Project description:Background: Drug combinations are the standard of care in cancer treatment. Identifying effective cancer drug combinations has become more challenging because of the increasing number of drugs. However, a substantial number of cancer drugs stumble at Phase III clinical trials despite exhibiting favourable efficacy in the earlier Phase. Methods: We analysed recent Phase II cancer trials comprising 2165 response rates to uncover trends in cancer therapies and used a null model of non-interacting agents to infer synergistic and antagonistic drug combinations. We compared our latest efficacy dataset with a previous dataset to assess the progress of cancer therapy. Results: Targeted therapies reach higher response rates when used in combination with cytotoxic drugs. We identify four synergistic and 10 antagonistic combinations based on the observed and expected response rates. We demonstrate that recent targeted agents have not significantly increased the response rates. Conclusions: We conclude that either we are not making progress or response rate measured by tumour shrinkage is not a reliable surrogate endpoint for the targeted agents.
Project description:Pancreatic cancer is a devastating disease with very poor prognosis. Currently, surgery followed by adjuvant chemotherapy represents the only curative option which, unfortunately, is only available for a small group of patients. The majority of pancreatic cancer cases are diagnosed at advanced or metastatic stage when surgical resection is not possible and treatment options are limited. Thus, novel and more effective therapeutic strategies are urgently needed. Molecular profiling together with targeted therapies against key hallmarks of pancreatic cancer appear as a promising approach that could overcome the limitations of conventional chemo- and radio-therapy. In this review, we focus on the latest personalised and multimodal targeted therapies currently undergoing phase II or III clinical trials. We discuss the most promising findings of agents targeting surface receptors, angiogenesis, DNA damage and cell cycle arrest, key signalling pathways, immunotherapies, and the tumour microenvironment.
Project description:Mesothelioma is a rare malignancy of the pleura with limited therapeutic options. Despite the desperate need to develop better treatment for this disease, the rarity of the tumor type creates formidable challenges in clinical research. Nonetheless, several novel agents are under investigation. Most efforts are directed toward improving standard first-line therapy with pemetrexed and cisplatin, or developing effective second-line treatments. Several classes of drugs are being explored, including those that impact DNA transcription, cell-cycle progression, angiogenesis, and immune tolerance. This article describes several ongoing or recently completed phase II and III trials using novel agents vorinostat, everolimus, CBP501, MORAb-009, NGR-hTNF, WT1 vaccine, bevacizumab, cediranib, and thalidomide.
Project description:Novel oncology drugs often fail to progress from preclinical experiments to FDA approval. Therefore, determining which preclinical or clinical factors associate with drug activity could accelerate development of effective therapies. We investigated whether preclinical metrics and patient characteristics are associated with objective response rate (ORR) in phase II clinical trials of targeted therapies for non-small cell lung cancer (NSCLC). We developed a reproducible process to select a single phase II trial and supporting preclinical publication for a given drug-indication pair, which we defined as the pairing of a small molecule inhibitor (e.g., crizotinib) with the specific patient population for which it was designed to work (e.g., patients with an ALK aberration). We demonstrated that robust drug activity in mice, as measured by change in tumor size, is independently associated with improved ORR in phase II clinical trials. The number of mice utilized in experiments, the number of publications referencing the drug for NSCLC before the phase II clinical trial, and whether the drug was approved for a cancer other than NSCLC also significantly correlated with ORR. Among clinical characteristics, sex, race, histology, and smoking history were significantly associated with ORR. Further research into metrics that correlate with drug activity has the potential to optimize selection of novel therapies for clinical trials and enrich the drug development pipeline, particularly for patients with targetable genetic aberrations and rare cancers.
Project description:The GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In chronic lymphocytic leukaemia (CLL) (GALACTIC) was a seamless phase II/III trial designed to test whether consolidation with obinutuzumab is safe and eradicates minimal residual disease (MRD) and, subsequently, whether this leads to prolonged progression-free survival (PFS) in patients with CLL who have recently responded to chemo-immunotherapy. Patients with a response 3-24 months after chemotherapy were assessed for MRD. MRD-positive patients were randomised to receive consolidation therapy with obinutuzumab or no consolidation. The trial closed after the phase II part due to slow recruitment. In all, 48 patients enrolled of whom 19 were MRD negative and were monitored. Of the 29 MRD-positive patients, 14 were randomised to receive consolidation and 15 to no consolidation. At 6 months after randomisation, 10 and 13 consolidated patients achieved MRD negativity by flow cytometry (sensitivity 10-4 ) in bone marrow and peripheral blood respectively. PFS was significantly better in consolidated patients compared to non-consolidated patients (p = 0.001). No difference was observed in PFS, overall survival or duration of MRD negativity when comparing the 10 MRD-negative patients after consolidation with the 19 MRD-negative patients in the monitoring group. Common adverse events in the consolidation arm were thrombocytopenia, infection, and cough. Only 1% of events were infusion-related reactions. This observation provides further evidence that consolidation to achieve MRD negativity improves outcomes in CLL and that obinutuzumab is well tolerated in patients with low levels of disease.
Project description:PurposePhase II cancer clinical trial designs commonly incorporate an interim analysis for lack of efficacy. To strictly and ethically implement such designs, one should suspend accrual in cases where pending patient outcomes can affect early termination decisions. This article aims to evaluate various options for accrual suspension and illustrate how the suspension strategy affects operating characteristics of the trial.MethodsWe define a strict suspension strategy for determining whether one should continue, suspend, or restart accrual at any point within the trial. The strategy is compared to a naive implementation of suspension and a strategy of no suspension. We evaluate the methods' operating characteristics by simulation.ResultsThe suspension strategy has little effect on type I error, power, and early termination probability. Methods that involve stricter suspension policies generally lead to smaller but longer trials. Differences across strategies are substantial when the ratio of enrollment rate to outcome availability rate is high.ConclusionThe suspension strategy is most relevant in trials that accrue rapidly and require lengthy observation of each subject. The choice of suspension strategy involves a tradeoff between the cost of implementing a potentially complex suspension algorithm in real time versus the cost of enrolling more patients and exposing them to a potentially toxic and ineffective treatment regimen.
Project description:Acute ischemic stroke is a devastating cause of death and disability, consequences of which depend on the time from ischemia onset to treatment, the affected brain region, and its size. The main targets of ischemic stroke therapy aim to restore tissue perfusion in the ischemic penumbra in order to decrease the total infarct area by maintaining blood flow. Advances in research of pathological process and pathways during acute ischemia have resulted in improvement of new treatment strategies apart from restoring perfusion. Additionally, limiting the injury severity by manipulating the molecular mechanisms during ischemia has become a promising approach, especially in animal research. The purpose of this article is to review completed and ongoing phases I and II trials for the treatment of acute ischemic stroke, reviewing studies on antithrombotic, thrombolytic, neuroprotective, and antineuroinflammatory drugs that may translate into more effective treatments.
Project description:Designing and interpreting single-arm phase II trials of combinations of agents is challenging because it can be difficult, based on historical data, to identify levels of activity for which the combination would be worth pursuing. We identified Cancer Therapy Evaluation Program single-arm combination trials that were activated in 2008-2017 and tabulated their design characteristics and results. Positive trials were evaluated as to whether they provided credible evidence that the combination was better than its constituents. A total of 125 trials were identified, and 120 trials had results available. Twelve had designs where eligible patients were required to be resistant or refractory to all but one element of the combination. Only 17.8% of the 45 positive trials were deemed to provide credible evidence that the combination was better than its constituents. Of the 10 positive trials with observed rates 10 percentage points higher than their upper (alternative hypothesis) targets, only five were deemed to provide such credible evidence. Many trials were definitively negative, with observed clinical activity at or below their lower (null hypothesis) targets. Ideally, use of single-arm combination trials should be restricted to settings where each agent is known to have minimal monotherapy activity (and a randomized trial is infeasible). In these settings, an observed signal is attributable to synergy and thus could be used to decide whether the combination is worth pursuing. In other settings, credible evidence can still be obtained if the observed activity is much higher than expected, but experience suggests that this is a rare occurrence.
Project description:ObjectiveTo evaluate a training intervention aimed at improving healthcare professionals' communication with cancer patients about randomised clinical trials.DesignBefore and after evaluation of training programme.SettingMembers of the National Cancer Research Network, Scottish Trials Network, and the Welsh Cancer Trials Network.Participants101 healthcare professionals (33 clinicians and 68 research nurses).InterventionFour modules delivered by a trained facilitator using videotapes and interactive exercises to cover general issues about discussing randomised clinical trials with patients, problems specific to adjuvant trials, trials with palliation as the goal, and trials where patients had a strong preference for one treatment arm.Main outcome measuresBefore and after the intervention, participants were videotaped discussing a trial with an actor portraying a patient. These consultations were assessed for presence of information required by good clinical practice guidelines. The actor patients gave an assessment after each interview. Participants reported their self confidence about key aspects of trial discussion.ResultsAnalysis of the videotaped consultations showed that, after intervention, significantly more participants displayed key communication behaviours such as explaining randomisation (69 v 81, odds ratio 2.33, P = 0.033), checking patients' understanding (11 v 31, odds ratio 3.22, P = 0.002), and discussing standard treatment (73 v 88, odds ratio 4.75, P = 0.005) and side effects (69 v 85, odds ratio 3.29, P = 0.006). Participants' self confidence increased significantly (P < 0.001) across all areas. Actor patients' ratings of participants' communication showed significant improvements for 12/15 key items.ConclusionThis intensive 8 hour intervention significantly improved participants' confidence and competence when communicating about randomised clinical trials.
Project description:This review presents an integrated analysis of the current-state-of-the-art in nucleic acid nanotherapies and highlights the importance of nanotechnology in the delivery of nucleic acid therapies. While there is no one dominant nanodesign, the diversity of nanodesigns and delivery of different siRNAs, miRNA and DNA to inhibit more than 20 targets in seven disease states in Phase II/III clinical trials reflects the potential of nucleic acid therapies to treat intractable diseases and non-druggable targets. We provide benchmarks to aid in comparing the design, proof-of-concept studies and clinical trials. From this, we demonstrate the importance of generating a strategic framework for integrating clinical 'wish lists' for a means to treat intractable diseases with engineering 'design checklists' for nucleic acid nanotherapies.