Clinical trials in cancer

Published on 09/04/2015 by admin

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25 Clinical trials in cancer

TV. Ajithkumar, HM. Hatcher

Introduction

Research and development is an important aspect of cancer management. Cancer drugs have to undergo rigorous evaluation before approval for clinical use. However, technological developments, such as a new surgical or radiotherapy technique, often do not undergo such complex procedures. They are approved if they are proven not to be harmful and they meet the appropriate quality control measures. In fact, many of the new radiotherapy techniques are approved for clinical use without any robust comparative data on the clinical efficacy.

Traditionally the clinical efficacy of drugs is studied through several phases of clinical trial after initial pre clinical studies. Each of these trials is aimed at generating sufficient evidence on the safety, dosing, efficacy and feasibility of use. This process is expensive and time consuming (Figure 25.1), which often leads to very high costs of effective treatments preventing their general use and often prompting policy makers to adopt rationing strategies based on cost-effectiveness.

image

Figure 25.1 Process of drug discovery.

New methods of trial design are constantly evolving, both to address the length of time to take a drug from development into practice and to answer questions which apply to newer drugs. For example targeted treatments may incorporate an assessment of the efficiency in affecting that target or in measuring the sub-population who may benefit most from an effective but expensive treatment.

Preclinical stage

The preclinical stage involves screening of potential agents and their testing on animal models. Initial testing may be performed on cell lines or tumour explants before moving to an animal model. Preclinical studies establish that the potential agent is not lethal, safe to use and that there is some indication of activity in the medical condition studied.

Clinical trials

Phase I

Phase I studies are the first human application of a new drug or drug combination. The aim of this phase is to establish the dose and schedule of the experimental agent for efficacy testing in a phase II study based on the maximum tolerated dose (MTD) of the new agent. Phase I studies are typically single arm, open label, sequential studies that include patients with good performance status (PS 0-2) and for whom there is no standard treatment option. The MTD is determined by progressively increasing the dose in small cohorts until the dose limiting toxicity (DLT) is achieved. DLT is defined as grade 4 non-haematological toxicity or a grade 3 or more haematological toxicity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) (p. 38). MTD dose is defined as the dose below the level the DLT is met or the dose level at which the DLT is seen. There are a number of components to the design of a phase I study and there are various dose escalation methods to find out the maximum tolerated dose (Box 25.1). Phase I trial design is a specialized topic and is beyond the scope of this chapter (see Further reading).

Box 25.1
Components of phase I study design and methods of dose escalation

Design components of a phase I study

• Starting dose – usually image of the animal dose
• Dose increment
• Dose escalation method
• Number of patients per dose level
• Specification of dose-limiting-toxicity (DLT)
• Target toxicity level
• Definition of maximum tolerated dose (MTD)
• Recommended dose and patient selection for phase II trial

Dose escalation methods

• Rule-based design – based on no prior assumption of the dose-toxicity curve and allows dose escalation and de-escalation of dose with diminishing fractions of preceding dose depending on the absence or presence of severe toxicity in the previous cohort of patients treated.

• 3 + 3 design – most frequently used method. The classical assumption is toxicity increases with dose. It starts with a cohort of three patients and subsequent cohorts are treated at increasing level.
• Accelerated titration design
• Pharmacologically guided dose escalation

• Model based designs – are complex and use statistical models that actively seek a dose level that produces a pre-specified probability of dose toxicity using dose-toxicity curve calculated from all enrolled patients. Examples include:

• Continual reassessment method
• Escalation with overdose control
• Designs that use time-to-event endpoints
• Designs that use toxicity and efficacy as endpoints

Phase II

Phase II studies are done to assess the activity, safety and feasibility of new drug. There are many options for the design of a phase II trial. A phase II study can either be completed in a single stage or as two stages. In two stage study, the first stage is to evaluate the treatment efficacy (phase IIA) and in the second stage (phase IIB) is to identify promising agents to send to phase III for additional evaluation. Phase IIA design is to test short-term tumour response, whereas phase IIB design compares two or more regimes which have demonstrated some initial efficacy.

Randomized phase II trials are increasingly being used in cancer. These studies randomize patients to new treatment or standard treatment or to a number of new treatments. Randomization is to ensure a similar patient population in each group and not to do a statistical test to compare treatment groups. These trials are not adequately powered to do this and this is the purpose of a phase III trial. Treatment outcomes are ranked according to activity, safety and feasibility to take the drug forward to phase III study.

Phase III

The aim of a phase III study (also called randomized controlled trials) is to establish the efficacy of a new treatment compared with an existing standard treatment or observation/placebo where there is no standard treatment. It also helps to establish whether the new treatment has less toxicity compared with the standard treatment. Randomization reduces bias by balancing the characteristics of study population. Design of a phase III study is complex (Box 25.2). It requires large patient numbers to ensure adequate statistical power which frequently necessitates international cooperation and is very costly. Modern trials are incorporating translational studies to try to target the new drug to the population most likely to benefit. This may affect the inclusion criteria e.g. presence of an EGFR mutation for entry into a trial for an antibody against the EGFR receptor.

Box 25.2
Phase III study

• Identify a select group of patients and define eligibility criteria.
• Identify meaningful and reliable outcome measures (endpoints).
• Randomization process and stratification of study group.
• Statistical considerations – sample size based on expected benefit, method of data analysis etc.
• Phase III study designs:

• Parallel-group design – patients are randomized to two or more treatment group.
• Cross-over design – patients will receive both the new and control treatment.
• Factorial design – includes double randomization so that the same study group is used to answer two research questions.
• Adaptive design – starts with a number of new treatments, and the treatments found to be inactive can be dropped.
• Discontinuation design – only patients who respond to treatment remain in the trial and then randomized to a continuation or discontinuation of treatment.

Phase IV studies

Phase IV studies are post-marketing studies done to learn more about the side effects, safety, and long term risk-benefits of the drug in a wider context than in clinical trial. The various study designs are given in Box 25.3.

Box 25.3
Phase IV study designs

• Post-phase III ‘continuation’ trial – is done to identify the long-term efficacy, common dose-related adverse effects (AEs) and reasons for discontinuation.
• Phase V ‘naturalistic’ trial – done to analyse effectiveness and common dose-related AEs and also can assess patient reported outcomes.
• Prospective cohort design – to assess long-term effectiveness in routine practice (>2 years)
• Retrospective cohort – rapid study of a representative patient sample, often poor quality.
• Case control – to identify rare AEs.
• Large computerized databases and record linkage – to identify rare idiosyncratic AEs and to correlate AEs with laboratory value and prescribing data. This design needs >10,000 patients.

Ethics and good clinical practice

In order to protect patient safety and to ensure the reliability of any trial data all trials should be conducted according to good clinical practice (GCP) which has been developed according to international guidelines. Part of this process means that the trials must be peer reviewed and reviewed by an ethics committee to ensure that the trial seems appropriate, safe and adheres to these international guidelines (International Conference on Harmonization ICH). These have now been incorporated into the 2004 Medicines for Human Use (Clinical Trials) Regulations and the recent EU Directive on Good Clinical Practice, which apply to all trials within Europe. Similar practices have also been adopted in North America.

Recruiting patients into a clinical trial

A number of issues need to be considered when recruiting patients into clinical trial ranging from explaining the trial itself to giving a realistic picture of the potential risks and benefits. Consent is a complex process which does not simply refer to the signing of a form but with good clinical practice has to ensure that the patient has adequately understood what is involved and has given their consent freely. It should be made clear that consent can be withdrawn at any time without affecting their future care to avoid pressurizing already vulnerable individuals into believing they have to agree to please their medical carers. Good clinical practice also states that patients should be given adequate time to reflect on the information received and be able to discuss with family, friends or their general practitioner. Key areas to be covered when discussing a trial with a patient are listed in Box 25.4.

Box 25.4
Cancer clinical trials – what to tell the patient?

• Type of study and objective – should be clear and properly explained to patients. This is important to get a right balance in the beginning in the minds of patients and their families. They should not be left with an impression that either they are simply ‘guinea pigs’ or the treatment is going to give them an imminent cure.

• Phase I studies – is to decide toxicity and maximum tolerated dose and only a small percentage is expected to respond. Classically less than 5% of patients would benefit. This has improved by a few percent with targeted treatments.
• Phase II studies – is to test the activity of a new drug for a particular type of cancer.
• Phase III studies – standard treatment is compared with a new treatment and it may take years to show any benefit or even, harm.

• Purpose of clinical trials – it is important to tell patients that though, in many situations we have standard treatments, most of the treatments may not be the best. Hence there is a continuous attempt to improve the success of existing treatment with new clinical studies.
• All the studies discussed with patients have undergone rigorous ethical procedures before approval to ensure participants’ safety and to safeguard their human rights.
• Patients have the right to decline to participate which does not compromise future care and they can withdraw from the trial at any point without affecting their future treatment.
• Need to explain the trial process – such as type of study, cannot choose the treatment in phase III study, need for frequent tests, follow-up appointments, complete a number of forms etc.
• Funding of trial – even if a trial is funded by pharmaceutical companies, the trial process is done according to national/international regulations. There is no financial incentive for the doctors or other healthcare professionals enrolling patients into the study.

Advances in clinical trials

The current process of cancer clinical trial design is costly and lengthy. Studies show that the overall cost of introduction of a drug to clinical use is approximately 1 billion dollars and that for a target molecule is 1.4 billion dollars. This process also takes an average of 12–14 years. The phase 0 trial design has been proposed as a solution (Box 25.5). This may expedite the identification of new target molecules and bring potentially active molecules into routine clinical use faster.

Box 25.5
Phase 0 trial

Phase 0 trial – are first-in-human trials with no therapeutic or diagnostic intent, in a limited number of patients (<15) using subtherapeutic doses over a limited period to establish a drug-target effect. (See Figure 25.2). These are established as means to address the pitfalls of phase I–III studies and to expedite the development of new investigational targeted agents. These methods may also be included within a classical phase I trial.

These studies help to:

• Study whether the investigational drug affects the alleged target in the desired manner.
• Provide further pharmacokinetic (PK) and pharmacodynamic (PD) data.
• Validate biomarker assays for target modulation effects.
• Select most promising molecule based further evaluations using very sensitive imaging technologies.

Under these studies, dose escalation is allowed provided it is to modulate the target, not to determine MTD. Phase 0 trials provide critical human PK and PD data which help to directly proceed to phase I/II study or a combination with an established agent, thus expediting the development of agents or combination of agents likely to have clinical activity. Using the new design, the National Cancer Institute evaluated the effect of a PARP inhibitor, ABT 888 in tumour tissue which led to a phase I study of ABT-888 with chemotherapy. The phase 0 study met its primary objective within 5 months, even before any of the planned phase I study started patient accrual (see Figure 25.2).

image

Figure 25.2 Phases of the clinical trials.

Other advances include development of novel trial designs or the use of alternative statistical methods. Translational studies are now integrating biological questions with clinical developments. In terms of drugs, trials are now moving on to examine the best way to combine novel agents, either with other novel agents or chemotherapy.

Oncology remains one of the most evidence-based specialties at the forefront of clinical trial development.

Further reading

Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst. 2009;101(10):708-720.

Kummar S, Doroshow JH, Tomaszewski, et al. Phase 0 clinical trials: recommendations from the Task Force on Methodology for the Development of Innovative Cancer Therapies. Eur J Cancer. 2009;45(5):741-746.

Eisenhauer EA, O’Dwyer PJ, Christian M, Humphrey JS. Phase I clinical trial design in cancer drug development. J Clin Oncol. 2000;18:684-692.

Lee JJ, Feng L. Randomized phase II designs in cancer clinical trials: current status and future directions. J Clin Oncol. 2005;23(19):4450-4457.

Green S, Bendetti J, Crowley J. Clinical Trials in Oncology, Second edition. London: Chapman and Hall; 2003.

Eisenhauer EA, Twelves C, Buyse M. Phase I cancer clinical trials. Oxford: Oxford University Press; 2006.

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