Challenges in Designing and Conducting
Clinical Trials in Oncology
Barbara Melosky, MD, FRCPC
Objectives
• Provide an overview of key issues and challenges in designing and
conducting oncology clinical trials
• Discuss regional and country-specific issues
• Highlight issues in the era of personalised medicine
What Is a Clinical Trial?
• Mechanism to learn how to improve treatments
• Mechanism to introduce new treatment techniques (procedures) or new drugs
• Method to build on prior knowledge of technique or drug
What Is NOT a Clinical Trial?
• Random experiments by devious physicians looking to make money or
become famous
• Crazed make-work project for nurses and data collectors
• A way to avoid animal rights activists
• Conspiracy to get drugs/products into the market
HOW TO OPEN A TRIAL: The Long Journey
PI is approached about a potential trial
1.
2.
3.
4.
5.
6.
ISSUES TO CONSIDER
Medical need
Costs per patient
Can it accrue?
Workload implications
Strategic value
Academic value
TRIAL APPROVED
REB
Resource
Impact
Analysis
CONTRACT
WAITLIST
Key Components of a Clinical Trial
• Identification of a relevant clinical question
– Better treatment or schedule?
• An answerable question
– Statistics (numbers, power of the intervention, results expected)
• Realistic intervention or treatment
– Plan for the future
• Discussed by peer experts and ethics boards
Type 1 Error (Alpha)
• Probability of rejecting the null hypothesis when it is in fact true (i.e. no
difference)
• Not as big a concern for early phase (exploratory studies)
• More of an issue for phase III trials
Type II Error (Beta)
• Probability of accepting null hypothesis when it is false
• Power = 1-Beta
• Don’t want to do this in early phase studies or will not proceed further
Sample Size Calculation
• Based on 3 factors:
– Delta (expected difference between arms)
– Alpha
– Beta
• Need to consider:
– How many patients can be reasonably accrued
– How much time
– How much money
Online Sample Size Calculators
• Simon 2-stage:
http://www.cscc.unc.edu/cscc/aivanova/SimonsTwoStageDesign.aspx
• Traditional design: http://www.stat.ubc.ca/~rollin/stats/ssize/b2.html
Phases of Trials
• Phase I: Looks at side effects and doses
– Any suggestion of particular type of cancer that might be more sensitive
• Phase II: Looks for a suggestion of efficacy in a specific cancer (e.g. lung
cancer)
– Usually about 75 people per study
• Phase III: Is this new treatment better than the standard treatment?
– Often randomised or with a placebo arm
Phase I
• Assess tolerance of drug/device
• Find maximum tolerated dose (MTD)/recommended phase II dose (RP2D)
• Generally small sizes
– Standard 3+3 design
Standard Phase I Design
Phase I
• Pharmacokinetics (PK)
• Pharmacodynamics (PD)
• Preliminary efficacy
– Phase 1b
Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer
Julie R. Brahmer, M.D., Scott S. Tykodi, M.D., Ph.D., Laura Q.M. Chow, M.D., Wen-Jen Hwu, M.D., Ph.D., Suzanne L. Topalian, M.D., Patrick
Hwu, M.D., Charles G. Drake, M.D., Ph.D., Luis H. Camacho, M.D., M.P.H., John Kauh, M.D., Kunle Odunsi, M.D., Ph.D., Henry C. Pitot, M.D.,
Omid Hamid, M.D., Shailender Bhatia, M.D., Renato Martins, M.D., M.P.H., Keith Eaton, M.D., Ph.D., Shuming Chen, Ph.D., Theresa M. Salay,
M.S., Suresh Alaparthy, Ph.D., Joseph F. Grosso, Ph.D., Alan J. Korman, Ph.D., Susan M. Parker, Ph.D., Shruti Agrawal, Ph.D., Stacie M.
Goldberg, M.D., Drew M. Pardoll, M.D., Ph.D., Ashok Gupta, M.D., Ph.D., and Jon M. Wigginton, M.D.
Abstract
BACKGROUND:
Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of
tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in
vitro and mediates antitumor activity in preclinical models.
METHODS:
In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per
kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week
cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression.
RESULTS:
As of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17
with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer--had
received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that
investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be
evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with
renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of
16 patients with at least 1 year of follow-up.
CONCLUSIONS:
Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged
stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer,
melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.).
Brahmer JR, et al. N Engl J Med. 2012 Jun 28;366(26):2455-65. Epub 2012 Jun 2.
SAFETY
A maximum tolerated dose was not reached. The median duration of therapy was 12 weeks (range, 2 to 111 weeks) (Table S2A
in the Supplementary Appendix). A relative dose intensity of at least 90% was achieved in 86% of patients. Of the 207 patients,
23 (11%) discontinued treatment because of an adverse event; of these events, 12 (6%) were considered by investigators to be
related to treatment (Tables S2B and S3A in the Supplementary Appendix).
PHARMACOKINETICS AND PHARMACODYNAMICS
Serum levels of anti–PD-L1 antibody increased in a dose-dependent manner from 1 to 10 mg per kilogram in 131 patients who
were evaluated. The geometric mean area under the curve (0 to 14 days) for doses of 1 mg, 3 mg, and 10 mg per kilogram
were 2210, 7750, and 36,620 µg per milliliter per hour, respectively (coefficient of variation, 34 to 59%). After the first dose,
geometric mean peak levels at these dose levels were 27, 83, and 272 µg per milliliter, respectively (coefficient of variation, 30
to 34%). The half-life of anti–PD-L1 antibody was estimated from population pharmacokinetics as approximately 15 days. PDL1 receptor occupancy on CD3+ peripheral-blood mononuclear cells was assessed in 29 patients with melanoma at the end of
one cycle of treatment, at doses of 1 to 10 mg per kilogram. Median receptor occupancy exceeded 65% for all groups (Fig. S2
in the Supplementary Appendix).
Brahmer JR, et al. N Engl J Med. 2012 Jun 28;366(26):2455-65. Epub 2012 Jun 2.
Table 1.
Adverse Events of Special Interest in 207 Patients Receiving Anti-PD-L1
Antibody
Anti-PD-L1,
0.3 mg/kg (N=3)
Event
All
Grades
Grade
3 or 4
Anti-PD-L1,
1 mg/kg (N=37)
All
Grades
Grade
3 or 4
Anti-PD-L1,
3 mg/kg (N=42)
All
Grades
Grade
3 or 4
Anti-PD-L1,
10 mg/kg (N=125)
Anti-PD-L1,
Total (N=207)
All
Grades
Grade
3 or 4
All
Grades
Grade
3 or 4
Number of patients (%)
Any adverse event of special
interest††
1 (33)
0
18 (49)
2 (5)
14 (33)
2 (5)
48 (38)
6 (5)
81 (39)
10 (5)
Any rash
0
0
5 (14)
0
1 (2)
0
8 (6)
0
14 (7)
0
Pruritus
0
0
6 (16)
0
3 (7)
0
3 (2)
0
12 (6)
0
Vitiligo
0
0
3 (8)
0
1 (2)
0
1 (1)
0
5 (2)
0
Pruritic rash
0
0
1 (3)
0
1 (2)
0
2 (2)
0
4 (2)
0
Macular rash
0
0
2 (5)
0
1 (2)
0
0
0
3 (1)
0
Erythema
0
0
2 (5)
0
0
0
0
0
2 (1)
0
Erythematous rash
0
0
0
0
1 (2)
0
1 (1)
0
2 (1)
0
1 (33)
0
4 (11)
0
6 (14)
0
8 (6)
0
19 (9)
0
0
0
0
0
2 (5)
0
19 (15)
1 (1)
21 (10)
1 (<1)
Hypothyroidism
0
0
0
0
1 (2)
0
5 (4)
0
6 (3)
0
Adrenal insufficiency
0
0
0
0
1 (2)
1 (2)
1 (1)
0
2 (1)
1 (<1)
Autoimmune thyroiditis
0
0
2 (5)
0
0
0
0
0
2 (1)
0
0
0
0
0
2 (5)
0
0
0
2 (1)
0
0
0
1 (3)
0
0
0
2 (2)
0
3 (1)
0
Skin or subcutaneous disorder
Gastrointestinal disorder
Diarrhea
Procedural complication
Infusion-related reaction
Endocrine disorder
Eye disorder
Dry eye
Immune-system disorder
Hypersensitivity
Laboratory investigation
†The numbers reported within a column may not add up to the total number reported because patients who had more than one adverse event were counted for each event but
were counted only once for “any adverse events of special interest.”
Brahmer JR, et al. N Engl J Med. 2012 Jun 28;366(26):2455-65. Epub 2012 Jun 2.
Table 2
Clinical Activity of Anti–PD-L1 Antibody in the Efficacy Population.*
Tumor Type and Dose
No. of
patients
Objective Response
Duration of
Response
Stable Disease ≥24 Weeks
Rate of Progression-free
Survival at 24 Weeks
No. of
patients
% (95% CI)
Mo
No. of
patients
% (95% CI)
% (95% CI)
Melanoma
0.3 mg/kg
1
0
0 (0–98)
NA
0
0 (0–98)
NA
1 mg/kg
18
1
6 (0–27)
6.9
6
33 (13–59)
39 (16–61)
3 mg/kg
17
5¶
29 (10–56)
23.5+, 22.9+, 16.2+,
4.1+, 3.5
3
18 (4–43)
47 (21–72)
10 mg/kg
16
3‖
19 (4–46)
20.8+, 16.6, 2.8
5
31 (11–59)
44 (19–68)
All doses
52
9
17 (8–30)
14
27 (16–41)
42 (28–56)
All patients, 1 mg/kg
11
0
0 (0–29)
NA
0
0 (0–29)
NA
All patients, 3 mg/kg
13
1
8 (0–36)
2.3+
1
8 (0–36)
34 (7–60)
Squamous subtype
4
0
0 (0–60)
NA
1
25 (0–81)
50 (1–99)
Nonsquamous subtype
9
1
11 (0–48)
ND
0
0 (0–34)
25 (0–55)
25
4
16 (5–36)
16.6+, 12.6+, 9.8, 3.5
5
20 (7–41)
46 (25–67)
Squamous subtype
8
1
13 (0–53)
ND
2
25 (3–65)
47 (10–83)
Nonsquamous subtype
17
3
18 (4–43)
ND
3
18 (4–43)
46 (20–72)
49
5
10 (3–22)
6
12 (5–25)
31 (17–45)
Squamous subtype
13
1
8 (0–36)
ND
3
23 (5–54)
43 (15–71)
Nonsquamous subtype
36
4
11 (3–26)
ND
3
8 (2–23)
26 (10–42)
1
0
0 (0–98)
NA
0
0 (0–98)
NA
3 mg/kg
1
0
0 (0–98)
NA
0
0 (0–98)
NA
10 mg/kg
16
1
6 (0–30)
1.3+
3
19 (4–46)
25 (4–46)
All doses
17
1
6 (0–29)
3
18 (4–43)
22 (2–43)
17
2
12 (2–36)
7
41 (18–67)
53 (29–77)
Non–small-cell lung cancer
All patients, 10 mg/kg
All patients, all doses
Ovarian cancer
Renal-cell cancer, 10 mg/kg
17, 4
* The efficacy population included 160 patients in whom a response could be evaluated and who initiated treatment by August 1, 2011. These patients had measurable disease at a baseline tumor assessment and at least one of the following: an assessment of
tumor burden during the study, clinical progression, or death. NA denotes not applicable, and ND not determined. † Objective response rates (including both complete response and partial response) are based on confirmed responses only, with 95% confidence
intervals calculated with the use of the Clopper–Pearson method. ‡ The duration of response is the time from the first response to the time of documented disease progression, death, censoring of data (denoted by a plus sign), or last tumor assessment. § The rate
of progression-free survival was the proportion of patients who did not have disease progression and were alive at 24 weeks, as calculated by the Kaplan–Meier method. The Greenwood method was used to calculate confidence intervals. ¶ Two of these patients
had a complete response. ‖One of these patients had a complete response.
Phase II
• Performed in patients with same cancer
• Assess efficacy
• Can be single arm or randomised
– Interpret results with caution!
– The MetMab Saga
Onartuzumab: A One-armed (Monovalent) anti-MET Antibody
Ridgway JBB, et al. Protein Eng 1996; Nguyen TH, et al. Cancer Gene Ther 2003; Kong-Beltran M, et al. Cancer Cell 2004; Martens
T, et al. Clin Cancer Res 2006; Merchant M, et al. Proc Natl Acad Sci USA 2013.
Courtesy of Barbara Melosky, MD.
Phase II:
Erlotinib ± Onartuzumab 2nd/3rd-line NSCLC
1:1
Key eligibility:
• Stage IIIB/IV
• 2nd/3rd-line
• Tissue
• PS 0–2
n=137
Spigel DR et al. J Clin Oncol. 2013;31:4105-14.
R
A
N
D
O
M
I
S
A
T
I
O
N
Arm A
n=68
Placebo
+
erlotinib
Onartuzumab
Arm B
n=69
+
erlotinib
Efficacy in Met Diagnostic Positive Patients
OS: HR = 0.37, p = 0.002
PFS: HR = 0.53, p = 0.04
MetMAb +
erlotinib
2.9
Median (mo)
1.0
1.0
0.8
0.8
Probability of Survival
Probability of Progression Free
Median (mo)
Placebo +
erlotinib
1.5
0.6
0.4
0.2
0.0
Placebo +
erlotinib
3.8
MetMAb +
erlotinib
12.6
0.6
0.4
0.2
0.0
0
3
6
9
12
15
Time to Progression (months)
Spigel DR et al. J Clin Oncol. 2013;31:4105-14.
18
0
3
6
9
12
15
18
Overall Survival (months)
21
ASCO 2014 PHASE lll
OAM4971g: Overall Survival Results
NEGATIVE TRIAL
Courtesy of Barbara Melosky, MD.
Phase III
• Larger samples (~60-5000), multicentre
• Control group (placebo or active control)
• Randomisation
• Safety and QOL
BR.21 Trial
Endpoints
Patients
• Stage IIIB/IV
• NSCLC with PS
0–3
• Previously treated
Erlotinib
150 mg daily
2:1 randomisation
Placebo
Shepherd et al. N Engl J Med. 2005;353:123-132.
Primary
• Overall survival (OS)
Secondary
• Progression-free
survival (PFS)
• Response rate (RR)
• Safety
• Quality of life (QoL)
• Duration of response
BR.21: Overall Survival
1.00
Erlotinib
(n=488)
Placebo
(n=243)
Median Survival (months)
6.7
4.7
1-year survival (%)
31
21
Survival distribution function
Endpoint
HR = 0.70 (95% CI, 0.58-0.85); P<0.001
0.75
0.50
31%
42.5% improvement in median survival
0.25
Erlotinib
Placebo
21%
0
0
5
10
15
Survival time (months)
Shepherd et al. N Engl J Med. 2005;353:123-132.
20
25
30
Phase IV
• Studies performed to assess long-term side effects/efficacy
• Open labeled
• May be a way to give access to new therapies
ENDPOINTS
DFS
• Time from randomisation until objective tumour recurrence or death
• Accepted by FDA as a primary endpoint for drug approval
• Useful in adjuvant trials: long-term follow-up
– Catches long-term toxicity and second malignancies
PFS
• Time from randomisation until objective tumour progression or death
• Accepted by FDA as a primary endpoint for drug approval
– Especially with quality of life
• Definition of tumour progression should be carefully detailed in the protocol
IPASS: First-line Study Design
Endpoints
Patients
Primary
• Chemo-naive
• Age
≥18 years
• Adenocarcinoma
histology
• Never or light exsmokers
• Life expectancy
≥12 weeks
• PS 0-2
• Measurable stage IIIB/
IV disease
Gefitinib
(250 mg/day)
• PFS (non-inferiority)
Secondary
1:1 randomisation
Carboplatin
(AUC 5 or 6)/
paclitaxel
(200 mg/m2)
3 weekly
• ORR
• OS
• QoL
• Disease-related symptoms
• Safety and tolerability
Exploratory
• Biomarkers
• EGFR mutation
• EGFR gene copy number
• EGFR protein expression
Mok et al 2009
Courtesy of Barbara Melosky, MD.
Courtesy of Barbara Melosky, MD.
TTP
• Time from randomisation until objective tumour progression (RECIST)
• TTP does not include deaths
• Accepted by FDA as a primary endpoint for drug approval
TTF
• Time from randomisation to discontinuation of treatment for any reason
– Disease progression, death and treatment toxicity
– Treatment toxicity
• Patient or physician withdrawal, or patient intolerance
– TTF is not recommended as a regulatory endpoint for drug approval
OS
• Time from randomisation to death for any reason
• Gold endpoint
• No bias
• DEAD is DEAD
PFS VS OS
ASCO 2008: FLEX
FLEX
Study Design
NSCLC
wet IIIB/IV
EGFRexpressing
Chemotherapy +
Cetuximab
Chemotherapy
Primary Endpoints OS
Chemotherapy (CT)
Cetuximab
Cisplatin 80 mg/m2 day 1
Initial dose 400 mg/m2
Vinorelbine 25 (30) mg/m2 days 1, 8
Then 250 mg/m2 weekly
Every 3 weeks, up to 6 cycles
Pirker et al. Lancet. 2009;373:1525-1531.
Maintenance
Cetuximab until
PD or intolerable
toxicity
Flex Results
100
Overall Survival (%)
90
80
Median OS
1-Y OS
CV + Cetuximab
11.3 mo
47%
CV
10.1 mo
42%
70
HR: 0.871; P=0.044
60
50
40
30
20
10
0
0
6
12
18
24
30
Months
CV + Cetuximab
CV
P-value
RR
36%
29%
.012
PFS
4.8 mo
4.8 mo
NS
TTF
4.2 mo
3.7 mo
.015
Pirker R et al. J Clin Oncol. 2008;26:3.
First-line Bevacizumab in NSCLC:
Two Positive Phase III Trials
E45991
Trial commenced 2001
Endpoint
CP x 6 (n=444)
Stage IIIB/IV
non-sq. NSCLC
(n=878)
OS
Bevacizumab (15 mg/kg)
q3w + CP x 6 (n=434)
AVAiL2
Trial commenced 2005
Stage IIIB/IV
non-sq. NSCLC
(n=1,043)
PD*
2
R
A
N
D
O
M
I
S
E
1
1
2
Bevacizumab (15 mg/kg)
q3w + CG x 6 (n=351)
Bevacizumab
PD
Bevacizumab
PD
Placebo + CG x 6
(n=347)
PD*
Placebo + CG x 6
Bevacizumab (7.5 mg/kg)
q3w + CG x 6 (n=345)
*No crossover permitted.
CG = cisplatin/gemcitabine
1. Sandler et al. N Engl J Med. 2006; 2. Reck et al. J Clin Oncol. 2009.
Bevacizumab
PD
PFS
E4599 Overall Survival
12 mo 24 mo RR
PC
44% 15% 15%
PCB
51% 23% 35%
1.0
Probability
0.8
HR: 0.79 (0.67, 0.92)
P = .003
0.6
Medians: 10.3, 12.3
0.4
0.2
0
0
6
12
18
Months
Sandler et al. N Engl J Med. 2006;355:2542-2550.
24
30
36
AVAiL
• Original endpoint OS
• When E4599 came out showing improved PFS and OS, endpoint in AVAiL
changed to PFS
• Follow-up of patients q3 months did not change
Reck M et al. J Clin Oncol. 2009;27:1227-34.
Progression-free Survival
1.0
Probability of PFS
Placebo
+ CG
0.8
HR
(95% CI)
p value
0.6
Median PFS
(months)
6.2
Bev
7.5 mg/kg
+ CG
Bev
15 mg/kg
+ CG
0.75
(0.64–0.87)
0.85
(0.73–1.00)
0.0003
0.0456
6.8
6.6
0.4
0.2
0
0
6
12
18
24
30
3
5
0
0
0
0
Time (months)
No. at risk
Placebo + CG
Bev 7.5 mg/kg + CG
Bev 15 mg/kg + CG
2008 IASLC/ESMO update.
347
345
351
178
214
200
34
63
57
12
18
12
AVAiL: No Significant Benefit in OS
Placebo
+ CG
1.0
HR
(95% CI)
Probability of OS
0.8
p value
Median PFS
(months)
13.1
Bev
7.5 mg/kg
+ CG
Bev
15 mg/kg
+ CG
0.93
(0.78–1.11)
1.03
(0.86–1.23)
0.42
0.76
13.6
13.4
0.6
0.4
0.2
0
0
6
12
18
Time (months)
ESMO 2008.
24
30
36
AVAiL: High Proportion of Patients Received
Post-Protocol Therapies
Post-protocol therapy
Placebo
+ CG
% (n)
Bev 7.5 mg/kg
+ CG
% (n)
Bev 15 mg/kg
+ CG
% (n)
Any treatment, % (n)
65 (224)
61 (210)
61 (214)
TKIs
41 (92)
48 (100)
42 (90)
Chemotherapy
73 (164)
65 (137)
69 (147)
Angiogenesis inhibitors
<1 (2)
<1 (2)
<1 (3)
Surgical and medical
procedures
26 (60)
34 (71)
27 (57)
Type, % (n)
AVAiL: Trend Towards Improved OS in Bevacizumab-Treated Patients Not
Receiving Post-Protocol Therapies
1.0
Median OS
(95% CI)
Bev
No 2nd-line
Bev
8.7 (7.8-9.9)
Placebo
7.3 (5.9-8.9)
Probability of OS
HR (p value)
0.8
Bev to placebo
0.84 (0.20)
0.6
0.4
0.2
Bev without 2nd-line
Placebo without 2nd-line
n=123
n=272
0
10
20
Time (months)
30
40
Country-specific Issues
• US represents 50% of global market
• Pharma will ensure US representation on trials
• The remainder will come from:
– China
– India
– Eastern Europe
– Latin America
– Europe
– Canada
Clinical Trial Trends
• More global, more competitive environment
• Larger trials:
– 6 vs 3 months of FOLFOX stage III colon, N=10,000
• Tissue required for colorectal, breast, lymphoma…
Tissue Collection Challenges
• Tissue collection vital: eligibility, correlative studies
• Pathology departments reluctant to send blocks:
– REB of other institutions not acknowledged
– Concern about exhausting archival tissue
– Costs of processing and shipping
Biggest Trend in Clinical Trials
• Biomarker-driven!
• Narrower eligibility – cancer subsets:
– Bevacizumab in triple-negative breast cancer
– KRAS wild type in colorectal (60%)…RAS wild type in colorectal (45%)…future
(30%)
– ALK NSCLC (4%)
– ROS NSCLC (1%)
PD-L1 Biomarker Short History
• Feb 2008: Roche acquires Ventana Medical Systems
– PD-L1 IHC (MPDL3280A)
• Dec 2011: BMS collaborates with Dako for the
development of pharmacodiagnostic predictive tests
(including PD-L1)
• May 2014: Merck collaborates with Dako to develop a
companion diagnostic test for the analysis of tumour PD-L1
• June 2014: MedImmune/AZ MEDI4736 announces
agreement with Ventana to develop PD-L1 test
INVESTIGATOR-INITIATED TRIALS
Treatment of rash secondary to erlotinib
PANCANADIAN RASH TRIAL WITH EGFR
INHIBITORS
Barbara Melosky, Helen Anderson, Ron Burkes, Quincy Chu, Desiree Hao, Vincent Ho, Cheryl Ho, Wendy Lam, Christopher Lee, Natasha Leighl,
Nevin Murray, Sophie Sun, Robert Winston, Janessa Laskin
Corresponding author: bmelosky@bccancer.bc.ca
Erlotinib-induced Rash
• Affects 50% – 75% of patients
• Most often appears on the face
and chest
• May be severe
• May limit exposure to erlotinib,
compromising efficacy
Study Design
Incidence of Rash and Time to Severe Grade 3 Rash
Incidence of
any rash
n (%)
ARM 1
(N=50)
84%
ARM 2
(N=50)
84%
Arm 3
(N=50)
82%
Incidence of
Grade 3 rash
n (%)
P value
Mean (days)
to Grade 3
rash onset
P value
9.5%
P=
0.034
Arm 1 vs 3
17.4
P = 0.0147
14.3%
P=
0.065
Arm 2 vs 3
13.3
34.1%
12
Overall Survival
Not significant but Arm 3 does the worst
Conclusions ASCO 2014
• Prophylactic minocycline reduces the incidence of severe EGFR inhibitor–
induced rash without influencing efficacy
• Prophylactic minocycline should be considered upon initiation of EGFR
inhibitors
• Rash is a predictive factor of survival and should be treated
Investigator-Initiated Trial
• My idea
• PanCanadian trial
• Randomised prospective
• Took 5 years! (first 2 were contract)
• Budget 500,000…900,000
• End of day: Completed it, presented it at ASCO and publishing it
Who Benefits From Clinical Research?
… or who doesn’t?
RESEARCHERS TAKE BETTER CARE OF PATIENTS
RESEARCH SAVES MONEY
RESEARCH DRIVES CME
RESEARCH SAVES LIVES
RESEARCH BRINGS GRANTS
PATIENT ACCESS TO NEW AGENTS
STATE-OF-THE-ART FACILITIES
JOB CREATION
RECRUIT THE BEST BY BEING THE BEST
Who Benefits? The Patient!
IT’S COMPLICATED !
Courtesy of Barbara Melosky, MD.