A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965

A 47-year-old man with metastatic melanoma presented with refractory hyperlactaemic acidosis following the first dose of the mono-carboxylase transporter 1 inhibitor AZD3965 within a "first time in man" clinical trial. The mechanism of the agent and the temporal relationship suggested that this event was potentially drug related and recruitment was suspended. However, urinary metabolomics showed extensive abnormalities even prior to drug administration, leading to investigations for an underlying metabolic disorder. The lack of clinical symptoms from the elevated lactate and low blood glucose suggested a diagnosis of "hyper-Warburgism", where the high tumour burden was associated with extensive glucose uptake and lactate efflux from malignant cells, and the subsequent impact on blood biochemistry. This was supported by an FDG-PET scan showing extensive glucose uptake in numerous metastases and lack of uptake in the brain. A review of the literature showed 16 case reports of "hyper-Warburgism" in non-haematological malignancies, none of them with melanoma, with most associated with a poor outcome. The patient was treated symptomatically, but died 2 months later. The development of AZD3965 continues with the exclusion of patients with elevated plasma lactate at screening added to the protocol as a safety measure. Trial identification number ClinicalTrials.Gov. NCT01791595

The introduction of the Cancer Research UK Stratified Medicine Programme 2 (CRUK SMP2) in North East England; lessons learned and experience gained

Introduction: The CRUK SMP2 programme was set-up to evaluate the feasibility of performing large scale molecular analysis within the NHS on the (often small) diagnostic biopsies obtained in NSCLC. The results are used to allocate patients to an appropriate molecular therapy within the “umbrella” MATRIX trial. Newcastle opened SMP2 on 01/10/2014. Here we report our first year’s experience. Methods: NSCLC patients with PS 0–2 were consented onto the CRUK SMP2. Matched residual diagnostic tissue and blood were sent to All Wales Genetics Laboratory, Cardiff. Samples with >70ng DNA were assessed for 28 oncogenes using Next Genuine Sequencing on the Illumina SMP2 panel. Results: 116 patients were consented from 6/10/14–1/10/15 referred from 12 oncologists. The data on patient/sample flow is shown in Fig 1. Median survival was 161 days from consent. The 1st sample was sent to Cardiff on 28/1/15 as the Illumina panel was undergoing fi- nal validation. 50 samples have been sent; 11 had insufficient DNA; these samples had lower cell number (but with no impact of necrosis/tumour proportion); The most commonly altered gene was K-Ras (13 of 22 adenocarcinomas). Only 2 patients with results from >25 of the 28 genes had no tier 1 or 2 ie potentially treatable molecular abnormalities. The median time from consent to result was 109 days (range 45–250) with delays occurring throughout the pathway. Conclusion: Patients and oncologists are keen to be involved in molecular profiling; but patients need to be consented early to allow results to guide therapy. Prioritisation of samples is key. Not all samples are suitable for analysis due to small cell number or low tumour proportion. Molecular analysis may require extra resource in pathology, if it is to become standard of care. The first 4 patients to start treatment on MATRIX were enrolled from 27/8/15 in Newcastle. Disclosure: All authors have declared no conflicts of interest

Phase I/II study of DHA–paclitaxel in combination with carboplatin in patients with advanced malignant solid tumours

DHA–paclitaxel is a conjugate of paclitaxel and the fatty acid, docosahexaenoic acid. Preclinical studies have demonstrated increased activity, relative to paclitaxel, with the potential for an improved therapeutic ratio. We conducted a phase I study to determine the maximum tolerated doses of DHA–paclitaxel and carboplatin when administered in combination. Two cohorts of patients were treated: carboplatin AUC 5 with DHA–paclitaxel 660 mg m-2 and carboplatin AUC 5 with DHA–paclitaxel 880 mg m-2. Both drugs were given on day 1 every 21 days. A total of 15 patients were enrolled with a median age of 59 years (range 33–71). All patients had advanced cancer refractory to standard treatment, performance status 0–2 and were without major organ dysfunction. A total of 54 cycles of treatment were delivered. No dose-limiting toxicity (DLT) was seen in the first cohort of three patients. In an expanded second cohort, neutropenia was the main DLT, occurring in the first cycle of treatment in five of 12 patients: three of these patients and one additional patient also experienced dose-limiting grade 3 transient rises in liver transaminases. No alopecia was seen and one patient developed clinically significant neuropathy. One partial response was seen in a patient with advanced adenocarcinoma of the oesophago-gastric junction and 12 patients had stable disease with a median time to progression of 184 days (range 60–506 days). The recommended phase II dose in pretreated patients is Carboplatin AUC 5 and DHA–paclitaxel 660 mg m-2 given every 21 days. Further studies with Carboplatin AUC 5 and DHA-paclitaxel 880 mg m-2, given every 28 days, are warranted in chemo-naive patients

The National Lung Matrix Trial of personalized therapy in lung cancer

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke1,2,3. As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug–biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy—including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug–biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke

A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours

BACKGROUND: Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) is essential in cellular processing of DNA damage via the base excision repair pathway (BER). The PARP inhibition can be directly cytotoxic to tumour cells and augments the anti-tumour effects of DNA-damaging agents. This study evaluated the optimally tolerated dose of olaparib (4-(3--4-fluorophenyl) methyl-1(2H)-one; AZD2281, KU0059436), a potent PARP inhibitor, with dacarbazine and assessed safety, toxicity, clinical pharmacokinetics and efficacy of combination treatment. PATIENTS AND METHODS: Patients with advanced cancer received olaparib (20-200 mg PO) on days 1-7 with dacarbazine (600-800 mg m(-2) IV) on day 1 (cycle 2, day 2) of a 21-day cycle. An expansion cohort of chemonaive melanoma patients was treated at an optimally tolerated dose. The BER enzyme, methylpurine-DNA glycosylase and its substrate 7-methylguanine were quantified in peripheral blood mononuclear cells. RESULTS: The optimal combination to proceed to phase II was defined as 100 mg bd olaparib with 600 mg m(-2) dacarbazine. Dose-limiting toxicities were neutropaenia and thrombocytopaenia. There were two partial responses, both in patients with melanoma. CONCLUSION: This study defined a tolerable dose of olaparib in combination with dacarbazine, but there were no responses in chemonaive melanoma patients, demonstrating no clinical advantage over single-agent dacarbazine at these doses

A phase Ib dose-finding, pharmacokinetic study of the focal adhesion kinase inhibitor GSK2256098 and trametinib in patients with advanced solid tumours

BACKGROUND: Combined focal adhesion kinase (FAK) and MEK inhibition may provide greater anticancer effect than FAK monotherapy. METHODS: This dose-finding phase Ib study (adaptive 3 + 3 design) determined the maximum tolerated dose (MTD) of trametinib and the FAK inhibitor GSK2256098 in combination. Eligible patients had mesothelioma or other solid tumours with probable mitogen activated protein kinase pathway activation. Adverse events (AEs), dose-limiting toxicities, disease progression and pharmacokinetics/pharmacodynamics were analysed. RESULTS: Thirty-four subjects were enrolled. The GSK2256098/trametinib MTDs were 500 mg twice daily (BID)/0.375 mg once daily (QD) (high/low) and 250 mg BID/0.5 mg QD (low/high). The most common AEs were nausea, diarrhoea, decreased appetite, pruritus, fatigue and rash; none were grade 4. Systemic exposure to trametinib increased when co-administered with GSK2256098, versus trametinib monotherapy; GSK2256098 pharmacokinetics were unaffected by concomitant trametinib. Median progression-free survival (PFS) was 11.8 weeks (95% CI: 6.1-24.1) in subjects with mesothelioma and was longer with Merlin-negative versus Merlin-positive tumours (15.0 vs 7.3 weeks). CONCLUSIONS: Trametinib exposure increased when co-administered with GSK2256098, but not vice versa. Mesothelioma patients with loss of Merlin had longer PFS than subjects with wild-type, although support for efficacy with this combination was limited. Safety profiles were acceptable up to the MTD