Dose Limiting Toxicity (DLT) and Common Toxicity Criteria (CTC) / Common Terminology Criteria for Adverse Events (CTCAE)

For the early clinical phase trials, especially first-in-man oncology studies, the major objective is usually to identify a safe dose, such as the MTD (maximal tolerated dose),  the highest dose that can be given with acceptable toxicity, and establish the safety profile. To identify the MTD, dose escalation studies are usually conducted. The determination of the MTD is based on the occurrence of the DLT (dose limiting toxicity), Dose-Limiting toxicity is defined to be a toxicity that prevents further administration of the agent at that dose level. One of the criteria for FDA to approve a Breakthrough Therapy designation for an experimental drug is that the experimental drug can significantly improve safety profile compared to available therapy (e.g., less dose-limiting toxicity for an oncology agent), with evidence of similar efficacy.

The choice of DLT (dose-limiting toxicity) may vary from study to study based on the natural history of the disease and the level of toxicity expected from standard therapy. For example, one might accept a greater degree of toxicity for a patient with end-stage cancer who has no other options, but less toxicity for a healthy individual getting a preventive medicine. 

The DLT has close relationship with the CTC (common toxicity criteria) and CTCAE (common terminology criteria for adverse events).

CTC (Common Toxicity Criteria) is the precursor of what is today named the Common Terminology Criteria for Adverse Events (CTCAE). The original CTC was developed by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) in 1983 to aid in the documentation and analysis of adverse effects of chemotherapy. CTC, like CTCAE, included terms and a severity grading scale with descriptions of the allowed grades of each term. Starting from v3, the CTC was replaced by CTCAE v3.

CTCAE is a list of terms (adverse events) commonly encountered in oncology interventions. Each AE term is defined and associated with a rating scale of severity that indicates the severity of the AE. The rating scale is used in the definition of protocols parameters (Eligibility; Maximum Tolerated Dose; Dose modification; etc) and indicates what is reasonable to document, report, and analyze for patient safety oversight based on current oncology research interventions. CTCAE is available only in English and the most recent version of CTCAE is verion 4.0. In the new CTCAE v4.0, the AE terms are organized by the System Organ Classes (SOCs) defined by the Medical Dictionary for Regulatory Activities (MedDRA). CTCAE has been developed from the earlier vocabulary known as CTC (Common Toxicity Criteria).

While CTC / CTCAE were developed by NCI, they were being used for clinical trials outside cancer trials such as AIDS/HIV trials, hypertension trials, and others.

The definition of Dose-limiting Toxicity (DLT) is determined by the individual protocol, not the CTC or CTCAE. Although it would be convenient to assume that all Grade 3 adverse events based on CTC or CTCAE represent dose limiting toxicities, this may not be appropriate. Grade 3 or 4 adverse events (based on CTC or CTCAE) of complications such as nausea and vomiting can be controlled with appropriate supportive care measures and may not constitute DLTs. Prolonged grade 2 toxicities can be considered DLTs depending on the schedule of drug administration. Acceptable DLTs or adverse events vary with the patient population and the anticipated outcome of the treatment. More severe adverse events may be acceptable with a potentially curative regimen than with a palliative treatment.

Typically in clinical trials, investigators will base their clinical judgment to grade all reported adverse events (AEs) during the study with three categories: mild, moderate, and severe.

Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not             interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities.

Severe: An event that prevents normal everyday activities.

For oncology trials, the Grading should be based on CTCAE as following:

Grade 0 No Adverse Event	Sign/symptom within normal limits
Grade 1 Mild Adverse Event	Minor Mild symptoms and intervention not indicated Non-prescription intervention indicated No specific medical intervention Asymptomatic laboratory finding only Radiographic finding only Marginal clinical relevance
Grade 2 Moderate Adverse Event	Intervention indicated Minimal, local, noninvasive intervention (e.g. packing, cautery) Limiting instrumental ADL (e.g., shopping; laundry; transportation; ability to conduct finances)
Grade 3 Severe Adverse Event	Medically significant but not life-threatening Inpatient or prolongation of hospitalization indicated Important medical event that does not result in hospitalization but may jeopardize the patient or may require intervention either to prevent hospitalization or to prevent the AE from becoming life-threatening or potentially resulting in death Disabling - results in persistent or significant disability or incapacity Limiting self care ADL (e.g., getting in and out of bed; dressing; eating; getting around inside; bathing; using the toilet)
Grade 4 Life-threatening Adverse Event	Life-threatening consequences       Urgent intervention indicated Urgent operative intervention indicated Patient is at risk of death at the time of the event if immediate intervention is not undertaken
Grade 5 Fatal Adverse Event	Death

To map the CTCAE grading to AE severity / intensity, any AE graded as 1 using CTCAE can be categorized as mild, 2 be categorized as moderate and ≥3 be categorized as severe.

There are considerable discussions about the standardization in determining the dose limiting toxicities.

§         Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents – Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies, an European Organisation for Research and Treatment of Cancer-led study

§         Defining dose-limiting toxicity for phase 1 trials of molecularly targeted agents: Results of a DLT-TARGETT international survey

§         Definition of dose-limiting toxicity in phase I cancer clinical trials of molecularly targeted agents

§         Heterogeneity in the definition of dose-limiting toxicity in phase I cancer clinical trials of molecularly targeted agents: A review of the literature

§         Criteria for defining dose-limiting criteria

In a paper by Paoletti et al “Defining dose-limiting toxicity for phase 1 trials of molecularly targeted agents: Results of a DLT-TARGETT international survey”, it was stated “DLT is traditionally defined as any grade 3–4 non-haematological or grade 4 haematological toxicity at least possibly related to the treatment, occurring during the first cycle of treatment. Some adjustments to this definition have been widely accepted, such as febrile neutropenia, or neutropenia grade 4 lasting more than 7 days or abnormal laboratory values rated as a DLT only in the presence of clinical symptoms.”

In study by Angevin et al “Phase I Study of Dovitinib (TKI258), an Oral FGFR, VEGFR, and PDGFR Inhibitor, in Advanced or Metastatic Renal Cell Carcinoma”, the following DLT criteria were provided in the study protocol appendix. 

Alternative phase I dose escalation study designs: CRM, BLRM, mTPI, and PGDE

The "3 + 3 design" is the most commonly used design in phase I dose escalation study and over 95% of phase I clinical trials in oncology use the "3 + 3 design". However, in some situations, the "3 + 3 design" may not be the best choice for finding the maximum tolerable dose (MTD) and alternative dose escalation study designs are necessary.

Cytel's EAST software version 6.3 introduced a new module 'ESCALATE' which includes additional phase I dose escalation study designs. In additional to the standard "3 + 3 design", it contains the following designs:

• CRM (Continual Reassessment Method)
• Modified CRM 
• BLRM (Bayesian Logistic Regression Method)
• mTPI (Modified Toxicity Probability Interval Design)

where CRM, modified CRM, and BLRM are model based method and mTPI is a mixture of both rule-based and model based method. 

The original CRM is a Bayesian model-based method and uses all available information from doses to guide assignment of the next dose cohort. A CRM simulator can be downloaded from MD Anderson biostatistics website. The modified CRM makes the CRM more like the "3 + 3 design" (can start at lowest dose, allow multiple patients per cohort, do not allow skipping when escalating) for acceptability. A CRM and modified CRM program developed by Dr Steven Piantados can be downloaded from his website. BLRM is commonly used with overdose control (so called EWOC - Escalation With Overdose Control). In this method, models begin with initial estimates of knowledge based on prior clinical data or pre-clinical data. Models are then updated with new information as it becomes available. Updated information forms the basis of dose escalation recommendations. The principles of Bayesian Logistic regression models are:

• precision of model estimates incorporated into dosing decisions 
• restriction of the chance of exposing patients to excessive toxicity, whilst allowing clinicians to make informed dosing decisions based on estimated probabilities of under-dosing and targeted-dosing 

mTPI is Bayesian like CRM and BLRM, but rule-based like the "3 + 3 design". The method is proposed by Yuan Ji et al in their paper "a modified toxicity probability interval method for dose-finding trials". The method can be implemented by excel add-on or R scripts (download for free).

These methods and their usage with EAST ESCALATE module were explained in a free online Webinar "New module for Phase 1 dose escalation study design". ESCALATE module in EAST can perform simulation and interim monitoring for each of these methods.

Phase I Clinical Trial Design by Drs. Rubinstein and Simon discussed additional study designs for phase I dose escalation studies in addition to the "3 + 3 design", original CRM, and amendments and alteration of CRMs:

Accelerated titration designs which are characterized by (i) A rapid initial escalation phase; (ii) Intra-patient dose escalation; and (iii) Analysis of results using a model that incorporates parameters for intra-patient variation in toxic effects, cumulative toxicity and steepness of dose-toxicity effects. The analytic model incorporates data from all courses of therapy and for graded toxicity levels.

Pharmacokinetically Guided Dose Escalation (PGDE) which is based on the mouse and human AUC to escalate to an MTD by targeting a maximal tolerated AUC. The efficiency of PGDE relies on the assumption that drug toxicity is really a function of drug AUC, and that equivalent AUC for human and mouse will result in equivalent toxicity.

Further readings:

• Phase 1 Trial Design: Is 3 + 3 the Best?
• Dose Escalation Methods in Phase I Cancer Clinical Trials
• Bayesian Continual Reassessment Method Designs for Phase I Dose-Finding Trials
• Phase I dose‑escalation study of the HSP90 inhibitor AUY922 in Japanese patients with advanced solid tumors
• Phase I Dose-Escalation Study of LCL161, an Oral Inhibitor of Apoptosis Proteins Inhibitor, in Patients With Advanced Solid Tumors

Phase I Dose Escalation Study Design: "3 + 3 Design"

For the first-in-human clinical trial, the dose escalation study design is often utilized. in dose escalation study, subjects are enrolled in cohorts (batches) with increasing doses. whether or not the study goes further to the higher dose depends on the assessment of the previous dose. The assessment is mainly based on the DLT (dose limiting toxicity) - side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment.

Dose escalation study can be with placebo control or without placebo control. For a dose escalation study with placebo control, the placebo control is within each dose cohort, not across the cohorts. A dose escalation study without placebo control is often used in studies for life-threatening diseases such as cancers and AIDS. 

The most common dose escalation study design is the rule-based "3 + 3 design". The "3 + 3 design" can be depicted as below: 

  The "3 + 3 design" is clearly explained in FDA guidance "Clinical Considerations for Therapeutic Cancer Vaccines" as following: 

The traditional standard dose escalation schedule in the development of cancer therapeutics uses the so-called “3 + 3 design” to avoid selection of a phase 2 clinical trial dose that causes a treatment-limiting toxicity in more than 17% of subjects, a standard considered acceptable as an outpatient therapeutic for patients with limited options and life-threatening diseases. In a “3 + 3 design,” three patients are initially enrolled into a given dose cohort. If there is no DLT observed in any of these subjects, the trial proceeds to enroll additional subjects into the next higher dose cohort. If one subject develops a DLT at a specific dose, an additional three subjects are enrolled into that same dose cohort. Development of DLTs in more than 1 of 6 subjects in a specific dose cohort suggests that the MTD has been exceeded, and further dose escalation is not pursued.

In summary, the "3 + 3 design" is:

• Rule based design
• Start by allocating lowest dose level to first cohort
• Adaptively escalate/de-escalate based on observed DLTs
• Repeat until MTD obtained or trial is stopped

The "3 + 3 design" is very straight forward, robust, simple and can be very well understood by clinicians and investigators. However, the "3 + 3 design" has its limitations. It is limitations may be summarized as the followings: 

• Ignores dosage history other than previous cohort
• Same action under qualitatively different situations (e.g., 0/3 and 1/6 lead to same action)
• Ignores uncertainty (if true DLT rate is p = 0.5, 11% of the time we will see 0 or 1 DLT in 6 patients)
• Cannot re-escalate
• Fixed cohort sizes (either 3 or 6)
• Pre-defined dose levels to be potentially tested
• Low probability of selecting true MTD
• High variability in MTD estimates
• MTD is not a dose with any particular probability of DLT, but in the range from 20% to 25% DLT.
• Can not estimate MTD with target probability of DLT less than 20% or greater than 33%.
• Not all toxicity data of all patients are used to determine the MTD.
• Many patients are likely to be treated at low doses.

The limitations are also cited in FDA's guidance "Clinical Considerations for Therapeutic Cancer Vaccines":

Many cancer vaccine trials have used the “3 + 3 design,” and the results show that, except in very rare situations, an MTD for a cancer vaccine may not be identified. In these trials, the dose-toxicity curve may be so flat that the highest dose that can be administered is limited by manufacturing or anatomic issues rather than toxicity. Therefore, this “3 + 3 design” may not be the most suitable approach to gathering information from early phase trials of cancer vaccines, and alternative trial designs should be considered.

Given the relatively acceptable safety profile of some classes of cancer vaccines, alternative dose-escalation approaches, such as accelerated titration or continuous reassessment, may be considered instead of the standard “3 + 3 design”. When using such designs, the protocol should describe acceptable parameters for the dosing endpoint (supported by data). Irrespective of which dose-escalation approach is chosen, the study protocol should clearly define DLTs, the subject “off-treatment” criteria, and the study stopping rules that will ensure subject safety. When no DLT is expected or achieved, optimization of other outcomes, such as the immune response, can be useful to identify doses for subsequent studies.

Because of these limitations, the alternative phase I dose escalation study designs have been proposed and used in the practice. These methods are:

• CRM (Continual Reassessment Method)
• Modified CRM 
• BLRM (Bayesian Logistic Regression Method)
• mTPI (Modified Toxicity Probability Interval Design)