Challenges in implementing model-based phase I designs in a grant-funded clinical trials unit

Background

For a clinical trials unit to run its first model-based, phase I trial, the statistician, chief investigator, and trial manager must all acquire a new set of skills. These trials also require a different approach to funding and data collection.

Challenges and discussion

From the statisticians’ viewpoint, we highlight what is needed to move from running rule-based, early-phase trials to running a model-based phase I study as we experienced it in our trials unit located in the United Kingdom. Our example is CHARIOT, a dose-finding trial using the time-to-event continual reassessment method. It consists of three stages and aims to discover the maximum tolerated dose of the combination of radiotherapy, chemotherapy, and the ataxia telangiectasia mutated Rad3-related inhibitor M6620 (previously known as VX-970) in patients with oesophageal cancer. We present the challenges we faced in designing this trial and how we overcame them as a way of demystifying the conduct of a model-based trial in a grant-funded clinical trials unit.

Conclusions

Although we appreciate that undertaking model-based trials requires additional time and effort, they are feasible to implement and, once suitable tools such as guiding publications and document templates become available, the design and set-up process will be easier and more efficient.

     

Designs for single- or multiple-agent phase I trials

Phase I trials of cytotoxic agents in oncology are usually dose-finding studies that involve a single cytotoxic agent. Many statistical methods have been proposed for these trials, all of which are based on the assumption of a monotonic dose-toxicity curve. For single-agent trials, this is a valid assumption. In many trials, however, investigators are interested in finding the maximally tolerated dose based on escalating multiple cytotoxic agents. When there are multiple agents, monotonicity of the dose-toxicity curve is not clearly defined. In this article we present a design for phase I trials in which the toxicity probabilities follow a partial order, meaning that there are pairs of treatments for which the ordering of the toxicity probabilities is not known at the start of the trial. We compare the new design to existing methods for simple orders and investigate the properties of the design for two partial orders.     

Sequential designs for ordinal phase I clinical trials

Sequential designs for phase I clinical trials which incorporate maximum likelihood estimates (MLE) as data accrue are inherently problematic because of limited data for estimation early on. We address this problem for small phase I clinical trials with ordinal responses. In particular, we explore the problem of the nonexistence of the MLE of the logistic parameters under a proportional odds model with one predictor. We incorporate the probability of an undetermined MLE as a restriction, as well as ethical considerations, into a proposed sequential optimal approach, which consists of a start‐up design, a follow‐on design and a sequential dose‐finding design. Comparisons with nonparametric sequential designs are also performed based on simulation studies with parameters drawn from a real data set.     

Design and analysis of phase I clinical trials

The Phase I clinical trial is a study intended to estimate the so-called maximum tolerable dose (MTD) of a new drug. Although there exists more or less a standard type of design for such trials, its development has been largely ad hoc. As usually implemented, the trial design has no intrinsic property that provides a generally satisfactory basis for estimation of the MTD. In this paper, the standard design and several simple alternatives are compared with regard to the conservativeness of the design and with regard to point and interval estimation of an MTD (33rd percentile) with small sample sizes. Using a Markov chain representation, we found several designs to be nearly as conservative as the standard design in terms of the proportion of patients entered at higher dose levels. In Monte Carlo simulations, two two-stage designs are found to provide reduced bias in maximum likelihood estimation of the MTD in less than ideal dose-response settings. Of the three methods considered for determining confidence intervals--the delta method, a method based on Fieller's theorem, and a likelihood ratio method--none was able to provide both usefully narrow intervals and coverage probabilities close to nominal.     

A curve-free method for phase I clinical trials

Consider the problem of finding the dose that is as high as possible subject to having a controlled rate of toxicity. The problem is commonplace in oncology Phase I clinical trials. Such a dose is often called the maximum tolerated dose (MTD) since it represents a necessary trade-off between efficacy and toxicity. The continual reassessment method (CRM) is an improvement over traditional up-and-down schemes for estimating the MTD. It is based on a Bayesian approach and on the assumption that the dose-toxicity relationship follows a specific response curve, e.g., the logistic or power curve. The purpose of this paper is to illustrate how the assumption of a specific curve used in the CRM is not necessary and can actually hinder the efficient use of prior inputs. An alternative curve-free method in which the probabilities of toxicity are modeled directly as an unknown multidimensional parameter is presented. To that purpose, a product-of-beta prior (PBP) is introduced and shown to bring about logical improvements. Practical improvements are illustrated by simulation results.     

Monitoring late-onset toxicities in phase I trials using predicted risks

Late-onset (LO) toxicities are a serious concern in many phase I trials. Since most dose-limiting toxicities occur soon after therapy begins, most dose-finding methods use a binary indicator of toxicity occurring within a short initial time period. If an agent causes LO toxicities, however, an undesirably large number of patients may be treated at toxic doses before any toxicities are observed. A method addressing this problem is the time-to-event continual reassessment method (TITE-CRM, Cheung and Chappell, 2000). We propose a Bayesian dose-finding method similar to the TITE-CRM in which doses are chosen using time-to-toxicity data. The new aspect of our method is a set of rules, based on predictive probabilities, that temporarily suspend accrual if the risk of toxicity at prospective doses for future patients is unacceptably high. If additional follow-up data reduce the predicted risk of toxicity to an acceptable level, then accrual is restarted, and this process may be repeated several times during the trial. A simulation study shows that the proposed method provides a greater degree of safety than the TITE-CRM, while still reliably choosing the preferred dose. This advantage increases with accrual rate, but the price of this additional safety is that the trial takes longer to complete on average.     

PA-CRM: A continuous reassessment method for pediatric phase I oncology trials with concurrent adult trials

Pediatric phase I trials are usually carried out after the adult trial testing the same agent has started, but not completed yet. As the pediatric trial progresses, in light of the accrued interim data from the concurrent adult trial, the pediatric protocol often is amended to modify the original pediatric dose escalation design. In practice, this is done frequently in an ad hoc way, interrupting patient accrual and slowing down the trial. We developed a pediatric-continuous reassessment method (PA-CRM) to streamline this process, providing a more efficient and rigorous method to find the maximum tolerated dose for pediatric phase I oncology trials. We use a discounted joint likelihood of the adult and pediatric data, with a discount parameter controlling information borrowing between pediatric and adult trials. According to the interim adult and pediatric data, the discount parameter is adaptively updated using the Bayesian model averaging method. Numerical study shows that the PA-CRM improves the efficiency and accuracy of the pediatric trial and is robust to various model assumptions.     

Nitric oxide promotes germ cell necrosis in the delayed phase after experimental testicular torsion of rat

The purpose of this study is to determine whether inducible nitric oxide synthase (iNOS) is involved in the pathogenesis of testicular ischemia-reperfusion (I/R) injury in association with germ cell death, through either necrosis or apoptosis. Western blot analysis showed that iNOS expression was markedly increased 1 h after ischemia, and was accompanied by a huge nitric oxide (NO) production, as measured by the Griess method, with a peak at 48 h of reperfusion. Immunohistochemistry showed that iNOS was expressed predominantly in the macrophage-like cells infiltrated in the interstitial tissues of the testis. Intraperitoneal injection of aminoguanidine (AMG) (400 mg/day), the inhibitor of iNOS, reduced NO production by 57.7% at 96 h of reperfusion. Calpain activation and proteolysis of alpha-fodrin induced by I/R were inhibited by AMG. Germ cell apoptosis was demonstrated by in situ TUNEL and DNA fragmentation on agarose gel electrophoresis. Germ cell apoptosis was maximally induced at 24 h of reperfusion, and was not inhibited by AMG. NO produced by iNOS in the delayed phase of reperfusion promoted alpha-fodrin proteolysis, which is closely associated with necrosis. Inducible NOS inhibition combined with calpain inhibition may improve impaired spermatogenesis after testicular torsion.     

Manufacturing mesenchymal stromal cells for phase I clinical trials

Mesenchymal stromal cells (MSCs) are multipotent progenitor cells capable of differentiating into adipocytes, osteoblasts and chondroblasts as well as secreting a vast array of soluble mediators. This potentially makes MSCs important mediators of a variety of therapeutic applications. They are actively under evaluation for immunomodulatory purposes such as graft-versus-host disease and Crohn’s disease as well as regenerative applications such as stroke and congestive heart failure. We report our method of generating clinical-grade MSCs together with suggestions gathered from manufacturing experience in our Good Manufacturing Practices facility.     

Incidence of carcinoma in situ of germ cells in contralateral testis of men with testicular tumours.

Biopsy specimens from the contralateral testicle in 50 consecutive patients with germinal testicular cancer were examined for carcinoma in situ. Three out of 21 men with seminomas and one out of 29 with other types of germinal cancer (8%) had carcinoma in situ in the contralateral testicle without any clinical signs. One of these men developed early invasive germ-cell cancer 46 months after carcinoma in situ was first diagnosed. The others have been followed up for less than a year without signs of tumour growth. If these results are confirmed routine biopsy of the contralateral testicle in patients with germinal cancer may be indicated.     

Pathobiology of testicular germ cell tumors: views and news

Human germ cell tumors (GCTs) are a heterogeneous group of neoplasms. They can occur in different anatomic locations, predominantly in the gonads (both ovary and testis) and in the midline of the body, including the retroperitoneal, mediastinal and hypothalamus/pineal gland regions. This distribution has been related to the migration routefollowed by primordial germ cells from the yolk sac to the genital ridge. The clinical behavior of these tumors depends on the sex of the patient, the age at clinical presentation and the histology of the tumor, Within the testis, three groups of GCTs can be distinguished; (I) yolk sac tumors and teratomas of neonates and infants; (II) seminomas and nonseminomas of adolescents and adults, the so-called testicular germ cell tumors; and (III) spermatocytic seminomas. This review discusses the histology, epidemiology and chromosomal constitution of GCT, in particular of the seminomas and nonseminomas of the adult testis, including their precursor, carcinoma in situ. In addition, the available data on the molecular basis of treatment sensitivity and resistance of GCT are reviewed.     

Safety evaluation of BacoMind in healthy volunteers: a phase I study.

BacoMind is an enriched phytochemical composition of Bacopa monniera (B. monniera), a common medicinal plant used in the traditional systems of medicine as a memory-enhancing agent. BacoMind was standardized with reference to bioactive compounds and was evaluated for short-term safety and tolerability in healthy adult volunteers. The study plan employed randomized, open label, dose escalation design. Each of 23 participants were orally given one single capsule of BacoMind daily for 30 days, i.e., 300 mg for first 15 days and 450 mg for next 15 days. Detailed examination of clinical, hematological, biochemical and electrocardiographic parameters done in pre and post-treatment periods did not indicate any untoward effects in any of the treated volunteers. Mild adverse events related to gastrointestinal system were observed in the trial, which subsided spontaneously. BacoMind was found to meet the safety criteria at the dose administered for the given duration of trial period in healthy adult volunteers.     

Sequential designs for phase I clinical trials with late-onset toxicities

Traditional designs for phase I clinical trials require each patient (or small group of patients) to be completely followed before the next patient or group is assigned. In situations such as when evaluating late-onset effects of radiation or toxicities from chemopreventive agents, this may result in trials of impractically long duration. We propose a new method, called the time-to-event continual reassessment method (TITE-CRM), that allows patients to be entered in a staggered fashion. It is an extension of the continual reassessment method (CRM; O'Quigley, Pepe, and Fisher, 1990, Biometrics 46, 33-48). We also note that this time-to-toxicity approach can be applied to extend other designs for studies of short-term toxicities. We prove that the recommended dose given by the TITE-CRM converges to the correct level under certain conditions. A simulation study shows our method's accuracy and safety are comparable with CRM's while the former takes a much shorter trial duration: a trial that would take up to 12 years to complete by the CRM could be reduced to 2-4 years by our method.     

Aurora B expression in post-puberal testicular germ cell tumours

Aurora/Ipl1-related kinases are a conserved family of proteins that are essential for the regulation of chromosome segregation and cytokinesis during mitosis. Aberrant expression and activity of these kinases occur in a wide range of human tumours and have been implicated in mechanisms leading to mitotic spindle aberrations, aneuploidy, and genomic instability. Previous studies of our group have shown that Aurora B expression is restricted to specific germinal cells. In this study, we have evaluated by immunohistochemical analysis Aurora B expression in post-puberal testicular germ cell tumours (22 seminomas, 2 teratomas, 15 embryonal carcinomas, 5 mixed germinal tumours with a prominent yolk sac tumour component and 1 choriocarcinoma). The Aurora B protein expression was detected in all intratubular germ cell tumours, seminomas and embryonal carcinomas analysed but not in teratomas and yolk sac carcinomas. The immunohistochemical data were further confirmed by Western blot analysis. In addition, the kinase Aurora B was vigorously expressed in GC-1 cells line derived from murine spermatogonia. The block of Aurora B function induced by a pharmacological inhibitor significantly reduced the growth of GC-1 cells suggesting that Aurora B is a potential therapeutic target. J. Cell. Physiol. 221: 435–439, 2009. © 2009 Wiley-Liss, Inc.     

Identification and characterization of a novel testicular germ cell-specific gene Ggnbp1

A novel gene Ggnbp1 was identified during yeast two-hybrid screening of gametogenetin protein 1 (GGN1)-interacting proteins. Ggnbp1 gene was found in mouse, rat, and human genomes but not in sequenced yeast, worms, fly, or fish genomes. Northern blotting analysis revealed that the gene was specifically expressed in the testis but not expressed in the other tissues. In situ hybridization showed that it was testicular germ cell-specific and was specifically expressed in later primary spermatocytes, meiotic cells, and early round spermatids. Western blotting analysis detected a protein of expected size in and only in the testis. By making membrane and cytosolic fractions of germ cells, we were able to show that GGNBP1 associated with the membrane. The identification and characterization of a novel germ cell-specific gene Ggnbp1 is the first step toward the defining of the functions of Ggnbp1 in spermatogenesis.     

A phase I study of intrapleural Corynebacterium parvum after complete resection of bronchogenic carcinoma

Summary Corynebacterium parvum (C. parvum) was instilled into the pleural space via the chest tube in 11 patients after curative resection for lung cancer. Doses were escalated from 20–70 mg in approximately every third patient in an attempt to determine the maximum tolerated dose. Fever and chest pain were the only toxicities encountered; severity and duration were not dose-related. Six of seven surgical stage I patients were alive and free of recurrence with a median follow-up of 2 1/2 years. A single patient developed light-chain-producing multiple myeloma 1 year after C. parvum injection.American Cancer Society Clinical Fellow     

Functional role of caspases in heat-induced testicular germ cell apoptosis

In the present study, we determined whether a pan caspase inhibitor could prevent or attenuate heat-induced germ cell apoptosis. Groups of five adult (8 wk old) C57BL/6 mice pretreated with vehicle (DMSO) or Quinoline-Val-Asp (Ome)-CH2-O-Ph (Q-VD-OPH), a new generation broad-spectrum caspase inhibitor, were exposed once to local testicular heating (43 degrees C for 15 min) and killed 6 h later. The inhibitor (40 mg/kg body weight) or vehicle was administered intraperitoneally (i.p.) 1 h before local testicular heating. Germ cell apoptosis was detected by TUNEL assay and quantitated as number of apoptotic germ cells per 100 Sertoli cells at stages XI-XII. Compared with controls (16.8 +/- 3.1), mild testicular hyperthermia within 6 h resulted in a marked activation (277.3 +/- 21.6) of germ cell apoptosis, as previously reported by us. Q-VD-OPH at this dose markedly inhibited caspase 3 activation and significantly prevented (by 67.0%) heat-induced germ cell apoptosis. Q-VD-OPH-mediated rescue of germ cells was independent of cytosolic translocation of mitochondrial cytochrome c and DIABLO. Electron microscopy further revealed normal appearance of these rescued cells. Similar protection from heat-induced germ cell apoptosis was also noted after pretreatment with minocycline, a second-generation tetracycline that effectively inhibits cytochrome c release and, in turn, caspase activation. Collectively, the present study emphasizes the role of caspases in heat-induced germ cell apoptosis.     

Role of Sertoli cells in injury-associated testicular germ cell apoptosis

This review examines experimental models of Sertoli cell injury resulting in germ cell apoptosis. Since germ cells exist in an environment created by Sertoli cells, paracrine signaling between these intimately associated cells must regulate the process of germ cell death. Germ cell apoptosis may be signaled by a decrease in Sertoli cell pro-survival factors, an increase in Sertoli cell pro-apoptotic factors, or both. The different models of Sertoli cell injury indicate that spermatogenesis is susceptible to disruption, and that targeting critical Sertoli cell functions can lead to rapid and massive germ cell death.     

Clinical trials with oncolytic reovirus: Moving beyond phase I into combinations with standard therapeutics

It is time for those working on oncolytic viruses to take stock of the status of the field. We now have at our disposal an array of potential therapeutic agents, and are beginning to conduct early-phase clinical trials in patients with relapsed/metastatic cancers. By drawing on lessons learned during the development of other biological therapies, such as monoclonal antibodies and targeted small molecule inhibitors, we are now in a position to chart the course of the next wave of trials that will go beyond the phase I studies of safety and feasibility. In this article we review our approach to the development of oncolytic viruses as cancer therapeutics. In doing so, we emphasise the fact that this process is modular and involves multiple iterative steps between the laboratory and the clinic. Ultimately, at least in the medium term, the future of oncolytic virotherapy lies in combination regimens with standard anti-cancer agents such as radiation and chemotherapy.