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Is the “3+3” dose escalation phase 1 clinical trial design suitable for
therapeutic cancer vaccine development? A recommendation for alternative
design
Osama E. Rahma1’ 3, Emily Gammoh1, Richard M. Simon2 and Samir N. Khleif1, 4
1Vaccine Branch, National Cancer Institute, Bethesda, MD, USA
2Biometric Research Branch, National Cancer Institute, Rockville, MD, USA
3Division of Hematology/Oncology, University of Virginia, Charlottesville, VA, USA
4 Georgia Health Sciences Cancer Center, Augusta, GA, USA
Running Title: An alternative design for cancer vaccine trials.
Keywords: Cancer, Vaccine, Phase I, Trial, Design.
Financial support: This research was supported by the Intramural Research Program of the NIH,
National Cancer Institute, Center for Cancer Research. The content of this publication does not
necessarily reflect the views or policies of the Department of Health and Human Services, nor
does mention of trade names, commercial products, or organizations imply endorsement by the
US Government. The material submitted in this manuscript for publication has not been
previously reported nor is it under consideration for publication elsewhere.
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Correspondence should be sent to:
Samir N. Khleif
Georgia Regent University Cancer Center
1411 Laney Walker Blvd
Augusta, GA 30912
Phone: 706-721-6744
Fax: 706-721-0469
E-mail: skhleif@gru.edu
Conflict of interest: The authors declare no conflict of interest.
Word count: 4075. Tables: 4. Figures: 2. Supplemental Files: 3.
Translational Relevance
The traditional phase I dose escalation design has been used by investigators in early therapeutic
cancer vaccine development for decades. However, in contrast to cytotoxic agents, this design
may not be applicable for therapeutic cancer vaccines given their unique mechanism of action
and their relatively limited toxicities. The data presented in this report support the lack of
correlation between dose escalation and cancer vaccines’ toxicities or cellular immune responses
except for certain cases. In addition, this current report presents a novel design for therapeutic
cancer vaccines early development. This design may allow investigators to conduct early phase
clinical trials in cancer vaccines without the need to enroll large number of patients in order to
identify the safe and immune active dose. Subsequently, the identified safe and immune active
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dose could be used in combination with other agents in phase II/III clinical trials. This would
provide clinical investigators with a new tool to conduct clinical trials in cancer immunotherapy.
Abstract
Purpose: Phase 1 clinical trials are generally conducted to identify the maximum tolerated dose
(MTD) or the biologically active dose (BAD) using a traditional dose escalation design. This
design may not be applied to cancer vaccines, given their unique mechanism of action. The FDA
recently published “Guidance for Industry: Clinical Considerations for Therapeutic Cancer
Vaccines.” However, many questions about the design of cancer vaccine studies remain
unanswered. Experimental Design: We analyzed the toxicity profile in 239 phase 1 therapeutic
cancer vaccine trials. We addressed the ability of dose escalation to determine the MTD or the
BAD in trials that used a dose escalation design. Results: The rate of grade 3/4 vaccine-related
systemic toxicities was 1.25 adverse event per 100 patients and 2 per 1000 vaccines. Only 2 out
of the 127 dose escalation trials reported vaccine-related dose limiting toxicities, both of which
used bacterial vector vaccines. Out of the 116 trials analyzed for the dose-immune response
relationship, we found a statistically significant dose-immune response correlation only when the
immune response was measured by antibodies (p<0.001) or delayed type hypersensitivity
(p<0.05). However, the increase in cellular immune response did not appear further sustainable
with the continued increase in dose. Conclusions: Our analysis suggests that the risks of serious
toxicities with therapeutic cancer vaccines are extremely low and that toxicities do not correlate
with dose levels. Accordingly, the conventional dose escalation design is not suitable for cancer
vaccines with few exceptions. Here we propose an alternative design for therapeutic cancer
vaccine development.
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Introduction
Traditionally the first-in-human clinical trials conducted in oncology drug development are
phase 1 safe-dose-seeking trials. Since the establishment of the Federal Food, Drug, and
Cosmetic Act in 1938, all drug manufacturers are required to prove drug safety prior to
marketing (1). A later amendment passed in 1962 required that not only safety must be
demonstrated but efficacy as well (2). These regulations created a strong motivation for the
design of clinical trials. In the late 1970s the guidelines for phase 1 trials of anti-cancer drugs
were established, and they have remained largely unchanged to this day (3). Finding the
maximum tolerated dose (MTD) was set as the primary goal for phase 1 trials, because at that
time, most anti-cancer drugs were cytotoxic agents. These drugs exhibit a dose-toxicity
relationship that was also considered to hold for efficacy. Therefore, the highest tolerated dose
was assumed to be the most efficacious (4). Although toxicity is an important endpoint in phase
1 trials testing cytotoxic agents, newer drugs such as molecular targeted agents (MTAs) are often
characterized by a dose-response curve that plateaus at a dose less than the MTD (5-7). In such
cases, the preferred effect can be provided without considerable toxicity. Furthermore, the anti-
tumor effects of most successful recently developed targeted agents have been mediated via
measurable pharmacodynamic effects on their targets. Therefore, identifying a biologically
active dose (BAD) has become an important goal for phase 1 trials testing MTAs (6). Cancer
vaccines have emerged as a promising novel modality and identifying their MTD and BAD using
the traditional phase 1 design has been a challenge (8). Cancer vaccines produce their effect by
modulating the immune system to target specific antigens on cancer cells. This mechanism of
action is not expected to be dose-related or to induce severe toxicity. Accordingly, the FDA
realized the need to change the paradigm in early cancer vaccine development (9). To date there
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has been no extensive analysis of cancer vaccine toxicity or the dose-safety and dose-immune
response relationships. In this paper, we have attempted to provide such analyses. We also
describe an alternative design strategy for the conduct of early therapeutic cancer vaccine clinical
trials, and we identify the circumstances in which a traditional dose escalation design is
appropriate.
Materials and Methods
Inclusion criteria and trials classification
In order to establish our database for analysis we searched PubMed for all phase 1, phase1/2, and
pilot studies for therapeutic cancer vaccines conducted from 1990 through 2011, excluding all
trials for combination treatments and studies that did not use the NCI Common Toxicity Criteria.
The vaccine studies were classified according to vaccine type. Some studies used vaccines that
fell under more than one category. To simplify the analysis, the method of delivery (e.g.,
dendritic cells) was used as the main guideline for classification.
Toxicity analysis
We reported the number of systemic vaccine-related grade 3/4 toxicities, number of treated
patients and number of administered vaccines by vaccine category. We then examined the dose-
toxicity relationship in the dose escalation trials, specifically looking for dose limiting toxicities
(DLTs). Vaccine-related toxicities are defined as grade 3/4 toxicities that are possibly, probably,
or definitely related to the vaccine, excluding local reactions, constitutional symptoms, and
adjuvant-related events.
Dose-immune response meta-analysis
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To address the question of whether dose escalation could lead to a better immune response, we
performed a meta-analysis on all dose escalation trials that reported the number of immune
responders per dose level. Trials included in the meta-analysis were those dose escalation trials
analyzed earlier for toxicity in addition to phase 2 trials that used dose escalation to determine
the dose that induces the best immune response as a primary endpoint.
Furthermore, we analyzed the correlation of immunological response with dose level for each of
the immune assay endpoints. This analysis included all studies that reported results with a given
endpoint regardless of the type of vaccine. Statistical significance was based on a test for trend,
which is essentially equivalent to an evaluation of whether the response (0 for no immunological
response vs. 1 for immunological response) is linearly correlated with dose level (1, 2, etc.). For
each study s, a value was computed where yi denotes the response for the i’th patient
in the study, di denotes the dose level (1, 2, etc.) of the i’th patient in the study and n is the
number of patients in the study. A large value of Ts indicates a relationship of response to dose,
but the size of Ts depends on the number of patients in the study, the number of dose levels, and
the distribution of patients per dose level. A standardized statistic was calculated for each study
by subtracting off the mean and dividing by the square root of the variance under the null
hypothesis of no trend of response to dose; i.e., . The studies were combined
by computing an unweighted average of the values, i.e., . The statistical significance of
was evaluated by computing its exact permutation distribution. That is, for each study, the
assignment of doses to patients was permuted randomly; new values of and were calculated
for the permuted data. This was repeated thousands of times resulting in the distribution of
under the null hypothesis. A one-tailed significance level is the area of the tail of the null
1
n
s i ii
T y d=
=
' ( ) /s sT T E V= −
'sT 'T 'T
'sT 'T
'T
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distribution beyond the actual value of for the real un-permuted data. A two-tailed
significance level is taken as twice the one-sided value. The calculations were programmed in
the R statistical programming language.
Results
Therapeutic Cancer Vaccine Trials
We reviewed 239 phase 1, phase1/2, and pilot therapeutic cancer vaccine studies published
between 1990 and 2011. We classified these trials into cellular (autologous or allogeneic), and
synthetic vaccines based on the type of vaccination. Cellular-based vaccines (autologous or
allogeneic tumor cell–based vaccines) utilize the whole cells or cell lysates as the source of
antigens, which allows multiple antigens to be simultaneously targeted without being
prospectively identified. Autologous vaccines were sub-classified into dendritic and tumor cell
vaccines. Synthetic vaccines are administered directly to the patients or utilize a vector to deliver
the antigen. Synthetic vaccines were sub-classified into peptide, DNA, RNA, viral, bacterial,
anti-idiotypic, and liposomal vaccines. A full list of the 239 analyzed trials is reported in
supplemental table 1, in addition to the range of the administered vaccine doses. An aggregate
total of 4,952 patients were enrolled in these trials. Trials using synthetic vaccines accounted for
the greatest number (135 trials), enrolling 2,853 patients, constituting more than half the total
patients (57.61%). Autologous vaccines constituted 87 trials and 34.17% of the total patients
(1,692 patients). There were 17 allogeneic vaccine trials with 407 treated patients (8.22% of the
total patients) (Table 1).
Vaccine-related toxicity
Vaccine-related toxicity in relation to the number of treated patients
'T
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Here, we report the incidence of vaccine-related toxicity in relation to the number of treated
patients (Table 1). We found that amongst the 4,952 patients assessed, a total of 162 grade three
and 5 grade four treatment-related toxicities were reported. Of these toxicities, 60 were local
reactions, 40 were constitutional symptoms, and 5 were related to the adjuvants used in the
vaccines. The rest, 62 systemic adverse events, were reported by the investigators to be at least
“possibly related” to the vaccines. This constitutes 1.25 adverse events per 100 patients. Of these
62 events 23 were reported to be “possibly related,” 1 “probably related,” and 16 “definitely
related” to the vaccines. The relationship of the remaining 22 events to the vaccines could not be
determined because of the advanced stage of disease. We further analyzed these adverse events
based on the type of cancer vaccines. We found that autologous vaccine trials had a vaccine-
related toxicity rate of 1.36 events per 100 patients (23 events of the total 62 events). Five
toxicities were reported in the allogeneic and 35 in the synthetic vaccine trials, giving a vaccine-
related toxicity rate of 1.23 events per 100 patients in each group. The highest vaccine-related
toxicity rate among the synthetic vaccines was reported in the bacterial vector trials (a total of 7
events, 3.97 events per 100 patients).
Vaccine-related toxicity in relation to the number of administered vaccines
We also evaluated the incidence of toxicities in relation to the total number of administered
vaccines (Table 2). Only 206 of the 239 trials stated the total number of administered vaccines,
and were included in this analysis. These 206 trials treated in aggregate a total of 4,024 patients
who received a total of 21,835 vaccines and experienced a total of 120 grade 3/4 toxicities. Of
these 120 toxicities, 43 were systemic vaccine-related grade 3/4, accounting for 2 adverse events
per 1000 vaccines. Autologous vaccines had the lowest systemic vaccine-related toxicity rate
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(1.4 adverse events per 1000 vaccines), followed by the synthetic vaccines (2.1 adverse events
per 1000 vaccines), and the allogeneic vaccines (2.6 adverse events per 1000 vaccines).
Dose-related toxicity
To determine whether there is any relationship between dose and toxicity, we analyzed the dose-
adverse event relationship in the trials that used a dose escalation design (Table 3). Of the 239
trials, 127 used a vaccine dose escalation design, treating a total of 2,985 patients. Amongst these
127 dose escalation trials, only 22 (17%) reported toxicities of grade 3/4, a total of 98 events.
Forty of these 98 events were systemic, non-constitutional, and vaccine-related. To further
investigate whether a dose-toxicity correlation existed, we performed two analyses:
1) Vaccine-related toxicity in relation to the dose where it occurred
In the first analysis, we identified the dose level where these 40 systemic vaccine-related
toxicities occurred in each of the 22 trials. Seven of these 22 trials did not specify the dose at
which the toxicities occurred (24 systemic toxicities) (10-16). In the remaining 15 trials, only 6
reported the toxicities at the highest dose level (10 systemic toxicities). Two out of these 6 trials
that reported toxicities at the highest dose level used bacterial vaccines (17, 18), and the rest used
autologous (19), DNA (20), viral (21), or liposomal vaccines (22). Two toxicities occurred in the
middle dose level in one trial that used a bacterial vaccine, with no further toxicity occurring
when the dose was escalated (23). Four toxicities occurred at the lowest dose level in 3 trials, 2
with peptide vaccines (24, 25) and one with a liposomal vaccine (22). Interestingly, none of these
trials reported further toxicities when the dose was escalated (Supplemental Table 2).
2) Trials with vaccine-related DLTs
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In the second analysis, we evaluated whether dose escalation resulted in a DLT. Accordingly, we
analyzed the 22 dose escalation trials that reported grade 3/4 systemic vaccine-related toxicities
for evidence of DLT. We found that only 3 of these 22 trials (15, 21, 26) reported DLTs (Tables
3 and 4). Amongst these, one trial, reported by Dols et al., used allogeneic vaccine and attributed
the DLT of nausea and vomiting to the adjuvant (GM-CSF). There were no life-threatening side
effects on this trial (26). The two other trials, reported by Maciag et al. and Guthmann et al.,
attributed the DLTs to the vaccines, both of which used bacterial vectors of live-attenuated
Listeria monocytogenes and Neisseria meningitidis, respectively (15, 21). In both trials the DLT
was consisted of hypotension that was successfully controlled with IV fluids and supporting
medications. All the trials that used bacterial vector vaccines are described in supplemental table
3.
Dose-immune response analysis
In order to determine whether vaccine dose affects the resultant immune response, we reviewed
the dose escalation trials that reported the number of immune responders at each dose level. Only
106 out of the 127 dose escalation trials reported the number of immune responders at each dose
level. We also included 10 additional phase 2 trials that used a dose escalation design and tested
for immune response as a primary endpoint. Accordingly, we identified 116 trials that could be
analyzed for correlation between dose of the vaccine and immune response.
Dose-immune response relationship based on the trials’ reports
Out of these 116 trials, only 2 reported a statistically significant dose-immune response
correlation. The immune response was measured by antibodies in both of these trials. One used
an allogeneic vaccine (11) and the other used an anti-idiotypic vaccine (27).
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Dose-immune response relationship based on the meta-analysis results
Furthermore, we analyzed the relationship of immunological response with dose level based on
the assay that was used to measure the immune response. These assays included delayed-type
hypersensitivity (DTH), T-cell proliferation, interferon-γ ELISPOT, and tetramer assay in
addition, at times, to humoral immune response. We found a statistically significant correlation
between the vaccine dose and the immune response only when the immune response was
measured by antibodies (p<0.001) or DTH (p <0.05). None of the other assays showed a trend
that was statistically significant at a two-tailed 5% level. The results for tetramer assay and T-cell
proliferation were of borderline significance, with a two-tailed significance level of about 10%.
The borderline significance of the tetramer result was driven by a single study reported by
Dangoor et al. that used plasmid DNA and a recombinant modified Vaccinia Virus Ankara
(MVA), both expressing epitopes from five melanoma antigens (18). Without the Dangoor et al.
study, the two-sided p value for the remaining 10 studies did not approach significance. The
borderline significance for T-cell proliferation was similarly non-robust. Only 5 studies were
available that reported results for T-cell proliferation, all were small, and none showed strong
evidence of correlation between the vaccine dose and the immune response. Removal of the
study by Pinilla-Ibarz et al. (28), which used a bcr-abl fusion peptide vaccine, resulted in a two-
tailed p value of 0.26, which did not approach significance.
Since DTH was the only assay that showed a significant dose-cellular immune response
correlation, we examined whether the percentage of DTH immune responders, on a specific trial,
is increased with increasing the dose level (Figure 1). A total of 19 trials reported the immune
response by DTH. We found that the percentage of responders between dose level 1 and dose
level 2 increased or maintained the same in 12 out of these 19 trials, while it trended downward
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in 7 (Figure1a). Amongst the 12 trials that showed an increase or no change in the percentage of
responders, 8 trials continued to show an increase when the dose was escalated from dose level 2
to dose level 3 (Figure 1b). However, only 4 out of these 8 trials continued to increase the dose
to level 4 with only 2 out of these 4 trials reporting an increased immune response by DTH
(Figure 1c). Although the number of patients per dose level in individual trials is limited, the data
indicate the relationship between dose and DTH immune response, although statistically
significant, was variable and inconsistent.
Discussion
The traditional phase 1 dose escalation clinical trial design has been implemented in the
development of cancer vaccines for more than two decades. However, the utility of this design
has been questioned by many investigators and regulatory agencies, including the FDA and the
European Medicines Agency (EMA) (9, 29). Although therapeutic cancer vaccines are generally
expected to have a relatively safe profile and dose-independent efficacy, to date there has been
no systemic evaluation that provides objective evidence to address this issue. Here, and for the
first time, we provide evidence-based proof for limited serious adverse events and lack of dose-
related toxicity for therapeutic cancer vaccines. We found the incidence of grade 3/4 vaccine-
related systemic toxicities to be 1.25 per 100 treated patients and 2 per 1000 administered
vaccines. Moreover, vaccine-related DLTs were found in only 2 of the 127 dose escalation
toxicity-seeking clinical trials reviewed. Both of these clinical trials used bacterial vaccine
vectors. Accordingly, we propose that, with the exception of bacterial vector vaccines, the
traditional dose escalation design to determine MTD is not warranted in the development of
cancer vaccines. Noteworthy, all the cancer vaccine trials that we reviewed here were in early
development and had no clinical efficacy. In addition, there is a possibility that there may be a
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correlation between dose escalation and local or constitutional symptoms since these were not
taken into account in our dose-toxicity relationship analyses. However, these symptoms are not
relevant to the determination of the DLT since they are all manageable toxicities.
Phase 1 trials may also be used to determine the BAD (6, 8). Our analysis of the included trials
in this meta-analysis suggested that the vaccine dose does not increase the rate of the cellular
immune response as measured by some immune assays. Although increasing the vaccine dose
was associated with an increase in immune response rate, as measured by DTH in some trials,
the increase in immune response did not appear consistent or sustainable with further dose
escalation. Our analysis is limited by the fact that most of the trials used experimental immune
assays that have not been validated in order to accurately evaluate the induced cellular immune
response (30). It was also limited by the fact that these phase I trials were not designed with the
objective of characterizing the relationship between dose and immunological response or even
determining whether there is a dose response. Furthermore, the relationship between dose
escalation and the degree of the induced immune response was not addressed in this manuscript
since only a minority of the reviewed trials addressed this point. Detecting a dose that is
biologically active is different from detecting the minimal dose that is biologically active or
determining whether there is a relationship between dose and immunological response. We
suggest that the standard 3+3 phase I design is not generally adequate in detecting a minimal
BAD or the relationship between dose and immunological response in therapeutic cancer
vaccines.
Need for alternative designs for early development of therapeutic cancer vaccines
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The FDA has recently recognized the need for changing the way therapeutic cancer vaccine trials
are being conducted (9). Our results, described above, support that conclusion. The incidence of
dose limiting toxicity in such trials has been very low and consequently the use of designs
developed for the detection of MTD is generally not appropriate.
A “Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines” has been
recently issued by the FDA (9). That Guidance recognizes the inapplicability of the traditional
3+3 design, but indicates that a dose escalation design be used to determine the BAD and that the
selection of the starting “safe” dose for cancer vaccines should be supported by preclinical and/or
prior human safety data. Developing a safe starting dose based on preclinical testing is, however,
not a feasible option in the majority of cancer vaccines due to the species-specific presentation
and recognition of such antigens and variation in immune response activity. In addition, the
results of our review suggest that the dose-escalation approach is problematic for most cancer
vaccines since neither toxicity nor cellular immune response appears consistently related to dose.
Suggested alternative designs by others
Few alternative designs have been considered to replace the traditional dose escalation 3+3 phase
1 design for cancer vaccines. Messer et al. described a combined phase 1/2 design where a phase
1 dose escalation trial serves as an interim safety analysis prior to proceeding to phase 2 (31).
On the other hand, Korn et al. described an initial accelerated phase design where one patient per
dose level is treated until a biological response occurs. After the first response is seen, cohorts of
3-6 patients are treated per dose level in a traditional dose escalation phase (32). Hunsberger et
al. described two stages of dose escalation in order to reach a molecular targeted endpoint. The
first stage uses a 3+3 traditional escalation and the second is developed to continue to escalate
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the dose as long as the biological response rate is increasing (33). Simon et al. described
alternative phase 2 designs for early cancer vaccine trial development (34). The cancer vaccine
clinical trial working group (CVCTWG) has proposed a proof-of-principal trial design that
combines some aspects of phase 1 and 2 trials in patients “without rapidly progressive disease”
(35). Importantly, all of these suggested alternative designs are using a dose escalation method,
which, as we have shown, rarely determines toxicity or biological activity measured by cellular
immune response.
New purposed alternative design
Assumptions in early cancer vaccines development
Here, we suggest an alternative design for cancer vaccine development. To determine the starting
dose of the vaccine, we need to take into account the following assumptions: 1) A cellular
immune response is necessary to induce clinical efficacy. Immune response had been used as a
surrogate for cancer vaccine efficacy in clinical trials (36-39). Many investigators have shown
that patients who generate a T-cell immune response are more likely to have longer survival
compared to non-immune responders (40-42). 2) Cancer vaccine dose does not consistently
correlate with either toxicity or with the prevalence of induction of cellular immune response. 3)
A vaccine as a single agent isn’t enough to induce clinical efficacy, and combination therapy is
needed (43). Accordingly, it is crucial to optimize the cellular immune response generated by a
cancer vaccine when designing an early phase clinical trial by combining the vaccine with other
agents such as immune modulators. Based on the above, our suggested design proposes to define
a dose that can induce an immune response and then combine the selected dose with the
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appropriate immune modulating agents or other therapeutic modalities in order to obtain a better
outcome.
Step 1. Determining a starting dose of a vaccine
We propose a 2-step design (Figure 2). The first step is to determine an immune response-
inducing dose. This would be used in step 2, a phase 2 trial testing the combination of cancer
vaccine and immune modulating agents or other therapeutic modalities. Accordingly, the
intention, first, is to determine a dose that can generate an immune response of a cancer vaccine,
or immune active dose (IAD). Since local adjuvant is often used in combination with the
vaccine, both the vaccine and the adjuvant are considered one entity in our design. The method
of determining the IAD will be dependent on whether the vaccine belongs to a class of vaccines
that has been previously tested in humans. If the vaccine class has been administered in humans
and found to be non-toxic (e.g., a peptide), then we propose using the same IAD shown in
previous trials in a phase 2 combination approach with immune modulators and/or other
therapies. On the other hand, if the vaccine belongs to a class that had been used before and
found to be toxic in humans (e.g., bacterial vectors, as shown above), or a new self-antigen that
is crucial for a vital organ or function (e.g., angiogenesis antigens), then we recommend using
the traditional 3+3 dose escalation design.
Finally, if the tested vaccine is considered “novel” or belongs to a class that has not been tested
before and is expected to be non-toxic, we recommend using a “One Patient Escalation Design
(OPED)” to determine the dose of the antigen that is active in at least one patient. By using the
OPED, one patient per tested dose is treated until an immune response is induced in order to
determine the IAD. To confirm the dose as the IAD, the same dose will be administered to an
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expanded group of patients. Having a precise estimate of the immunological response rate at that
dose is not the goal; rather the goal is to confirm that there is some biological activity at that
dose. We propose the following approach: if the expected cellular immune response rate, with
the vaccine alone at that dose is 30%, the probability of obtaining no responses in an expansion
cohort of 7 patients is .082. So from this perspective, in order to make sure that the initial
response was real, it would be appropriate to expand the cohort at that dose level, one patient at a
time, until achieving an additional response. If no additional response is seen in 7 patients, then
we will stop adding patients and will continue escalation of one patient at a time until we obtain
an immunological response with a confirmatory expansion cohort. However, if an additional
immune response is observed in the expanded cohort, no more patients will be enrolled since the
purpose of adding more patients is to confirm the first immune response.
If the probability of immune response is denoted by p and is independent of dose, then the
number of patients treated until the first response is observed has a geometric distribution; the
probability that the first response occurs at the n’th patient is where q=(1-p). The
probability that the IAD will be confirmed by studying up to 7 patients at the dose level giving a
response is 1 . When p=0.33, the probability that the IAD occurs at the first dose level is
0.31 and the mean dose level at which it occurs is 3. The probability that the IAD is confirmed is
0.94. When p=0.5, the probability that the IAD occurs at the first dose level is 0.496 and the
mean dose level at which it occurs is 2. The probability that the IAD is confirmed is 0.99. If there
is a dose-immunological response relation, then the probability that the first response occurs at
the n’th patient is .
Step 2. Combining the vaccine with immune modulating agents or other therapeutic agents
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The second step is to combine the vaccine with immune modulating agent, chemotherapeutic
agent or other cancer therapy agent referred to as “X” in order to enhance the cancer vaccine
efficacy. During this step the vaccine and the adjuvant are considered one entity and referred to
as “vaccine”. During this step, we recommend using the vaccine’s IAD that is identified in the
first step and setting the ‘’X’’ dose based on its safety profile. If “X” had no known DLT, then
we recommend combining the vaccine with the same “X” dose that was used before. On the
other hand, if “X” has a known DLT then we recommend combining the vaccine with an “X”
dose that is below its MTD. However, if the “X” DLT is unknown (testing a novel agent), then
we recommend proceeding to a traditional phase 1 (3+3) design by escalating the “X” dose in
combination with a fixed dose of the vaccine (IAD). Enhancing the cancer vaccine efficacy
further may require adding another agent “Y” (e.g., immune modulator, chemotherapy or
targeted agent) to the combination of (vaccine + X). In this case, the combination of vaccine and
X should be treated as one entity (vaccine + X) and the ‘’Y’’ dose could be changed based on its
safety profile in a similar method that is used when combing the vaccine with “X”. More agents
could be added to the combination of (vaccine + X + Y) in a similar fashion (Figure 2). Simon et
al. has described a variety of phase 2 designs that can be used for optimizing a vaccine-based
regimen (34).
Advantages and limitations of the new purposed design
Our suggested design has many advantages including the ability to identify the safe and immune
active dose without the need to enroll a large number of patients unless the study is testing a
vaccine class that is known to be toxic. Our design also allows for enhancing the vaccine
efficacy by combining the vaccine with other agents. However, our recommendation may have
some limitations since it does not take into account the possible cumulative toxicities of cancer
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vaccines and the lack of validation of immunological assays. Nevertheless, our suggested design
may represent a step forward in therapeutic cancer vaccine development and needs to be tested in
the future.
References
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26. Dols A, Smith JW, 2nd, Meijer SL, Fox BA, Hu HM, Walker E, et al. Vaccination of women with metastatic breast cancer, using a costimulatory gene (CD80)-modified, HLA-A2-matched, allogeneic, breast cancer cell line: clinical and immunological results. Human gene therapy. 2003;14:1117-23. 27. Brett BT, Smith SC, Bouvier CV, Michaeli D, Hochhauser D, Davidson BR, et al. Phase II study of anti-gastrin-17 antibodies, raised to G17DT, in advanced pancreatic cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002;20:4225-31. 28. Pinilla-Ibarz J, Cathcart K, Korontsvit T, Soignet S, Bocchia M, Caggiano J, et al. Vaccination of patients with chronic myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune responses. Blood. 2000;95:1781-7. 29. (EMEA) EMA. GUIDELINE ON THE CLINICAL DEVELOPMENT OF PRODUCTS FOR SPECIFIC
IMMUNOTHERAPY. 2008 [cited; Available from: www.ema.europa.eu/docs/en_GB/document.../WC500003605.pdf 30. Keilholz U, Weber J, Finke JH, Gabrilovich DI, Kast WM, Disis ML, et al. Immunologic monitoring of cancer vaccine therapy: results of a workshop sponsored by the Society for Biological Therapy. J Immunother. 2002;25:97-138. 31. Messer K, Natarajan L, Ball ED, Lane TA. Toxicity-evaluation designs for phase I/II cancer immunotherapy trials. Statistics in medicine. 2010;29:712-20. 32. Korn EL, Arbuck SG, Pluda JM, Simon R, Kaplan RS, Christian MC, et al. Clinical trial designs for cytostatic agents: are new approaches needed?. J Clin Oncol. 2001;19:265-72. 33. Hunsberger S, Rubinstein LV, Dancey J, Korn EL. Dose escalation trial designs based on a molecularly targeted endpoint. Statistics in medicine. 2005;24:2171-81. 34. Simon R. Clinical trial designs for therapeutic cancer vaccines. Cancer treatment and research. 2005;123:339-50. 35. Hoos A, Parmiani G, Hege K, Sznol M, Loibner H, Eggermont A, et al. A clinical development paradigm for cancer vaccines and related biologics. J Immunother. 2007;30:1-15. 36. Disis ML. Immunologic biomarkers as correlates of clinical response to cancer immunotherapy. Cancer immunology, immunotherapy : CII. 2011;60:433-42. 37. O'Meara MM, Disis ML. Therapeutic cancer vaccines and translating vaccinomics science to the global health clinic: emerging applications toward proof of concept. OMICS. 2011;15:579-88. 38. Slota M, Lim JB, Dang Y, Disis ML. ELISpot for measuring human immune responses to vaccines. Expert Rev Vaccines. 2011;10:299-306. 39. Broussard EK, Disis ML. TNM staging in colorectal cancer: T is for T cell and M is for memory. J Clin Oncol. 2011;29:601-3. 40. Slingluff CL, Jr., Petroni GR, Olson W, Czarkowski A, Grosh WW, Smolkin M, et al. Helper T-cell responses and clinical activity of a melanoma vaccine with multiple peptides from MAGE and melanocytic differentiation antigens. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26:4973-80. 41. Kirkwood JM, Lee S, Moschos SJ, Albertini MR, Michalak JC, Sander C, et al. Immunogenicity and antitumor effects of vaccination with peptide vaccine+/-granulocyte-monocyte colony-stimulating factor and/or IFN-alpha2b in advanced metastatic melanoma: Eastern Cooperative Oncology Group Phase II Trial E1696. Clin Cancer Res. 2009;15:1443-51. 42. Rahma OE, Ashtar E, Czystowska M, Szajnik ME, Wieckowski E, Bernstein S, et al. A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients. Cancer Immunol Immunother. 2012;61:373-84.
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Table 1. Vaccine-related toxicities based on the number of treated patients
Vaccine trials All Grade 3/4 AE *Systemic Vaccine-
Related Grade 3/4 AE
Vaccine Category
No. Trials
No.
Patients
No.
Events
%
Events
No.
Events
%
Events
Autologous 87 1692 37 2.19 23 1.36
DC 57 922 9 0.98 3 0.33
Tumor 30 770 28 3.64 20 2.60
Allogeneic 17 407 22 5.41 5 1.23
Synthetic 135 2853 108 3.79 35 1.23
Peptide 68 1333 40 3.00 11 0.83
DNA 17 311 1 0.32 1 0.32
RNA 2 36 0 0 0 0
Virus 30 662 23 3.47 13 1.96
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Bacteria 6 126 27 21.43 7 3.97
Anti-idiotypic 10 362 15 4.14 0 0
Liposomal 2 23 2 8.70 2 8.70
Total 239 4952 167 3.37 62 1.25
Table 2. Vaccine-related toxicities based on the number of administered vaccines
Vaccine Trials All Grade 3/4
AE
*Systemic Vaccine-Related Grade 3/4
AE
Vaccine Category
No.
Trials
No.
Patients
No.
Vaccines
No.
Events
%
Events
No.
Events
%
Events
Autologous 73 1301 5722 20 0.35 8 0.14
DC 51 796 3424 9 0.26 3 0.09
Tumor 22 505 2298 11 0.48 5 0.22
Allogeneic 16 347 1874 22 1.17 5 0.26
Synthetic 117 2376 14239 78 0.55 30 0.21
Peptide 61 1183 7637 37 0.48 9 0.12
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DNA 15 259 1388 1 0.07 1 0.07
RNA 2 36 335 0 0 0 0
Virus 27 535 2365 22 0.93 13 0.55
Bacteria 4 80 530 9 1.70 5 0.94
Anti-idiotypic 7 266 1938 7 0.36 0 0
Liposomal 1 17 46 2 4.35 2 4.35
Total 206 4024 21835 120 0.55 43 0.20
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Table 3. Dose-toxicity relationship
Vaccine Category
No.
Trials
No.
Patients
Grade 3/4
No.
Trials with DLT
No. Trials
No.
Events
*No. Systemic Vaccine-Related
AE
Autologous 40 847 2 11 8 0
DC 27 466 0 0 0 0
Tumor 13 381 2 11 8 0
Allogeneic 5 130 3 20 5 1
Synthetic 83 2008 17 67 27 2
Peptide 36 852 7 10 7 0
DNA 12 208 1 1 1 0
Virus 26 592 7 47 17 0
Bacteria 4 81 4 27 7 2
Anti-idiotypic 8 339 1 7 0 0
Liposomal 1 17 1 2 2 0
Total 127 2985 22 98 40 3
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Table 4. Trials with Dose Limiting Toxicities (DLTs)
Trial Vaccine used Toxicity DLT
Dols, 2003 Allogenic HER2/neu+
breast cancer cells (SC) with GM-CSF or BCG
Nausea
Vomiting
1 patient due to
GM-CSF
Maciag, 2009
Listeria monocytogenes secreting HPV-16 E7
fused to Lm listeriolysin O (IV)
Hypotension 3 patients at highest dose
level
Guthmann, 2004 GM3 ganglioside with Neisseria meningitidis outer membrane (IM)
Hypotension 1 patient at
highest dose level
Table and figure legends
Table 1. Vaccine-related toxicities based on the number of treated patients: The number of
grade 3/4 adverse events (AE) in relation to the number of treated patients. * Systemic vaccine-
related adverse events are all grade 3/4 toxicities possibly, probably or defiantly related to the
vaccine except for local reactions and constitutional symptoms.
Table 2. Vaccine-related toxicities based on the number of administered vaccines: The
number of grade 3/4 adverse events (AE) in relation to the number of administered vaccines. *
Systemic vaccine-related adverse events are all grade 3/4 toxicities possibly, probably or
defiantly related to the vaccine except for local reactions and constitutional symptoms.
Table 3. Dose-toxicity relationship: The number of grade 3/4 adverse events (AE) in dose
escalation trials and the number of trials that identified DLTs. * Systemic vaccine-related
adverse events are all grade 3/4 toxicities possibly, probably or defiantly related to the vaccine
except for local reactions and constitutional symptoms.
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27
Table 4. Trials with Dose Limiting Toxicities (DLTs): Dose escalation trials with dose
limiting toxicities (DLTs). Abbreviations: SC, subcutaneously; IV, intravenously; IM,
intramuscularly.
Figure 1. The change in the percentage of immune responders on each trial measured by DTH
from dose level 1 (D1) to 2 (D2) (Figure 1a); dose level 2 (D2) to 3 (D3) (Figure. 1b) and dose
level 3 (D3) to 4 (D4) (Figure. 1c). Trials that showed an increase in the percentage of immune
responders are marked in blue while trials that showed no change or decrease in the percentage
of responders are marked in red.
Figure 2. The suggested alternative design for early cancer vaccine development
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0
20
40
60
80
100
120
D2 D3
Imm
un
e R
esp
on
se %
0
20
40
60
80
100
120
D1 D2
Imm
un
e R
esp
on
se %
(3)
0
10
20
30
40
50
60
70
80
D3 D4
Imm
un
e R
esp
on
se %
A B
C
Figure 1
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Figure 2. Alternative Clinical Trial Design For Cancer Vaccine
Step 1. Determining a starting dose of a vaccine
Step 2. Combination Design “Vaccine + X”
(X is an immune modulator, chemotherapy or targeted agent)
X had no DLT X had a DLT X’ DLT is unknown
Use the same dose Use the dose below MTD Proceed to traditional phase 1
Vaccine class that is used before & found
to be toxic (e.g., bacterial vector)
Vaccine class that is used before & found
to be non-toxic (e.g., peptide)
Vaccine class that is not used before &
not expected to be toxic
Proceed to traditional phase 1 trial
Use Immune Active Dose (IAD) from
previous clinical trials
One Patient Escalation Design (OPED) •One patient per tested dose is treated until an immune
response is induced (IAD).
•Then expand that dose level, one patient at a time,
until achieving an additional immune response.
•If no additional immune response in 7 patients, stop
adding patients and continue escalation of one patient
at a time.
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Published OnlineFirst July 18, 2014.Clin Cancer Res Osama E Rahma, Emily Gammoh, Richard Simon, et al. recommendation for alternative designfor therapeutic cancer vaccine development? A Is the "3+3" dose escalation phase 1 clinical trial design suitable
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