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Cancer clinical trial phases and design

Introduction to cancer clinical trials

Although the percentage of patients with cancer who are enrolled in clinical trials is estimated to be <5% (with some analyses suggesting ~7% to 16%, depending on setting), such trials represent an important link between cancer research and clinical practice.1,2 Clinical trials serve as the foundation for evidence-based medicine by addressing specific clinical questions that may lead to improvements in current clinical practice.3

Phases of clinical development

Investigating the efficacy and safety of an agent or combination of agents through clinical trials involves multiple phases of development, beginning with smaller Phase I trials and culminating in larger, randomized Phase III trials. Phase IV trials may also be conducted to gather additional information.4-6

Clinical trials by phase5-7

Trial phase

Definition

I Initial trial of a drug in humans for dosing, safety, and early efficacy information (20-80 patients*)
II Subsequent trial of a drug's safety and efficacy in a particular disease setting (100-300 patients*)
III Larger trial comparing a drug with best available therapy to confirm efficacy and safety; often used for drug approval (100-3000 patients*)
IV Trial conducted after US Food and Drug Administration (FDA) approval to gain additional information about the drug's risks and benefits. Phase IV studies can range in study size, from a few hundred to a few thousand participants.

*The patient numbers cited here apply to clinical trials in general.

Design of clinical trials

When designing a clinical trial, it is important to define a number of parameters in order to generate meaningful results. These parameters include5:

  • Patient population to be studied
  • Treatment(s) to be investigated
  • Endpoints
  • How the trial will be conducted (eg, randomized vs nonrandomized)

When selecting the patient population to be studied in a clinical trial, investigators should include patients who are likely to benefit from the intervention being tested.8 The population should also be selected such that the results of the trial can be generalized to patients in clinical practice. Overall, the more diverse the patient population, the more generalizable the results may be to the wider patient population.9

In order to study a patient population of the appropriate disease state and level of diversity, investigators define criteria that determine whether or not a patient is eligible for a trial. Inclusion and exclusion criteria can include patient characteristics (eg, age) as well as disease- and treatment-specific characteristics (eg, number and type of prior therapies).9

Use of controls in a clinical trial

In controlled trials—most Phase III and some Phase II trials—the agent or regimen being investigated is compared to a control. The control may be either a placebo (if no effective therapies are available for the disease being studied) or a standard treatment—one in wide use and considered effective at the time the trial is designed.10,11

Selecting primary and secondary endpoints

Efficacy and safety in clinical trials are measured by means of certain predetermined endpoints, or outcomes, that the trial is designed to evaluate.2 These may include clinical endpoints, such as survival, as well as surrogate endpoints, which are expected to predict for a clinical outcome.8

The primary endpoint is the key measure from which clinical benefit is assessed. The primary endpoint selected by the investigators impacts the number of patients needed for the trial and must be determined before the trial is initiated.12 Secondary endpoints are other outcomes that provide additional and potentially valuable information about the treatment being tested.8 The trial protocol should prespecify secondary endpoints to increase the likelihood that statistical analysis of those endpoints will be valid.8

Selection of the primary endpoint in a clinical trial requires consideration of several factors.

  • What is the most clinically meaningful measure of benefit that could guide treatment decision making in this disease state and patient population?
  • Can the trial be conducted in a reasonable time frame?
    • Some endpoints require longer follow-up than others, lengthening the time required to complete trials and obtain meaningful results13
  • Can a sufficient number of patients be recruited to complete the trial?
    • Some endpoints necessitate larger trials in order to demonstrate statistically significant differences between arms, potentially creating difficulties in recruitment13

Conducting the trial

When the trial population, treatment, and endpoints have been identified and defined, the trial design is not yet complete. In Phase III and some Phase II trials, the patient population may be randomized and stratified. The gold standard in clinical research is a scientifically rigorous, randomized, and well-controlled trial.8

Components of clinical trial design9

Component

Definition

Purpose

Randomization Patients are randomly assigned to one of the trial arms (experimental or control) Reduces investigator and sample bias
Stratification

Patients are sorted by characteristics (eg, extent of disease) that could influence the outcome of the trial

  • Creates randomized groups that are comparable in prognosis
Allows investigators to examine the effects of the treatment in patient subgroups

Efficacy endpoints in oncology clinical trials

The following table shows a number of efficacy endpoints. Each of these endpoints is associated with certain advantages and limitations. Although the endpoint definitions provided here are from FDA guidance, please note that individual clinical trials may use different definitions.

Commonly used efficacy endpoints in oncology clinical trials: advantages and limitations14

Endpoints

Definition

Advantages

Limitations

Overall survival (OS)

Time from randomization* until death from any cause
  • Universally accepted measure of direct benefit
  • Easily and precisely measured
  • May require a larger trial population and longer follow-up to show statistical difference between groups
  • May be affected by crossover or subsequent therapies
  • Includes deaths unrelated to cancer
Progression-free survival (PFS)
Time from randomization* until disease progression or death
  • Requires small sample size and shorter follow-up time compared with OS
  • Includes measurement of stable disease (SD)
  • Not affected by crossover or subsequent therapies
  • Generally based on objective and quantitative assessment
  • Validation as a surrogate for survival can be difficult in some treatment settings
  • Not precisely measured (ie, measurement may be subject to bias)
  • Definition may vary among trials
  • Requires frequent radiologic or other assessments
  • Requires balanced timing of assessment among treatment arms
Time to progression (TTP)
Time from randomization* until objective tumor progression; does not include deaths
Time to treatment failure (TTF)
Time from randomization* to discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death
  • Useful in settings in which toxicity is potentially as serious as disease progression (eg, allogeneic stem cell transplant)
  • Does not adequately distinguish efficacy from other variables, such as toxicity
Event-free survival (EFS)
Time from randomization* to disease progression, death, or discontinuation of treatment for any reason (eg, toxicity, patient preference, or initiation of a new treatment without documented progression)
  • Similar to PFS; may be useful in evaluation of highly toxic therapies

  • Initiation of next therapy is subjective. Generally not encouraged by regulatory agencies because it combines efficacy, toxicity, and patient withdrawal

Time to next treatment (TTNT)
Time from end of primary treatment to institution of next therapy
  • For incurable diseases, may provide an endpoint meaningful to patients

  • Not commonly used as a primary endpoint
  • Subject to variability in practice patterns
Objective response rate (ORR)
Proportion of patients with reduction in tumor burden of a predefined amount
  • Can be assessed in single-arm trials
  • Requires a smaller population and can be assessed earlier, compared with survival trials
  • Effect is attributable directly to the drug, not the natural history of the disease
  • Not a comprehensive measure of drug activity

*Not all trials are randomized. In nonrandomized trials, time from study enrollment is commonly used.

Safety endpoints in cancer clinical trials

Toxicity criteria in oncology/hematology clinical trials

To standardize the reporting of adverse events in clinical trials, the National Cancer Institute (NCI) has developed Common Terminology Criteria for Adverse Events (NCI CTCAE). The NCI CTCAE was most recently updated in November 2017 (version 5.0). Clinical trials that began earlier than this date may use earlier versions of the NCI CTCAE when reporting adverse events. According to the NCI CTCAE, adverse events are reported by grade (level of severity) on a scale of 1 to 5. Generally, the descriptions follow the guidelines below.15,16

NCI CTCAE definitions of severity for adverse events16

Grade

Degree of severity

1 Mild, with mild or no symptoms; no interventions required
2 Moderate; minimal intervention indicated; some limitation of activities
3 Severe but not life-threatening; hospitalization required; limitation of patient's ability to care for him/herself
4 Life-threatening; urgent intervention required
5 Death related to adverse event

Common adverse events by grade16

The following table shows NCI CTCAE grades for some adverse events commonly observed in clinical trials in oncology/hematology. This list is not all-inclusive; please consult the NCI CTCAE for a full list of adverse event criteria.

Adverse event

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Cytopenias
Anemia Hgb <LLN to 10.0 g/dL Hgb <10.0 g/dL to 8.0 g/dL Hgb <8.0 g/dL; transfusion indicated Life-threatening consequences; urgent intervention indicated Death
Neutropenia Neutrophils <LLN to 1500/mm3 <1500/mm3 to 1000/mm3 <1000/mm3 to 500/mm3 <500/mm3 N/A
Thrombocytopenia Platelets <LLN to 75,000/mm3 <75,000/mm3 to 50,000/mm3 <50,000/mm3 to 25,000/mm3 <25,000/mm3 N/A
Hepatic
Hepatic failure N/A N/A Asterixis; mild encephalopathy; limitation of self-care Moderate to severe encephalopathy; coma; life-threatening consequences Death
Renal
Creatinine increase >ULN to 1.5 × ULN >1.5 to 3.0 × baseline; >1.5 to 3.0 × ULN >3.0 × baseline; >3.0 to 6.0 × ULN >6.0 × ULN N/A
Other
Fatigue Relieved by rest Not relieved by rest; limitation of instrumental ADL Not relieved by rest; limitation of self-care ADL N/A N/A
Febrile neutropenia N/A N/A ANC <1000/mm3 with single temperature reading >38.3°C (101.0°F) or sustained temperature ≥38.0°C (100.4°F) for >1 hour Life-threatening consequences; urgent intervention indicated Death
Fever 38.0°C to 39.0°C (100.4°F to 102.2°F) >39.0°C to 40.0°C (102.3°F to 104.0°F) >40.0°C (>104.0°F), lasting ≤24 hours >40.0°C (>104.0°F), lasting >24 hours Death
Infections and infestations Asymptomatic or mild symptoms; observations only; intervention not indicated Moderate symptoms; minimal intervention indicated; limitation of instrumental ADL Severe or medically significant but not immediately life threatening; hospitalization indicated; limitation of self-care ADL Life-threatening consequences; urgent intervention indicated Death
Infusion reactions Mild, transient reaction; interruption/intervention not indicated Interruption indicated, but responds promptly to symptomatic treatment; prophylactic medications indicated for ≤24 hours Prolonged (not rapidly responsive to treatment and/or infusion interruption); recurrence of symptoms following initial improvement; hospitalization indicated Life-threatening consequences; urgent intervention indicated Death

ADL=activities of daily living; ANC=absolute neutrophil count; LLN=lower limit of normal; ULN=upper limit of normal.

    • Unger JM, Hershman DL, Albain KS, et al. Patient income level and cancer clinical trial participation. J Clin Oncol. 2013;31(5):536-542.

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