[CLINICAL SUMMARY DOCUMENT]{.smallcaps}

[FOR THE]{.smallcaps}

[ONCOLOGIC DRUGS ADVISORY COMMITTEE]{.smallcaps}

#### CAMPTOSAR + 5-FU/LV FOR FIRST-LINE TREATMENT OF METASTATIC COLORECTAL CANCER: A POST-MARKETING RE-EVALUATION OF SAFETY

#### Isagani M. Chico, MD

#### Donna J. Griebel, MD

Division of Oncology Drug Products

In April 2000, Camptosar was approved for first line treatment of
metastatic colorectal carcinoma. The approval was based on a significant
survival advantage demonstrated in the CPT-11+5FU/LV treatment arms of
two randomized controlled trials, Study 0038 and Study V303. Study 0038
(U.S.) was a three-arm trial comparing CPT-11+ 5FU/LV weekly x 4 (bolus,
Saltz Regimen), 5FU/LV daily x 5 (Mayo Clinic Regimen), and single agent
CPT-11. Study V303 compared two infusional regimens of 5FU/LV, each in
combination with CPT-11, to the same infusional regimens without CPT-11.

A year later, in April 2001, a prespecified interim analysis of a North
Central Cancer Treatment Group (NCCTG) trial, N9741, found a
disproportionately high number of early deaths (deaths within 60 days of
starting treatment on study) in the Saltz regimen control arm compared
to two oxaliplatin combination regimens (4.8% on the Saltz arm vs. 1.8%
on each of the oxaliplatin combination arms). This finding led to an
unplanned interim safety analysis of a Cancer and Leukemia Group B
(CALGB) adjuvant trial, C89803, that compared adjuvant treatment with
the Saltz regimen to the weekly 5FU/LV Roswell Park regimen. A higher
early death rate on the Saltz regimen was again observed (2.2% vs. 0.8%
on the Roswell Park regimen arm). Based on these interim analyses, one
unplanned, accrual to the NCCTG trail was temporarily suspended until
the trial was redesigned, and the CALGB study was permanently closed to
new accrual.

In response to the findings of these two interim analyses, P&U funded a
panel organized by Theradex to review patient records of the early
deaths in the cooperative group trials. The review panel was charged
with assigning attribution for death, reviewing the patients'
management, reviewing chemotherapy administration and adherence to the
protocol dose modification guidelines, and identifying patient
characteristics associated with increased risk of death on the Saltz
arm. The results of that review and the recommendations of the panel
were published in the Journal of Clinical Oncology in September
2001.[^1]

The review panel found that the deaths on the Saltz arms of these
studies also occurred earlier than on the control arm -- median time to
death 29 days (n=29) vs. 47 days (n=5) on the Roswell Park comparator
arm of the adjuvant trial. They found that the primary cause of
drug-related death was a combination of chemotherapy-induced diarrhea,
neutropenia, fever, and consequent dehydration and electrolyte
abnormalities. In addition, a number of patients had fatal vascular
events (both arterial and venous). These vascular events were considered
to be potentially treatment-related, but a specific pharmacological
basis for causality was not proposed. The panel was unable to clearly
define a high-risk patient profile, although they suggested that older
patients might be at higher risk for death on the Saltz regimen. Poor
performance status was not clearly associated with risk of death. They
did not find problems related to adherence to protocol guidelines for
treatment/dose modification, but did note that there were isolated
dosing errors and reported that antibiotic use was often "delayed",
"prematurely discontinued', or "inappropriately selected" in a number of
patients, possibly contributing to their deaths.

The panel made the following recommendations based upon their review:

1.  Health care providers should be made more aware of the
    gastrointestinal and vascular syndromes associated with
    CPT-11+5FU/LV bolus regimen.

2.  Patient monitoring should be heightened in frequency (i.e., weekly
    assessment at least in the first cycle of treatment), with closer
    follow-up for signs of dehydration and allowance should be made for
    resolution of gastrointestinal and hematologic toxicity syndromes.
    They suggested that older individuals should be followed "especially
    closely."

3.  Supportive care of patients treated with the Saltz regimen should be
    heightened; including adding an oral fluoroquinolone to the
    management of diarrhea, hospitalizing patients if diarrhea persists
    \>48 hours and initiating antibiotics during hospitalization if the
    patient has prolonged diarrhea, even with an adequate neutrophil
    count.

4.  Specific recommendations for modifying dosing were not given by the
    panel. However, treatment related recommendations included;
    requiring that diarrhea and abdominal cramps resolve for at least 24
    hours before resuming treatment, and that pre-treatment CBC's should
    be performed no more than 48 hours before scheduled treatment. The
    panel suggested that dose modification criteria should incorporate
    toxicity grade and duration, the need for supportive care after the
    prior dose, and the interval since resolution of toxicity.

A "Dear Health Care Provider" letter to notify physicians of the
findings in the cooperative group trial was distributed by P&U in May
2001. The recommendations of the review panel were available to the
public in September. In response to these reports, there have been
proposals made for altering the Saltz regimen, including reducing the
starting dose by 20% and changing the schedule to incorporate a week of
rest after the second week of treatment.. The NCCTG trial was changed to
incorporate treatment interruption for grade 2 toxicity and to increase
the dose reduction for grade 3 toxicity to two dose levels. The
guidelines for administering the Saltz bolus regimen that are currently
found in the product label are those followed in the randomized,
controlled trial that served as the basis for the approval of this
regimen, Study 0038.Whether these newly proposed changes will adequately
improve safety while retaining the efficacy of the Saltz regimen will be
unknown without prospective study.

The patient safety issues raised by the findings of the cooperative
group trials must be examined carefully, and any proposals to address
these issues deserve serious consideration. The purpose of this advisory
committee meeting is to critically evaluate the observations of early
deaths in the cooperative group trials in light of the more extensive
and mature data sets from the trials that were the basis of Camptosar's
approval for first line treatment of colorectal cancer, and consider the
most appropriate regulatory action that should be taken to respond to
these findings. The potential alternatives from a regulatory standpoint
include no action, modification of the label to incorporate measures to
enhance supportive care, modification of the Saltz regimen's
administration schedule and/or dose modification scheme in the label, or
removal of the Saltz regimen from the label. The product label includes
an alternative administration schedule of the CPT-11+5FU/LV combination,
an infusional biweekly schedule called the Doulliard regimen, that was
used in one of the first line indication licensing trials. If available
data justify removal of the Saltz regimen from the product label, this
infusional regimen would still remain as an approved treatment regimen
for first line treatment of metastatic disease. The GI Intergroup
Executive Committee met earlier this fall and concluded that this
infusional combination regimen should be the regimen used for future
Intergroup investigations.

The following sections summarize the FDA's review of the findings of the
cooperative group trials in the context of the two licensing studies
that were the basis of Camptosar's approval for first line treatment of
colorectal carcinoma.

## FDA Review of Early Deaths on the Cooperative Group Trials

The FDA reviewed the records of the 29 patients who died in the
cooperative group trials and was unable to identify characteristics that
placed patients at high risk for early death with the Saltz regimen.
There was a slight preponderance of females and patients greater than 65
years of age in this group. (The current Camptosar label states in the
Pharmacokinetics in Special Populations section that no change in
starting dose is recommended for geriatric patients receiving the weekly
dosage schedule, and the Geriatric Use subsection of the Warnings
section states that patients greater than 65 years of age should be
closely monitored because of a greater risk of late diarrhea in this
population.) Only 2/29 had a performance status greater than 1. FDA
review concurred with the findings that most deaths occurred within 4
weeks of starting treatment. Most patients received two full doses of
chemotherapy before it was either terminated or modified, and 14 of the
29 had no dose modification up to the time of their death. Five of the
patients who met criteria for dose reduction were not given
appropriately reduced doses. The fact that so many patients were treated
at full dose on a weekly regimen up to the events that led to their
death suggests that once the adverse events occur, there is little
opportunity to alter the course with dose modification.

## FDA Analysis of Early Deaths in the Licensing trials 0038 and V303

Unlike the NCCTG and the CALGB trials, the rate of death within 60 days
of starting treatment in the Saltz regimen arm (bolus CPT-11+5FU/LV) of
licensing study 0038 was similar to the corresponding control arm. The
rate of death within 60 days of starting therapy in the Saltz regimen
arm of 0038 is actually higher than observed on the Saltz regimen arms
of the cooperative group trials. The median time to death in patients
who died within 60 days in both arms of Study 0038 was similar to that
in the cooperative group trials, 28 days. (see Table 7, FDA full report)

The Camptosar product label reports that the rate of [deaths within 30
days of any treatment]{.underline} on study was 9% in the Saltz regimen
arm of Study 0038 and 4% in the Douillard arm of Study V303. These
percentages are higher than the rates presented as [deaths within 60
days of starting treatment]{.underline} in these studies. It has been
argued that inclusion of an "early deaths" analysis in the product label
would have provided some context for evaluating the rates observed in
the cooperative group trial interim analyses. Deaths are analyzed within
the context of an NDA submission and review as deaths that occur within
30 days of drug administration throughout the entire study. This is
considered a valid and meaningful method of comparison because the full
data set from the trial is analyzed and the temporal relationship with
drug administration implies the drug's potential role in the death,
while avoiding the bias introduced by assigning causality.. Reporting
deaths within 60 days of starting therapy conveys information regarding
the prevalence and severity of early, acute toxicity. Early deaths raise
questions about the appropriateness of starting dose and the management
of toxicity, both from a supportive care and a dose modification
standpoint. The licensing trial datasets were queried with these
questions in mind and the findings are discussed below.

## Reanalysis of Camptosar Licensing Trials for First-Line Treatment of Metastatic Colorectal Cancer

There are two administration schedules of CPT-11+5FU/LV approved for the
first-line treatment of metastatic colorectal carcinoma, the Saltz
regimen and the Douillard regimen. The safety profiles of both approved
first line treatment regimens were reviewed. Differences between the two
administration schedules observed in the cross-study comparisons
presented could be secondary to unrecognized differences in the patient
populations. Although the study populations appeared similar, Study V303
enrolled fewer patients with performance status 2 and allowed enrollment
of patients with a history of radiotherapy.

A combination of GI and hematologic syndromes was observed in most
patients who died within 60 days of starting treatment with both the
Saltz regimen and the 5-FU/LV control in Study 0038. The predominance of
GI+Heme/Infectious syndromes (60% for Saltz in Study 0038 ) is similar
to that observed in the cooperative group trials.

The incidence of Grade 3/ 4 diarrhea and mucositis in the overall
populations of the CPT-11+5FU/LV arms was similar between Study 0038 and
V303. Grade 3 or 4 neutropenia was higher on the Saltz regimen, but
neutropenic fever was only slightly higher. Considering all cycles, the
incidence of fever with neutropenia was higher with the Saltz regimen
(16%) compared to the Douillard regimen (5.5%). Grade 3 and 4 vomiting
was more common on the Saltz regimen. The overall incidence of arterial
and venous thromboembolic events was similar between the Saltz and
Douillard regimens. The rate of discontinuations due to adverse events
between patients treated with the Saltz and Douillard regimens was
relatively similar.

A majority of the patients require dose reductions in [both
arms]{.underline} of Study 0038. (see Table16, full report) There is a
sharp drop (about 27%) in the proportion of patients treated with full
doses of the Saltz regimen between the second and third week of the
first cycle. Only 47% of patients received full-dose therapy by the
second cycle. The survival advantage associated with the Saltz regimen
was demonstrated despite significant reductions in doses.

In Study V303, there was a more gradual decline in the proportion of
patients treated at full doses in [both]{.underline} treatment arms.
(see Table 19, full report) More than 85% of patients received full
doses at the second cycle and 80% at the third. The much higher
proportion of patients treated with full doses in this study compared to
Study 0038 may indicate better patient tolerance of the higher biweekly
dose of Camptosar and infusional 5-FU regimen utilized in this study.
There was a somewhat higher proportion of deaths in the first 60 days
after starting treatment in Study 0038 compared to V303, but
unidentified differences in patient characteristics or supportive care
measures could have contributed to these apparent differences across
studies.

The preponderance of early deaths and the marked dose reductions
necessary within one cycle on Study 0038 argue that the starting dose
and/or dose modification guidelines for the Saltz regimen should be
modified. The major dose change recommended by the Theradex panel was to
hold treatment for grade 2 diarrhea or abdominal cramping. P&U has
proposed to change the dose modification guidelines in the product label
to recommend holding treatment for either grade 2 diarrhea or
neutropenia. If the protocol for Study 0038 had required a treatment
hold for Grade 2 toxicity, over half (8/15) of the patients who died
within 60 days of starting treatment on the Saltz regimen in that study
would have been impacted A total of 45 (20%) patients on the Saltz arm
of 0038 (analysis includes all patients, not just those died within 60
days of starting treatment) initially presented with a Grade 2 event
that became worse upon continuous treatment. This group of patients
would have been affected by the proposed dose modification change. On
the other hand, 47 (21%) patients who initially presented with a grade 2
event did not worsen with continuous treatment. The dose intensity in
this group of patients would have been affected adversely had this dose
modification been followed. The sponsor's labeling proposal retains the
current label's instructions to resume treatment in subsequent cycles at
full doses in patients who experienced grade 2 toxicity, despite the new
plan to reduce within-cycle weekly doses for within-cycle toxicity.

The current product label states that for grade 3 toxicity the dose
should be held until resolution to at least grade 2 and then resumed
with a one dose level reduction. The proposed label changes submitted by
P&U retain the one dose level reduction, but now require toxicity to
resolve to at least grade 1 before resuming treatment. For Grade 3
adverse events, some ongoing studies have proposed a reduction of TWO
dose levels. Of the 225 patients treated in the Saltz regimen arm of
Study 0038, 81 (36%) presented with a Grade 3 or 4 event initially.
These events clustered between the third and fourth weeks of the first
cycle.

The use of quinolones as prophylactic treatment once grade 4 or
persistent diarrhea was observed was specified in Study V303, but not in
Study 0038. It is difficult to infer from the licensing trials' database
whether use of antibiotics prevented life threatening sepsis or
infections. Quinolones were used in both studies. The Theradex panel
recommended quinolone use for persistent diarrhea, diarrhea accompanied
by fever, or prophylaxis if ANC\<500, and P&U has incorporated those
recommendations in the proposed product label changes. P&U has added
that "antibiotic support" should be started in patients who develop
ileus, and in keeping with the panel recommendations has proposed that
the label state that patients should be provided with a prescription for
oral fluoroquinalone (a 7 day course) when they start treatment, to use
as needed.

## SUMMARY OF ISSUES

A disproportionate number of early deaths on the Saltz regimen arms of
two cooperative group studies prompted those trials to be placed on
clinical hold and has led to serious re-evaluation of the safety of this
approved regimen. The data monitoring committees that performed the
interim analyses of the cooperative group trials were not evaluating a
mature data set, and one of the interim analyses performed was not a
prespecifed analysis. When the early death data from these analyses are
compared to mortality data from the licensing trial, the absolute death
rates and events that preceded deaths on the Saltz arms appear similar
to those observed in the licensing trial. These observations are made
with the caveat that there are inherent flaws in performing [cross
study]{.underline} comparisons. The [within study]{.underline}
comparison of the early death rate associated with the Saltz regimen in
the licensing trial was similar to its 5FU/LV control arm, whereas the
[within study]{.underline} comparisons in the cooperative group trials
found that early deaths on the Saltz arms occurred at a
disproportionately higher rate than the controls.

A panel of colorectal cancer experts who reviewed the patients' records
from these cooperative group trials has proposed changes in the use of
the Saltz regimen to enhance its safety. Others have proposed altering
the regimen's doses and schedule. The pattern of early dose modification
in a substantial portion of the patients treated with the Saltz regimen
in licensing Study 0038 suggests that its starting dose may be high. The
sponsor has proposed labeling changes that retain the starting dose and
administration schedule, but employs more aggressive dose modification
in response to observed toxicity. It is unclear whether these changes
will affect the efficacy of the regimen, an issue that not only impacts
the ability of an altered Saltz regimen to serve as a control arm in
efficacy trials, but more importantly, challenges the safety of
retaining the regimen in the product label without adequate supportive
data.

The Douillard regimen (continuous infusion) is also approved in the
United States. Review of the adverse events and patterns of dose
modification in the licensing study indicate that this regimen might
have a more acceptable safety profile compared to the Saltz regimen, but
there has been no "head to head" comparison of the two regimens to fully
support this. The GI Intergroup Executive Committee members have
recently recommended that the Douillard regimen be used by the group in
future studies that utilize a CPT-11+5FU/LV arm.

Labeling modifications that affect a regimen's administration should
ideally be prospectively studied to evaluate their impact on safety and
efficacy. Study designs that could clearly demonstrate safety and
efficacy of a "modified" version of the Saltz regimen need to be
discussed, as concern has been raised over the practicality of enrolling
the large numbers of patients required to demonstrate noninferiority of
a modified Saltz regimen in terms of survival. In the meantime, the
Agency must determine the most appropriate regulatory response to
address the current safety concerns. This decision hinges on whether the
safety concerns raised by the cooperative group interim analyses are
valid. If the ODAC believes that they are, then the committee will need
to consider to what extent the label should be modified to adequately
protect the safety of cancer patients.

[^1]: Rothenberg M, Meropol N, Poplin E, Van Cutsem E, Wadler S. JCO,
    Vol 19, No. 18, 2001: 3801-3807.