Maximum Tolerable Dose (MTD) and Dose-Limiting Toxicities (DLTs)

According to Wiley Encyclopedia of Clinical Trials, the maximum tolerable dose (MTD) is defined as: 

The “Maximum Tolerable Dose” (MTD), also known as the “Maximum Tolerated Dose” or the “Maximally Tolerated Dose”, is defined as the dose that produces an “acceptable” level of toxicity or that, if exceeded, would put animals or patients at “unacceptable” risk for toxicity. Besides determining animal toxicology, establishing the MTD is the main objective of Phase I clinical trials, mostly in cancer and HIV treatment in which relatively high doses of drugs are usually chosen to achieve the greatest possible beneficial antitumor effect. Definition of the MTD usually relies on the sample, as MTD is defined as the dose level at which more than two patients over six experienced dose-limiting toxicity (DLT). More recently, the MTD has been defined as the dose that produces a certain frequency of DLT within the treated patient population. In this framework, the MTD is estimated from the data using Bayes or maximum likelihood inference. In all these designs, the MTD is established for one initial administration or treatment course of a cytotoxic experimental agent, ignoring efficacy. To address these issues, the maximum tolerated schedule and the most successful dose have been proposed to be used rather than a conventional MTD. Finally, the concept of MTD that uses toxicity as a surrogate endpoint for efficacy in cytotoxic Phase I trials has been also controversial. Interests in alternatives to MTD have gained recently when dealing with new cytostatic agents that may produce relatively minimal organ toxicity, compared with standard cytotoxics. New optimal doses should be defined in the near future.

The clinical trials with the objective of determining the MTD are designed as dose-escalation studies with patients enrolled into the low dose group and then gradually into the high dose group. The patients who are enrolled under the same dose level below to the same dose cohort. The determination of the MTD relies on the identification of the dose-limiting toxicities (DLTs). Prior to escalating the dose cohort, the safety and tolerability in the previous cohort will be assessed and evaluated. 

According to NCI, DLTs are defined as side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. In early-phase clinical trials, DTLs are defined so that the escalation of the dose cohort to the higher dose level can be determined based on the observed # of DTLs, which are subsequently used to determine the maximum tolerable dose (MTD). 

The dose-escalation study for determining the MTD is the most common first-in-human study design in oncology studies. The DTLs are usually defined as grade 3 or above drug-related adverse events defined by the common toxicity criteria for AEs (CTCAE) maintained by the National Cancer Institute (NCI). 

In non-oncology studies, the CTCAE criteria can still be used to define DTLs. But we also see some non-oncology studies with the customer-defined DLTs criteria.

Here are some examples of how the DTLs are described in oncology clinical trials with MTD as the purpose.  

A Multicenter Phase I Gene Therapy Clinical Trial Involving Intraperitoneal Administration of E1A-Lipid Complex in Patients with Recurrent Epithelial Ovarian Cancer Overexpressing HER-2/neu Oncogene

Toxicity during therapy was categorized as unrelated to, probably, possibly, or definitely related to E1A lipid complex. The dose-limiting toxicity was defined as the highest dose at which at least 2 of the 6 patients experienced National Cancer Institute Common Toxicity Criteria grade 3 or 4 drug-related toxicity during the course of therapy. Maximum tolerated dose was defined at one dose level below dose-limiting toxicity

Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial

Dose escalation proceeded from 2 × 108 to 2 × 1012 particles without occurrence of any dose-limiting toxicities. Specifically, no treatment-emergent clinical hepatotoxicity occurred during dose-escalation, despite pre-existing liver abnormalities due to intrahepatic metastases in over half of the patients at baseline. Transient low grade (1– 2) transaminitis was documented in three patients (following single agent virus) and was classified by the investigator as ‘possibly attributable’ to ONYX-015 (6 × 1011 and 2 × 1012 particles); the laboratory abnormalities resolved within 12 days and did not reoccur after subsequent treatments. Four patients had liver-related adverse events reported (hyperbilirubinemia) that were classified as ‘unrelated’ to ONYX-015 and were associated with intrahepatic tumor progression. The highest dose administered (2 × 1012 particles) was shown to be well-tolerated in three patients. The 2 × 1012 particle dose level therefore appears to be well-tolerated, and the maximum dose that could be administered based on manufacturing capabilities was the MTD for the study

Redefining Dose-Limiting Toxicity

Dose-limiting toxicities (DLTs) traditionally are defined by the occurrence of severe toxicities during the first cycle of systemic cancer therapy. Such toxicities are assessed according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) classification, and usually encompass all grade 3 or higher toxicities with the exception of grade 3 nonfebrile neutropenia and alopecia. This broad definition dates back to the development of conventional cytotoxic chemotherapeutic agents, and is not applicable to the toxicity profile of modern molecularly targeted therapies (MTTs), which now constitute the vast majority of drugs evaluated in phase 1 trials. Despite this shift in drug development, the old definition of DLT is still used for most clinical trials. However, a few clinical trials are beginning to update their definition of DLT, and now tend to add variations to that common DLT definition backbone. The most frequent changes include the addition of some a priori untreatable or irreversible grade 2 toxicities (eg, neurotoxicities, ocular toxicities, or cardiac toxicities), prolonged grade 2 toxicities (ie, grade 2 toxicities lasting longer than a certain period), or the prolongation of the DLT period. However, these changes are still rare and most phase 1 clinical trials still use the traditional DLT definition.

Lenalidomide in Treating Patients With AIDS-Associated Kaposi's Sarcoma

Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Using a 3+3 design, the MTD is defined as the level at which 0/6 or 1/6 patients experiences at dose-limiting toxicity in the first cycle.

Here are some examples of how the DTLs are described in non-oncology clinical trials with MTD as the purpose.  

The LIPid Intensive Drug Therapy for Sepsis - Pilot (LIPIDS-P) Phase I/II Trial

LIPid Intensive Drug therapy for SepsisPilot (LIPIDS-P): Phase I/II clinical trial protocol of lipid emulsion therapy for stabilising cholesterol levels in sepsis and septic shock

Safety and Tolerability Study of Allogeneic Mesenchymal Stem Cell Infusion in Adults With Cystic Fibrosis (CEASE-CF)

Dose limiting toxicity (DLT), triggered by occurrence in the first 24 hours after hMSC infusion of grade ≥3 infusion-related allergic toxicities [ Time Frame: 24 hours ]

 Phase 1b Study of PD-0332991 in Combination With T-DM1(Trastuzumab-DM1)

Toxicity will be assessed using the Common Terminology Criteria of Adverse Events (CTCAE) version 4.0 grading scale. Dose- limiting toxicity-DLT is defined as any drug-related grade 3 non-hematologic toxicity or grade 4 hematologic toxicity lasting >28 days after the last day of therapy. If two patients experience drug-related DLT, the maximal tolerated dose (MTD) for the combination in HER2-positive breast cancer patients has been exceeded, enrollment to that dose will stop, and the next lower dose will be designated the MTD. An additional 15 patients will be treated at the MTD or the maximal 200mg po daily PD-0332991 dose in combination with T-DM1 to confirm safety. Treatment cycles will continue until disease progression or withdrawal from study.

Histone Deacetylase Inhibitor LBH589 in Addition to Corticosteroids in Patients With Acute Graft Versus Host Disease (GVHD)

Dose limiting toxicity (DLT) is defined by the occurrence of Common Toxicity Criteria (CTC) grade 3 or greater toxicity that is unexpected with transplantation, except for hematological toxicity, where DLT is defined as absolute neutrophil count (ANC) <750, and for those participants who were platelet transfusion independent is defined as platelets <10 K.

We can identify the clinical trials on clinicaltrials.gov with the purpose of identifying the MTDs and DLTs. The vast majority of these studies are oncology studies or studies in serious conditions - these studies are usually conducted in patients (not healthy volunteers) and must be registered on clinicaltrials.gov even it is a phase I study - the phase I studies in healthy volunteers are exempted from the clinicaltrias.gov registration.