Novel Designs of Early Phase Trials for Cancer Therapeutics

States

Preface

Impressive advances in the field of cancer therapeutics beginning at the turn of the last century have yielded a rapidly growing number of effective anticancer therapies with novel mechanisms of action. For example, the advent of targeted molecular therapeutics designed to selectively impact specific tumor types, and, more recently, immunotherapies that harness the power of the body’s own immune system to attack malignant cells have dramatically altered the therapeutic landscape. These changes have directly impacted our approach to early-phase clinical trials and, to a large extent, have upended many traditional strategies in drug development that were executed unchanged for many decades.

Nowhere is this tectonic shift in strategic thinking felt more acutely than in the arena of first-in-human and first-in-cancer patient clinical trials. The infusion of scientific thinking and translational research that now permeates early-phase clinical trial designs in oncology is a welcome step forward. Clinicians and other early-phase clinical trial stakeholders must be well versed in molecularly profiling, biomarkers, and translational research, and they can no long rely upon simplistic, algorithmic, study designs that dominated the field of oncology drug development for so many decades.

In the modern era the early-phase oncology clinical trialist must now design and implement studies of greater complexity than in yesteryear, but the potential payoffs in terms of speed and efficiency are huge. In the following 13 chapters, leading experts in the field of early-phase clinical trials provide a clear and distinct road map for navigating these shifting paradigms. Included are biostatistical, operational and regulatory perspectives as well as discussions on dose selection, precision medicine, molecular profiling, and on the rational integration of biomarkers into early-phase studies. Additional perspectives on specific classes of new cancer therapies of growing importance in cancer drug development include overviews of immuno-oncology agents and cell-based therapies, and the impact these are having on early-phase clinical trials. Finally, the role of imaging, drug combinations, and patient reported outcomes are discussed.

Although the range and scope of this book are broad, we, nonetheless, hope that the careful reader will be well prepared to meet the considerable challenges of bringing the next wave of transformational therapies to cancer patients everywhere.

Chapter 1

Changing Landscape of Early Phase Clinical Trials

Beyond the Horizon

Khanh Do¹, Chris H. Takimoto² and Shivaani Kummar³,    ¹Dana-Farber Cancer Institute, Boston, MA, United States,    ²Forty Seven, Inc., Menlo Park, CA, United States,    ³Stanford University, Palo Alto, CA, United States

Abstract

The field of oncology has evolved dramatically over the past 60 years. The growing complexity of clinical trials presents a number of logistical challenges, driving the escalating costs of drug development. As trial designs evolve to meet the pace of early drug development, financial considerations need to be taken into account in addition to safety and efficacy.

Keywords

Drug approval; trial design; molecular targeted agents; precision medicine

1.1 Historical Perspective

The field of drug development has evolved dramatically over the past 60 years, beginning with the first law put in place to protect against misbranding and adulteration of foods, drinks, and drugs—the 1906 Pure Food and Drugs Act. It would take an additional 30 years before the 1938 Food, Drug and Cosmetic Act was passed, which required premarket proof of safety before a drug could go on the market. This was enacted in response to several deaths that occurred when the elixir sulfanilamide, which contained a solvent analog of antifreeze, was marketed as an antiinfective. More recently, 2012 marked the 50-year anniversary of the 1962 Kefauver-Harris Amendment to the Food, Drug and Cosmetic Act that required drug manufacturers to provide proof of efficacy and safety before a drug application could be approved. This landmark piece of legislation was enacted in response to birth defects arising from the use of thalidomide, which at the time was marketed as a sedative and widely prescribed in Europe and Canada. Shortly after this, the FDA formalized the drug review process, delineating each step and phase in the development of investigational agents. Informed consent would now be required of participants in clinical trials and reporting of adverse drug reactions to the FDA would be mandated. Together with increasing legislative hurdles came longer review processes before a drug could come to market. Currently, in the field of oncology, the likelihood of FDA approval for drugs entering clinical development in Phase 1 studies is estimated at 6.7%, the lowest of all investigational drugs reviewed by the FDA during the period of January 1, 2003 to December 31, 2011 [1]. In response to increasing pressure from patients, patient advocates, and Congress to improve patient access to investigational drugs, the FDA Safety and Innovation Act of 2012 (FDASIA) was passed, which established two modifications to the Food, Drug and Cosmetic Act. First, this Act allowed for a new breakthrough therapy designation for investigational drugs. Second, in an effort to expedite the development and review of drugs intended to treat a serious condition and have preliminary clinical evidence indicating that the drug demonstrates substantial improvement over available therapy on a clinically significant endpoint it allowed for expansion of the statute regarding accelerated approval of investigational agents [2].

Historically, the majority of oncology drugs in development prior to the 1990s were cytotoxic agents. The principles of early drug development initially focused on defining the highest tolerable dose based on observations of direct correlation between dose and cell killing of cytotoxic agents [3]. Phase 1 trials accordingly serve as the cornerstone of drug development, shepherding the transition from the preclinical to clinical stage, testing the safe and maximum tolerable dose (MTD) of a drug in order to define the recommended dose to be carried forward in Phase 2 trials. Rule-based designs have traditionally been the most accepted and widely used of early phase clinical trial designs [4]. In particular, the 3 + 3 design remains the prevailing method used in Phase 1 clinical trial design. The structure of this design assumes that toxicity increases with dose and involves enrollment of three-patient cohorts in escalating preestablished dose levels with the starting dose extrapolated from animal toxicology data. Escalation proceeds until two patients experience dose-limiting toxicities (DLT) in a cohort of three to six patients, whereupon the dose level below this toxic dose level is designated the recommended dose for Phase 2 trials (RP2D). While this design is simple to implement and allows for gathering of data to establish PK-toxicity curves, critics have argued that it requires an excessive number of escalation steps, which prolongs the time required to reach MTD. This also increases the exposure of a disproportionate number of patients to subtherapeutic doses [5–7].

Over the past decade and a half, evolving knowledge of the human genome and molecular pathways has resulted in an exponential growth in the development of molecularly targeted agents (MTAs). Unlike cytotoxic agents, MTAs can demonstrate delayed or cumulative low-grade toxicities that may not be captured within a predefined DLT-assessment window. Additionally, dose may not directly correlate with toxicity or efficacy, depending on the mechanism of action of the agent and the exposures required for target engagement. In response to these challenges, newer strategies for dose escalation have included accelerated titration designs and model-based designs. Accelerated titration designs have the advantage of allowing for rapid dose escalation in single patient cohorts, as well as intrapatient dose escalation, thereby minimizing the proportion of patients potentially treated at subtherapeutic doses [8]. An analysis of 270 published Phase 1 studies from 1997 to 2008 showed that studies using accelerated titration designs resulted in the evaluation of a greater number of dose levels (7 vs 5, P=0.0001) and reduced numbers of patients treated at doses below the RP2D (46% vs 56%, P=0.0001) [9]. In accelerated titration designs, dose escalations occur in increments of either 40% or 100% until a DLT or two moderate toxicities are observed, whereupon the dose escalation and stopping rules revert to the 3 + 3 design. Some of these accelerated design have the drawback of allowing for intrapatient dose escalation with regard to delineating toxicity data. Specifically, a single patient may contribute data for more than one dose level and delayed toxicities may be masked by presumed cumulative toxicities. Additionally, analyses comparing 3 + 3 design and accelerated titration designs have not shown convincing data that accelerated titration designs shorten the overall accrual time nor increase the efficacy of Phase 1 trials [9]. Other rule-based designs have been proposed, including the isotonic regression model [10], improvements on the original up-and-down design [11], accelerated biased coin up-and-down design [12], and the rolling six design [13]. Attempts have also been made to propose the use of pharmacologic data to guide dose escalation, however, the logistical practicality of this model, requiring real-time patient pharmacokinetic (PK) data and variability in the PKs between patients and challenges in extrapolation of plasma exposure data from one patient to the next, has limited the widespread acceptance of this model [14].

Alternatively, model-based designs use mathematical modeling based on Bayesian probability statistics to predict a dose level, which would produce a prespecified probability of DLT using real-time cumulative toxicity data from all enrolled patients, thereby producing a dose-toxicity probability curve that allows for computation of the optimal safe dose for the next cohort of patients. The continual reassessment method (CRM) was the first Bayesian model-based method to be adopted in Phase 1 trial designs [15]. In this design, the estimation of probability of encountering a DLT is updated for each new patient entering the study, allowing for multiple dose escalations and de-escalations, until the prespecified probability of DLT at the estimated MTD level is achieved. Multiple modifications of the original CRM design have been developed with the aim of enhancing safety, including restricting dose escalation to one level at a time [16], allowing for treatment of several patients at the same dose level [17], expanding the cohort of patients at the RP2D [18,19], and implementing overdose control in an effort to limit exposing patients to potentially higher toxic doses [20,21]. More recently, additional modifications of the CRM model have been proposed to account for low-grade chronic toxicities often seen with MTAs, e.g., using ordinal toxicity outcomes [22–26] and late-onset or cumulative toxicities using a time-to-event continual reassessment method (TITE-CRM) [27]. A practical challenge with the implementation of model-based approaches is the need for real-time biostatistical support, which may not be readily available at all institutions.

1.2 Current Trends

With evolving selectivity of each generation of MTAs, the biologic effective dose has emerged as the more relevant endpoint in early phase clinical trials. While toxicity remains an important endpoint, the highly selective nature of MTAs results in widening of the dose-toxicity curves and a RP2D that may be well below the MTD. Increasingly, more trials are now incorporating mandated biopsies to further explore the pharmacodynamic (PD) effects of receptor occupancy and target inhibition in tumors in an effort to characterize the biologically active dose. A greater emphasis is also being placed on characterization of the PK–PD relationship to guide the decision on the declaration of the RP2D. In line with this shift in paradigm in oncology drug development, various novel approaches including the TriCRM method have been proposed, to address the incorporation of toxicity and efficacy data into the estimation of the biologically effective dose [28]. In response to the complexity of incorporating PD endpoints in early clinical trial modeling, the Task Force on Methodology for the Development of Innovative Cancer Therapies was developed to provide guidance on dose escalation methods specific for molecularly targeted compounds [29]. The Task Force acknowledged the importance of establishing the biologically active dose range for future development of targeted agent combinations where overlapping toxicities have the potential to limit the tolerability of administering both agents in full doses. With increasing emphasis on PD-driven trials, more attention has been drawn to the challenges of tissue acquisition and assay performance. In an effort to address the call for development of more sensitive and specific biomarkers and enhance the efficiency of investigational drug development, the National Cancer Institute Investigational Drug Steering Committee and Biomarker Task Force was charged with the development of guidelines for the incorporation of biomarker studies in early clinical trials of novel agents and set the standards for assay performance [30]. Although the evaluation of safety remains the primary goal of early clinical trials, assessment of efficacy and PK/PD parameters are emerging as the key objectives in the new era of drug development where advances in next-generation sequencing can provide rapid genomic mutation profiles of tumors.

Phase 1 trials are increasingly being used as a platform to explore predictive biomarkers and to enable early evaluation of antitumor efficacy by enriching subsets of patients selected according to molecular criteria who are expected to most likely respond to a particular MTA, focusing on ever smaller subsets of patients. This paradigm shift in oncology drug development has culminated in the precision-medicine based approach where the selection of patients is limited to certain mutations of interest or presence of target, based on the mechanism of action of the agent being studied. The ability to identify and treat specific subsets of patients based on presence of a molecular target has increased the complexity of early phase trials and has necessitated multicenter collaborations.

These patient enrichment strategies have been utilized in order to enroll fewer patients, demonstrate larger treatment effects, and expedite the drug development process. However, apart from identifying the mutations of interest and designing agents that effectively target these alterations; this approach presents the logistical challenge of patient selection and timely enrollment. The clinical trial demonstrating high response rate and clinical benefit for crizotinib in patients with nonsmall cell lung cancer carrying the EML4-ALK rearrangement screened approximately 1500 tumor samples to enroll the required 82 patients [31]. The need to obtain archival or fresh tumor tissue for screening, laboratory infrastructure to perform adequately qualified assays in a clinically relevant time frame for patient selection, and treatment of selected patients requires an infrastructure that allows the study to be conducted in multiple centers with adequate oversight. To aid in overcoming potential barriers to fulfilling these requirements, the Moonshot Initiative was announced and tasked with the mission of accelerating cancer discovery by breaking down administrative and financial barriers, increasing data sharing across research sectors, and enhancing collaboration between the public and private sectors [32].

Together, the advent of MTAs and concept of precision medicine has resulted in Phase 1 trials evolving from relatively simple safety and dose finding studies to larger trials with proof-of-mechanism, proof-of-concept, and recently, registration intent. The desire to expedite development of promising anticancer therapeutics has resulted in the so-called seamless Phase 1 design with an initial dose escalation phase followed by multi-arm expansion cohorts exploring dose, schedule, and efficacy in various histologies. Phase 1 trials have therefore transformed from small 20 to 30 patient trials, to trials enrolling a few hundred to over a 1000 patients. This is exemplified by the Phase 1 trial of pembrolizumab, an anti-programmed cell death protein-1 antibody. The initial dose escalation phase of this trial enrolled a total of 10 patients, with 13 patients participating in the intrapatient dose escalation portion of the first-in-human (FIH) trial [33]. Over 2.5 years and after multiple amendments, the patient number treated on this FIH trial expanded to >1100 enrolled in nine distinct expansion cohorts [34].

The growing complexity of clinical trials presents a number of logistical challenges. In an effort to expedite patient accrual, industry-sponsored studies now commonly utilize multiple participating centers in order to fill slots on a competitive basis and often depend on contract research organizations to oversee conduct of the trial across multiple sites and meet timelines. Additionally, as trials become more PD-centric, the costs of supporting these assays are major financial considerations for the conduct of trials. Currently, the median number of procedures performed per trial has increased by 57% (105.9 procedures in the period between 2000 and 2003 to 166.6 procedures between 2008 and 2011), with a 211% increase in the median number of case report forms per protocol comparing the same time periods [35]. The increasing complexity and larger size of clinical trials has also contributed to the escalating costs of drug development, going from 1 billion dollars in the decade of the 1990s to 2.6 billion dollars over the past decade. As trial designs evolve to meet the pace of early drug development, these financial considerations need to be taken into account during the initial stages of development. It is therefore likely that we can expect increasing legislation in the years to come, to maintain oversight of multicenter trials in a continuing effort to monitor safety and efficacy.

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Chapter 2

Requirements for Filing an Investigational New Drug Application

R. Rita Misra¹ and Bhanumati Ramineni²,    ¹National Cancer Institute, Frederick, MD, United States,    ²National Institutes of Health, Rockville, MD, United States

Abstract

In the United States, Federal law requires that a drug or biologic product be the subject of an approved marketing application before it is transported across state lines. Before the sponsor (the individual or entity that is responsible) for the clinical investigation of a drug ships the drug to investigators in another state, they must seek exemption from that legal requirement. An Investigational New Drug application, filed with the US Food and Drug Administration is the means through which the sponsor obtains such an exemption.

Keywords

Clinical investigation; Investigational New Drug; investigator; sponsor

In the United States, Federal law requires that a drug or biologic product be the subject of an approved marketing application before it is transported across state lines. Before the sponsor (the individual or entity that is responsible) for the clinical investigation of a drug ships the drug to investigators in another state, they must seek exemption from that legal requirement. An Investigational New Drug (IND) application, filed with the US Food and Drug Administration (FDA) is the means through which the sponsor obtains such an