Sentinel Dosing (Sentinel Subject) and Staggering Enrollment in First-in-Human (FIH) Clinical Trials

First-in-human (FIH) study is a type of clinical trial in which a new drug, procedure, or treatment is tested in humans for the first time. FIH studies take place after the new treatment has been tested in laboratory and animal studies and are usually conducted as phase I clinical trials. 

FIH study can be conducted in healthy volunteers (usually the case) or in patients.(in some special situations). Even though the new drug, procedure, or treatment has been thoroughly tested in pre-clinical studies before initiating the FIH study, the conservative approaches may still needed to be taken to ensure the safety of the study participants when designing the FIH study . 

FIH study can also be designed as phase 0 study or exploratory IND study as discussed in a previous post. 

FIH study may be designed as a single ascending dose (SAD) study where the healthy volunteers are enrolled and dosed in cohorts in dose-escalation fashion, i.e., the next dose cohort will only be enrolled after the safety data from the previous cohorts has been reviewed. FIH study may also be designed as dose-escalation study to identify the maximum tolerable dose (MTD) - such as the "3+3 design". 

Even with the SAD or dose escalation study designs, if it is uncertain there are still potential risks to the participants, additional precautions may be taken: sentinel dosing (sentinel subject) and staggering enrollment. 

Sentinel Dosing (Sentinel Subject): 

For the FIH study in healthy volunteers, the subjects are recruited to the clinical research unit (CRU, also called Phase I clinic). A cohort of subjects will be confined in the CRU to be dosed, observed, and evaluated. All subjects in the same dose cohort will be dosed at the same time. The study starts with the lowest dose cohort and then moves to higher dose cohorts. 

While dosing by cohort approach is usually safe, unexpected incidences can still occur. If the unexpected adverse events cause the harm to the study participants, it affects all participants in the entire cohort. Below are two examples where the phase I trial participants died or severely injured after receiving the experiment treatment in FIH Phase I studies. 

• Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412
• French study’s death recalls 2006 UK clinical trial disaster - Were mistakes repeated?

To prevent this from happening, a strategy called sentinel dosing is often practiced so that one person in the first cohort of participants is dosed in advance of the full study or in advance of any full cohort. The very first subject who receive the sentinel dose is called 'sentinel subject'. 

Sentinel dosing was mentioned in EMA guidance "Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products":

It is considered appropriate to design the administration of the first dose in any cohort so that a single subject receives a single dose of the active IMP (often known as sentinel dosing). Flexibility in this approach is allowed but should be on a risk-proportionate basis with a clear scientific rationale for any proposals not to use this strategy.

When the study design includes the use of placebo it would be appropriate to allow for one subject on active and one on placebo to be dosed simultaneously prior to dosing the remaining subjects in the cohort. This approach is expected for all single and multiple dosing cohorts, in order to reduce the risks associated with exposing all subjects in a cohort simultaneously. This sentinel approach may continue or also start to be appropriate at later stages of study design, e.g. on the steep part of the dose response curve, when approaching target saturation levels or the maximum clinical exposure levels defined in the protocol (see sections 7.5 and 8.2.9), in case of non-linear PK, or in light of emerging clinical signs or adverse events that do not meet stopping criteria. There should be an adequate period of time between the administration of treatment to these first subjects in a cohort and the remaining subjects in the cohort to observe for any reactions and adverse events. The duration of the interval of observation will depend on the PK and PD characteristics and the level of uncertainty associated with the product (see section 4). At the end of the observation period, there should be a clearly defined review of all available data for the sentinel subjects before dosing of further subjects in the cohort, with dose stopping rules in place to prevent further dosing if any rule is met (see also section 8.2.10).

Staggering Enrollment

Majority of phase I studies are conducted in healthy volunteers where the same cohort of subjects are recruited and confined at the clinical research unit (a single center) for dosing and post-dose measures and observations. In some situations (such as oncology studies, gene therapy trials, studies using human-plasma derived products), phase I studies are conducted in patients and are not ethical to be conducted in healthy volunteers. The patients will usually be recruited from multiple sites - so called multi-center phase I clinical trials. 

In multi-center phase I clinical trials, before multiple sites can start to recruit patients, a 'staggering enrollment' approach may be employed to minimize the potential harms caused by the innovative therapies. With the 'staggering enrollment' approach, after the first patient is enrolled, the second patient will only be enrolled after the first patient has been followed-up for a period of time and thoroughly evaluated for the safety measures. The third patient or the parallel enrollment will only be started after the second patient has been followed-up and thoroughly evaluated. 

The 'staggering enrollment' approach was used in the first-in-human trials in CAR-T trial and in gene therapy trials.  

The first CAR-T approval was for Novartis’s Kymriah (tisagenlecleucel) for the treatment of Acute lymphocytic leukemia (ALL). The tisagenlecleucel was originally developed by UPENN and FIH study was conducted by the UPENN. In their FIH study for CAR-T, the enrollment was staggering: 

“Staggered enrollment on the CNS3 cohort: infusion of any subsequent patient on the CNS3 cohort will be delayed until 21 days after the prior CNS3 patient’s infusion to allow for toxicity monitoring.”

For Bluebird’s Beti-cel in treatment of β-thalassemia patients requiring regular red blood cell (RBC) transfusions, their FIH trial also employed a staggering enrollment strategy:

“Initially, subjects with β-thalassemia major of the βE/β0 genotype will be enrolled in this study, and treatment will be staggered. The second subject will begin myeloablative conditioning only after the first subject 1) engrafts (defined as an absolute neutrophil count [ANC] ≥0.5 × 109/L for 3 consecutive days); and 2) has no LentiGlobin® BB305 Drug Product treatment-related serious adverse event (SAE) unexpected to occur with autologous HSCT. After Subject 2 meets these same criteria, parallel enrollment will be opened to additional subjects with the βE/β0 genotype.” 

'Staggering enrollment' may also be employed for the logistic reason. For a specific investigational site, the investigator and the study coordinator may not have the resource to enroll multiple patients all at once. They just don't have the manpower to do that. 'Staggering enrollment' approach allows the site to enroll one patient at a time. 

Human Preclinical Studies and Phase 0 Clinical Trials

The drug development process includes various steps from discovery (discovery of a new compound or biological product) to preclinical research (measuring the safety, toxicity, and efficacy in animal models), and then to clinical trials (testing the safety and efficacy in humans - either healthy volunteers or patients). The clinical trials are phased from phase 1 & 2 (early phase trials) to phase 3 (pivotal, confirmatory, late-phase trials), and to phase 4 (post-marketing clinical trials). A diagram indicates various stages of drug development. With innovative clinical trial designs, the clinical trial phases are blurred, for example, seamless phase 1/2 trial and seamless 2/3 trial. In rare disease areas, the drug development process may not have all phases of clinical trials. The adequate and well-controlled study may be phase 3, phase 2, or phase 1 (for example, expansion cohort studies).

Preclinical development, also called preclinical study or nonclinical study, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug safety data are collected, typically in laboratory animals. Traditionally, the phase 1 study may be the first-in-human trials with the purpose of studying the drug's:

• pharmacokinetics (ADME: absorption, distribution, metabolism, and excretion) and pharmacodynamics (enzyme, protein,...) 
• toxicity, safety and side effects associated with increasing doses
• maximum tolerable dose
• early evidence of effectiveness

There are now two new steps that may be utilized in drug development: Preclinical human studies and phase 0 clinical trials. A revised drug development diagram is as follows: 

Human pre-clinical studies are those pre-clinical studies utilizing the human subjects (either utilizing the specimens collected from human subjects or performing testing in human decedents). Human pre-clinical studies are 'pre-clinical' because they are not conducted under IND (investigational new drug) and they are conducted for collecting the data to support the IND-enabling studies. 

In a paper by Abdallah et al, "A novel prostate cancer immunotherapy using prostate-specific antigen peptides and Candida skin test reagent as an adjuvant", they described a human pre-clinical study where peptides based on the prostate-specific antigen amino acid sequences were evaluated in terms of their recognition by peripheral immune cells from prostate cancer patients using interferon-γ enzyme-linked immunospot assay. A sample size of 10 patients with prostate cancer was selected for the study. The authors concluded: 

"We described a human preclinical study of a novel prostate cancer immunotherapy consisting of PSA peptides and Candida skin test reagent as an adjuvant. As solubility and formulation have been developed, it would be feasible to further evaluate the utility of this new therapy particularly when a proportion of prostate cancer patients seem to have immune cells with the ability to recognize these PSA peptides already. Therefore, whether this immunotherapy may enhance immune responses to PSA leading to tumor regression should be examined."

Dr. Locke's team in UAB recently conducted pioneer xenotransplantation of a gene-modified pig kidney. The study was described in the paper by Porrett et al "First clinical-grade porcine kidney xenotransplant using a human decedent model". The pig kidney was transplanted to a human decedent (brain dead patient). The purposes of this human preclinical study were stated as the following:

"Xenotransplantation is arguably the most pragmatic solution to the organ shortage crisis, but safety and efficacy concerns have limited advancement into humans. In preparation for a phase I clinical trial of porcine renal xenotransplantation at the University of Alabama at Birmingham, we asked what gaps in knowledge must be filled before such a clinical trial could be ethically offered to research subjects. We thus aimed to develop a human preclinical model which would permit the in vivo evaluation of critical safety and feasibility tenets of the pig-to-NHP model without risk to a living human. Our study was designed to test five central questions: (1) Is the current suite of porcine genetic modifications sufficient to avoid hyperacute rejection in humans? (2) Would prospective flow-based crossmatching correlate with graft survival free of hyperacute rejection? (3) Would life-threatening intraoperative complications occur during a renal porcine xenotransplant? (4) Would porcine cells and/or pathogens be detected in the blood of a human recipient? (5) Could porcine renal xenotransplantation be safely performed under the conditions necessary for a clinical trial? To this end, we designed and performed this experiment under clinical-grade conditions which included the transplantation of 10-GE porcine kidneys designed specifically for human transplantation into the conventional anatomic position using processes and facilities in compliance with multiple regulatory agencies."

In human preclinical studies, while human subjects are involved, there is no IND needed. Consents by the patients (in the first example) or by the relatives (in the second example) are needed. 

Phase 0 Clinical Trial: the concept of phase 0 clinical trial came from the FDA's guidance for industry "Exploratory IND Studies". The term 'phase 0 clinical trial' was not used in the guidance, but was used for exploratory IND studies. Phase 0 clinical trial may now be called 'early phase 1' clinical trial, for example, in NIH.gov website and in clinicaltrials.gov:

According to the FDA guidance "Exploratory IND Studies", the exploratory IND studies (therefore phase 0 clinical trials or early phase 1 clinical trials) are defined as the following:

"Exploratory IND studies usually involve very limited human exposure and have no therapeutic or diagnostic intent. Such studies can serve a number of useful goals. For example, an exploratory IND study can help sponsors

• Determine whether a mechanism of action defined in experimental systems can also be observed in humans (e.g., a binding property or inhibition of an enzyme)
• Provide important information on pharmacokinetics (PK)
• Select the most promising lead product from a group of candidates5 designed to interact with a particular therapeutic target in humans, based on PK or pharmacodynamic (PD) properties
• Explore a product’s biodistribution characteristics using various imaging technologies

 Whatever the goal of the study, exploratory IND studies can help identify, early in the process, promising candidates for continued development and eliminate those lacking promise. As a result, exploratory IND studies may help reduce the number of human subjects and resources, including the amount of candidate product, needed to identify promising drugs. The studies discussed in this guidance involve dosing a limited number of subjects with a limited range of doses for a limited period of time.

Existing regulations provide more flexibility with regard to the preclinical testing requirements for exploratory IND studies than for traditional IND studies. However, sponsors submitting the kinds of studies described in this guidance have not always taken full advantage of that flexibility. Sponsors often provide more supporting information in their INDs than is required by the regulations. Because exploratory IND studies involve administering either subpharmacologic doses of a product, or doses expected to produce a pharmacologic, but not a toxic, effect, the potential risk to human subjects is less than for a traditional phase 1 study that, for example, seeks to establish a maximally tolerated dose. Because exploratory IND studies present fewer potential risks than do traditional phase 1 studies that look for dose-limiting toxicities, such limited exploratory IND investigations in humans can be initiated with less, or different, preclinical support than is required for traditional IND studies.  "

In cancer.org website,"Types and Phases of Clinical Trials", Phase 0 clinical trials were specifically mentioned: 

Phase 0 clinical trials: Exploring if and how a new drug may work

Even though phase 0 studies are done in humans, this type of study isn’t like the other phases of clinical trials. The purpose of this phase is to help speed up and streamline the drug approval process. Phase 0 studies may help researchers find out if the drugs do what they’re expected to do. This may help save time and money that would have been spent on later phase trials.

Phase 0 studies use only a few small doses of a new drug in a few people. They might test whether the drug reaches the tumor, how the drug acts in the human body, and how cancer cells in the human body respond to the drug. People in these studies might need extra tests such as biopsies, scans, and blood samples as part of the process.

Unlike other phases of clinical trials, there’s almost no chance the people in phase 0 trials will benefit. The benefit will be for other people in the future. And because drug doses are low, there’s also less risk to those in the trial.

Phase 0 studies aren’t widely used, and there are some drugs for which they wouldn’t be helpful. Phase 0 studies are very small, often with fewer than 15 people, and the drug is given only for a short time. They’re not a required part of testing a new drug.

Phase 0 clinical trials are mainly conducted in the oncology area and there are quite some phase 0 (or early phase 1) studies are listed in clinicaltrials.gov. An example of a phase 0 study was published in JCO (Kummar et al 2009 "Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies").

Serial Blood Sample Timepoints for Comparing Pharmacokinetics Profiles Between Two Different Dose Frequencies

It is very common in the drug development process that the dosing frequency needs to be studied. The dosing frequency is usually based on the pharmacokinetic profiles. In multiple-dose studies, the dose frequency decides the dosing interval: QD for once daily, BID for twice daily, and TID for three times daily. 

Usually, to compare the pharmacokinetic profiles, serial blood samples will be taken over the period of the dosing interval (between the previous dose and the next dose).  The area under the curve (AUC) will then be calculated over the dosing interval (commonly denoted as tau).

• For QD dose, Tau = 24 hours, AUCtau is AUC[0-24 hours]
• For BID dose, Tau = 12 hours, AUCtau is AUC[0-12 hours]
• For TID dose, Tau = 8 hours, AUCtau is AUC[0-8 hours]

It will be straightforward to select the Pharmacokinetics (PK) sampling time points if two drugs/formulations to be compared have the same dose interval. However, in practice, we often need to compare the PK profiles for two drugs/formulations with different dose intervals, for example, between QD versus BID, or between QD versus TID.  

For comparison of PK profiles between QD dose, BID dose, and TID dose, one will need to compare AUC[0-24 hours] with 2 x AUC[0-12 hours] for BID and with 3 x AUC[0-8 hours] for TID.

For QD dosing, serial PK samples will be collected over 24 hours. For BID dosing and TID dosing, there are two different ways to decide the serial PK samples:

For BID dosing,   

1. serial PK samples can also be collected over 24 hours, the calculated AUC[0-24 hours] can directly be compared with AUC[0-24 hours] from QD dosing even though there will be an extra dose at the middle of the 24 hours period. 
2. serial PK samples can be collected over 12 hours, then the calculated AUC[0-12 hours] needs to be multiplied by 2 in order to be compared with AUC[0-24 hours]

For TID dosing, 

1. serial PK samples can also be collected over 24 hours, the calculated AUC[0-24 hours] can directly be compared with AUC[0-24 hours] from QD dosing even though there will be two extra doses during the 24 hours period. 
2. serial PK samples can be collected over 8 hours, then the calculated AUC[0-8 hours] needs to be multiplied by 3 in order to be compared with AUC[0-24 hours]

In a study by Dawra et al, "A PK/PD study comparing twice-daily to once-daily dosing regimens of ertugliflozin in healthy subjects", the blood samples were collected for QD and BID as the followings:

For each period, blood samples for PK analysis were collected for QD dosing as follows: on days 4, 5, and 6 before administration of the morning dose, and at 0.5, 1, 2, 3, 4, 8, 12, and 24 hours after the morning dose on day 6. For BID dosing, blood samples were collected at 0.5, 1, 2, 3, 4, 8, 12 (preevening dose), 12.5, 13, 14, 15, 16, 20, and 24 hours after the morning dose on day 6.            

Notice that the blood samples for BID were collected at 0.5, 1, 2, 3, 4, 8, 12 post the morning dose and then 0.5, 1, 2, 3, 4, 8, 12 post the evening dose. 

The PK profiles for OD and BID doses are displayed in the figures below: 

This approach of the PK blood sampling schema will require an extensive number of blood draws. For the BID dose, two serial PK samples need to be drawn; for the TID dose, three serial PK samples need to be drawn. The advantage is to capture the potential impact of the circadian and diurnal cycles. 

In some situations, too many blood sample draws may not be practical, and an alternative approach needs to be taken. For example, in pediatric PK studies, the number of blood sample draws may be limited due to the restriction in the total blood volume. 

One of the alternative approaches is to draw the serial PK samples only for one dose interval, not draw additional serial PK samples after the next dose. For example, for the BID dose, the serial PK samples are drawn over 12 hours period assuming that the PK profiles after the evening dose will be the same as the PK profiles over 12 hours post the morning dose. The AUC[0-12 hours] needs to be multiplied by 2 before comparing it to the AUC[0-24 hours] for QD dose. 

In a study to compare the IVIG (every four weeks dosing schedule) and SCIG (weekly dose schedule), the serial PK samples for IVIG were drawn over 4 week period, and the serial PK samples for SCIG were drawn over 1 week period (instead of 4 week period). To compare the AUCs between IVIG and SCIG, the AUC[0-7 days] was multiplied by 4 before comparing it to the AUC[0-28 days]. With this approach, the next three weekly intervals are assumed to have the same PK profiles as the first weekly interval. We can also say that the PK profiles for the next three intervals (dotted lines) are projected or simulated.  This approach was accepted by the FDA and PK results were included in the product label. The PK profiles for IVIG and SCIG are displayed below (the dotted portion for SCIG was projected). 

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. 

Early Phase Trial to Find Maximal Tolerated Dose (MTD) - 3+3, CRM, and BOIN Designs

In early-phase clinical trials, determining the dose range and therapeutic window is critical. The purpose of the early-phase studies may just be to identify the maximum tolerated dose or maximum tolerable dose. 

Definition of maximum tolerated dose (MTD)

The highest dose of a drug or treatment that does not cause unacceptable side effects. The maximum tolerated dose is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found. Also called MTD.

The studies for identifying the MTD are usually designed as a dose-escalation study and the dose-escalation study is defined as:

A study that determines the best dose of a new drug or treatment. In a dose-escalation study, the dose of the test drug is increased a little at a time in different groups of people (also called cohort) until the highest dose that does not cause harmful side effects is found. A dose-escalation study may also measure ways that the drug is used by the body and is often done as part of a phase I clinical trial. These trials usually include a small number of patients and may include healthy volunteers.

In dose-escalation studies, within each dose cohort, a placebo group can be included even though the majority of the dose-escalation studies for MTD are designed without placebo controls.

Identifying MTD is based on the number of dose-limiting toxicities (DTLs)that are observed in each dose cohort. DTLs 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 practice, DTLs are often defined as grade 3 or above adverse events according to Common Terminology Criteria for Adverse Events (CTCAEs) especially in the oncology area even though other customer-defined criteria for DTLs may be used in non-oncology areas. 

Clinical trials to identify the MTD are generally needed for phase I studies directly conducted in patients, not healthy volunteers. Areas that the phase I studies are conducted in patients, not healthy volunteers, include oncology drugs, drugs in severe diseases such as AIDS, Sepsis, ARDS, etc., the gene and cell therapies, human-plasma derived products.

There are different types of clinical trial designs for identifying the MTD. The commonly used designs are 3+3 design, Continuous Reassessment Method (CRM), and Bayesian Optimal INterval design (BOIN). 

3+3 Design was discussed in an early post Phase I Dose Escalation Study Design: "3 + 3 Design". It is a straightforward rule-based method and requires no statistical calculations. 3+3 design is the most frequently used method for identifying the MTD. 

The CRM is a model-based design for phase I trials, which aims to find the maximum tolerated dose (MTD) of a new therapy. The CRM has been shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3 design. With CRM design, statistical inferences on the model parameter(s) need to be made using likelihood-based or Bayesian approaches and DLT probability at each dose needs to be estimated. The patient is assigned to the next dose level based on the probability of patients with DLTs at the current dose level. The toxicity risk of other dose levels is based on accrued data, which improves trial efficiency. 

Following articles or videos provided a great introduction/reference about the CRM method: 

• Wheeler et al (2019) How to design a dose-finding study using the continual reassessment method
• Garrett-Mayer:  The continuous reassessment method for dose-finding studies: A tutorial
• PHASE I CLINICAL TRIALS:CONTINUAL REASSESSMENT METHOD (CRM)
• O'Quigley, Pepe, Fisher (1990) Continual reassessment method: a practical design for phase 1 clinical trials in cancer

The BOIN design shares the simplicity of the 3+3 design, which makes the decision of dose escalation/de-escalation by comparing the observed DLT rate with 0/3, 1/3, 2/3, 0/6, 1/6, and 2/6. The BOIN design makes the decision by comparing with two fixed boundaries, λe and λd, which is arguably even simpler.

BOIN design are described and explained in the following article and video:

• Yuan, Hess, et al (2016) Bayesian Optimal Interval Design: A Simpleand Well-Performing Design for Phase IOncology Trials
• BOIN: a novel platform for designing early phase single-agent and drug-combination clinical trials

Software for Sample Size Calculation for Phase I MTD Finding Studies:

• Cytel's EAST software has a module 'ESCALATE' containing the sample size calculations for 3+3, CRM, BLRM, mTPI, comb2BLRM, and PIPE methods. 

• trialdesign.org is a website developed and maintained by a research team at MD Anderson Cancer and it contains the literature and software for phase I designs including CRM and BOIN. 

Additional Videos: 

• Detangle modern dose-finding designs: A tutorial
• Designs of dose escalation studies in phase I oncology trials
• Practical Model-based Approaches for Phase 1 Oncology Trials
• Phase 1 Dose Escalation Trials with ESCALATE