Download Alex A. Adjei, Roswell Park Cancer Institute, Buffalo, NY

Alex A. Adjei,
Roswell Park Cancer Institute, Buffalo, NY
CHALLENGES IN DESIGNING PHASE I
CLINICAL TRIALS IN THE ERA OF TARGETED
THERAPIES
Phase I study endpoints have not changed
•To define :
•Dose, toxicity, pharmacology (efficacy)
–Identify DLTs
–Identify the MTD
–Assess pharmacokinetics
•Evaluate target modulation
Pharmacology is Important !
Phase I – Classical Eligibility Criteria
•“Conventional” eligibility criteria – examples:
–Refractory advanced solid tumors
–Good PS ( ECOG 0 or 1)
–Adequate organ function ( bone marrow,
liver, kidney)
–Specification about time interval between
prior therapy and initiation of study
treatment
–No serious uncontrolled medical disorder
or active infection
Phase I – Eligibility Criteria in the Targeted Therapy Era
• “Agent-specific” eligibility criteria – examples:
– Specific organ function:
• Cardiac function restrictions (e.g. QTc
<450–470 ms, LVEF >45%, etc.)
• uncontrolled hypertension
• proteinuria
• hyperlipidemia
• Hgb A1c < 7%
• Retinal disease
– Prohibited medications - risk of interaction with study drug
• Anticoagulants (coumadin, low molecular weight heparin)
• Steroids (immunotherapeutic agents)
• Potent CYP inhibitors/inducers
Dose-limiting toxicities
• Toxicities that are considered to be
unacceptable, and limit further dose escalation
• Defined in advance of starting trial
• Classically based on cycle 1 toxicity
• Examples:
–ANC <500 for 5 or 7 days
–ANC <500 of any duration with fever
–PLT <10,000 or 25,000
–Grade 3 or greater non-hematological toxicity
Definition of DLT in the era of targeted agents
–Diarrhea: ≥ Grade 3 in spite of adequate antidiarrheal therapy
(loperamide)
–Nausea and vomiting: ≥ Grade 3 in spite of adequate
anti-emetic prophylaxis and therapy (steroids, 5HT3
antagonists)
–Hypertension: ≥ Grade 3 in spite of adequate therapy
–Hyperglycemia: ≥ Grade 3 in spite of adequate therapy
(metformin)
–Triglycerides/Cholesterol ≥ Grade 3 in spite of adequate
therapy
–Inability to take at least 90% of drug doses in a cycle
(continuous oral meds)
–Grade 2 chronic unremitting toxicity
How quickly do you escalate?
Phase I trial design: Dose escalation
•Attributed to a merchant from Pisa in the
13th century
–Leonardo Bonacci, 1170–1240; aka
Fibonacci
•Outlined series (0,1, 1, 2, 3, 5, 8, 13, 21,
34, 55, 89, 144…) in a book, “Liber abacus”
Phase I trials: Dose escalation
The modified Fibonacci schedule
Cohort
1
2
3
4
5
6 and higher
Dose
n
2n
3.3 n
5n
7n
Escalation (%)
First dose
100%
67%
50%
40%
25–33%
Phase I standard 3 + 3 design
DLT
Dose
Recommended dose
3 pts
3 pts
3 pts
3 pts
3 pts
Eisenhauer EA, et al. J Clin Oncol 2000;18:684–692.
Starting dose
+
3 pts
DLT
3 pts
Classic Phase I trial design limitations
• Wide confidence intervals
•Patients treated at ineffective doses in
first cohorts
• High risk of severe toxicities at late cohorts
• Chronic toxicities usually cannot be assessed
• Cumulative toxicities usually cannot be
identified
•Uncommon toxicities will be missed
Phase I Studies and Infrequent
Toxicities
Probability of NOT observing a serious
toxicity occuring at a rate of:
Number of patients
10%
20%
1
0.90
0.80
2
0.81
0.64
3
0.73
0.51
6
0.53
0.26
10
0.35
0.11
15
0.21
0.04
Probability of overlooking a toxicity:
POT(p) = (1-p)n; n = sample size, p = true toxicity rate
Intra-patient dose escalation
• Treat patients at dose level 1
• Dose level 2 is well tolerated and patients at
dose level 1 have no toxicities
• Patients at level 1 are escalated to level 2
Why isn’t IPDE more widely used?
• Makes evaluation of chronic toxicities difficult
• The proverbial 1 responder at dose level 1
Phase I study of EKB569
March 29, 2001
September 19, 2001
Problem : Inadequate
Pharmacology for Oral
Targeted Agents in Phase I
-Relevant Drug Interactions
-Food Effects
DA Smith el al, BJCP, 2009
INDIVIDUAL AUC’S – CBZ AND KTZ
DA Smith el al, BJCP, 2009
LAPATINIB – FOOD EFFECT
Koch el al, JCO, 2009
• Do innovative phase I designs make a
significant difference in novel drug
development ?
Novel designs – wish list
•Maximize safety
– patients exposed to DLT
–Safe RP2D
•Maximize chance of benefit
–  patients exposed to likely sub-therapeutic doses of drugs
• Efficiency ( N patients ,  speed)
• Reduce time trial is on hold
Frequentist
Rule-based
Bayesian
Model-based
Lots of pushing and shoving
amongst the statisticians !!!
Frequentist designs
design
Description
ROLLING 6
2-6 PATIENTS ADDED TO Dl- Dl dependent on N enrolled
evaluable / with DLT
pk guided
Double until target AUC (40% of murine at LD10) then modified
Fibonacci
Accelerated
titration
Double dose until target toxicity (<DLT) then switch to more
conservative (e.g. fibonacci until MTD.
N
INC
IPDE
Switch rule
1A
3
40
N
NA
2B
1
40
Y
C1
3B
1
100
Y
C1
4B
1
100
Y
Any
Adaptive - Grade dependent increments
Phase I trial design
Accelerated Titrated Design (Rule-based)
• First proposed by Simon et al (J Natl Cancer
Inst 1997)
• Several variations exist:
–usual is doubling dose in single-patient
cohorts till Grade 2 toxicity
–then revert to standard 3+3 design using a
40% dose escalation
–Intra-patient dose escalation allowed in
some variations
• More rapid initial escalation
Accelerated Titrated Design
DLT
Dose
Recommended dose
GR 2 Toxicity
3 pts
3 pts
1 pt
1 pt
1 pt
Eisenhauer EA, et al. J Clin Oncol 2000;18:684–692.
Starting dose
+
3 pts
DLT
3 pts
Bayesian designs
Escalation Scheme
Description
Modified continual
reassessment method
(mCRM)
Preset estimated MTD and dose levels. Update
MTD statistically on basis of each pt’s data.
TriCRM
incorporates both toxicity and efficacy data
into the estimation of the biologically optimal
dose – but OR takes time to mature… (phase I/II
better?)
Ewoc (escalation with
overdose control)
Uses real time toxicity data to make decisions
http://www.cancerbiostats.onc.jhmi.edu/software.cfm
http://sisyphus.emory.edu/software_ewoc.php
Many more variations, some including pk
Phase I trial design: Non-cytotoxic agents
• MTD may not be the goal of Phase I as
specificity of effect may be lost at MTD
• Pharmacological effect may not equal
biological effect
• Goal: Identify OBED
• Paradox: Requires early development and
integration of (usually unvalidated)
measures of biological effect into Phase I
OBED = optimal biologically effective dose.
Optimum biological dose
• An inherently flawed concept for most oral agents
• Flat doses are typically administered
• Variable absorption
• Variable transport
• Variable metabolism
• Variable exposure
• Small numbers of patients studied
• Are we sure of the target ? biomarker ?
• Agent may not have a classical first-cycle DLT but easy to
identify an intolerable chronic dose (2-6 cycles)
What’s the target?
• Sorafenib (Raf kinase inhibitor) VEGFR1–3
• 5-Azacytidine (antimetabolite) methylation
• Lenalinomide (angiogenesis) IMID
• Imatinib (PDGFR) bcr-abl, kit
• Crizotinib (MET) EML4/ALK
• Iniparib (PARP) ??????
Erlotinib PK
Patnaik A, et al. Clin Cancer Res 2006;12:7406–7413.
Phase II study of the MEK inhibitor, CI-1040
Steady State CI-1040 Plasma Concentration
Concentration (ng/mL)
1000
100
10
Course 1
Course 2
Course 3
Course 4 or later
Expected Concentration
1
0
4
8
12
Time (hr)
Rinehart et al. J Clin Oncol. 2004;22:456-62.
16
20
24
Enzastaurin, an Oral Protein Kinase C Inhibitor
Carducci et al, JCO, 2006
Average Steady State Concentrations of Individual Patients
Carducci et al, 2006
Phase III study of Enzastaurin vs Lomustine in GBM
Wick et al, JCO, 2010
Unusual Toxicities of Targeted Agents
Signal Transduction Inhibitors (Dy and Adjei, CA-A, 2013 in press)
Cutaneous toxicities
Radiation dermatitis
Paronychia
Trichomegaly
Onycholysis
Posterior Reversible Encephalopathy Syndrome (PRES)
Vatalanib
Bevacizumab
Sorafenib
MEK inhibitor – Blurred vision
2002
CSR: Subretinal fluid
2112
Combination Phase I Studies
Energy stress
GF
GF
GRs
GRs
LKB
IRS
RAS
PI3K
AMPK
PIP3
Raf
PDK
TSC2
Akt
PI3K inhibitors
(e.g., BEZ235)
ERK
Rheb
MEK
RSK
SIN1
Rictor
mTOR mLST8
PRAS40
Raptor
mTOR
Rapalogs
(e.g., Rapamycin)
p70S6K
4EBP1
mLST8
S6
eIF4E
Protein synthesis
(Cyclin D, c-Myc, etc)
Combinations will be Key to
“Cure” of Epithelial Cancers
Common DLTs
Other “Challenging” Combinations
•IGF-1R inhibitors + Erlotinib
•Erlotinib + PI3-Kinase/mTOR
inhibitors
•Sorafenib/VEGFR Inhibitors +
mTOR inhibitors
•Proteasome Inhibitors + HSP 90
Inhibitors
Phase I Study of Drug A combined with Drug B
Single agent doses (100 mg for drug A; 80mg for drug B)
Dose
Level
Drug A
1
2
3
4
5
aC-raf-truncated
cwt
(305–680), bFull length (1–680);
and V599E-truncated BRAF (410–765).
50 mg
75 mg
75 mg
100 mg
100 mg
Drug B
40 mg
40 mg
60 mg
60 mg
80 mg
Phase I Study of Sorafenib combined with Gefitinib
Part A
Part B
n=12
n=20
Randomization
Randomization
400 mg bid
sorafenib (n=9)*
Cohort 1
Cohort 2
(n=6)
200 mg bid sorafenib
plus
250 mg qd gefitinib
(n=6)
400 mg bid sorafenib
plus
250 mg qd gefitinib
250 mg
gefitinib (n=10)
Run-in phase
250 mg
gefitinib (n=6)
400 mg bid
sorafenib (n=10)**
400 mg bid sorafenib
plus
250 mg gefitinib (n=10)***
*three of these patients discontinued treatment after receiving sorafenib 400 mg bid
**three of these patients received 200 mg bid due to a dosing error
***n=9 for sorafenib and n=1 for gefitinib
Adjei AA et al, CCR, 2007
Pharmacologic Principles of Drug
Combination
•Therapeutic Index is important
•Agents should have non-overlapping
DLTs
•Ability to administer full doses of each
agent
•Schedule and sequence may be
important
•True cytotoxic synergy is important