-escalation trial ( NCT02998567 ) of guadecitabine and pembrolizumab in patients with advanced solid tumors. hypothesized will overcome resistance. Methods Patients received (45 mg/m 2 or 30 , administered subcutaneously on days 1–4), (200 mg intravenously starting from cycle onwards) every 3 weeks. Primary endpoints were safety,...
Objective. Published data show that plasma creatinine falls steadily during the first 28 days of life and levels in neonatal period are higher more premature infants. However, best reference commence on day 2 life. The objective this study was to document how changes 48 hours examine reason for apparently high preterm infants, compared with maternal levels. Design. A prospective observational a regional intensive care unit. Patients. total 42 mean gestational age 29.4 weeks (range: 23–35),...
BackgroundWe have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised inhibiting signalling the dual m-TORC1/2 inhibitor patients receiving weekly paclitaxel could improve outcomes such patients.Patients and methodsIn dose escalation, (80 mg/m2) was given 6/7 weeks combination two intermittent schedules of vistusertib (dosing starting on day paclitaxel): schedule A, dosed bd for 3 consecutive days per week (3/7 days) B, 2...
2506 Background: RO5126766 is a potent RAF and MEK inhibitor with activity in xenografts models of RAS RAF-mutated cancers. We present data from the RAS/RAF-mutated advanced solid tumor cohort initial results for multiple myeloma (MM) cohort. Methods: Patients KRAS, NRAS or BRAF-mutant tumours were treated RO5127566 using novel schedule:4mg twice weekly 4-week cycles. For MM patients, it was given 3 weeks out 4 co-administration dexamethasone authorised. Response assessment completed RECIST...
Abstract Background: Preclinical experiments in-vitro show MEK inhibitors can cause upregulation of p-FAK in KRASM cells. The combination a and FAK inhibitor could overcome this in-vivo. Methods: We are conducting an open label phase I dose escalation with expansion study (NCT03875820). Dose evaluated twice week schedule (Mon/Thurs) CH5126766/VS-6766 (CH) 3 weeks out 4 day dosing defactinib (Def) administered 4. levels explored were cohort 1 (CH 3.2 mg, 200 mg Def), 2a Def mg) 2b 400 mg)....
Abstract Background: Dying cells play an important role in CD8+ T cell-mediated immunity. While apoptosis is mainly immunologically silent, necroptosis immunogenic and can more efficiently initiate adaptive immune response that could be augmented by checkpoint inhibition (ICI). Inhibitor of Apoptosis (IAP) proteins are key gatekeepers how a cell dies, frequently overexpressed cancer. ASTX660 (tolinapant) triple blocker cIAP1/2 XIAP, sensitizing cancer to death ligands through ripoptosome...
Abstract Background: There is an urgent need for better trial designs to assess targeted drug combinations. We proposed a novel intrapatient (intrapt) dose escalation design optimize exposures, minimize pharmacokinetic (PK) variability and reduce patient (pt) numbers needed (Yap et al, JCO 2013). In vivo synergy between PARP PI3K pathway inhibition was seen in BRCA1-related sporadic cancers (Juvekar al; Ibrahim Cancer Discov 2012), providing rationale this study. Methods: Two-stage...
Abstract Background: Preclinical synergy between PARP and PI3K pathway inhibition in BRCA m sporadic cancers provided rationale for this trial. Methods: Ola 300mg BID was combined with 2 schedules of AZD BID: 4 days on 3 off (4/7) 5 (2/7) using a novel intrapatient dose escalation design (Michalarea et al, AACR 2015). Cohort expansion pts gBRCA tumors relevant somatic mutations or BRCAness phenotype, assessed regimens: (1) + 400mg 4/7 (2) 640mg 2/7 AZD. Targeted next generation sequencing...
2503 Background: ONX-0801 is a first-in-class alpha folate receptor (AFR) targeted thymidylate synthase inhibitor, engineered to differentially accumulate 6000-fold in AFR overexpressing cancer cells. Methods: A 3+3 dose escalation design was used and two IV schedules were explored. Schedule A, weekly dosing (QW) schedule B, once every 2 weeks (Q2W). cycle consisted of 4 treatment stopped after 6 cycles both schedules. An expansion cohort evaluate clinical activity patients with high grade...
Abstract Purpose: CT900 is a novel small molecule thymidylate synthase inhibitor that binds to α-folate receptor (α-FR) and thus selectively taken up by α-FR–overexpressing tumors. Patients Methods: A 3+3 dose escalation design was used. During escalation, doses of 1–6 mg/m2 weekly 2–12 every 2 weeks (q2Wk) intravenously were evaluated. with high-grade serous ovarian cancer enrolled in the expansion cohorts. Results: 109 patients enrolled: 42 67 At dose/schedule 12 mg/m2/q2Wk (with without...
Abstract Background KRAS is a known oncogenic driver in non-small cell lung cancer (NSCLC), with G12C and G12V mutations occurring ~13% ~7% of the NSCLC ( adenocarcinoma subtype). The dual RAF-MEK inhibitor VS-6766 has shown single agent activity against mutated (Guo C et al Lancet Oncology 2020, 21:1478-88). Based on pre-clinical data, we hypothesised that augmented focal adhesion kinase (FAK) signalling mechanism resistance to MEK inhibition devised current clinical trial. We have...
9018 Background: VS-6766 is a small molecule RAF/MEK clamp that results in the reduction of p-MEK and p-ERK. Preclinical data show synergy with mTOR inhibitor everolimus across panel KRAS mutated (mt) NSCLC cell lines. This clinical trial evaluated safety efficacy novel intermittent regimen an expansion mt (NCT02407509). Methods: The used 3+3 dose escalation design once week schedule A, if tolerated, twice B (Mon-Thu or Tue-Fri) for both drugs on 3 weeks on/1 off, 28 day cycle. Patients RAS...
1051 Background: PI3K and CDK4/6 inhibitors synergise in ER+ve –ve PIK3CA-mt breast cancer (BC) models. Escalation phase of this study set recommended 2 dose (RP2D) at P 125mg on a 3/1 scheme plus T 2mg daily ( Lim, ASCO 2017). Here we present the results expansion cohorts for BC patients (pts). Methods: The primary objective was to assess confirmed response rate (ORR) + FUL triplet pts with measurable HER2-ve advanced BC, up two prior lines chemotherapy disease. PIK3CA mutation assessed...
3087 Background: Oncogenic hyperactivation of the PI3K pathway is common in multiple cancers, with preclinical data showing that CDK4/6 inhibitors sensitise PIK3CA mutant cancers to inhibitors. We report activity P+T solid tumors activation, along PD biomarker analysis. Methods: previously reported dose escalation phase identifying 125mg P given 3-weeks-on, 1-week-off combination T 2mg as recommended 2 (R2PD, Lim, ASCO 2017). results confirmed activating mutations (mts) pathway, from and...
2582 Background: RO5126766 is a novel MEK inhibitor with functional RAF inhibition. A dose escalation Phase 1 study, comparing 2 intermittent schedules, has previously been reported, recommended phase (RP2D) of 4 mg twice weekly (Monday/Thursday (M/Th)). We now present results from the expansion cohort this which aims to assess tolerability and preliminary activity in pts KRAS, NRAS or BRAFmutated tumours. Methods: Pts BRAF mutated tumours were treated at RP2D M/Th week cycles. Tumour...
Abstract Background PTEN loss of function is frequent in GBM correlating with poor prognosis, impaired antitumor responses and reduced efficacy Immune Checkpoint Inhibitors (ICI). Ipat a potent, selective, small-molecule inhibitor Akt. efficiently depletes FOXP3+ regulatory T cells from the tumor microenvironment (TME) resulting increased infiltration effector solid tumors (Lopez 2020, AACR). We hypothesize that Akt inhibition glioblastomas may deplete TME suppressive immune cells, render...
TPS5105 Background: Tumor-infiltrating inflammatory myeloid cells promote prostate cancer (PC) growth and therapeutic resistance. Myeloid release interleukin-23 (IL-23) to fuel tumor via JAK2-STAT3 signalling facilitate tumor-promoting T helper 17 (T H 17) differentiation in PC models vivo. IL-23 blockade reverses resistance AR-targeting vivo; we hypothesise that targeting can be an effective strategy for CRPC. Tildrakizumab, anti-IL-23 (p19) monoclonal antibody, is FDA/EMA approved treating...
Abstract Background: Hyperactivation of the PI3K/AKT pathway correlates with impaired antitumour response, including reduced T cell infiltration into tumour and efficacy immune checkpoint inhibitors (ICIs). PTEN loss function, often observed in GBM, may contribute to refractoriness ICIs this disease. Methods: The Ice-CAP A2 cohort assessed safety, pharmacodynamic, preliminary clinical activity Ipa (200mg or 400mg OD) + A (1200mg Q3W) pts potentially resectable relapsed WHO Grade IV GBM. Key...