# 

# 

# 

# Issues in the Clinical Development of Investigational Agents Being Evaluated for the Post-surgical Adjuvant Treatment of High-Risk (Stages IIb and III) Melanoma

# 

# 

# Oncology Drugs Advisory Committee

####### February 27, 2002

# 

# Table of Contents

[Table of Contents 2](#table-of-contents)

[Background 2](#background)

[Applications for investigational agents submitted to CBER for the
treatment of melanoma
3](#applications-for-investigational-agents-submitted-to-cber-for-the-treatment-of-melanoma)

[Efficacy supplement for Intron A 5](#efficacy-supplement-for-intron-a)

[Multicenter, randomized controlled trials of IFN in the adjuvant
treatment of melanoma
6](#multicenter-randomized-controlled-trials-of-ifn-in-the-adjuvant-treatment-of-melanoma)

[INTRONA high dose 6](#introna-high-dose)

[ECOG EST 1684 6](#ecog-est-1684)

[ECOG 1690/S9111/C9190 7](#ecog-1690s9111c9190)

[ECOG 1694 9](#ecog-1694)

[ECOG EST 2696 10](#ecog-est-2696)

[INTRONA low dose 11](#introna-low-dose)

[Rusciani et. al. 11](#rusciani-et.-al.)

[ECOG 1690/S9222/C9190 12](#ecog-1690s9222c9190)

[Scottish Melanoma Group 12](#scottish-melanoma-group)

[Roferon‑A high dose 13](#roferona-high-dose)

[NCCTG 83-7052 13](#ncctg-83-7052)

[Roferon‑A low dose 14](#roferona-low-dose)

[WHO CT 16 14](#who-ct-16)

[M 23031 15](#m-23031)

[UKCCCR 16](#ukcccr)

[AMCG 16](#amcg)

[Low-dose interferon (unspecified) 17](#low-dose-interferon-unspecified)

[EORTC 18871 17](#eortc-18871)

[Overview of randomized, observational controlled studies of Interferon
for the adjuvant treatment of melanoma
19](#overview-of-randomized-observational-controlled-studies-of-interferon-for-the-adjuvant-treatment-of-melanoma)

[Methodology 19](#methodology)

[Search method and criteria for inclusion
19](#search-method-and-criteria-for-inclusion)

[Results 20](#results)

[Progression free survival 20](#progression-free-survival)

[Overall survival 21](#overall-survival)

[Data to support the effectiveness of adjuvant treatment in breast and
colorectal cancer
22](#data-to-support-the-effectiveness-of-adjuvant-treatment-in-breast-and-colorectal-cancer)

[Colon Cancer 22](#colon-cancer)

[Breast cancer 24](#breast-cancer)

[Tamoxifen 24](#tamoxifen)

[Taxol 26](#taxol)

[Summary 27](#summary)

[Bibliography 28](#bibliography)

# Background

The incidence of malignant melanoma in recent years has risen steadily
worldwide at a rate of approximately 5% annually.[^1]^,^[^2] During the
last forty years, the number of cases of malignant melanoma in the
United States has almost tripled. Projections for the year 2001 are
estimated at a total of 51, 400 new cases with 7,800 deaths. [^3]

Melanoma is predominantly a disease of Caucasians, occurring somewhat
more commonly in males (male to female ratio is 1.2:1). The median age
at diagnosis is 50.[^4] Prognostic factors for patients with cutaneous
primary sites include gender, age, tumor ulceration, and clinical
stage.[^5]

The disease staging classification system most often used in recent
years is the classification system devised by the American Joint
Committee on Cancer (AJCC).[^6] The staging is based on tumor size,
presence or absence of nodal involvement, and presence or absence of
metastases. Staging of the primary tumor lesion may be based upon lesion
thickness \[Breslow system\] or extent of invasion into adjacent tissues
\[Clark system\]. A simplified version of the 1992 AJCC classification
is presented in table 1. An updated version of this classification
system that includes other prognostic factors (such as presence/absence
of ulceration in the primary lesion) has been formally approved by the
AJCC and will become official with the publication of the sixth edition
of the AJCC Cancer Staging Manual in 2002.[^7]

+-----+-------+---------------+--------------------------------+-------+
| St  | Bres  | TNM           | Nodal involvement and          | 5     |
| age | low's |               | metastatic sites               | -year |
|     | thic  |               |                                | sur   |
|     | kness |               |                                | vival |
|     | (mm)  |               |                                | (%)   |
+-----+-------+---------------+--------------------------------+-------+
| I A | \     | T1, N0, M0    | \-\-\--                        | 97    |
|     | <0.76 |               |                                |       |
| I B |       | T2, N0, M0    |                                |       |
|     | 0.7   |               |                                |       |
|     | 6-1.5 |               |                                |       |
+-----+-------+---------------+--------------------------------+-------+
| II  | 1     | T3, N0, M0    | \-\-\--                        | 79    |
| A   | .51-4 |               |                                |       |
|     |       | T4, N0, M0    |                                |       |
| II  | \>4   |               |                                |       |
| B   |       |               |                                |       |
+-----+-------+---------------+--------------------------------+-------+
| III | Any   | Any T, N1, M0 | N1: positive node 3 cm         | 53    |
|     |       | or            |                                |       |
|     |       |               | N2: positive node \> 3cm       |       |
|     |       | Any T, N2 M0  | and/or in-transit metastases   |       |
+-----+-------+---------------+--------------------------------+-------+
| IV  | Any   | Any T, Any N, | M1a: metastases in skin,       | 17    |
|     |       | M1a or M1b    | subcutaneous tissue or lymph   |       |
|     |       |               | node(s) beyond the regional    |       |
|     |       |               | basin                          |       |
|     |       |               |                                |       |
|     |       |               | M1b: visceral metastases       |       |
+-----+-------+---------------+--------------------------------+-------+
| *   |       |               |                                |       |
| *Ta |       |               |                                |       |
| ble |       |               |                                |       |
|  1. |       |               |                                |       |
| A   |       |               |                                |       |
| JCC |       |               |                                |       |
| cl  |       |               |                                |       |
| ass |       |               |                                |       |
| ifi |       |               |                                |       |
| cat |       |               |                                |       |
| ion |       |               |                                |       |
| (1  |       |               |                                |       |
| 992 |       |               |                                |       |
| )** |       |               |                                |       |
+-----+-------+---------------+--------------------------------+-------+

Most cases of melanoma are diagnosed at a relatively early stage. The
distribution according to stage of disease at presentation is stage I
(64 %), stage II (23%), stage III (9%), and stage IV (5%).[^8] When
diagnosed at an early stage (stage I), surgical resection results in
10-year cure rates of approximately 95%. Increasing thickness (or extent
of invasion of the local tumor) and the involvement of regional nodes,
while resectable, carry a higher risk of recurrence. Patients with
dissemination to distant organs have a median survival of 4 to 8 months
with a 5-year survival rate of approximately 15%. Complete surgical
extirpation of tumor is generally not an option, thus treatment options
are limited to systemic therapy (chemotherapy and/or biological
therapies) and radiation therapy for palliation. Systemic therapy has
not been shown to prolong survival.

The optimal surgical treatment of melanoma has been examined in several
large controlled studies [^9]^,^[^10]^,^[^11]^,^[^12]^,^[^13] and will
not be reviewed in this document. Because of the increased risk of
recurrence with thicker lesions and/or nodal involvement, post-surgical,
adjuvant treatment is considered for those subjects with more advanced
localized disease. The only drug approved for the post-surgical,
adjuvant treatment of melanoma is interferon alpha 2b (INTRON A).
However due to the toxicity profile associated with the approved dose
and schedule, strong interest continues in the development of new agents
for this indication. Since the approval of INTRONA in 1995, there has
been controversy regarding the benefits conferred by INTRONA,
particularly with regard to the effect on survival, which has continued
to evolve as the results of additional trials have become available.
Based on the evidence accumulated over time, CBER would seeks input
regarding whether INTRONA should be considered the standard of care and,
if so, requests guidance on the patient populations and trial designs
that are appropriate for clinical development programs for
investigational agents in this clinical setting.

As background, the following information is reviewed in this document

-   An overview of the submissions to CBER for biological products being
    studied for the treatment of melanoma

```{=html}
<!-- -->
```
-   A review of the clinical trial and data supporting the original
    approval of INTRONA;

```{=html}
<!-- -->
```
-   The results of additional trials using both INTRONA and ROFERON A at
    a variety of doses and schedules

```{=html}
<!-- -->
```
-   Overviews of the results of randomized, controlled trials, conducted
    by CBER staff and an independent meta-analysis of essentially the
    same dataset

```{=html}
<!-- -->
```
-   The data used to support approval of adjuvant therapy for colon and
    breast cancer.

# Applications for investigational agents submitted to CBER for the treatment of melanoma

We reviewed the CBER database to identify investigational new drug
applications (INDs) evaluating agents for the treatment of melanoma
alone or for the treatment of melanoma in addition to other
malignancies. Between the years 1975 and 2000, CBER received a total of
2665 applications for investigational agents being evaluated for cancer
treatment. Of these, 196 (7%) INDs contained protocols for agents being
evaluated for the treatment of melanoma. The majority of the INDs (\>70
%) were for agents being evaluated only for the treatment of melanoma
and 106 INDs (54%) are currently active. Figure 1 shows the number of
IND applications submitted for agents being evaluated for the treatment
of melanoma between 1975 and 2000. Over the past decade, the number of
submissions for investigational agents in this area has dramatically
increased.

  -----------------------------------------------------------------------
  ![](media/image1.wmf)

  **Fig 1. Number of INDs for the indication of melanoma (active and
  non-active) years 1975-2000**
  -----------------------------------------------------------------------

In order to further determine the extent of activity, we requested the
annual reports for all of the INDs identified by this search. The annual
reports contain progress reports for each trial conducted under an IND.
Annual reports were submitted to 157 INDs; it is assumed that the
remaining 39 INDs (20%) may have never enrolled subjects. Of the 157
INDs where annual reports were filed, the annual reports for 147 INDs
(94% of all annual reports) were easily retrieved and reviewed. The
information from these 145 reports are likely to be representative of
the activity in studies conducted under IND for this field over the last
25 years. Table 2 summarizes information on patient accrual to these
studies.

  ------------- ------------- ---------- ---------- ---------- ----------------
                Phase of                                       Total
                development                                    

                I             I/II       II         III        

  Number of     112           29         102        18         253
  studies                                                      

  Number of     2,940         486        5,906      4,376      17,999
  subjects                                                     

  **Table 2.                                                   
  Number of                                                    
  studies                                                      
  conducted and                                                
  subjects                                                     
  accrued by                                                   
  phase years                                                  
  1975-2000**                                                  
  ------------- ------------- ---------- ---------- ---------- ----------------

There is a variety of products being investigated under IND. They
include cellular therapies, cytokines, monoclonal antibodies and gene
transfer products. The major category of investigational products relies
on induction of an immunogenic response and is broadly characterized as
tumor vaccines. Tumor vaccines include products consisting of modified
(through gene transfer or chemical modification) or unmodified, intact,
autologous or allogeneic, tumor cell vaccines, tumor cell lysates or
fragments, peptide vaccines, and tumor antigens presented by dendritic
cells.

It is difficult to determine the exact proportion of subjects with
locally advanced or metastatic disease in many INDs, due to the broad
eligibility criteria of many Phase 1 and 2 study and the lack of detail
in the annual reports. However, roughly one-third of the active INDs
appear, from annual report information, to be enrolling subjects for
post-surgical adjuvant treatment. Among the 18 Phase 3 studies listed in
Table 2, 9 were/are being conducted in the adjuvant setting and 9
have/are being conducted in patients with metastatic or unresectable
disease. The Phase 3 studies of adjuvant therapy, which have been
completed and reported, are the three ECOG/Intergroup studies of
Interferon 2b, the NCCTG study of Interferon 2a, and the three studies
of Melacine described in the Corixa briefing document.

Approximately 9,000 subjects have been enrolled in early (Phase 1 and 2)
sudies of investigational agents. The endpoints of such studies
generally include an assessment of the toxicity profile, immunogenic
response (for tumor vaccines), cytokine induction (for cytokine agents).
Data that suggest anti-tumor activity is less frequently obtained in
early studies. When conducted in subjects with unresectable or
metastatic disease, objective tumor response may be measured. In the
review of annual reports, the objective tumor response rates have been
reported in small numbers (10%) of subjects enrolled. In some studies,
data are also collected to measure time-to-progression, disease-free
and/or overall survival, however the interpretation of such data in
uncontrolled or historically-controlled studies is extremely difficult.

The safety profile of the investigational agents varies according to
product class and, for cytokines, the dose and schedule. As a general
rule, tumor vaccine strategies have not been associated with serious or
severe toxicities, with the following exceptions: 1) procurement of
autologous tumor (or tumor-infiltrating lymphocytes) which involves a
major surgical procedure. For subjects with locally advanced disease,
such a procedure culd be done as part of routine care, but for subjects
with metastatic disease, who undergo resection solely for the purposes
of vaccine preparation, such toxicity is considered integral to the
therapy itself. 2) hematopoietic growth factor administration
(mobilization) and apheresis for collection of peripheral blood for
manufacture of dendritic cells, 3) toxicities associated with cytokines
administered as "immunomodulators", 4) local, injection site reactions,
including ulceration and necrosis, attributed to adjuvants such as BCG,
DETOX, QS 21, and 5) the potential for induction of immunogenicity
directed against normal tissues. There has been no clear evidence of
inadvertent induction of autoimmune phenomena associated with any tumor
vaccine. There are isolated reports of the occurrence of
melanoma-associated retinopathy, but the correlation with any specific
intervention is weak.

## Efficacy supplement for Intron A

In February 1995, Schering Plough filed an efficacy supplement to their
Product License Application (PLA) Supplement for INTRONA (Interferon
2b). The data in the supplement consisted of the results of E1684, a
randomized, observational-control study of Interferon 2b as an adjunct
to surgical resection for adjuvant treatment of malignant melanoma. The
application was presented to the Oncology Drugs Advisory Committee
(ODAC) in July 1995. The application rested primarily on the results of
Interferon 2b, although the published reports of antitumor activity
(objective response rates) of Interferon 2b in patients with metastatic
disease were also noted as supportive. The committee recommended
approval based on the highly significant effect on relapse-free survival
as well as the magnitude of the effect, and the nearly significant
effects on overall survival in this single study. The improvement in
median RFS was approximately 9 months (1.72 vs. 0.98 yrs; p=0.009
unstratified log-rank test, two-sided). The improvement in median
overall survival was 12 months (3.8 yrs vs. 2.8 yrs; p=0.06 unstratified
log-rank test, two-sided).

The labeled indication states: "INTRONA Interferon alfa-2b, recombinant
for Injection is indicated as adjuvant to surgical treatment in patients
18 years of age or older with malignant melanoma who are free of disease
but at high risk for systemic recurrence within 56 days of surgery."

# Multicenter, randomized controlled trials of IFN in the adjuvant treatment of melanoma

The results of randomized studies of alpha interferons for the adjuvant
treatment of melanoma are summarized below with a composite synopsis
presented in Table 3. Copies of the original publications are appended
to this document. The studies are listed by product used (INTRONA
\[Interferon 2b\], ROFERON A \[Interferon 2a\], or unknown) and, for
each product, further segregated by dose (high vs. low).

## INTRONA high dose

### ECOG EST 1684

EST 1684 was a randomized, observational-control study conducted by
several NCI-cooperative groups with the Eastern Cooperative Oncology
Group (ECOG) as the lead group. [^14] This study was the primary basis
for approval of INTRONA for post-surgical adjuvant treatment of
high-risk melanoma. The results of all four Intergroup trials that used
the approved dose and scheduled of Interferon 2b, were reported by
Kirkwood in 2001 in an overview of the series of trials.[^15] Drs.
Kirkwood and Ibrahim will present an overview of these four trials, with
updated results.

EST 1684 was a prospective, multicenter, randomized, observational
control study in which patients were randomly assigned post-operatively
to observation or to one year of adjuvant Interferon 2b. The study was
open to subjects with T4 lesions (4.0 mm) without nodal involvement
(T4N0), and subjects with nodal involvement at presentation (T1-4 cN0pN1
or T1-4 cN1pN1) or with nodal involvement at the time of recurrence. All
subjects were required to have had a regional lymph node dissection.
Subjects were randomized in a 1:1 allocation, with stratification for
stage and clinical/pathological presentation, within 56 days of
definitive surgery. The study arms consisted of:

1.  Interferon 2b 20 MIU/m^2^ intravenously five times per week for 4
    weeks (induction therapy) followed by Interferon 2b 10 MIU/m^2^
    subcutaneously three times per week for 48 weeks (maintenance
    therapy).

2.  Observation

The study objectives and analytic plan were revised several times during
the conduct of the trial. The original primary objective appeared to be
a comparison of relapse-free survival (RFS), with a proposal to detect
an increase in RFS rate at two-years from 25% to 40%, with a one-sided
test at an alpha of 0.05. Subsequent revisions appeared to change the
primary objective to a comparison of survival (OS) outcomes at 2 years.
In the analysis by Schering, and as described by Kirkwood in the
publications, the final analysis of the study considered comparisons of
both RFS and OS as primary objectives of the study.

A total of 287 patients were enrolled. The analyses presented are based
upon FDA's review of the efficacy supplement, in a modified
intent-to-treat population of 280 subjects who did not refuse treatment
assignment (3 subjects randomized to Interferon 2b and 4 subjects
randomized to observation). The study arms were balanced with respect to
prognostic variables with the important exception of tumor ulceration,
which was present more frequently in subjects in the observation group.
The population was predominantly composed of subjects with nodal
involvement; there were 174 subjects (62%) with nodal recurrence, 41
(15%) with T1-4 cN1pN1 disease, 34 (12%) with T1-4 cN0pN1 disease and 31
(11%) with T4N0 disease. Both RFS and OS were prolonged in the
Interferon 2b group as compared to observation. The improvement in
median RFS was approximately 9 months (1.72 vs. 0.98 yrs; p=0.009
unstratified log-rank test, 2-sided; p=0.003, stratified log-rank). The
improvement in median overall survival was 12 months (3.8 yrs vs. 2.8
yrs; p=0.06 unstratified log-rank test, 2-sided; p=0.045 stratified
log-rank test).

  ----------------------------------------------------- ----------------------------------------------------
  ![](media/image2.jpeg){width="2.6770833333333335in"   ![](media/image3.jpeg){width="2.660416666666667in"
  height="2.1618055555555555in"}                        height="2.216666666666667in"}

  Disease free survival                                 Overall survival

  **Fig 2. Kaplan-Meier estimates ECOG 1684 (from the   
  published report)**                                   
  ----------------------------------------------------- ----------------------------------------------------

### ECOG 1690/S9111/C9190

The ECOG Intergroup investigators initiated a second randomized,
controlled trial, while the data from ECOG 1684 were maturing. The data
from this study were submitted to and reviewed by FDA, and have been
incorporated into labeling for INTRONA.[^16] The design of this trial
was very similar to EST 1684, with two exceptions; the differences were
that subjects with clinically negative nodes were not required to
undergo elective regional lymph node dissection and there was a third
study arm utilizing "low-dose" Interferon 2b. The three treatment groups
were:

1.  High dose Interferon 2b: 20 MIU /m^2^given intravenously five times
    per week for 4 weeks then 10 MIU /m^2^ given subcutaneously three
    times per week for 11 months for a total of one year of treatment.

2.  Low dose of Interferon 2b: 3 MIU /m^2^/day given subcutaneously
    three times per week for two years.

3.  Observation.

The study had two co-primary endpoints, relapse-free and overall
survival, with two pair-wise comparisons, high-dose interferon vs.
observation and low-dose interferon vs. observation, for both RFS and
OS. Each comparison was to be conducted at a final type I error rate of
0.025. A group sequential design using the cure rate model determined
the sample size and power. The design was based on a desire to detect a
10% increase in the cure rate and a 50% relative increase in the median
relapse-free survival (or overall survival) for those not cured with an
83% power.

Six hundred forty-two patients were enrolled (215 in the high dose
group, 215 in the low dose group and 212 in the observation group).
Twenty-five percent of the subjects had T4 cN0 disease, 11% with T1-4
cN0pN1 disease, 13% with T1-4 cN1 disease and 51% with nodal recurrence.
The treatment groups were balanced with respect to stage of disease and
number of positive nodes at lymphadenectomy. Relapse-free survival was
prolonged in subjects receiving high dose Interferon 2b as compared to
the observation group \[median RFS 2.4 years vs. 1.6 years; p= 0.054,
stratified log-rank\] but this was not a statistically significant
difference after adjustment for the multiplicity of analyses. Overall
survival was not prolonged for the high dose Interferon 2b group as
compared to the observational group \[median OS 5.1 years vs. 5.9 years;
p= 0.92, stratified log-rank\]. The results for the low dose arm and
comparisons to the observational control arm are described in the
subsection for low-dose Interferon 2b.

+----------------------------------+-----------------------------------+
| ![](media/image4.jp              | ![](media/image5.j                |
| eg){width="3.0548611111111112in" | peg){width="3.1131944444444444in" |
| height="1.929861111111111in"}    | height="1.88125in"}               |
+----------------------------------+-----------------------------------+
| Disease free survival            | Overall survival                  |
+----------------------------------+-----------------------------------+
| Solid line: High dose interferon |                                   |
|                                  |                                   |
| Dotted line: Low dose interferon |                                   |
|                                  |                                   |
| Dashed line: Observation         |                                   |
+----------------------------------+-----------------------------------+
| **Fig 3. Kaplan-Meier estimates  |                                   |
| ECOG 1690 (from the published    |                                   |
| report)**                        |                                   |
+----------------------------------+-----------------------------------+

### ECOG 1694

The ECOG Intergroup conducted a randomized comparison of high-dose
Interferon 2b with a ganglioside vaccine GM2-KLH/QS 21.[^17] The GM2
ganglioside antigen is well- defined antigen expressed on melanoma; the
vaccine had elicited immunological responses in subjects enrolled in
phase II studies. [^18] Eligibility criteria were similar to E1684 and
E1690 (T4 cN0, T1-4 cN0pN1, T1-4 cN1, and T1-4 with nodal recurrence).
Patients with deep primary lesions with microscopic satellite lesions
within 2 cm of the primary tumor were eligible; however, T4 patients
with gross subcutaneous invasion or grossly apparent satellite lesions
were not eligible. Patients were not required to undergo regional
lymphadenectomy in the absence of clinical evidence of node involvement.
Patients were randomized within 56 of definitive surgery and were
stratified by stage, gender, and number of positive nodes.

The treatment groups were:

1.  Interferon 2b 20 MIU /m^2^ intravenously five times per week for 4
    weeks then 10 MIU /m^2^ subcutaneously, three times per week for 11
    months (total treatment of one year).

2.  GM2-KLH/QS 21 subcutaneously on day 1, 8, 15, and 22 then 8
    additional vaccinations administered every 12 weeks.

As described in the publication, the study had two co-primary endpoints,
relapse-free and overall survival. Each comparison was to be conducted
using a one-sided test with a final, overall type I error rate of 0.025.
A group sequential design using the cure rate model determined the
sample size and power. The sample size was based on a desire to detect a
10% increase in the cure rate with 80% power and a 51% relative increase
in the median relapse-free survival for those not cured with an 86%
power for the GM2-KLH/QS 21 group over the reference (Interferon 2b
group). There were pre-specified interim analyses and pre-specified
boundaries for early termination.

The study accrued 880 patients between June 1996 and October 1999. The
study populations were balanced for baseline variables and prognostic
factors; 36% of the subjects enrolled had nodal recurrence and 23% had
T4cN0 disease (of these one-third were confirmed to be pathologically
negative). The data safety monitoring committee terminated the trial
after a boundary was crossed at an interim analysis. Since the original
intent of the trial was to demonstrate the superiority of the GM2 arm,
hazard ratios of greater than 1.0 indicate a poorer outcome for
GM2-treated subjects as compared to Interferon 2b-treated subjects.
There was a significant increase in relapse-free survival (HR =1.49,
p=0.00045, one sided, log-rank) and overall survival (HR =1.38, p=0.023,
one sided, log-rank) for subjects in the interferon 2b group as compared
to the GM2 group in analyses of the ITT population. Similar findings
were also observed in the eligible population (n= 774), where the 2-year
RFS rate was 62% in the interferon 2b group vs. 49% in the GM2-treated
subjects; the 2-year OS rates were 78% and 73% in the interferon 2b- and
GM2- treated groups, respectively.

+-----------------------------------+----------------------------------+
| ![](media/image6.png)             | ![](media/image7.png)            |
+-----------------------------------+----------------------------------+
| Disease free survival             | Overall survival                 |
+-----------------------------------+----------------------------------+
| Solid line: Interferon            |                                  |
|                                   |                                  |
| Dotted line: GMK vaccine          |                                  |
+-----------------------------------+----------------------------------+
| **Fig 4. Kaplan-Meier estimates   |                                  |
| ECOG EST 1694 (from the published |                                  |
| report)**                         |                                  |
+-----------------------------------+----------------------------------+

### ECOG EST 2696

In parallel to study E1694, the Eastern Cooperative Oncology Group
conducted a phase II study in a more advanced patient population.[^19]
The trial was undertaken to evaluate the toxicity and other effects of
the established adjuvant high-dose IFNa2b regimen in relation to immune
responses to GM2-KLH/QS 21 and to evaluate the potential clinical and
immunologic effects of the combined therapies.

Patients were eligible for this study if they were free of disease after
complete surgical resection for IV melanoma. Patients were also eligible
for this study if they had stage IIB or stage III disease but were
ineligible for E1694 because more than 56 days had elapsed since
surgery. Patients were required to enter this study within 1 year of
definitive surgery and be NED at study entry.

Patients were randomized to three arms.

1.  Arm A: GM2-KLH/QS 21 GM2-KLH/QS 21 subcutaneously on day 1, 8, 15,
    and 22 then 8 vaccinations every 12 weeks and Interferon 2b 20 MIU
    /m^2^ intravenously five times per week for 4 weeks, starting on
    study day 1, then 10 MIU /m^2^ subcutaneously, three times per week
    for 48 weeks.

2.  Arm B: GM2-KLH/QS 21 subcutaneously on day 1, 8, 15, and 22 then 8
    vaccinations every 12 weeks and Interferon 2b 20 MIU /m^2^
    intravenously five times per week for 4 weeks, starting on study day
    28, then 10 MIU /m^2^ subcutaneously, three times per week for 48
    weeks.

```{=html}
<!-- -->
```
3.  Arm C: GM2-KLH/QS 21 subcutaneously on day 1, 8, 15, and 22 then 8
    vaccinations every 12 weeks.

The primary endpoint of the study was a comparison of the humoral
response rates to GM2 vaccine between study arms A vs. C and study arms
B vs. C, to determine if concurrent or sequential interferon treatment
substantially impaired the ability to generate a humoral immune response
to the GM2 vaccine. Secondary endpoints included comparisons of RFS and
OS.

One hundred and seven patients were entered in study E 2696.
Relapse-free survival was shorter in Arm C (non-interferon containing
treatment group) as compared to the Interferon-containing groups. The
median RFS was not reached for arm A at the time of the published
report, whereas the median RFS for arm B was 30.7 months (95% CI, 27 to
53 months) and the median RFS for arm C was 14.8 months (95% confidence
interval \[CI\], 5 to 29 months). The study was not sufficiently mature
to analyze overall survival and none of the treatment groups reached the
median survival time.

+-------------------------------------+--------------------------------+
| ![](media/image                     |                                |
| 8.jpeg){width="3.265277777777778in" |                                |
| height="1.8847222222222222in"}      |                                |
+-------------------------------------+--------------------------------+
| Disease free survival               |                                |
+-------------------------------------+--------------------------------+
| Solid line: GM2-KLH/QS 21 plus high |                                |
| dose interferon started at day 1    |                                |
|                                     |                                |
| Dotted line: GM2-KLH/QS 21 plus     |                                |
| high dose interferon started at day |                                |
| 28                                  |                                |
|                                     |                                |
| Dotted line: GM2-KLH/QS 21          |                                |
+-------------------------------------+--------------------------------+
| **Fig 5. Kaplan-Meier estimates     |                                |
| ECOG 2696 (from the published       |                                |
| report)**                           |                                |
+-------------------------------------+--------------------------------+

## INTRONA low dose

### Rusciani et. al.

A multicenter, randomized, observational-control study was reported by
Rusciani in 1997.[^20] The study was open to subjects with stage I
(pT1/pT2 N0 M0) and stage II (pT3/pT4 N0 M0) malignant melanoma.
Patients were stratified according to stage and tumor thickness.
Treatment consisted of Interferon 2b 3 MU intramuscularly three times
per week for 6 months followed by one-month rest interval; these cycles
were repeated for a total treatment period of 3 years.

Three and 5-year recurrence rates were compared using Fisher's exact
test; the comparisons were provided separately for subjects with stage I
and stage II disease. There were 154 patients enrolled; of these 84 were
randomized to Interferon 2b and 70 to observation. Among patients with
stage I disease, 33 were randomized to Interferon 2b and 40 to
observation, while among patients with stage II disease, 51 were
randomized to Interferon 2b and 30 to observation. The reasons for this
degree of imbalance in a study where stratified randomization reportedly
occurred is not explained in the publication. At three years, 87%
(73/84) of the interferon patients and 70% (49/70) of the control
patients were without recurrence (an improvement of 17%, 95% CI: 4%,
30%). Among the subjects with stage II disease, the DFS rates at 3-years
were significantly different, in favor of the Interferon 2b-treatment
subjects. Data on survival were not provided in the report.

### ECOG 1690/S9222/C9190

The ECOG Intergroup investigators initiated a second randomized,
controlled trial, pending the results of ECOG 1684. The results of this
study were reviewed by FDA and the data incorporated into the labeling
for INTRON A.^13^ The design of this trial was very similar to E 1684,
with two exceptions; the differences were that subjects subjects with
clinically negative regional nodes were not required to undergo elective
regional lymph node dissection and there was a third treatment group
("low-dose" Interferon 2b). The three treatment groups were:

1.  High dose Interferon 2b: 20 MIU /m^2^given intravenously five times
    per week for 4 weeks then 10 MIU /m^2^ given subcutaneously three
    times per week for 11 months for a total of one year of treatment.

2.  Low dose of Interferon 2b: 3 MIU /m^2^/day given subcutaneously
    three times per week for two years.

3.  Observation.

The study had co-primary endpoints, relapse-free and overall survival.
There were two, planned, pair-wise comparisons, high-dose interferon vs.
observation and low-dose interferon vs. observation, for both RFS and
OS. Each comparison was to be conducted at a final type I error rate of
0.025. A group sequential design using the cure rate model determined
the sample size and power. The design was based on a desire to detect a
10% increase in the cure rate and a 50% relative increase in the median
relapse-free survival (or overall survival) for those not cured with an
83% power.

Six hundred forty-two patients were enrolled (215 in the high dose
group, 215 in the low dose group and 212 in the observation group).
Twenty-five percent of the subjects had T4 cNO disease, 11% with T-14
cN0pN1 disease, 13% with T1-4 cN1 disease and 51% with nodal recurrence.
The treatment groups were balanced with respect to disease stage and
number of positive nodes at lymphadenectomy. There were no significant
differences between the low-dose Interferon 2b group and observation
groups with respect to RFS (2.3 vs. 1.6 years; p=0.1, stratified
log-rank) or OS (median not reached vs. 5.9 years; p=0.7, stratified
log-rank).

### Scottish Melanoma Group

The results of a prospective, multicenter, randomized controlled study,
conducted by the Scottish Melanoma Group, were reported by Cameron et.
al. in 2001.[^21] Subjects with primary lesions \>3 mm (T4 and some T3
lesions) or with clinically detected, histologically-confirmed nodal
metastases (N1-N2) were eligible. Randomization was stratified by gender
and disease status. The treatment arms were:

1.  Interferon 2b 3 Million Units SC 3 times per week for a total of six
    months.

2.  Observation

Ninety-six patients were enrolled between 1988 and 1993. Although median
DFS (22 vs. 9 mos) and OS (39 vs. 27 mos) were prolonged in the
Interferon 2b arm these differences were not statistically significant.

  ---------------------------------------------------- ------------------------------------------------------
  ![](media/image9.jpeg){width="2.688888888888889in"   ![](media/image10.jpeg){width="2.6590277777777778in"
  height="2.040277777777778in"}                        height="1.9638888888888888in"}

  Disease free survival                                Overall survival

  **Fig 6. Kaplan-Meier estimates SMG (from the        
  published report)**                                  
  ---------------------------------------------------- ------------------------------------------------------

## Roferon‑A high dose

### NCCTG 83-7052

The North Central Cancer Treatment Group (NCCTG) conducted a
prospective, randomized, observation-control, multicenter trial of
Interferon 2a as post surgical adjuvant therapy. [^22] Subjects with
malignant melanoma with a primary tumor thickness of \>1.69 mm or those
with regional node involvement at diagnosis or recurrence were eligible.
Routine node dissection was not required in subjects with clinically
negative nodes. Subjects were randomized within 42 days of definitive
surgery. The treatment groups were:

1.  Interferon 2a 20x10^6^ U/m^2^ intramuscularly three times per week
    for 12 weeks

2.  Observation.

Two hundred sixty-four patients were enrolled between October 1984 and
March 1990. Of these, 262 were evaluable (131 in the treatment group and
131 in the control group). The treatment arms were balanced with regard
to prognostic factors. Sixty-one percent of patients had stage II
disease. Follow-up duration ranged from 4.1 years to 10.1 years, with a
median of 6.1 years. There were no significant differences between the
Interferon 2a and observation groups with respect to RFS (2.4 years vs.
2.0 years; p=0.24, log-rank) or overall survival (6 years vs. 4.4 yrs,
p=0.53, log-rank).

  ----------------------------------------------------- -----------------------------------------------------
  ![](media/image11.jpeg){width="2.567361111111111in"   ![](media/image12.jpeg){width="2.498611111111111in"
  height="1.8833333333333333in"}                        height="1.8659722222222221in"}

  Disease free survival                                 Overall survival

  **Fig 7. Kaplan-Meier estimates NCCTG 83-7052 (from   
  the published report)**                               
  ----------------------------------------------------- -----------------------------------------------------

## Roferon‑A low dose

### WHO CT 16

The results of a randomized, multicenter, observational control study of
Interferon 2a was reported by Cascinelli et. al. in 2001.[^23] Patients
with cutaneous malignant melanoma and pathologically involved regional
nodes at diagnosis or at recurrence were eligible. Patients were
randomized to receive recombinant Interferon 2a, 3 MIU subcutaneously 3
times per week for 3 years, or no further therapy after surgery.

Four hundred forty-four patients were enrolled at 23 centers between
July 1990 and December 1993. There were 225 patients randomized to the
Interferon 2a arm and 219 to the observational group. There were no
differences in 5-year disease-free survival (28% vs. 28.4%, p=0.5) or
overall survival (35% vs. 37%; p=0.7).

  ----------------------------------------------------- -----------------------------------------------------
  ![](media/image13.jpeg){width="2.852777777777778in"   ![](media/image14.jpeg){width="2.717361111111111in"
  height="1.7215277777777778in"}                        height="1.7395833333333333in"}

  Disease free survival                                 Overall survival

  **Fig 8. Kaplan-Meier estimates WHO CT 16 (from the   
  published report)**                                   
  ----------------------------------------------------- -----------------------------------------------------

### M 23031

This multicenter, randomized, observational control study of Interferon
2a was published by Grob in 1998.[^24] The results of this trial were
also reviewed by the FDA and presented to the ODAC on September 17,
1999.

#### Subjects with histologically confirmed AJCC stage II (tumor thickness \>1.5 mm) and with no evidence of nodal involvement, cutaneous spread, or visceral metastases were eligible. Regional node dissection was required only for subjects with palpable adenopathy; such subjects were eligible if the nodes were pathologically negative. Patients were randomized within 6 weeks of tumor excision; randomization was stratified by center. The study arms were:

#### Interferon 2a 3 MIU IU administered intramuscularly or subcutaneously 3 times per week for 18 months.

#### Observation.

#### 

The primary study objective was disease-free interval; secondary
objectives were overall survival and assessment of safety profile. The
protocol provided for interim analyses and boundaries for early study
termination for overwhelming efficacy or for futility.

There were 499 patients enrolled and randomized from 32 centers in
France between February 1990 and December 1993. The study arms were
balanced with respect to gender, age, and Breslow thickness. The median
thickness was 2.5 mm in the Interferon 2a group and 2.6 mm in the
observational group. Three interim analyses were performed (less than
planned) and accrual to the study was stopped after the third analysis
when the boundary was crossed. The timing of the "final" efficacy
analysis was not clearly specified in the protocol, therefore FDA
requested and obtained additional follow-up information. The data
presented represent that additional follow-up period. The median
disease-free interval was prolonged in the Interferon 2a arm as compared
to the observational control (5.9 vs. 4.6 yrs; p=0.095, log-rank). There
were 138 deaths on study at the time that FDA reviewed the data; 76
(31%) in the observation arm and 62 (25%) in the Interferon 2a arm. In
an unadjusted comparison of survival between the two treatment groups,
survival was prolonged but not significantly different (p=0.09, log
rank) in the Interferon 2a group.

  ----------------------------------------------------- -----------------------------------------------------
  ![](media/image15.png){width="2.3847222222222224in"   ![](media/image16.png){width="2.3965277777777776in"
  height="1.725in"}                                     height="1.6347222222222222in"}

  Disease free survival                                 Overall survival

  **Fig 9. Kaplan-Meier estimates M 23031 (from the     
  published report)**                                   
  ----------------------------------------------------- -----------------------------------------------------

### UKCCCR

The preliminary results of a prospective, multicenter, randomized,
observational-control study conducted by the United Kingdom
Co-Ordinating Committee on Cancer Research (UKCCCR) were published in
2001.[^25] The primary objectives of this randomized trial are to assess
the effects of treatment with Interferon 2a on overall survival (OS) and
event free survival (EFS) in patients with high risk (Stage IIB, III)
melanoma. Secondary objectives are to assess the interaction of
interferon therapy with age and gender. The treatment arms were:

1.  Interferon 2a 3 MU three times per week until recurrence or for two
    years

2.  Observation.

Between October 1995 and November 2000, 654 patients with completely
resected high- risk melanoma were entered into the study; 327 patients
were allocated to receive Interferon 2a and 325 were allocated to
observation. The arms of the study were well balanced for gender, age
and stage. The study population consisted of 125 subjects (19%) with T4
disease (tumor thickness 4 mm), 82 subjects (12%) with nodal
involvement, 73 subjects (11%) with non-nodal superficial recurrence,
and 374 subjects (57%) with nodal recurrence. Median follow-up was 489
days (range 2-1885 days) at the time these analyses. There were no
differences in four-year survival rates (52% vs. 50%, p=1.0) or
four-year EFS rates (33% vs. 29%, p=0.2) for the Interferon 2a and
observational groups, respectively.

### AMCG

The results of this multicenter, randomized, observational-control,
study conducted by the Austrian Melanoma Cooperative Group were reported
by Pehamberger in 1998. [^26] These data were also reviewed by the FDA
and presented at the September 17, 1999 ODAC meeting.

Adults with primary cutaneous malignant melanoma, a tumor thickness of
1.5 mm, and no evidence of regional and/or distant metastases (stage II
AJCC) were eligible. After excision of the primary, patients were
randomized to receive Interferon 2a or no further treatment. For
subjects randomized to Interferon 2a, treatment was initiated 4 weeks
after surgery. The treatment arms were:

1.  Interferon 2a 3 MIU daily, SC injection for 3 weeks (induction
    phase), Interferon 2a 3 MIU three times per week for 49 weeks.

2.  Observation.

The primary study objective was an assessment of the effect on
disease-free interval (DFI).

Three hundred eleven patients from seven institutions were enrolled
between February 1990 and September 1994 in the study. The treatment
groups were balanced with regard to gender and Breslow thickness; there
was a statistically significant difference in the median age between the
two treatment groups (56 yrs vs. 53 yrs, p=0.009) in the observation and
Interferon 2a groups, respectively. As of Dec. 31, 1995, 37 of 154 (24%)
patients had progressed in the Interferon 2a arm as compared to 57 of157
(36%) patients in the observation arm. A prolongation of the
disease-free interval (p=0.04, log-rank test) was observed in patients
who were receiving adjuvant interferon as compared with those treated by
surgery alone; median DFI was not reached in the Interferon 2a arm and
was 4.1 years in the observational group.

  ------------------------------------------------------ -----------------------------------
  ![](media/image17.jpeg){width="2.9277777777777776in"   
  height="1.9673611111111111in"}                         

  Disease free survival                                  

  **Fig 10. Kaplan-Meier estimates AMCG (from the        
  published report)**                                    
  ------------------------------------------------------ -----------------------------------

## Low-dose interferon (unspecified)

### EORTC 18871

In 1987 the EORTC-MCG initiated a prospective, randomized, three-arm
trial. Preliminary results were published in abstract form.[^27] The
initial treatment arms were 1) low dose recombinant interferon alfa
IFN-2 (1MU) administered SC every other day for 12 months, 2)
recombinant IFN- (0.2 mg) administered SC every other day for 12 months,
and 3) an observational control group. The Association of Medical
Oncology (AIO), branch of the German Cancer Society, added a fourth arm
with Iscodor (an herbal extract) and a two-monthly quality of life
exploration for the same treatment period.

From 1987 to 1996, a total of 830 patients were randomized to one of the
3 (EORTC) or 4 (AIO) treatment/observation arms and followed for a
median of 5.5 years. All randomized patients were followed for the time
to progression and duration of survival. A total of 513 relapses and 435
deaths have been reported. At 6 years, the disease-free interval (DFI)
rate was 34% and the survival was 42% for the entire study population.
There were no significant differences in disease-free interval (p=0.6,
log-rank) or survival (p=0.7, log-rank) in an analysis of treatment
comparisons stratified by the initial stage at randomization. The data
for reduction in relative risk for DFI were reported as follows: 0.9
(95% CI: 0.75, 1.18) for the IFN-2 group as compared to observation, 1.0
(95% CI: 0.8, 1.26) for the IFN- group as compared to observation, and
1.33 (95% CI: 0.93, 1.89) for Iscador compared to observation.

<table>
<colgroup>
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 1%" />
<col style="width: 23%" />
<col style="width: 2%" />
<col style="width: 13%" />
<col style="width: 1%" />
<col style="width: 25%" />
</colgroup>
<tbody>
<tr class="odd">
<td><h2 id="authorstudy">Author/study</h2></td>
<td colspan="2"><h3 id="staging">Staging</h3>
<p>(AJCC)<a href="#fn1" class="footnote-ref" id="fnref1"
role="doc-noteref"><sup>1</sup></a></p></td>
<td><strong>Method</strong></td>
<td colspan="3"><p><strong># of patients</strong></p>
<p><strong>randomized</strong></p></td>
<td><h3 id="treatment">Treatment</h3></td>
<td colspan="2"><h3 id="publication">Publication</h3></td>
<td colspan="2"><h3 id="p-values">p-values</h3>
<p>(as described in the publication)</p></td>
</tr>
<tr class="even">
<td colspan="12">IFN 2b Intron-A</td>
</tr>
<tr class="odd">
<td colspan="2"><p>Kirkwood</p>
<p>(ECOG 1684)</p>
<p>[1984-1992]</p></td>
<td>Stage IIB and III</td>
<td colspan="2">pathological<a href="#fn2" class="footnote-ref"
id="fnref2" role="doc-noteref"><sup>2</sup></a></td>
<td><p>280</p>
<p>31 IIB</p>
<p>249 III</p></td>
<td colspan="3"><p>20 MIU/m<sup>2</sup> IV 5x/wk x 4 wk</p>
<p>then 10 MIU/m<sup>2</sup> SC 3x/wk x 11 mo</p>
<p><em><strong>vs.</strong></em> observation</p></td>
<td colspan="2"><p><em>J Clin Oncol</em></p>
<p>vol 14, 1996</p></td>
<td><p>DFS: p = 0.004</p>
<p>OS: p = 0.04</p></td>
</tr>
<tr class="even">
<td colspan="2"><p>Kirkwood intergroup</p>
<p>(ECOG 1690)</p>
<p>[1990-1995]</p></td>
<td>Stage IIB and III</td>
<td colspan="2">clinical</td>
<td><p>608</p>
<p>155 IIB</p>
<p>450 III</p></td>
<td colspan="3"><p>20 MIU/m<sup>2</sup> IV 5x/wk x 4 wk</p>
<p>then 10 MIU/m<sup>2</sup> SC 3x/wk x 11 mo</p>
<p><em><strong>vs.</strong></em> 3 MIU SC 3x/wk x 2 yr</p>
<p><em><strong>vs.</strong></em> observation</p></td>
<td colspan="2"><p><em>J Clin Oncol</em></p>
<p>Vol 12, 2000</p></td>
<td><p>High dose DFS: p = 0.054, OS: p = 0.995</p>
<p>Low dose DFS: p= 0.171, OS: p = 0.813</p></td>
</tr>
<tr class="odd">
<td colspan="2"><p>Kirkwood intergroup</p>
<p>(ECOG 1694)</p>
<p>[1996-1999]</p></td>
<td>Stage IIB and III</td>
<td colspan="2">clinical</td>
<td><p>880</p>
<p>202 II</p>
<p>678 III</p></td>
<td colspan="3"><p>20 MIU/m<sup>2</sup> IV 5x/wk x 4 wk</p>
<p>then 10 MIU/m<sup>2</sup> SC 3x/wk x 11 mo</p>
<p><em><strong>vs.</strong></em> GMK 1 ml SC day 1, 8, 15, 22</p>
<p>then every 12 weeks (week 12 to 96)</p></td>
<td colspan="2"><p><em>J Clin Oncol</em></p>
<p>vol 19, 2001</p></td>
<td><p>DFS: p = 0.0007</p>
<p>OS: p = 0.035</p></td>
</tr>
<tr class="even">
<td colspan="2">Rusciani</td>
<td><p>Stage I</p>
<p>and II</p></td>
<td colspan="2">clinical</td>
<td><p>174</p>
<p>33I</p>
<p>51II</p></td>
<td colspan="3"><p>3 MIU IM 3x/wk for 6 mo (1 cycle) for a total of 6
cycles</p>
<p><em><strong>vs.</strong></em> observation</p></td>
<td colspan="2"><p id="cancer" class="heading">Cancer</p>
<p>vol 79, 1997</p></td>
<td><p>DFS: p = 0.02</p>
<p>OS: p = no data</p></td>
</tr>
<tr class="odd">
<td colspan="2"><p>Cameron</p>
<p>Scottish Melanoma Group</p>
<p>[1988-1993]</p></td>
<td><p>Stage II</p>
<p>and III</p></td>
<td colspan="2">pathological</td>
<td><p>96</p>
<p>34 II</p>
<p>63 III</p></td>
<td colspan="3"><p>3 MIU SC 3x/wk x 6 mo</p>
<p><em><strong>vs.</strong></em> observation</p></td>
<td colspan="2"><p id="br-j-cancer" class="heading">Br J Cancer</p>
<p>Vol 84, 2001</p></td>
<td><p>DFS: p &gt; 0.1</p>
<p>OS: p &gt; 0.2</p></td>
</tr>
<tr class="even">
<td colspan="12">IFN 2a Roferon-A</td>
</tr>
<tr class="odd">
<td colspan="2"><p>Creagan</p>
<p>(NCCTG 83‑7052)</p>
<p>[1984-1990]</p></td>
<td><p>Stage II</p>
<p>and III</p></td>
<td colspan="2">clinical<a href="#fn3" class="footnote-ref" id="fnref3"
role="doc-noteref"><sup>3</sup></a></td>
<td><p>262</p>
<p>102 II</p>
<p>160 III</p></td>
<td colspan="3"><p>20 MIU/m<sup>2</sup> IM 3x/wk x 3 mo</p>
<p><em><strong>vs.</strong></em> observation</p></td>
<td colspan="2"><p id="j-clin-oncol" class="heading">J Clin Oncol</p>
<p>vol 13, 1995</p></td>
<td><p>DFS: p = 0.24</p>
<p>OS: p = 0.53</p></td>
</tr>
<tr class="even">
<td colspan="2"><p>Cascinelli</p>
<p>(WHO CT16)</p>
<p>[1990-1993]</p></td>
<td>Stage III</td>
<td colspan="2">pathological</td>
<td>426</td>
<td colspan="3"><p>3 MIU SC 3x/wk x 3 yr</p>
<p><em><strong>vs.</strong></em> observation</p></td>
<td colspan="2"><p><em>The Lancet</em></p>
<p>Vol 358, 2001</p></td>
<td><p>DFS: p = 0.5</p>
<p>OS: p = 0.72</p></td>
</tr>
<tr class="odd">
<td colspan="2"><p>Grob</p>
<p>M23031</p>
<p>[1990-1994]</p></td>
<td>Stage II</td>
<td colspan="2">clinical<a href="#fn4" class="footnote-ref" id="fnref4"
role="doc-noteref"><sup>4</sup></a></td>
<td>499</td>
<td colspan="3"><p>3 MIU IM or SC 3x/wk x 18 mo</p>
<p><em><strong>vs.</strong></em> observation</p></td>
<td colspan="2"><p><em>The Lancet</em></p>
<p>vol 351, 1998</p></td>
<td><p>DFS: p = 0.035</p>
<p>OS: p = 0.059</p></td>
</tr>
<tr class="even">
<td colspan="2"><p>Pehamberger</p>
<p>AMCG</p>
<p>[1990-1994]</p></td>
<td>Stage II</td>
<td colspan="2">clinical<sup>3</sup></td>
<td>311</td>
<td colspan="3"><p>3 MIU SC 7x/wk x 3 wk then 3 MIU 3x/wk x 1yr</p>
<p><em><strong>vs.</strong></em> observation</p></td>
<td colspan="2"><p><em>J Clin Oncol</em></p>
<p>vol 16, 1998</p></td>
<td><p>DFS: p = 0.02</p>
<p>OS: p = no data</p></td>
</tr>
<tr class="odd">
<td colspan="12"><strong>Table 3. Multicenter controlled trials of IFN
in the adjuvant treatment of melanoma</strong></td>
</tr>
</tbody>
</table>
<aside id="footnotes" class="footnotes footnotes-end-of-document"
role="doc-endnotes">
<hr />
<ol>
<li id="fn1"><p>Some of the studies reported the staging according to
WHO classification, this has been changed to AJCC for consistency.<a
href="#fnref1" class="footnote-back" role="doc-backlink">↩︎</a></p></li>
<li id="fn2"><p>Elective lymph node dissection was performed on all
clinically negative patients.<a href="#fnref2" class="footnote-back"
role="doc-backlink">↩︎</a></p></li>
<li id="fn3"><p>It is not clear from the paper if patients were
re-staged after pathological analysis of dissected lymph nodes.<a
href="#fnref3" class="footnote-back" role="doc-backlink">↩︎</a></p></li>
<li id="fn4"><p>No elective node dissection or sentinel-node dissection
was done.<a href="#fnref4" class="footnote-back"
role="doc-backlink">↩︎</a></p></li>
</ol>
</aside>

# Overview of randomized, observational controlled studies of Interferon for the adjuvant treatment of melanoma

This overview of all randomized trials of interferon in melanoma is an
updated version of an earlier overview presented at the Oncologic Drugs
Advisory Committee (ODAC) meeting of September 17, 1999. It includes
data from three additional randomized trials published during the last
three years. The data from these three trials provide additional support
to our earlier results showing a benefit of interferon on
progression-free survival and overall survival in surgically-resected
melanoma.

Wheatley et al [^28] published a summary of a meta-analysis of 10
published randomized trails of interferon alpha as adjuvant therapy for
melanoma. The reported estimates of odds ratios and 95% confidence
intervals associated with these estimates are almost identical to our
results presented in 1999 (see below). The abstract by Wheatley includes
data from two ongoing trials (EORTC and UKCCCR) that are not available
in the published literature. Since we did not have access to the data,
these two trials are not available in the FDA overview.

However, our analysis includes the published results from ECOG
E1694/S9512/C09081 trial Kirkwood^16^. This study was not included in
the meta-analysis of Wheatley^27^.

## Methodology

### Search method and criteria for inclusion

Our primary objective was to review and summarize data on the efficacy
of interferon alfa as an adjuvant therapy for the treatment of
surgically resected melanoma. The relapse-free survival and overall
survival were considered as the primary measures of efficacy. We focused
only on the data reported from randomized and well-controlled clinical
trials.

We searched, with the help of FDA Library staff, MEDLINE, EMBASE,
BIOSIS, LIFE SCIENCES, DERWENT, CANCERLIT, Cochrane Controlled Clinical
Trials, Cochrane Database of Systematic Reviews: Protocol, and
International Pharmaceutical Abstract data bases for available
literature on interferon therapy in melanoma. All references from 1990
to present categorized as "clinical trials", "controlled clinical
trials", "reviews", "meta analysis", "editorials", and "letter to
editor", and the abstracts of papers presented at the meetings were
searched. After evaluating abstracts from these publications, relevant
papers were obtained from the library.

To supplement our search of electronic databases, we examined the
bibliographies of the recent review papers and also contacted melanoma
investigators in U. S., Europe, and Australia to inquire about
interferon trials not reported in the scientific literature.

#### Analytical approach

Original individual patient data from most of these studies were not
available for our analyses. Thus, to evaluate all studies on equal
basis, we have used only the information given in the published
manuscript. If the numerical values of the needed data were given in the
manuscript they were used for this analysis. In some cases the necessary
data points were obtained by extrapolation from the data, figures, and
the results given in the journal manuscript. This may account for some
of the minor discrepancy between the results presented here and those
given in the original publication.

The estimates of odds of relapse or odds of death were obtained using (O
-- E) ("Observed" minus "Expected" numbers of relapses or deaths) method
of Peto.[^29] From the available data on the number of relapses and
deaths, the quantities (O -- E), standard deviations, odds of relapse,
odds of death, and 95% confidence intervals were calculated. The
estimated odds ratio is the ratio of odds of relapse or death in the
interferon arm to that in the control arm. An odds ratio of 0.75 means a
25% reduction in the odds of relapse or death.

## Results

### Progression free survival

After examining the results from these nine trials, two generalizations
can be made. First, in almost all studies, the Kaplan-Meier curves show
that the progression-free survival of interferon patients is better than
that of the observation patients. The interferon curves are always above
the observation curves. Second, the difference between the interferon
and the control arms is not always significant. In fact, the majority of
the studies show that the observed difference between the two arms is
not statistically significant (i.e., P\>0.05).

The odds of progression are given in figure 11. In all studies, the
point estimates of the odds ratio is less than one, indicating a
beneficial effect of interferon on increasing the time to progression.
The estimates of 95% confidence interval show that in many studies the
upper limit of the interval is \>1.0 indicating that points estimate (of
\<1.0) is not significantly different from 1.0.

The overall estimate of odds ratio for all studies is 0.79 (95% CI:
0.71, 0.89; p\<0.0001). In comparison, the estimated odds ratio for all
studies in the analysis by Wheatley is 0.84 (95% CI: 0.77, 0.92;
p=0.0001). The results for disease-free survival are presented in figure
11.

  -----------------------------------------------------------------------
  ![](media/image18.wmf)

  **Fig 11. Disease Free Survival**
  -----------------------------------------------------------------------

### Overall survival

The reported results on overall survival in individual studies are
similar to that on progression-free survival. The Kaplan-Meier curves of
interferon patients are always above the curves of control patients,
indicating a positive effect of interferon on overall survival. The K-M
curves from the study by Creagan^17^ shows that the interferon curve
crosses the control curve at around two years. But after a very small
time interval, it regains it position above the control curve.

The odds ratios were estimated from all available data and the results
are given in figure 12. Here again, all estimates of odds ratios are
\<1.0, indicating survival benefit. However, only one of these estimates
appears to be significantly different from 1.0 (Kirkwood ^16^). The
upper bounds of all other 95% confidence intervals include 1.0.

The estimate of odds ratio for all studies is 0.88 (95% CI: 0.77, 1.03;
p= 0.065). In comparison, the estimate of odds ratio given by Wheatley
is 0.90 (95% CI: 0.82, 1.00; p=0.05). The results for overall survival
are presented in figure 12.

  -----------------------------------------------------------------------
  ![](media/image19.wmf)

  **Fig 12. Overall Survival**
  -----------------------------------------------------------------------

# Data to support the effectiveness of adjuvant treatment in breast and colorectal cancer

## Colon Cancer

In February 1990 the results of two studies, provided to the FDA under
NDA 20-035, were presented to the Oncology Drugs Advisory Committee
(ODAC). These two studies, both conducted by the NCCTG and Mayo Clinic,
showed a significant reduction in relapse-free survival for the
combination of levamisole plus 5-fluorouracil as compared to resection
alone. The second study also showed a significant reduction in mortality
for subjects receiving adjuvant levamisole and 5-fluorouracil. The ODAC
recommended approval of the combination levamisole and 5-fluorouracil in
the adjuvant setting for stage III colon cancer, based upon a highly
significant effect on relapse-free survival in both studies and a highly
significant effect on survival in the second study.

A meta-analysis of published studies[^30] examined the results of a
group of phase III randomized studies wherein a total of 4,700 patients
with colon cancer were randomized to surgery followed by 5-FU vs.
surgery alone. Results of the meta-analysis showed no statistically
significant survival benefit with post surgical adjuvant 5-FU, thus the
absence of a 5FU control arm in the studies described below was not
required.

Two randomized, observational-control, studies were conducted by the
Mayo Clinic and North Central Cancer Therapy Group (NCTCG) assessing the
effect of addition of levamisole to 5-FU. The first study, reported by
Laurie, compared the effectiveness of the combination and of single
agent levamisole as post-surgical adjuvant therapy to resection alone.
[^31] Endpoints analyzed included time to recurrence and survival. The
study randomized participants to one of three arms:

A)  Resection followed by 5-FU plus levamisole for 1 year.

B)  Resection followed by Levamisole alone for 1 year.

C)  Resection alone.

The study accrued 408 patients between June 1978 and February 1984.
Results reviewed by the FDA indicated that the probabilities for
relapse-free survival at 5 years were 55% for the control, 45% for
levamisole alone, and 45% for 5-FU/levamisole. After correcting for the
influence of prognostic variables including location, grade of anaplasia
and stage, there was a significant improvement in RFS for the
5-FU/levamisole adjuvant group as compared to resection alone (p=0.005,
one-sided log-rank test) but no significant reduction in RFS for the
levamisole adjuvant group as compared to resection alone (p=0.06,
one-sided log-rank test). The overall reduction in recurrence rate for
levamisole alone was 24% (90% CI: -2 to 43%) and for 5-FU/levamisole was
37% (90% CI: 15 to 53%). The probabilities for overall survival at 5
years were 56% for the control, 59% for levamisole alone and 61% for
5-FU/levamisole. After correcting for the influence of prognostic
variables (location, grade of anaplasia and stage), there was no
evidence of a significant reduction in overall survival for the the
5-FU/levamisole adjuvant group as compared to resection alone (p=0.12,
one-sided log-rank test) or for the levamisole adjuvant group as
compared to resection alone (p=0.17, one-sided log-rank test).

The results of this study were considered sufficiently encouraging to
recommend a confirmatory trial. The second study proposed to essentially
duplicate the initial Mayo Clinic and NCCTG study with two exception:
patients with clinical stage II disease were randomized to either
resection alone or to resection followed by 5-FU/levamisole while those
with clinical stage III disease were randomized to the same original
three arms of resection, resection followed by levamisole alone and
resection followed by 5-FU/levamisole. However this second confirmatory
trial involved only patients with colon cancer, since the initial study
showed no benefit for either adjuvant treatment in rectal carcinoma. The
second study was conducted at multiple sites of the North Central Cancer
Therapy Group (NCTCG), South West Oncology Group (SWOG) and Eastern
Cooperative Oncology Group (ECOG).[^32] The study was open to subjects
with Stage B~2~ and Stage C disease. Those with Stage B~2~ were
randomized to adjuvant treatment with FU/levamisole or to observation,
whereas those with Stage C disease were randomized to one of three arms:
FU/levamisole, levamisole alone, or observation. Randomization for Stage
B~2~ subjects was stratified by extent of local invasion (into or
through serosa vs. extension into adjacent organs) and by interval since
surgery (7-20 days vs. 21-35 days). Randomization for Stage C subjects
was stratified by extent of local invasion, interval since surgery, and
number of involved nodes ([\<]{.underline}4 vs. \>4).

A total of 1229 patients were entered on study between March 1984 and
October 1987. Of these, 325 entered the Stage B~2~ study and 971 entered
the Stage C study. Among the 325 subjects enrolled in the Stage B~2~
study, 7 were deemed ineligible and excluded from analyses. After 3.5
years, 84% of the subjects in the FU/levamisole arm and 77% of those in
the observation arm were without evidence of recurrence. Survival data
was not mature (less than 70% of anticipated deaths had occurred), with
85% of the FU/levamisole group and 91% of the observation group alive at
3.5 years.

Forty-two of the 971 (4%) stage C subjects were deemed ineligible and
excluded from the analyses presented below. Among the eligible subjects
enrolled in the Stage C study, there was a significant reduction in time
to recurrence in the 5-FU/levamisole arm as compared to observation
alone (p=0.001, log rank 2-sided) but no significant difference in time
to recurrence for the single agent levamisole adjuvant group as compared
to observation (p=0.63). Using a stepwise proportional hazard regression
model to adjust for the influence of prognostic variables (depth of
invasion, serosal involvement, nodal involvement, local organ
involvement, grade of anaplasia, regional implant, and obstruction),
there remained a statistically significant advantage for relapse-free
survival in the 5-FU/levamisole arm as compared to observation (p=0.002,
log rank 2-sided). When compared to the observation group, the estimated
overall reduction in recurrence rate for 5-FU/levamisole was 38% (95%
CI: 20, 52%); the estimated reduction in recurrence rate for levamisole
alone was 5% (95 CI: -19, 25%). There was also a reduction in mortality
observed. In an analysis adjusting for prognostic variables, there was a
significant prolongation in survival (p=0.006, 2-sided log-rank)
favoring the 5-FU/levamisole arm compared to the observation arm. The
mortality rate at 3.5 years was 71% in the FU/levamisole arm and 55% in
the observation arm. The estimated reduction in mortality rate for
FU/levamisole recipients was 35% (95% CI, 13 to 51%) compared to the
observation group.

## Breast cancer

The following section summarizes the data used as the basis for approval
of Nolvadex and of Taxol for the adjuvant treatment of breast cancer.

### Tamoxifen

A supplemental application for Nolvadex, as a single agent to delay the
recurrence of breast cancer, was approved on Dec. 3, 1986. The approval
was based on the results of three studies, ECOG E 1178, the Toronto
study, and the NATO study. While all three of the studies showed a
significant improvement in disease-free survival, only one showed a
significant improvement in survival. As noted in the FDA review, the
recommendations of the NIH Consensus Development Conference on the
Adjuvant Chemotherapy for Breast Cancer had been held on September 9-11,
1985, were also considered during the review of this application. During
the conference, an overview of all randomized trials had been presented.

The first study, E 1178, was a randomized, placebo-controlled study
conducted in women age 65 years or greater with resectable breast
cancer. Randomization was stratified by number of positive nodes (1-3
vs. 4) and ER receptor status (positive, indeterminate, or unknown).
Subjects were randomized to tamoxifen, 10 mg b.i.d. or placebo. The
study endpoints were treatment failure, survival and morbidity. The
analytic plan was not completely clear; however, the study was powered
to detect a doubling of the median time to treatment failure, with 80%
power and an alpha of 10% (one-sided).

A total of 181 women were enrolled, of whom 170 were deemed evaluable.
Analyses were based on the evaluable patient group, with 86 subjects in
the tamoxifen group and 84 in the placebo-control group. The two study
arms were well-balanced with regard to baseline variables and prognostic
factors. The median disease-free survival was significantly longer in
the tamoxifen group (p=0.005), with median DFS of 5.7 yrs and 4.3 years
in the tamoxifen and placebo-control groups, respectively. Although
there were fewer deaths in the tamoxifen arm (21 vs. 28), there was no
significant difference in survival (p=0.33)

The Toronto study was a randomized, observational control trial
conducted at 10 institutions. The objectives of the study were to
determine if tamoxifen could prolong recurrence-free and/or overall
survival. The study was designed to detect a 15% increase in survival at
10 years, with a power of 0.80. The patient population was
post-menopausal women with resectable tumors (T1-3) and axillary node
involvement (N1) within 12 weeks of definitive surgery. The
randomization was stratified by pathologic tumor size, number of
involved nodes, and time since menopause. The study was amended to
enroll subjects who had undergone post-surgical radiotherapy; this
subgroup was randomized separately. Patients were randomized to receive
tamoxifen 10 mg t.i.d. for up to two years or to observation.

Four hundred patients were enrolled, of whom 275 were entered on the
main study and 125 were enrolled in the radiotherapy sub study. Analyses
were conducted in the eligible study population (390 subjects). The
study arms, both in the main and the sub study, were balanced with
respect to baseline characteristics and prognostic variables. In the
main study, there was a significant prolongation in disease-free
survival (p\<0.0001), with a median DFS of 3.0 years in the control
group while median survival had not yet been reached in the tamoxifen
arm. There was no difference in overall survival between the two arms
(p=0.50) with deaths in 24% of the control group and 21% of the
tamoxifen group at the time of the review. In the radiation sub study,
there were no differences in DFS or OS between the two study arms, with
median DFS of 2.7 years and 2.4 years and median OS of 4.9 years and 5.6
years in the tamoxifen and placebo-control groups, respectively.

The NATO study, a randomized, observational-control study was conducted
in post-menopausal and pre-menopausal women with resectable breast
cancer. Subjects with T4 lesions were excluded and pre-menopausal women
were required to have involved nodes. Randomization was not stratified
except for treatment center. Women were randomized to tamoxifen 10 mg
b.i.d. within 8 weeks of definitive surgery for up to two years or to
observation. The objectives of the study were to determine whether
tamoxifen therapy delayed distant recurrence or reduced mortality. The
sample size was chosen to detect a 10% improvement in 10-year survival
(increase from 45% to 55%) with 90% power.

A total of 1285 women were enrolled; 642 were randomized to tamoxifen
and 643 to observation. The distribution of pre- and post-menopausal
subjects and those with and without involved nodes were similar.
Estrogen receptor status was available for only 524 subjects; there were
significantly fewer ER positive subjects among the post-menopausal, node
positive subgroup who were randomized to tamoxifen. Other than that the
arms were balanced with respect to prognostic factors and entry
characteristics. In this study, both DFS (p=0.0001) and OS (p=0.0019)
were both significantly longer in the tamoxifen arm; the median for DFS
and OS had not been reached in either study arm at the time of the
review.

We note that a robust evidence for an effect on survival was not
contained in the application reviewed by FDA; evidence of this effect
was most clearly demonstrated in overviews of multiple randomized,
controlled trials, the first of which was published in 1988. In 1988,
The Early Breast Cancer Trialists' Collaborative Group (EBCTCG)
published a meta-analysis of systemic treatment of early breast cancer
by hormone, cytotoxic, or biologic therapy methods in randomized trials
involving 28, 896 women with stage I or II breast cancer.[^33] The
analysis utilized the information obtained in 28 trials of adjuvant
tamoxifen that enrolled 16,513 women. In all patients, a reduction of 16
% ([+]{.underline} 3%) in the odds of death was observed among women of
all ages assigned to tamoxifen. There was a clear reduction of mortality
among women 50 or older, for whom tamoxifen reduced the annual odds of
death during the first five years by about 20% (p\< 0.0001).

### Taxol

In September 1999, the results of an interim analysis of a Phase 3
Intergroup Study, submitted under NDA 20-262, were presented to the
Oncology Drugs Advisory Committee (ODAC). ODAC recommended approval of
Taxol for the adjuvant treatment of node-positive breast cancer
administered sequentially to standard doxorubicin-containing combination
chemotherapy based upon the findings of significant reductions in
disease-free and overall survival.

The Phase 3 intergroup study (Cancer and Leukemia Group B \[CALGB\],
Eastern Cooperative Oncology Group \[ECOG\], North Central Cancer
Treatment Group \[NCCTG\], and Southwest Oncology Group \[SWOG\])
randomized 3170 patients with node-positive breast carcinoma to adjuvant
therapy with Taxol or to no further chemotherapy following four courses
of doxorubicin and cyclophosphamide (AC). This multicenter trial was
conducted in women with histologically positive lymph nodes following
either a mastectomy or segmental mastectomy and nodal dissections. The 3
x 2 factorial study was designed to assess the efficacy and safety of
three different dose levels of doxorubicin (A) and to evaluate the
effect of the addition of Taxol administered following the completion of
doxorubicin and cyclophosphamide (AC) therapy. After stratification for
the number of positive lymph nodes (1-3, 4-9, or 10+), patients were
randomized to receive cyclophosphamide at a dose of 600 mg/m^2^ and
doxorubicin at doses of either 60 mg/m^2^ (on day 1), 75 mg/m^2^ (in two
divided doses on days 1 and 2), or 90 mg/m^2^ (in two divided doses on
days 1 and 2 with prophylactic G-CSF support and ciprofloxacin) every 3
weeks for four courses and either Taxol 175 mg/m^2^ as a 3-hour infusion
every 3 weeks for four additional courses or no additional chemotherapy.
Patients whose tumors were positive were to receive subsequent tamoxifen
treatment (20 mg daily for 5 years); patients who received segmental
mastectomies prior to study were to receive breast irradiation after
recovery from treatment-related toxicities.

At the time of the FDA analysis, median follow-up was 30.1 months. Of
the 2066 patients who were hormone receptor positive, 93% received
tamoxifen. The primary analyses of disease-free survival and overall
survival used multivariate Cox modeling which included Taxol
administration, doxorubicin dose, number of positive lymph nodes, tumor
size, menopausal status, and estrogen receptor status as factors. Based
on the model for disease-free survival, patients receiving AC followed
by Taxol had a 22% reduction in the risk of disease recurrence compared
to patients randomized to AC alone (Hazard Ratio \[HR\] = 0.78, 95% CI:
0.67, 0.91, p=0.0022). They also had a 26% reduction in the risk of
death (HR=0.74, 95% CI :0.60, 0.92, p=0.0065). For disease-free survival
and overall survival, p values were not adjusted for interim analysis.

# Summary

The data leading to the approval of INTRONA as an adjunct to surgical
resection for patients with malignant melanoma was based primarily on a
single, randomized, well-controlled trial showing a highly significant
effect on improvement in relapse-free survival and borderline evidence
of a statistically significant effect on survival. The magnitude of both
effects was large (9 month increase in median relapse-free survival and
12 month increase in median overall survival). Data from a limited
number of trials, where reproducible effects on disease-free, but not
overall survival, were demonstrated resulted in marketing approval of
agents indicated for the adjuvant treatment of colon and breast cancer.
The pattern observed with the Intergroup studies, in which effects on
DFS are more convincingly shown in several studies while consistent
effects that were not statistically significant were observed in each of
the confirmatory studies, was also observed in the trials used to
support the approvals for combination levamisole/5FU and for tamoxifen.
In the case of both INTRONA and tamoxifen, overview of data from
additional studies provides additional information and insight into the
effectiveness of these agents as adjuvant treatments. The overview by
FDA, and as confirmed by Wheatley, show a highly significant effect on
disease-free survival, although the effect on survival remains
borderline. An separate overview of the Intergroup studies will be
presented by Drs. Kirwood and Ibrahim to further elucidate the effects
of this specific dose and schedule of INTRONA and further clarify the
magnitude of effect for the purposes of designing non-inferiority
trials.

Balanced against this information is the consideration of the toxicity
of INTRONA at the approved dose and schedule. First, we note that there
have been no studies showing poorer survival in the INTRONA group. In E
1684, modification of the dose of INTRONA was required in 65% of the
patients due to adverse events. Adjuvant therapy was prematurely
discontinued in 8% of the patients during the induction phase of the
study and in 18% of the patients during the maintenance phase of the
study. The toxicity profile of INTRONA at this dose and schedule is
clinically significant but reversible with modification or cessation of
the drug. The most serious toxicities attributable to INTRONA are liver
failure in individuals with viral hepatitis, depression with suicidal
ideation and completed suicides, and retinopathy. All three of these
serious toxicities, as with the less serious toxicities, are reversible
with cessation or dose modifcation of the drug. The incidence of liver
failure was highest in the initial study (E1684) at 2% and has decreased
in successive trials. The incidence of suicidal ideation, also 2% in the
original trials, is reported less frequently in the successive trials.
The decrease in incidence appears to be due to improved recognition and
management of the toxicities. Retinopathy leading to loss of vision, has
not been reported in any of these clinical studies, however it has been
identified in post-marketing reports.

In considering the appropriate development path for investigational
agents, the FDA routinely considers the availability of alternative
treatment. In this setting, the data characterizing the safety and
efficacy of INTRONA have increased through a number of randomized,
well-controlled trials. Based on these data, it would appear that the
data supporting the clinical efficacy of INTRONA at the approved dose
and schedule are sufficient and convincing. In light of these data, CBER
believes that it would not be appropriate to enroll subjects who have
the potential to benefit from INTRON A therapy into trials of
investigational agents. However, we recognize that there may be
mitigating factors to be considered, such as the amount of information
regarding relative risks and benefits of a specific investigational
agent and the information to be gained at later stages of development
(Phase 3 trials) as compared to earlier studies. We ask the Committee to
consider a proposal to enroll and randomize subjects to receive an
investigational agent in clinical trials if the trials were sufficiently
well-designed to establish the effectiveness of the investigational
agent and subjects were adequately consented as to the nature of the
study and the potential to receive alternative therapy. This is the
situation with the proposal for a confirmatory Phase 3 trial for
Melacine. However initial studies of investigational agents, which are
designed to collect information on the toxicity profile and
immunological activity of an investigational biologic, can safely and
ethically be conducted in related clinical settings. Appropriate
patients might include subjects with metastatic disease (resected or
unresectable), subjects with earlier stage melanoma, subjects who have
relapsed following INTRON A or for whom INTRON A at the approved dose
and schedule is medically contraindicated. Therefore, we do not see a
need to enroll subjects who may benefit from INTRON A therapy in phase 1
and 2 trials of investigational agents. The consideration raised by
researchers that this is a restriction of patient autonomy seems
inconsistent with the approach recently recommended by the ODAC, during
the discussion of single patient INDs regarding that ability of subjects
to be fully informed with regard to the true risks and benefits of
investigational agents. We seek the committee's advice on whether
subjects should be allowed to enroll in early safety studies of
investigational agents, when there is an approved product of established
safety and efficacy available. If such studies are considered
appropriate, we ask the Committee to outline the factors and principles
under which such studies should be allowed to proceed, i.e., to discuss
when such studies would not represent an "unreasonable risk" to human
subjects.

# Bibliography

[^1]: Koh H. Cutaneous melanoma. Med. Prog. 325: 171-182. 1991.

[^2]: American Cancer Society Facts and Figures 2001: www. cancer. org/
    eprise/ main/ docroot/ stt/ stt_0.

[^3]: ^2^

[^4]: Landis SH, Murray T, Bolden S, et al: Cancer statistics 1998. CA
    48: 1998.

[^5]: Breslow A: Thickness, cross sectional areas and depth of invasion
    in the prognosis of cutaneous melanoma. Ann Surg172: 902-908, 1970.

[^6]: Behars OH, Henson DE, Hutter RVP *et al:* (eds): American Joint
    Committee on Cancer Manual for Staging of Cancer. Philadelphia, PA
    Lippincott 1992, 143-148.

[^7]: Balch CM, Buzaid AC, Soong SJ, *et al:* Final version of the
    American Joint Committee on Cancer staging system for cutaneous
    melanoma. *J. Clin Oncol* 19: 3635-3648. 2001.

[^8]: Chang AE, Hynds Karnell L, Menck HR *et al:* The National Cancer
    Data Base report on cutaneous and non cutaneous melanoma: A summary
    of 84,836 cases from the past decade Cancer 83: 1664- 1668, 1998

[^9]: Balch CM, Urist MM, Karakousis CP, et al: Efficacy of 2 cm
    surgical margins for intermediate thickness melanoma (1-4 mm):
    results of a multi-institutional randomized clinical trial. Ann
    Surg. 218: 262 1993.

[^10]: Sim FH, Taylor WF, Pritchard DJ, et al: Lymphadenectomy in the
    management of stage I melanoma: A prospective randomized study. Mayo
    Clin Proc 61: 697 1986.

[^11]: Veronesi U, Adamus J, Bandiera DC, et al. Inefficacy of immediate
    node dissection in stage I melanoma of the limbs N Engl J Med 297:
    627 1977.

[^12]: Veronesi U, Cascinelli N, Adamus J, et al: Thin stage primary
    cutaneous malignant melanoma Comparison of excision with margins 1
    or 3 cm. N Engl J Med 318: 1159 1988.

[^13]: Cascinelli N, Morabito A, Santinami M*et al:* Immediate or
    delayed dissection of regional nodes in patients with melanoma of
    the trunk: a randomised trial *Lancet* 351: 793-796 1998.

[^14]: Kirkwood JM, Strawderman MH, Ernstoff MS, et al: Interferon
    alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma:
    the Eastern Cooperative Oncology Group trial EST 1684 J. Clin Oncol
    14:7-17, 1996.

[^15]: Kirkwood JM Adjuvant therapy of high risk resected melanoma:
    relapse-free and overall survival effects of high-dose interferon
    alpha 2b in randomized controlled multicenter trials E1684 and E2696
    and intergroup trials E1690 and E1694. American Society of Clinical
    Oncology Educational Book 2001

[^16]: Kirkwood JM, Ibrahim J, Sondak V, et al: High- and Low-dose
    Interferon alfa-2b in high-risk melanoma: first analysis of
    intergroup trial E1690/S9111/C9190. J. Clin Oncol 12: 2444-2458,
    2000.

[^17]: Kirkwood JM, Ibrahim JG, Sosman JA et al: High dose interferon
    alfa-2b significantly prolongs relapse free and overall survival
    compared with the GM2-KLH/QS21 vaccine in patients with resected
    stage IIB/III melanoma: Results of intergroup Trial
    E1694/S9512/C509801. J. Clin Oncol 19: 2370-2380. 2001.

[^18]: Livingston PO, Wong GYC, Adluri S, et. al: Improved survival in
    stage III melanoma patients with GM2 antibodies: A randomized trial
    of adjuvant vaccination with GM2 ganglioside. J Clin Oncol 12:
    1036-1044. 1994

[^19]: Kirkwood JM, Ibrahim JG, Lawson DH et al: High-Dose Interferon
    Alfa-2b Does Not Diminish Antibody Response to GM2 Vaccination in
    Patients With Resected Melanoma: Results of the Multicenter Eastern
    Cooperative Oncology Group Phase II Trial E2696 J Clin Oncol 19:
    1430-1436. 2001

[^20]: Rusciani L, Petraglia S, Alotto M, *et al*: Postsurgical Adjuvant
    Therapy for Melanoma: Evaluation of a 3-Year Randomized Trial with
    Recombinant Interferon- after 3 and 5 Years of Follow-Up *Cancer*
    12:2354-2360. 1997.

[^21]: Cameron DA , Cornbleet MC, Mackie RM et al: Adjuvant interferon
    alpha 2b in high risk melanoma -- the Scottish study. British
    Journal of Cancer 84: 1146-1149. 2001

[^22]: Creagan ET, Dalton RJ, Ahmann DL. et al: Randomized, surgical
    adjuvant clinical trial of recombinant interferon alfa-2a in
    selected patients with malignant melanoma. J. Clin Oncol
    13:2776-2783, 1995.

[^23]: Cascinelli N, Belli F, MacKie RM et al: Effect of long-term
    adjuvant therapy with interferon alpha-2a in patients with regional
    node metastases from cutaneous melanoma: a randomised trial**.**
    Lancet \]358:866-9 2001.

[^24]: Grob JJ, Dreno B, De la Salmonier P, et al: Randomized trial of
    interferon alfa-2a as adjuvant therapy in resected primary melanoma
    thicker than 1.5 mm without clinically detectable node metastases.
    Lancet 351 (9120): 1905-10. 1998.

[^25]: Hancock BW, Wheatley K, Harrison M, et al: Aim high-adjuvant
    interferon in melanoma (high risk), a United Kingdom Coordinating
    Committee on Cancer Research (UKCCCR) randomised study of
    observation versus adjuvant low dose extended duration interferon
    alpha-2a in high risk resected malignant melanoma**.** J. Clin Oncol
    20:349a, 2001.

[^26]: Pehamberger H, Soyer P, Steiner A, et al: Adjuvant Interferon
    Alfa-2a Treatment in resected Primary Stage II Cutaneous Melanoma.
    J. Clin Oncol 16: 1425-1429, 1998.

[^27]: Kleeberg UR, Brocker EB, Lejauns F et al: Adjuvant trial in
    melanoma patients comparing rIFN-alpha to rIFN-gamma to locador to a
    control group after curative resection of high risk primary (\>3mm)
    or regional lymph node metastasis (EORTEC 18871) European J. of
    Cancer 35: supplement 4 S82, 1999.

[^28]: Wheatley K, Hancock B, Gore M, et al: Interferon as adjuvant
    therapy for melanoma: a meta-analysis of the randomized trials J.
    Clin Oncol 20: 349a, 2001.

[^29]: Peto R: Why do we need systematic overviews of randomized trials?
    Statistics in Medicine 6: 233-240, 1987.

[^30]: Buyse M, Zeleniuch-Jacquotte A, Chalmers TC: Adjuvant therapy of
    colon cancer: Why we still don't know. JAMA 259: 3571-3578. 1988

[^31]: Laurie JA, Moertel CG, Fleming TR, et al: Surgical adjuvant
    therapy of large-bowel carcinoma: an evaluation of levamisole and
    the combination of levamisole and fluorouracil. J Clin Oncol 7:
    1447-1456. 1989

[^32]: Moertel CG, Fleming TR, Macdonald JS et al Levamisole and
    fluorouracil for adjuvant therapy of resected colon carcinoma. N
    Engl J Med 3321: 352-358 1990

[^33]: Early Breast Cancer Trialists\' Collaborative Group. Effect of
    adjuvant tamoxifen and of cytotoxic therapy in mortality in early
    breast cancer: An overview of 61 randomized trials among 28, 896
    women. N Engl J Med 26: 1681-1692,1988.