Dose escalation study
Dose Escalation Study Design Example
(A Dose Escalation Study of Ender-G in Adults with Cancer)
Methods
Study Design
study of Ender-G enrolled
participants with various cancer types from
a single academic medical center in
Bethesda, Maryland, in the United States.
All participants were informed about the
study and potential risks and required to
provide written informed consent prior to
undergoing study-related procedures.
design was implemented 1
. Successive
cohorts of participants (3 participants
/cohort) were each started on a fixed dose
-f Ender-G. The protocol specified 100
mg/m2
administered intravenously, for the first
cohort. Successive cohorts were given
doses of 125 and 150 mg/m2
toxicities (DLTs, see Primary
Endpoint) were observed in >33% of
participants. If no DLTs were observed for
4 weeks after administration of the last dose
-f Ender-G, a new cohort was enrolled at
the next planned dose level. If DLTs were
-bserved in 1 participant in the cohort,
another 3 participants were treated with the
same dose level. The maximum-tolerated
dose (MTD) was defined as 1 dose level
below the dose in which DLTs were
-bserved in >33% of the participants. That
is, if DLTs were observed in at least 2 of 3
participants, the MTD was determined to be
the dose administered to the previous
cohort. Similarly, in a cohort of 6
participants, 3 of 6 participants would have
to experience DLTs to determine the MTD.
Common Terminology Criteria for Adverse
Events Version 3.0 (CTCAE 3.0)2
. If the
CTCAE 3.0 did not apply to an adverse
event, it was graded as mild, moderate, or
severe. DLT was defined as any CTCAE 3.0
Grade 3 or 4 adverse event determined to
be related to Ender-G.
physical exams, complete blood chemistry,
and urinalysis were conducted at weeks
1, 2, 4, and 8.
documents were reviewed and approved by
the hospital human subjects review board
and the study was performed in accordance
with the Declaration of Helsinki.
Patient Eligibility
clinically confirmed cancer and a World
Health Organization (WHO) performance
status < 3 were eligible for the study.
Exclusion criteria included clinically
significant electrocardiogram (ECG)
abnormalities and a white blood cell (WBC)
count  2,000/mm3
. Patients receiving
enzyme-inducing anticonvulsants, steroids,
-r other experimental drugs were excluded.
Patients with a history of migraines were
also excluded.
Study Objectives
establish the MTD of Ender-G in
participants with cancer.
The secondary outcomes were
pharmacokinetic and safety measures of
Ender-G in participants with cancer.
Results
Disposition of Participants
between January 2, 2018 and May 10, 2018
for three dose levels (Figure 1). The last
visit of the final participant for assessment
-f the primary and secondary outcomes was
-n August 29, 2018. Participant
characteristics are listed in Table 1.
ClinicalTrials.gov is a service of the
National Institutes of Health.
Dose Escalation Study Design Example 2 of 4 September 2019
Figure 1. Enrollment, Assignment and Retention of Study Participants.
Outcomes
Primary Endpoint
In order to determine the primary
endpoint, MTD, the number of participants
who experienced DLTs over an 8-week
period was assessed at each dose level. A
DLT was any Grade 3 or 4 adverse event
(AE) using the CTCAE 3.0 that was possibly
drug-related. CTCAE 3.0 Grade 3 is a
severe AE and Grade 4 is a life-threatening
-r disabling AE. Such events interfere with
activities of daily living and include: skin
toxicity, diarrhea or antidiarrheal therapy,
vomiting at same grade for >4 days despite
aggressive antiemetic therapy, central
nervous system, lung or renal toxicity or
elevation of liver transaminases or bilirubin
lasting more than 1 week. The MTD is
defined as the dose level below the dose at
which > 33% of participants experienced a
DLT. The MTD analysis population
consisted of all participants who received at
least one dose of Ender-G.
receiving the 100 mg/m2
participant experienced a DLT among the
three participants receiving 125 mg/m2
(Grade 4 vomiting), thus three more
participants were added to the cohort of
which none experienced a DLT. One
participant experienced a DLT among the
three participants receiving 150 mg/m2
(Grade 4 vomiting), thus three more
participants were added to the cohort of
which two experienced a DLT (Grade 3
renal toxicity and Grade 4 diarrhea). Three
DLTs in 3/6 participants (50%) at the 150
mg/m2 dose established the MTD as 125
mg/m2
ClinicalTrials.gov is a service of the
National Institutes of Health.
Dose Escalation Study Design Example 3 of 4 September 2019
Table 1. Baseline Demographics and Disease Characteristics of Participants
CHARACTERISTIC COHORT 1
100 mg/m2
N = 3
COHORT 2
125 mg/m2
N = 6
COHORT 3
150 mg/m2
N = 6
TOTAL
N = 15
Age, years, median (full range) 67 (43-72) 63 (36-74) 62.5 (42-82) 67 (3682)
Sex, n (%)
Race, n (%)
WHO performance statusa
, n (%)
Tumor type, n (%)
Number of prior chemotherapy
regimens, n (%)
a World Health Organization (WHO) performance status is measured on a scale from 0 to 5, with 0 =
Asymptomatic (Fully active, able to carry on all predisease activities without restriction.); 1 = Symptomatic
but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out
work of a light or sedentary nature. For example, light housework, office work.); 2 = Symptomatic, <50%
in bed during the day (Ambulatory and capable of all self-care but unable to carry out any work activities.
Up and about more than 50% of waking hours.); 3 = Symptomatic, >50% in bed, but not bedbound
(Capable of only limited self-care, confined to bed or chair 50% or more of waking hours.); 4 = Bedbound
(Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.); and 5 = Death
b NSCLC = non-small-cell lung cancer
Secondary Endpoints
the initial dose on day 1 and 0.25, 0.5, 0.75,
1, 2, 3, 4, 5, 6, 7, 8, 16, 24, 36, 48 and
72 hours post-dose for pharmacokinetic
analyses of Ender-G. Plasma
concentrations were determined using a
validated high-pressure liquid
chromatography method. Measurements
included maximum observed plasma
concentration of Ender-G (Cmax), time to
maximum observed plasma concentration of
Ender-G (Tmax), and area under the
concentration-time curve from 0 to 72 hours
post-dose.
The safety of Ender-G was summarized
by the number of participants experiencing
any on-treatment adverse event(s), serious
and non-serious, which were collected by
systematic assessment using terms from
the CTCAE 3.0. All participants in all
3 cohorts experienced at least one nonserious
adverse event. Serious adverse
events were considered to be Grade 3 or 4.
The results of the pharmacokinetic analyses
are presented in Table 2 and the summary
-f adverse events is in Table 3. 
ClinicalTrials.gov is a service of the
National Institutes of Health.
Dose Escalation Study Design Example 4 of 4 September 2019
Table 2. Pharmacokinetic Parameters for Each Cohort
COHORT DOSE
(mg/m2
NUMBER OF
PARTICIPANTS
Cmax
a
(mcg/mL)
AUC0-72b
((mcg/mL)*h)
Tmax
c
(hours)
1 100 3 0.535 (119) 7.41 (7.8) 5 (4 to 5)
2 125 6 1.10 (75) 18.1 (12.7) 5 (5 to 6)
3 150 6 1.58 (102) 18.8 (14.3) 5 (2 to 5)
a Geometric Mean (% Geometric Coefficient of Variation)
b Mean (Standard Deviation)
c Median (Full Range)
Table 3a. Participants with Grade 1 or 2 Adverse Events
ADVERSE EVENT COHORT 1
100 mg/m2
N = 3
COHORT 2
125 mg/m2
N = 6
COHORT 3
150 mg/m2
N = 6
Nausea 3 3 3
Diarrhea 1 3 2
Vomiting 1 3 5
Fatigue 1 2 6
Rash 1 3 5
Anorexia 3 1 4
Pain in extremity 2 2 4
Cough 2 2 4
Chills 2 1 3
Pyrexia 2 1 3
Headache 2 1 3
Dry skin 2 1 3
Pruritus 2 1 3
Table 3b. Participants with Grade 3 or 4 Adverse Events
ADVERSE EVENT COHORT 1
100 mg/m2
N = 3
COHORT 2
125 mg/m2
N = 6
COHORT 3
150 mg/m2
N = 6
Diarrhea- 0 0 1
Renal toxicity 0 0 1
Vomiting- 0 1 1