# Presentation: 275161

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

- Oncologic Drugs Advisory Committee
- February 27, 2002

## Adjuvant Treatment for Malignant Melanoma Outline of Presentation

- Survey of biological products being studied under IND for treatment of melanoma
- Basis for approval of  INTRON-A for adjuvant treatment of melanoma
- Overview of  randomized controlled trials with  adjuvant IFN alpha in melanoma
- Comparison of effect size to other adjuvant treatment

## Adjuvant Treatment for Malignant Melanoma Outline of PresentationInvited Speakers

- John M. Kirkwood, MD
**   ****Efficacy and Safety of High-Dose IFN-********2b in Patients With High-Risk Resected Cutaneous Melanoma**
**M. Kirkwood, MD**
- Joseph Ibrahim, PhD
**   ****Cure Rate Models and Adjuvant Trial Design for ECOG Melanoma Studies in the Past, Present, and Future**

## Adjuvant Treatment for Malignant Melanoma  Regulatory considerations

- 21 CFR 312.42 (b)(1)(I):  FDA may place an ongoing or proposed investigation on hold if it finds that *“Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury”*

## Adjuvant Treatment for Malignant Melanoma Evolution in Regulatory Approach

- Based on results of E1684 and E1690, enrollment of subjects with stage IIb and III disease in studies under IND was permitted due to absence of clear effect on survival
- Following the results of E1694 as well as other published literature, evidence of the effect on survival was strengthened

## Enrollment of subjects in trials of investigational agents was restricted for patients with Stage IIb and III disease to
Subjects medically unable to tolerate Intron A at the approved dose and schedule
Subjects with a prolonged interval between surgical resection and adjuvant therapy ( 6 months)
Recurrence on or following Intron A

- Subjects medically unable to tolerate Intron A at the approved dose and schedule
- Subjects with a prolonged interval between surgical resection and adjuvant therapy ( 6 months)
- Recurrence on or following Intron A

- Adjuvant Treatment for Malignant Melanoma Evolution in Regulatory Approach

## Adjuvant Treatment for Malignant Melanoma

- Investigational Agents Being Evaluated for the Treatment of Melanoma

## Adjuvant Treatment for Malignant Melanoma  Survey Approach

- CBER database reviewed for INDs submitted for cancer treatment between 1975 - 2000
- Of the 2,665 applications 196 (7%) were for treatment of melanoma
- Annual reports were assessed to identify the number of studies conducted and subjects accrued
- Analysis of IND activity  by product category

## Adjuvant Treatment for Malignant Melanoma  Number of INDs for the Treatment of Melanoma

- 1975-1980

- 1981-1985

- 1986-1990

- 1991-1995

- 1996-2000

- 0

- 20

- 40

- 60

- 80

- 100

- 96

- 72

- 18

- 5

- 3

- Number of  INDs

## Adjuvant Treatment for Malignant Melanoma  Number of Studies and Subjects Accrued by Phase of Study

- Adjuvant Treatment for Malignant Melanoma  Number of Studies and Subjects Accrued by Phase of Study

## Tumor vaccines
Gene transfer products 
Monoclonal antibodies
Cytokines
Cellular therapies

- Gene transfer products
- Monoclonal antibodies
- Cytokines
- Cellular therapies

- Adjuvant Treatment for Malignant Melanoma  Investigational Products

- Adjuvant Treatment for Malignant Melanoma  Investigational Products

- Vaccines

- Gene
- Transfer

- Monoclonal
- Antibodies

- Cytokines

- Cellular
- Therapies

- 0

- 20

- 40

- 60

- Percent of INDs

- Products

## Tumor vaccines
Tumor cell vaccines
Peptide vaccines
Antigens presented by dendritic cells
Tumor cell lysates or fragments

- Tumor cell vaccines
- Peptide vaccines
- Antigens presented by dendritic cells
- Tumor cell lysates or fragments

- Adjuvant Treatment for Malignant Melanoma  Investigational Products

## Adjuvant Treatment for Malignant Melanoma 

- Basis for Approval of
- INTRON-A and Supplemental Data Reviewed by FDA

## Adjuvant Treatment for Malignant Melanoma  Study ECOG 1684

- Efficacy Supplement filed February 1995
- Data presented at ODAC July 1995
- Approval December 1995

## Adjuvant Treatment for Malignant Melanoma  Study ECOG 1684

- Adjuvant Treatment for Malignant Melanoma  Study ECOG 1684

- Interferon alpha 2b 20 MIU/m2 IV 5x/wk x 4 wk
- then 10 MIU/m2 SC 3x/wk x 11 mo

- Histological Diagnosis

-   Surgical Excision and Regional LN Dissection

- Interferon b

- No Treatment

- Randomization

- N= 143

- N= 137

## Adjuvant Treatment for Malignant Melanoma  Study ECOG 1684

- Improvement in median RFS
- 9 months (1.72 *vs* 0.98 years p=0.009)
- Improvement in median OS
- 12 months (3.8 *vs* 2.8 years p=0.06)

## Adjuvant Treatment for Malignant Melanoma  K-M  estimates of DFS ECOG 1684(from the published report) 

- Interferon 2b

- No treatment

## Adjuvant Treatment for Malignant Melanoma  K-M  estimates of OS ECOG 1684 (from the published report) 

- Interferon 2b

- No treatment

## “INTRONA 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.”

- Adjuvant Treatment for Malignant Melanoma  Labeled Indication

## Adjuvant Treatment for Malignant Melanoma Study ECOG 1690

- Histological Diagnosis

- Surgical excision

- Randomization

- Interferon b High Dose

- No Treatment

- Interferon b Low Dose

- HIGH DOSE:   20 MIU/m2 IV 5x/wk x 4 wk then 10 MIU/m2 SC 3x/wk x 11 mo
- LOW DOSE:    3 MIU SC 3x/wk x 2 yr

- 140

- 215

- 215

## Adjuvant Treatment for Malignant Melanoma  K-M  estimates of DFS ECOG 1690 (from the published report) 

- Interferon 2b high dose

- No treatment

- Interferon 2b low dose

## Adjuvant Treatment for Malignant Melanoma  K-M  estimates of OS ECOG 1690 (from the published report) 

## Adjuvant Treatment for Malignant Melanoma  K-M Estimates of 3-year RFS and OS Studies E 1684 and E1690 (high dose)

| Study | 3-year RFS |  |  | 3-year OS |  |
| --- | --- | --- | --- | --- | --- |
|  | Intron A | Control |  | Intron A | Control |
| E 1684 | 41% | 32 % |  | 54 % | 48 % |
| E 1690 | 48% | 41 % |  | 62 % |  62 % |

## Non-serious adverse events are common
Serious adverse events are uncommon (<2%) 
Adverse events are reversible with dose modification and/or medical management 

- Serious adverse events are uncommon (<2%)
- Adverse events are reversible with dose modification and/or medical management

- Adjuvant Treatment for Malignant Melanoma Interferon 2b Adverse Events

## Serious Adverse events 
Liver failure
Depression with suicidal ideation
Retinopathy 

- Liver failure
- Depression with suicidal ideation
- Retinopathy

- Adjuvant Treatment for Malignant Melanoma Interferon 2b Adverse Events

## Adjuvant Treatment for Malignant Melanoma Use of INTRON-A in high risk melanoma Estimates for 2001

| Stage | IIB | III |
| --- | --- | --- |
| Incidence | 4,465 | 6,449 |
| Patients treated with Intron | 943
(21%) | 3,796
(59%) |

## Adjuvant Treatment for Malignant Melanoma 

**An Overview of the Published Literature**
- Jawahar Tiwari PhD

## Randomized trials
All observational concurrent controlled trials
Adjuvant treatment

- All observational concurrent controlled trials
- Adjuvant treatment

- Adjuvant Treatment for Malignant Melanoma Criteria for Inclusion

## Database searched (Jan 1990 Dec 2001)
MEDLINE,  EMBASE,  BIOSIS, LIFE SCIENCES,
DERWENT, CANCERLIT,
Cochrane Controlled Clinical Trials,
Cochrane Database of Systemic Reviews

- MEDLINE,  EMBASE,  BIOSIS, LIFE SCIENCES,
- DERWENT, CANCERLIT,
- Cochrane Controlled Clinical Trials,
- Cochrane Database of Systemic Reviews

- Adjuvant Treatment for Malignant Melanoma Search Methodology

## Individual patient data from FDA files
Summary data from published reports
Additional information from investigators

Estimates of odds (O - E) method
KM estimates of survival at 3 years

- Summary data from published reports
- Additional information from investigators
- Estimates of odds (O - E) method
- KM estimates of survival at 3 years

- Adjuvant Treatment for Malignant Melanoma  Analytic Approach

##  Adjuvant Treatment for Malignant Melanoma INTRON-A   High Dose

-  Adjuvant Treatment for Malignant Melanoma INTRON-A   High Dose

## Adjuvant Treatment for Malignant Melanoma  K-M  estimates of DFS and OS ECOG 1694 (from the published report) 

- Interferon 2b

- GMK vaccine

- DFS

- OS

- GMK vaccine

- Interferon 2b

## Adjuvant Treatment for Malignant Melanoma INTRON-A    Low Dose

- Adjuvant Treatment for Malignant Melanoma INTRON-A    Low Dose

## Adjuvant Treatment for Malignant Melanoma Rusciani et al. 1997  (from the published report)

- Recurrence rates at 3 year
- Control 30% (N=70)
- Interferon  2b 13% (N=84)
- Difference 17% (95% CI: 4% to 30%)

## Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFS  and OSScottish Melanoma Group (from the published report) 

- Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFS**  **and OSScottish Melanoma Group** **(from the published report)

- Interferon 2b

- No treatment

- Interferon 2b

- No treatment

- DFS

- OS

## Adjuvant Treatment for Malignant Melanoma ROFERON-A  High Dose and Low Dose

- Adjuvant Treatment for Malignant Melanoma ROFERON-A  High Dose and Low Dose

## Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFS and OSNCCTG 83-7052   (from the published report) 

- Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFS and OSNCCTG 83-7052**  **** **(from the published report)

- No treatment

- Interferon 2a

- No treatment

- Interferon 2a

- DFS

- OS

## Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFS WHO CT 16  (from the published report) 

- Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFS WHO CT 16** ** (from the published report)

- Interferon 2a

- No treatment

- Interferon 2a

- No treatment

- DFS

- OS

## Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFSM 23031   (from the published report) 

- Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFSM 23031** **  (from the published report)

- Interferon 2a

- No treatment

- DFS

- OS

- No treatment

- Interferon 2a

## Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFSAustrian Melanoma Cooperative Group   (from the published report) 

- Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFSAustrian Melanoma Cooperative Group   (from the published report)

- No treatment

- Interferon 2a

## Adjuvant Treatment for Malignant Melanoma Odds Ratio for Relapse

- Kirkwood (1996)

- Kirkwood (2000) 1690L

- Kirkwood (2000) 1690H

- Cameron (2000)

- Kirkwood (2001)

- Creagan (1995)

- Pehamberger (1998)

- Grob (1998)

- Cascinelli (2001)

- All studies (N=3536)

- 0.2

- 2

- 1

- 0.4

- 1.6

- Adjuvant Treatment for Malignant Melanoma Odds Ratio for Relapse

## Adjuvant Treatment for Malignant Melanoma Odds Ratio for Survival

- Adjuvant Treatment for Malignant Melanoma Odds Ratio for Survival

- 0.4

- 1

- 1.6

- 2

- All studies (N=3536)

- Kirkwood (1996)

- Kirkwood (2000) 1690L

- Kirkwood (2000) 1690H

- Cameron (2000)

- Kirkwood (2001)

- Creagan (1995)

- Pehamberger (1998)

- Grob (1998)

- Cascinelli (2001)

- 0.2

## Adjuvant Treatment for Malignant Melanoma Wheatley et. al. Meta-Analysis

- Data from 10 studies
- Largely based on published reports
- Includes :
- EORTC 18871 and 18952
- UKCCCR
- Does not include ECOG 1694
- Approximately 3700 patients

## Adjuvant Treatment for Malignant Melanoma Overview by FDA and Wheatley

- Adjuvant Treatment for Malignant Melanoma Overview by FDA and Wheatley

- FDA DFS

- Wheatley DFS

- FDA OS

- Wheatley OS

- 0.2

- 2

- 0.4

- 1.6

- 1

## Adjuvant Treatment for Malignant Melanoma  Overview

- Effect of IFN on 3-year survival
- 8-9 % absolute improvement in relapse-free survival
- 4-5% absolute improvement in overall survival

## Adjuvant Treatment for Malignant Melanoma  Summary

- Clinically important and convincing evidence of reduction in relapse
-  20% reduction in relapse rate; P< 0.0001
- Evidence of improved survival
- 10% reduction in death rate; P<0.065

## Adjuvant Treatment for Malignant Melanoma  Effect Size Adjuvant TreatmentRelative Reduction in the Odds of Recurrence and Death 

|  |  | recurrence rate % | death rate % |
| --- | --- | --- | --- |
| Melanoma | Interferon N=3536 | 20 | 10 |
| Colon cancer | 5FU/ Levamisole     N=929 | 38 | 35 |
| Breast cancer | Taxol
N=3170 | 22 | 26 |
|  | Tamoxifen     N=1129 | 22 | 18 |

## Adjuvant Treatment for Malignant Melanoma  K-M  estimates of DFS ECOG 1694 (from the published report) 

- Interferon 2b

- GMK vaccine

## Adjuvant Treatment for Malignant Melanoma  K-M  estimates of OSECOG 1694 (from the published report) 

- Interferon 2b

- GMK vaccine

## Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFS Scottish Melanoma Group (from the published report) 

- Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFS** **Scottish Melanoma Group** **(from the published report)

- Interferon 2b

- No treatment

## Adjuvant Treatment for Malignant Melanoma K-M estimate of OS Scottish Melanoma Group  (from the published report) 

- Interferon 2b

- No treatment

## Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFS WHO CT 16  (from the published report) 

- Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFS WHO CT 16** ** (from the published report)

- Interferon 2a

- No treatment

## Adjuvant Treatment for Malignant Melanoma K-M estimate of OS WHO CT 16 (from the published report) 

- Interferon 2a

- No treatment

## Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFSM 23031   (from the published report) 

- Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFSM 23031** **  (from the published report)

- Interferon 2a

- No treatment

## Adjuvant Treatment for Malignant Melanoma K-M estimate of OSM 23031  (from the published report) 

- Interferon 2a

- No treatment

## Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFSNCCTG 83-7052   (from the published report) 

- Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFSNCCTG 83-7052**  **** **(from the published report)

- No treatment

- Interferon 2a

## Adjuvant Treatment for Malignant Melanoma K-M estimate of OSNCCTG 83-7052  (from the published report) 

- No treatment

- Interferon 2a

## Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFSM 23031   (from the published report) 

- Adjuvant Treatment for Malignant Melanoma  K-M estimate of DFSM 23031** **  (from the published report)

- Interferon 2a

- No treatment

- DFS

- OS

- No treatment

- Interferon 2a

## Adjuvant Treatment for Malignant Melanoma  Colon Cancer5-FU levamisole

- Two studies, N= 408 and N= 1229
- In both studies subjects with stage II and III disease randomized to:
- 5-FU/levamisole
- Levamisole alone
- Observation

## Adjuvant Treatment for Malignant Melanoma  Colon Cancer5-FU levamisole

- <date/time>

- Adjuvant Treatment for Malignant Melanoma  Colon Cancer5-FU levamisole

- NCCTG/Mayo N=408
- RFS at 5 years
- 45% levamisole
- 55% 5-FU/levamisole
- 45% observation
- OS at 5 years
- 59% levamisole
- 61% 5-FU/levamisole
- 56% observation

## Adjuvant Treatment for Malignant Melanoma  Colon Cancer5-FU levamisole

- NCCTG/Mayo N=408
- Reduction in recurrence rate
- Levamisole alone: 27% (90% CI 2, 45%)
- 5FU/levamisole: 31% (90% CI 8, 48%)
- Reduction in death rate
- Levamisole alone: 18% (90% CI -10, +39%)
- 5FU/levamisole: 13% (90% CI -16, +34%)
*Laurie et.al. 1989*

## Adjuvant Treatment for Malignant Melanoma  Colon Cancer5-FU levamisole

- <date/time>

- Adjuvant Treatment for Malignant Melanoma  Colon Cancer5-FU levamisole

-  Intergroup NCCTG/SWOG/ECOG N=1229
- Overall reduction in RR
- 5 % levamisole
- 38 % 5-FU/levamisole
- OS at 3.5 years
- 71% 5-FU/levamisole
- 55% observation

## Adjuvant Treatment for Malignant Melanoma  Colon Cancer5-FU levamisole

-  Intergroup NCCTG/SWOG/ECOG N=929
- Reduction in recurrence rate (in Dukes C)
- Levamisole alone: 5% (95% CI: -19%, 25%)
- 5FU/levamisole: 38% (95% CI:20%, 52 %)
- Reduction in death rate (in Dukes C)
- Levamisole alone: 2% (95% CI: -28%, 35%)
- 5FU/levamisole: 35% (95%CI: 13%, 51%)

## Adjuvant Treatment for Malignant Melanoma  Breast CancerTaxol

- Intergroup CALGB/NCCTG/SWOG/ECOG N=3170
- First line adjuvant treatment doxorubicin and cyclophosphamide
- Subjects randomized to:
- 	Adjuvant Taxol
- 	Observation
- Reduction in disease recurrence
- 	HR= 0.78 (95% CI: 0.67, 0.91)
- Reduction in mortality
- 	HR = 0.74 (95% CI: 0.60, 0.92)

## Adjuvant Treatment for Malignant Melanoma  Breast CancerTamoxifen

- <date/time>

- Adjuvant Treatment for Malignant Melanoma  Breast CancerTamoxifen

## Adjuvant Treatment for Malignant Melanoma  K-M  estimates of DFS ECOG 1684(from the published report) 

## Adjuvant Treatment for Malignant Melanoma  K-M  estimates of OS ECOG 1684 (from the published report) 

## Adjuvant Treatment for Malignant Melanoma  K-M  estimates of DFS ECOG 1690 (from the published report) 

## Adjuvant Treatment for Malignant Melanoma  K-M  estimates of OS ECOG 1690 (from the published report) 

## Slide 72

##  Adjuvant Treatment for Malignant Melanoma INTRON-A   High Dose Results

-  Adjuvant Treatment for Malignant Melanoma INTRON-A   High Dose Results

## Adjuvant Treatment for Malignant Melanoma INTRON-A    Low Dose  Results

- Adjuvant Treatment for Malignant Melanoma INTRON-A    Low Dose  Results

## Adjuvant Treatment for Malignant Melanoma ROFERON-A  High Dose and Low DoseResults

- Adjuvant Treatment for Malignant Melanoma ROFERON-A  High Dose and Low DoseResults

## Adjuvant Treatment for Malignant Melanoma Odds Ratio for Survival

- <date/time>

- Kirkwood (1996)

- Kirkwood (2000) 1690L

- Kirkwood (2000) 1690H

- Cameron (2000)

- Kirkwood (2001)

- Creagan (1995)

- Pehamberger (1998)

- Grob (1998)

- Cascinelli (2001)

- 0

- 0

- .5

- 1

- 1.5

- 2

- Adjuvant Treatment for Malignant Melanoma Odds Ratio for Survival

- All studies (N=3536)

## Adjuvant Treatment for Malignant Melanoma Overview by FDA and Wheatley

- <date/time>

- Adjuvant Treatment for Malignant Melanoma Overview by FDA and Wheatley

- FDA DFS

- Wheatley DFS

-  FDA OS

-  Wheatley OS

- 0

- 0.5

- 1

- 1.5

- 2

## Adjuvant Treatment for Malignant Melanoma Odds Ratio for Relapse

- <date/time>

- Adjuvant Treatment for Malignant Melanoma Odds Ratio for Relapse

- Kirkwood (1996)

- Kirkwood (2000) 1690L

- Kirkwood (2000) 1690H

- Cameron (2000)

- Kirkwood (2001)

- Creagan (1995)

- Pehamberger (1998)

- Grob (1998)

- Cascinelli (2001)

- All studies (N=3536)

- 0

- 0.5

- 1

- 1.5

- 2