E5597. A Phase III Chemoprevention Trial of Selenium Supplementation in Persons with Resected Non-Small Cell Stage I Lung Cancer

1
E5597. A Phase III Chemoprevention Trial of
Selenium Supplementation in Persons with
ResectedNon-Small Cell Stage I Lung Cancer

• ECOG Staff
• Daniel D. Karp, MD, Chair
• Richard Feins, MD, Co-Chair, Thoracic Surgery
• David Harrington, PhD, Stats
• David Johnson, MD, Thoracic Committee Chair
• Gail Shaw, MD, FACP, Community Co-Chair
• Seena Aisner, MD, Pathology

Cooperative Group Coordinators Michael Liptay,
MD ACOSOG Gerald Clamon, MD CALGB Electra
Paskett, Ph.D. CALGB Randolph Marks, MD
NCCTG Charles Loprinzi, MD NCCTG Ciarin McNamee,
MD NCIC CTG Omer Kucuk, MD SWOG
2
Larry C. Clark, M.P.H, Ph.DIn Memorium

• Larry C. Clark, Ph.D., M.P.H., died March 20,
  2000 from prostate cancer. He was 51. Dr. Clark
  joined the faculty of the U. Arizona College of
  Medicine in1987. Until his death, he directed the
  Nutritional Prevention of Cancer Projects in
  Selenium at the Arizona Cancer Center.
• His research focused on the beneficial health
  effects of selenium in humans. His most widely
  known work was published in the Journal of the
  American Medical Association in December 1996.
• This study provided the first evidence that,
  while selenium had no benefit in reducing skin
  cancer incidence, nutritional supplementation
  with selenium may reduce the incidence of
  prostate, lung and colon cancers.

3
Selenium in Prostate Pre-Malignancy Jim Marshall

• Larry Clark Results
• Placebo / Control
• 498 / 482
• 43 / 23
• 11.9 / 6.3
• 1.0 .53
• SWOG 9917 Recruitment Goals
• High Grade Prostate Intracellular Neoplasia
  (HGPIN)
• Goal 800 1100 patients
• Randomize L-Selenomethionine vs Placebo
• Stratify for Vitamin E usage Yes / No

4
A Stylized Map of Selenium Distribution in the
U.S.
Selenium
Adequate
Variable
Low
adapted from www.ansci.cornell.edu/plants/toxi
cagents/selenium/map1.html
5
E 5597 Development Time Line
Larry Clark, PhD, MPH began studying Selenium in
the early 1980s. The Study was published in JAMA,
Dec. 96. It did not show decrease in skin
cancer but 30 decrease in lung, colon and
prostate cancer.
ECOG Planning Meeting, Tampa, FL, Jan 6, 1997

• With Special Thanks To
• Leslie Ford
• Waun Ki Hong
• Lori Minasian
• Howard Parnes
• Jack Ruckdeschel
• Gail Shaw
• Mary Steele

Bethesda Meeting October13, 1999
InterGroup 5597 Approved Oct. 2000
Michael Sporn Chemoprevention 1976
W.Ki Hong Head Neck Cancer 13cRA NEJM 86 90
MDACC 91025 Dec. 92 Mar 97
Follow - up
75 80 85 90 95
2000 2005
Clark LC et al. Effects of selenium
supplementation for cancer prevention in
carcinoma of the skin. JAMA 1996 2761957-1963.
6
When I talk to patients and discuss E5597, I am
going to tell them the followingThis is NOT a
research program testing something versus
nothingEVERY PATIENT WILL RECEIVE CAREFUL
SURVEILLANCE AND TREATMENT, along with oversight
by their respective cooperative group. Two-thirds
of the patients will also receive selenium
7
ECOG E5597 - Selenium Intergroup Prevention Study
in Resected Stage I NSCLC
Toll-free Hot Line 877-723-5597

• Objectives
• Reduce incidence of 2nd primary lung tumors
  (SPTs)
• Evaluate safety and toxicity of
  L-Seleno-methionine
• Compare overall and organ specific cancer
  mortality

• Selenium 200 microgms/day for 48 months
• Monitor for safety, SPTs and recurrence

• ELIGIBILITY
• Stage pT1N0 and pT2N0
• 6 36mo. post-op
• No prior Chemo or RT Rx
• Normal liver function
• ECOG PS gt 0 or 1
• gt 18 years old
• Compliance with run-in
• No dietary supplements
• No synchronous cancers

• Placebo daily for 48 months
• Monitor for safety, SPTs, and recurrence

Stratify by smoking status and gender
8
The 91025 Intergroup 13-CRA TrialStage I
Resected NSCLC 1989-1997

• 1256 pts randomized from Dec.92-Mar.97
• Study data are being finalized
• Preliminary report ASCO98 (Dr. Lippman)
• Data available for 1204 pts at that time.
• 153 recurrences 6.5 for T1 and 11.2 for T2
• 73 second primary tumors (SPTs)
• Approximately 4 in current or former smokers
• Only 1.6 in non-smokers
• What are the lessons of this study ?
• A Placebo-controlled study can be performed
• This patient group is a very important cohort for
  prospectively treated Stage I NSCLC.

Lippman SM, University of Texas-MD Anderson
Cancer Center Phase III, Double Blind,
Randomized Trial of 13-CRA vs Placebo to Prevent
Second Primary Tumors in Patients with Totally
Resected Stage I non-Small Cell Lung Cancer. (PDQ)
9
Selenium Shares Several Properties with Sulfur
1a 2a 3b 4b 5b 6b 7b 8 1b 2b 3a 4a 5a 6a 7a
0
He 2
Ne 10
F 9
O 8
N 7
C 6
B 5
Ar 18
Cl 17
Su 16
P 15
Si 14
Al
Sc 21
Ti 22
V 23
Cr 24
Mn 25
Fe 26
As
Se 34
Br 35
Kr 36
Selenium (Se 34) resembles sulfur. The
Recommended Daily Allowance (RDA) is 70
microgram. Current research programs use a tablet
containing 200 microgram L-selenomethionine.
Y 39
Zr 40
Nb 41
Mo 42
Sb 51
Te 52
I 53
Xe 54
Hf 72
Pb 82
Bi 83
Po 84
At 85
Rn 86
Eu 63
Gd 64
Tb 65
Dy 66
Ho 67
ER 68
Tm 69
Yb 70
Lanthinide Series
Lu 71
U 92
Np 93
Pu 94
Am 95
Cm 96
Bk 97
Cf 98
Es 99
Fm 100
Md 101
No 102
Actinide Series
Lr 103
10
Selenium Proposed Mechanisms of Action

• Stimulation of glutathione peroxidase thereby
  lowering tissue peroxides.
• Alterations in carcinogen metabolism.
• Production of cytotoxic selenium metabolites.
• Inhibition of protein synthesis.
• Inhibition of specific enzymes.
• Stimulation of apoptosis.

11
Selenium in Prostate Cell Lines Drs. Menter and
Lippman.

• Increased G2 arrest
• Analysis of Apoptosis by Na2SeO3 and SeMet
• Methods
• DAP/DNA
• TUNEL Assay
• Increased activity of Caspase 3
• Inhibits growth, induces apoptosis
• More active in androgen dependent cells (LNCaP)
• Dose dependent effects
• G2/M arrest via cdc2 kinase
• Apoptosis via caspase 3

12
Selenium Potential Side Effects

• Skin dermatitis, hair loss, itching, fingernail
  weakness.
• GI diarrhea, nausea, vomiting, constipation,
  metallic taste, belching.
• Neuro irritability.
• Constitutional weakness.
• Hepatic liver damage.
• Other garlic odor of breath and sweat.

13
E5597 Selenium Chemoprevention in Resected NSC
Stage I Lung Cancer Eligibility

• Stage 1A or 1B NSCLC (Carcinoid ineligible)
• At least 1 Mediastinal Node Sampled
• NO Chemotherapy or Radiation Therapy
• Not Taking Selenium Supplements

Chest Xray and normal LFTs within 8 wks No
Evidence of Recurrence
During Run-in Period, Participants MUST take AT
LEAST 75 of the Study Tablets
S
Eligible for Participation in 5597
T1N0 or T2 N0
3
6
9
12
15
18
21
24
27
30
33
36 months
CALGB accepts T1 ONLY
14
E5597 - Eligibility and Dietary Supplements
Taking gt50 micrograms of Selenium 3 times / week
more than 4 consecutive weeks during the prior
year
Ineligible
Week 1 2 3 4
5
Selenium Supplement MORE THAN 50 micrograms
One Year
Continue Supplement
Eligible
Stop Supplement 2 Weeks Prior to Registration
LESS THAN 50 micrograms Selenium
15
E5597 Selenium Stage I NSCLC ECOG Registration
Algorithm
Confirm Current Eligibility Checklist Completed
Pt. Meets All Eligibility Criteria for 5597.
Obtain Date Consent Form Was Signed
Obtain Date of IRB Approval
ECOG Coord Ctr forwards Cofirmation of
Registration to Institution
Rando or Web 617-632-2022
https//webpsm.dfci.harvard.edu.
Institutions call Central Randomization Desk or
WEB
ECOG verifies Successful Registration
ECOG provides Patient Sequence Number
N.B. Smoking Cessation Program Should Be Available
16
E5597 Selenium Stage I NSCLC SWOG Registration
Algorithm
Confirm Current Eligibility Checklist Completed
Pt. Meets All Eligibility Criteria for 5597.
Obtain Date Consent Form Was Signed
Obtain Date of IRB Approval
ECOG Coord Ctr forwards Registration to SWOG
Main Institu. CGOPs 206-667-4623
CCOPs 206-652-CCOP
SWOG calls ECOG Central Randomization Desk
SWOG notifies Institution of Successful
Registration
SWOG provides SWOG and ECOG Registration s
N.B. Smoking Cessation Program Should Be Available
17
E5597 Selenium Stage I NSCLC NCCTG Registration
Algorithm
Confirm Current Eligibility Checklist Completed
Pt. Meets All Eligibility Criteria for 5597.
Obtain Date Consent Form Was Signed
Obtain Date of IRB Approval
ECOG Coord Ctr forwards Registration to NCCTG
NCCTG Fax [phone]
NCCTG site faxes Elig checklist to 507-284-0885
NCCTG calls ECOGs Central Randomization Desk
If successful reg ECOG Seq assigned relayed
to site
N.B. Smoking Cessation Program Should Be Available
18
E5597 Selenium Stage I NSCLC ACOSOG
Registration Algorithm
Confirm Current Eligibility Checklist Completed
Pt. Meets All Eligibility Criteria for 5597.
Obtain Date Consent Form Was Signed
Obtain Date of IRB Approval
ECOG Coord Ctr forwards Registration to ACOSOG
ACOSOG WEB http//www. acosog.org
ECOG WEB https//webpsm. dfci.harvard.edu
ACOSOG WEB Registration available 24 hrs
Token provided, then access ECOG WEB page
If successful reg ECOG PT Seq assigned
N.B. Smoking Cessation Program Should Be Available
19
E5597 Selenium Stage I NSCLC CALGB Registration
Algorithm
Confirm Current Eligibility Checklist Completed
Pt. Meets All Eligibility Criteria for 5597.
Obtain Date Consent Form Was Signed
Obtain Date of IRB Approval
ECOG Coord Ctr forwards Registration to CALGB
CALGB Registrar 919-286-4704
CALGB Sites use direct registration privileges
Call CALGB registrar who will contact ECOG
If eligible, ECOG PT Seq assigned
N.B. Smoking Cessation Program Should Be Available
20
E5597 Four Week Run-in Period
S
M
T
W
T
F
S
Start Date
Earliest Randomization Date
Latest Randomization Date
Patients Must Be Randomized Between 3 6 Weeks
of Start Date of Run-in Period With Nutritional
Supplement

• Pt is eligible for Randomziation IF
• (S)He takes at least 21 of 28 tablets during
  Run-in Period. ( Check Calendar and Bottle) AND
• There is no evidence of recurrent disease.

21
E5597 L-SelenomethionineFormulation and Drug
Information

• Drug Provided Free by Cypress Systems
• Run-in Bottle Contains 35 Tabs
• Study Bottles Contain 200 Tabs
• Drug Delivery (Store at Room Temperature)
• Signed Drug Request Form
• Confirm IRB Approval is Up To Date (HHS 310)
• Drug Shipped by ProClinical on Next Business Day.
  (No Weekend or Holiday Shipping)
• Mon, Tue, or Wed requests will be received by the
  end of the Week.
• Thursday or Friday requests will be received on
  Tuesday of next week.

22
E5597 Randomization Process

• Refer to Section 4.0 of the protocol for Group
  specific randomization procedures.
• Stratification Factors
• Patient Demographics
• Smoking Status
• Active/Recent Smoker (Stopped LESS THAN 1 Yr Ago)
• Former Smoker (Stopper MORE THAN 1 Yr Ago)
• Never Smoked (FEWER THAN 100 cigarettes ever)

Smoking Cessation Program Should Be Available to
All Current Smokers
23
E5597 - Duration of Therapy

• Supplement Will Be Administered 4 Years
• Follow-up for 6 Years (10 year total
  participation)
• As always, patients will be followed indefinitely
  for survival and disease status.
• Reasons for Discontinuation
• Unacceptable Toxicity (Grade 2,3,or 4) or Death
• Patient Refusal to Continue
• Intercurrent Illness Necessitating Premature
  Termination
• Development of a Second Primary Tumor
• RECURRENT LUNG CANCER
• Treatment Should Be Interrupted During Surgery,
  Radiation, or Chemotherapy
• MAY BE RESTARTED FOLLOWING COMPLETION OF THERAPY

24
Eligibility Requirements for Patients Taking
Dietary Supplements

• Patients MUST NOT BEGIN NEW SUPPLEMENTS During
  the Study.
• Patients Already Taking Supplements Containing
  LESS THAN 50 (FIFTY) micrograms of Selenium HAVE
  THE OPTIONS
• Stop the Supplements 2 weeks prior to Study Entry
  OR
• Continue Their Supplements Throughout the Study
  Period.
• Definitions
• SUPPLEMENT Any non-food compound by mouth or
  injection intended to provide dietary factors
• TAKING REGULARLY Patients taking regular
  supplements for the majority of the time (3 times
  per week for more than 4 consecutive wks) during
  the year prior to participation.
• SELENIUM SUPPLEMENT Selenium in any form greater
  than 50 (fifty) micrograms/day

25
E5597 - Outstanding Collaboration
Ciaran McNamee, MD Hys Center, Edmonton, Alberta,
CANADA
Randolph Marks Charles Loprinzi Mayo Clinic,
Rochester, MN
Richard Feins U. Rochester, Rochester, NY
ACOSOG 5597
American College of Surgeons Onc Group
David Harrington ECOG Statistical Office
Omer Kucuk Wayne State U., Detroit, MI
CALGB 79803
Cancer and Acute Leukemia Group B
Gerald Clamon U. Iowa, Iowa City
Seena Aisner UMDNJ, Newark, NJ
ECOG 5597
Eastern Cooperative Oncology Group
Michael Liptay Evanston Hospital
NCIC CTG BR16
Nat Can Instit of Canada Ca Treat Grp
David Johnson Vanderbilt U., Nashville, TN
Electra Paskett CALGB Prevention Chair
NCCTG 5597
North Central Cancer Treatment Group
Gail Shaw Wright Community Chair, GA
Southwest Oncology Group
SWOG 5597