Is the “3+3” dose escalation phase 1 clinical trial design suitable … · 2014. 7. 18. · 3 dose could be used in combination with other agents in phase II/III clinical trials

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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.

Research. on January 28, 2021. © 2014 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on July 18, 2014; DOI: 10.1158/1078-0432.CCR-13-2671

http://clincancerres.aacrjournals.org/

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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: [email protected]

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.

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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




23

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




24

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




25

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




26

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.




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




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




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.




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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Is the “3+3” dose escalation phase 1 clinical trial design suitable … · 2014. 7. 18. · 3 dose could be used in combination with other agents in phase II/III clinical trials