Pre-clinical animal models are poor predictors of human toxicities in phase 1 oncology clinical trials.

BACKGROUND: Our objective was to determine the correlation between preclinical toxicity found in animal models (mouse, rat, dog and monkey) and clinical toxicity reported in patients participating in Phase 1 oncology clinical trials. METHODS: We obtained from two major early-Phase clinical trial centres, preclinical toxicities from investigational brochures and clinical toxicities from published Phase 1 trials for 108 drugs, including small molecules, biologics and conjugates. Toxicities were categorised according to Common Terminology Criteria for Adverse Events version 4.0. Human toxicities were also categorised based on their reported clinical grade (severity). Positive predictive values (PPV) and negative predictive values (NPV) were calculated to determine the probability that clinical studies would/would not show a particular toxicity category given that it was seen in preclinical toxicology analysis. Statistical analyses also included kappa statistics, and Matthews (MCC) and Spearman correlation coefficients. RESULTS: Overall, animal toxicity did not show strong correlation with human toxicity, with a median PPV of 0.65 and NPV of 0.50. Similar results were obtained based on kappa statistics and MCC. CONCLUSIONS: There is an urgent need to assess more novel approaches to the type and conduct of preclinical toxicity studies in an effort to provide better predictive value for human investigation.

Proportion of Patients in Phase I Oncology Trials Receiving Treatments That Are Ultimately Approved.

BACKGROUND: Phase I oncology trials are often regarded as a therapeutic option for patients. However, such claims have relied on surrogate measures of benefit, such as objective response. METHODS: Using a systematic search of publications, we assessed the therapeutic value of phase I cancer trial participation by determining the probability that patients will receive active doses of treatments that eventually receive FDA approval or a National Comprehensive Cancer Network (NCCN) guideline recommendation for their indication. ClinicalTrials.gov, PubMed, American Society of Clinical Oncology reports, NCCN guidelines, and Drugs@FDA were searched between May 1, 2018, and July 31, 2018. All statistical tests were 2-sided. RESULTS: A total of 1000 phase I oncology trials initiated between 2005 and 2010 and enrolling 32 582 patients were randomly sampled from 3229 eligible trials on ClinicalTrials.gov. A total of 386 (1.2%) patients received a treatment that was approved by the US Food and Drug Administration for their malignancy at a dose delivered in the trial; including NCCN guideline recommendations, the number and proportion are 1168 (3.6%). Meta-regression showed a statistically significantly greater proportion of patients receiving a drug that was ultimately FDA approved in biomarker trials (rate ratio = 4.49, 95% confidence interval [CI] = 1.53 to 13.23; P = .006) and single-indication trials (rate ratio = 3.32, 95% CI = 1.21 to 9.15; P = .02); proportions were statistically significantly lower for combination vs monotherapy trials (rate ratio = 0.09, 95% CI = 0.01 to 0.68; P = .02). CONCLUSIONS: One in 83 patients in phase I cancer trials received a treatment that was approved for their indication at the doses received. Given published estimates of serious adverse event rates of 10%-19%, this represents low therapeutic value for phase I trial participation.

Cancer-Related Internet Use and Online Social Networking Among Patients in an Early-Phase Clinical Trials Clinic at a Comprehensive Cancer Center.

PURPOSE: We examined patterns, correlates, and the impact of cancer-related Internet use among patients with advanced cancer in a phase I clinical trials clinic for molecularly targeted oncologic agents. METHODS: An anonymous questionnaire on Internet use for cancer-related purposes that incorporated input from phase I clinical trial oncologists and patients was self-administered by patients age ≥ 18 years in a phase I clinic. Multivariable modeling was used. Data were analyzed for the overall sample and by generation, which was defined by year of birth. RESULTS: Of 291 patients (52% women, 82% non-Hispanic white, 50% age ≤ 60 years), 62% were cancer-related Internet users (CIUs). Cancer-related Internet use was associated with an income of ≥ $60,000 (odds ratio, 2.42; P = .004). CIUs used the Internet to learn about their cancer (85%), treatment adverse effects (65%), clinical trials (52%), new alternative treatments (42%), and symptom management (41%). CIUs most frequently used the hospital Web site (70%) to learn about clinical trials, followed by ClinicalTrials.gov (42%) and search engines (41%). The emotional impact of Internet-derived cancer information on CIUs varied-56% felt empowered, 34% anxious, 29% relieved, and 17% confused. Cancer-related Internet information made 51% of patients from the Millennial (born after 1990) and Generation X/Y (born 1965 to 1990) CIU populations anxious compared with < 29% of CIUs from older generations (born 1964 and before). Most CIUs desired more online information about new experimental drugs (91%) and US Food and Drug Administration-approved drugs for cancer (72%). CONCLUSION: As most phase I patients use the Internet for cancer-related purposes, the Internet overall and hospital Web sites should provide more extensive, pertinent, and helpful information on clinical trials and cancer treatment to phase I patients.

The concordance between nonclinical and phase I clinical cardiovascular assessment from a cross-company data sharing initiative.

It is widely accepted that more needs to be done to bring new, safe, and efficacious drugs to the market. Cardiovascular toxicity detected both in early drug discovery as well as in the clinic, is a major contributor to the high failure rate of new molecules. The growth of translational safety offers a promising approach to improve the probability of success for new molecules. Here we describe a cross-company initiative to determine the concordance between the conscious telemetered dog and phase I outcome for 3 cardiovascular parameters. The data indicate that, in the context of the methods applied in this analysis, the ability to detect compounds that affect the corrected QT interval (QTc) was good within the 10-30x exposure range but the predictive or detective value for heart rate and diastolic blood pressure was poor. These findings may highlight opportunities to refine both the animal and the clinical study designs, as well as refocusing the assessment of value of dog cardiovascular assessments beyond phase 1. This investigation has also highlighted key considerations for cross-company data sharing and presents a unique learning opportunity to improve future translational projects.

Continual reassessment method vs. traditional empirically based design: modifications motivated by Phase I trials in pediatric oncology by the Pediatric Brain Tumor Consortium.

In this article we provide additional support for the use of a model-based design in pediatric Phase I trials and present our modifications to the continual reassessment method (CRM), which were largely motivated by specific challenges we encountered in the context of the Pediatric Brain Tumor Consortium trials. We also summarize the results of our extensive simulations studying the operating characteristics of our modified approach and contrasting it to the empirically based traditional method (TM). Compared to the TM, our simulations indicate that the modified version of CRM is more accurate, exposes fewer patients to potentially toxic doses, and tends to require fewer patients. Further, the CRM-based MTD has a consistent definition across trials, which is important, especially in a consortium setting where multiple agents are being tested in studies that are often running simultaneously and accruing from the same patient population.

Model-based decision making in early clinical development: minimizing the impact of a blood pressure adverse event.

We describe how modeling and simulation guided program decisions following a randomized placebo-controlled single-rising oral dose first-in-man trial of compound A where an undesired transient blood pressure (BP) elevation occurred in fasted healthy young adult males. We proposed a lumped-parameter pharmacokinetic-pharmacodynamic (PK/PD) model that captured important aspects of the BP homeostasis mechanism. Four conceptual units characterized the feedback PD model: a sinusoidal BP set point, an effect compartment, a linear effect model, and a system response. To explore approaches for minimizing the BP increase, we coupled the PD model to a modified PK model to guide oral controlled-release (CR) development. The proposed PK/PD model captured the central tendency of the observed data. The simulated BP response obtained with theoretical release rate profiles suggested some amelioration of the peak BP response with CR. This triggered subsequent CR formulation development; we used actual dissolution data from these candidate CR formulations in the PK/PD model to confirm a potential benefit in the peak BP response. Though this paradigm has yet to be tested in the clinic, our model-based approach provided a common rational framework to more fully utilize the limited available information for advancing the program.

Is there a role for herbal medicine in the treatment of pancreatic cancer?. Highlights from the "44th ASCO Annual Meeting". Chicago, IL, USA. May 30 - June 3, 2008.

One of the greatest challenges in the treatment of pancreatic cancer remains its inherent lack of beneficial response to cytotoxic chemotherapy. According to the encyclopedic knowledge on herbal medicine regimen and clinical experience accumulated for centuries, traditional Chinese medicine can provide new avenues for alternative treatments of pancreatic diseases. Chinese herbal extracts have been widely used for the treatment of various cancers, but objective information on their efficacy in pancreatic cancer is lacking. This article provides a summary of herbal medicine, presented at the Annual Meeting of ASCO, 2008. The clinical applications of these active compounds warrant further investigation in randomized, controlled clinical trials.

Trans-sodium crocetinate for treating hypoxia/ischemia.

BACKGROUND: Trans-sodium crocetinate (TSC) is a novel compound that offers promise as a treatment for conditions caused by hypoxia or ischemia. TSC was originally developed at the University of Virginia for hemorrhagic shock, as part of the battlefield casualty program sponsored by the US Office of Naval Research. Animal toxicology studies have demonstrated that high levels of TSC are well-tolerated, and a Phase I clinical study has shown that TSC is also safe in humans. OBJECTIVE: The drug acts via a mechanism that has not been previously exploited in a pharmaceutical. TSC increases the rate of oxygen diffusion between the erythrocytes and the tissues by altering the 'structure' of water in blood plasma. It does this by causing additional hydrogen bonds to form among the water molecules. CONCLUSION: Further development of TSC for hemorrhagic shock and other hypoxic/ischemic conditions is being done by Diffusion Pharmaceuticals LLC.

Regulation of c-Raf-1: therapeutic implications.

The mitogen activated protein kinase (MAPK) or Ras/Raf/MAPK kinase (MEK)/ERK signaling cascade is a ubiquitously expressed intracellular signaling pathway that transmits mitogenic stimuli to the nucleus through a series of sequential phosphorylation events and controls such cellular functions as proliferation, differentiation, and apoptosis. Components of this pathway such as ras and raf are oncogenes and as such aberrancy in their encoded proteins results in malignant transformation. The MAPK pathway is dysregulated in approximately 30% of all human tumors and therefore targeting specific components of this pathway that regulate pleiotropic cellular processes using such strategies as isoprenylation inhibitors, antisense oligodeoxyribonucleotides, and inhibitors of the kinase function represent attractive therapeutic options. raf kinase, a downstream effector of ras, has been known to be functionally aberrant in various human tumors. The 3 isoforms of raf have been studied extensively, and agents targeting c-raf are presently undergoing early-phase clinical testing. The outcomes of these trials have wide-ranging clinical implications in the management of cancers. This review addresses the rationale for targeting raf, the diverse cellular functions regulated by c-raf, and the current status of various pharmacological approaches targeting c-raf.