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Design and Analysis of Phase I Clinical Trials in Cancer Therapy

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Title: Design and Analysis of Phase I Clinical Trials in Cancer Therapy


1
Design and Analysis of Phase I Clinical Trials in
Cancer Therapy
  • Merrill J. Egorin, M.D.
  • University of Pittsburgh Cancer Institute
  • Modified from previous talks given by Alex Adjei
    others
  • I get to do it this year because Alex is not
    participating in the course no one else was
    silly enough to agree to do it.

2
Exposures Disclosures
  • I have the following financial relationships to
    disclose
  • Consultant for Novartis, Bristol-Myers Squibb,
    Saladax, Amplimed, Adherex, Johnson and Johnson,
    Daiichi Sankyo
  • Grant/Research support from Novartis,
    Bristol-Myers Squibb, Merck, Infinity, The NCI
  • Honoraria from Novartis, Bristol-Myers Squibb

3
Questions I Will Try to Cover
  • What are Phase I studies?
  • This is sort of easy to address.
  • Why do we do Phase I studies?
  • This seems sort of easy to address.
  • What do we need to do Phase I studies?
  • I think this should be rather straightforward.
  • How do we do Phase I studies?
  • This is a bag of worms!

4
Phase I Studies in Oncology
  • First evaluation of a new cancer therapy in
    humans
  • First-in-human single agent study
  • Last year someone said they were doing the
    second first-in-human study of some agent (I am
    still thinking about that!
  • Combination of novel agents
  • Combination novel agent and approved agent
  • Combination of approved standard agents?
    Combination of novel agent and radiation therapy
  • Eligible patients usually have refractory solid
    tumors of any type
  • Not necessarily the same definition used in other
    branches of medicine.

5
Why Do a Phase I Study? (Sort of Like Why Did the
Chicken Cross the Road?)
  • Primary objective (there can only be one of
    these.)
  • The critical information needed to do a phase II
    study.
  • MTD/toxicities
  • Secondary objectives (These are sexy, but
    secondary!)
  • PK (my favorite)
  • PD and biomarkers
  • Response (even the Pirates win sometimes

6
What Is Needed To Do A Phase I Study?
  • An Investigational New Drug Application (IND)
  • Provides a means of advancing from pre-clinical
    to clincal testing
  • Required for unmarketed/unaproved products
  • May be required for already marketed products
  • A formal application to study and intervention in
    patients
  • Commercial-sponsor usually a pharmaceutical
    company
  • Non-commercial
  • Investigator
  • Emergency use (e.g. single patient)
  • Treatment

7
IND Application
  • Should include
  • Chemistry, manufacturing, and control information
  • Animal pharmacology and toxicology
  • Genotoxicity
  • Toxicology
  • Histopathology
  • Non-clinical justification for proposed
    dose/schedule
  • Justification for duration of treatment
  • Prior use in humans if applicable
  • Clinical protocol and investigator information

8
IND Application
  • Informed consent (More on this later in the
    course)
  • Continued treatment beyond protocol?
  • Charging for intervention?
  • 30-day review clock
  • Clinical hold
  • Safety concerns
  • Design will not allow protocol objectives to be
    met
  • Teleconference between sponsor and division
    director about what is required to lift the hold
  • IND exemptions for studies of lawfully marketed
    cancer drug
  • Based on interpretation of risk
  • Dose, schedule, patient population

9
Phase I Patient Population
  • Conventional eligibility criteria
  • Advanced solid tumors unresponsive to standard
    therapies or for which there is no known
    effective treatment
  • Performance status (e.g. ECOG 0 or 1)
  • Adequate organ functions (e.g. ANC, platelets,
    creatinine, AST/ALT, bilirubin)
  • Specification about prior therapy allowed
  • Specification about time interval between prior
    therapy and initiation of study treatment
  • No serious uncontrolled medical disorder or
    active infection

10
Phase I Patient Population
  • Agent-specific eligibility criteria - examples
  • Restriction to certain patient populations must
    have strong scientific rationale
  • Specific organ functions
  • Example cardiac function restrictions (QTc lt
    450-470 ms, LVEF gt 45, etc) if preclinical data
    or prior clinical data of similar agents suggest
    cardiac risks
  • Example no recent (6-12 months) history of
    acute MI/unstable angina, cerebrovascular events,
    venous thromboembolism no uncontrolled
    hypertension no significant proteinuria for
    antiangiogenic agents
  • Prohibited medications if significant risk of
    interaction with study drug

11
A New Agent Merits Clinical Study If
  • It is biologically plausible that the agent may
    have activity in cancer (target seems valid and
    agent affects it)
  • There is reason to expect benefit for patients
    (preclinical or other evidence of efficacy)
  • There is reasonable expectation of safety
    (toxicology)
  • There are sufficient data on which to base a
    starting dose
  • Hirschfeld S, 2004

12
The 3 Basic Tenets Of Phase I Studies
  • Define a recommended dose
  • SAFELY (minimum of serious toxicities)
  • EFFICIENTLY (smallest possible of pts)
  • RELIABLY (high statistical confidence)
  • SAFETY TRUMPS EVERYTHING ELSE

13
Phase I Study Basic Design Principles
  • Start with a safe dose
  • Minimize of pts treated at sub-toxic/therapeutic
    doses
  • Escalate dose rapidly in the absence of toxicity
  • Escalate dose slowly in the presence of toxicity
  • Expand patient cohort at recommended phase II
    dose
  • Do you buy this argument?
  • If so, why?

14
Phase I Trials Fundamental Questions
  • If you believe the stuff on the previous slide,
    you must consider
  • At what dose do you start?
  • What are the endpoints?
  • How many patients per cohort?
  • How quickly do you escalate and by what method?

15
At what dose do you start ?
16
Preclinical Toxicology
  • Typically a rodent (mouse or rat) and non-rodent
    (dog or non-human primate) species
  • Animal organ-specific toxicities
  • Are not great predictors of human toxicity
  • Myelosuppression and gastrointestinal toxicity
    more predictable
  • Hepatic and renal toxicities large false
    positive rate
  • Toxicologic parameters
  • LD10 lethal dose in 10 of animals
  • TDL (toxic dose low) lowest dose that causes
    any toxicity in animals

17
Phase I Trials Starting Dose
  • 1/10th of the LD10 in rodents,
  • or
  • 1/3rd of the minimal toxic dose in large animals
  • Expressed as mg/m2
  • Freireich, et.al., Quantitative comparisons of
    toxicity of anticancer agents in mouse, rat, dog,
    monkey and man. Cancer Chemother. Repts.
    50219-244, 1966
  • These have historically been safe doses

18
Freireich EJ, et al, Cancer Chemother Rep
50219-244, 1966
19
What Are The Endpoints/Objectives?
20
Phase I Study Endpoints
  • Classical goals (we have not been smart enough to
    understand primary and secondary.
  • Primary
  • Identify the maximally tolerated dose (MTD) and
    recommended Phase II dose (RP2D)
  • Identify dose-limiting toxicities (DLTs)
  • Secondary
  • Pharmacokinetics
  • We have not been smart enough to recognize drug
    metabolism a
  • Pharmacodynamics (Clinical and now molecular)
  • Target modulation
  • Efficacy

21
Defining Toxicities NCI Common Toxicity
Criteria
  • Grade 1 mild
  • Grade 2 moderate
  • Grade 3 severe
  • Grade 4 life-threatening
  • Grade 5 fatal
  • Version 4 of the NCI Criteria are here.

22
Dose-Limiting Toxicities (DLT)
  • Toxicities that, due to their severity or
    duration, are considered unacceptable, and limit
    further dose escalation
  • Defined in advance of beginning trial
  • Classically based on cycle 1 toxicity
  • Examples
  • ANC lt 500/ml for ? 5 or 7 days
  • ANC lt 500/ml of any duration with fever
  • PLT lt 10,000 or 25,000/ml
  • Grade 3 or greater non-hematological toxicity
  • Inability to re-treat patient within 2 wks of
    scheduled treatment

23
Definition of DLT is Dynamic
  • Examples DLTs in 2008
  • 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
    anti-hypertensive therapy
  • Inability to take at least 90 of drug doses in a
    cycle (continuous oral meds)
  • Grade 2 chronic unremitting toxicity

24
Maximally Tolerated Dose (MTD)
  • Inconsistently defined as either
  • Dose at which ? 33 of pts experience
    unacceptable toxicity (DLT in ? 2 of 3 or ? 2 of
    6)
  • OR
  • 1 dose level below that
  • MTD level _at_ DLT (in Europe or Japan)
  • MTD level below DLT (in US)
  • 6-10 pts treated at the recommended Phase II dose
    (MTD or 1 dose level below)

25
Recap Trans-Atlantic Differences in Terminology
  • Important to note that
  • Maximum tolerated dose (MTD)
  • Usually means recommended dose in US
  • Usually means dose level above recommended dose
    in Europe and some other jurisdictions

26
How many patients per cohort?
27
Patients per Cohort Guiding Principles
  • Minimum needed to provide adequate toxicity
    information
  • Classically 3 patients per cohort
  • In some designs 1 patient per cohort until
    toxicity seen
  • If correlative studies are a major aim, may
    increase up to 6 patients per cohort

28
Phase I Standard 3 3 Design
Eisenhauer et al.
29
How quickly do you escalate?
30
Phase I Trial Design Dose Escalation
  • Escalation in decreasing steps (Hansen HH et
    al. Cancer Res. 1975)
  • Attributed to a 13th century Italian
  • Leonardo Fusano, aka
  • Leonardo di Pisa
  • Fibonacci
  • How many pairs of rabbits can be produced from
    a single pair under specified conditions? (1, 1,
    2, 3, 5, 8, 13, 21, 34, 55, 89, 144..) (Liber
    abaci)

31
Phase I Trials Dose Escalation
The Modified Fibonacci Schedule
32
Cohort Dose Escalation
33
Problems and Pitfalls
34
Phase I Study Assumptions
  • The higher the dose, the greater the likelihood
    of efficacy
  • Dose-related acute toxicity is regarded as a
    surrogate for efficacy
  • The highest safe dose is the dose most likely to
    be efficacious

35
Dose-response Efficacy and Toxicity
36
Modified Fibonacci Dose Escalation
  • Problems
  • Requires many patients
  • Takes a long time (really?)
  • May expose a substantial proportion of patients
    to low, ineffective doses

37
Classic Phase I Trials Design Limitations
  • Wide confidence intervals
  • Patients treated at ineffective doses in first
    cohorts
  • High risk of severe toxicities at late cohorts

38
Classic Phase I Trials Design Limitations
  • Chronic toxicities usually cannot be assessed
  • Cumulative toxicities usually cannot be
    identified
  • Uncommon toxicities will be missed

39
Phase I Studies and Infrequent Toxicities
Probability of overlooking a toxicity
POT(p) (1-p)n n sample size, p
true toxicity rate
40
Alternate Designs
  • Starting dose
  • Number of patients per dose level
  • Method/rapidity of dose escalation

41
Selection of Starting Dose for Phase I Trials
Retrospective analysis of 21 trials using
modified Fibonacci dose escalation
Unsafe defined as reaching MTD in ? 3 dose
levels Eisenhauer et al JCO (18), 2000
42
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 NOT DO THIS ALWAYS ?
  • Makes evaluation of chronic toxicities difficult
  • The proverbial 1 responder at dose level 1

43
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 33 design using a 40
    dose escalation
  • intrapatient dose escalation allowed in some
    variations
  • More rapid initial escalation

44
Accelerated Titrated Design
45
Accelerated Titrated Design Phase I Study of
Lonafarnib (SCH66336)
Adjei AA et al, Cancer Research, 2000
46
Phase I Trial Design Modified Continual
Assessment Method (MCRM Model-based)
  • Bayesian method
  • Pre-study probabilities based on preclinical or
    clinical data of similar agents
  • At each dose level, add clinical data to better
    estimate the probability of MTD being reached
  • Fixed dose levels, so that increments of
    escalation are still conservative

47
Modified Continual Assessment Method (MCRM
Model-based)
  • Example Pre-set dose levels of 10, 20, 40, 80,
    160, 250, 400
  • If after each dose level, the statistical model
    predicts a MTD higher than the next pre-set dose
    level, then dose escalation is allowed to the
    next pre-set dose level
  • Advantages
  • Allows more dose levels to be evaluated with a
    smaller number of patients
  • More patients treated at or closer to
    therapeutic dose
  • Disadvantages
  • Does not save time, not easily implemented if
    without access to biostatistician support

48
Phase I Trial Design Dose Escalation with
Overdose Control (EWOC Model-based)
  • Bayesian method
  • After each cohort of patients, the posterior
    distribution is updated with DLT data to obtain
    ?d (probability of DLT at dose d). The
    recommended dose is the one with the highest
    posterior probability of DLT in the ideal
    dosing category
  • The overdose control mandates that any dose that
    has gt 25 chance of being in the over-dosing or
    excessive over-dosing categories, or gt 5
    chance of being in the excess-overdosing
    category, is not considered for dosing

49
Estimated MTD Based on Bayesian Logistic Method
(Parameter Estimation With Overdose Control)
EXAMPLE of Probability of DLTs (Bayesian design)
50
Phase I Trial Design-Bayesian EWOC Model (Example
With 1 DLT in 4 Patients)
  • Posterior summaries for probabilities of DLT (in
    )
  • __________________________________________________
    ______________
  • Dose 0-0.16 0.16-0.33 0.33-0.6 0.6-1
    Median Overdose
  • mg Under- Targeted Over- Excessive DLT
    rate Control
  • /day dosing Toxicity dosing toxicity
  • __________________________________________________
    ______________
  • 2.5 95.7 3.3 0.5 0.4
    0.0 ok
  • 5 91.1 5.5 3.1 0.4
    0.2 ok
  • 10 82.9 9.1 6.7 1.3
    1.9 no3
  • 17.5 62.5 17.7 12.5 7.2
    8.8 no2,3
  • 25 40.0 21.2 19.3 19.5
    22.3 no1-3
  • 35 15.6 19.7 20.4 44.3
    53.7 no1-3
  • 45 9.9 12.5 19.9 57.7
    73.0 no1-3
  • 60 5.6 10.9 12.0 71.5
    86.5 no1-3
  • 75 3.2 7.7 12.7 76.4
    92.8 no1-3
  • 100 2.4 3.3 13.3 80.9
    96.6 no1-3
  • __________________________________________________
    ________________
  • 1 Escalation to this dose not possible, overdose
    control criterion
  • (P(overdosing or excessive tox)gt25) violated
  • 0/3
  • No first cycle DLTs
  • Bayesian model supports dose escalation in cohort
    2 (100 dose increment)

51
Phase I Trial Design-Bayesian EWOC Model Example
With ¼ DLTs
  • Posterior summaries for probabilities of DLT (in
    )
  • __________________________________________________
    ______________
  • Dose 0-0.16 0.16-0.33 0.33-0.6 0.6-1
    Median Overdose
  • mg Under- Targeted Over- Excessive DLT
    rate Control
  • /day dosing Toxicity dosing toxicity
  • __________________________________________________
    ______________
  • 2.5 48.1 28.4 16.4 7.1
    16.5 no2
  • 5 30.5 31.5 27.5 10.5
    26.4 no1,2
  • 10 16.5 23.7 37.3 22.4
    38.3 no1-3
  • 17.5 8.8 14.7 41.6 34.9
    50.3 no1-3
  • 25 6.1 9.9 37.6 46.4
    58.3 no1-3
  • 35 5.6 7.7 29.6 57.1
    65.6 no1-3
  • 45 3.7 7.6 24.5 64.1
    69.6 no1-3
  • 60 3.3 6.5 18.9 71.2
    75.1 no1-3
  • 75 2.4 6.1 15.3 76.1
    78.1 no1-3
  • 100 2.4 4.9 13.6 79.1
    82.3 no1-3
  • __________________________________________________
    ________________
  • 1 Escalation to this dose not possible, overdose
    control criterion
  • 1/4
  • First cycle DLT in first cohort
  • Bayesian model does not support dose escalation
    in cohort 2

52
Challenges to Developing Novel Non-Classical
Antineoplastic Agents
  • General requirement for long-term administration
    pharmacology and formulation critical
  • Difficulty in determining the optimal dose in
    phase I MTD versus OBD
  • Absent or low-level tumor regression as single
    agents problematic for making go no-go decisions
  • Need for large randomized trials to definitively
    assess clinical benefit need to maximize chance
    of success in phase III

53
Phase I Trial Design Non-Cytotoxic Agents
  • MTD may not be the goal of Phase I because
    specificity of effect may be lost at MTD
  • Pharmacologic effect may not equal biologic
    effect
  • Goal identify optimal biologically effective
    dose (OBED)
  • Paradox requires early development and
    integration of (usually unvalidated) measures of
    biologic effect into Phase I

54
Do We Need Correlative Studies ?
  • Conventional cytotoxic drugs have led to
    predictable effects on proliferating tissues
    (neutropenia, mucositis, diarrhea), thus enabling
    dose selection and confirming mechanisms of
    action
  • Targeted biological agents may or may not have
    predictable effects on normal tissues and often
    enter the clinic needing evidence/proof of
    mechanisms in patients

55
Do we need correlative studies ?
  • Therefore, biological correlative studies may be
    used to derive the best dose and schedule of an
    agent, and
  • To determine whether the drug is inducing the
    intended biological effect in the patient, and
  • To predict clinical benefit, although this
    generally requires testing in large randomized
    studies.

56
Alternative Endpoints
  • Minimum blood levels/AUC or other PK measure
  • Inhibition of target
  • In normal tissue
  • In tumor tissue
  • Need enough preclinical evidence to suggest that
    the above are reasonable endpoints with
    sufficient clinical promise
  • Must also pay attention to toxicity

57
Phase I Trial Design Non-Cytotoxic Agents -
Examples
  • Pre-clinically define target drug exposure
    Matrix Metalloproteinase Inhibitors
  • Define pharmacodynamic endpoint Bortezomib (70
    of 26S proteasome inhibition in PBMCs)
  • Use functional imaging as endpoint Vatalanib
    (DCE-MRI)
  • Use cumulative toxicities CI-1040 MEK
    Inhibitor, 800mg TID intolerable after 3 cycles
    of therapy
  • Problem If drug works, youre a genius. If it
    doesnt, youre a goat

58
Vatalanib (PTK/ZK) VEGF Receptor Tyrosine
Kinase Inhibitor
Extracellular
Intracellular
Adapted from Dvorak H. J Clin Oncol.
200220(21)4368-4380.
59
PTK/ZK Induced Significant Reduction in Tumor
Blood Flow in Metastatic Colorectal Cancer by
DCE-MRI
Reduction in tumor blood flow through liver
metastases secondary to colorectal cancer at day
2 is significantly correlated with improved early
clinical outcome
Thomas AL, et al. Semin Oncol. 20033032-38. Morg
an B, et al. J Clin Oncol. 2003213955-3964.
60
Using DCE-MRI to Establish the Optimal
Therapeutic Dose for Vatalanib
Morgan B, et al. J Clin Oncol. 2003213955-3964.
61
The Conundrum of Optimal Biologic Dose Phase
III PTK787/FOLFOX in CRC
PTK787 1250 mg QD
62
Phase I Trials of Agent Combinations
  • Initial dose-finding component often needed if
    you are planning a new combination for a phase II
    trial
  • Patients for dose-finding phase
  • Advanced solid tumors (all comers)
  • Advantage fast accrual
  • Disadvantage may not be representative of your
    patient population of interest
  • Specific patient population (e.g. same as phase
    II cohort)
  • Advantage population of interest, and early
    glimpse at antitumor activity in disease of
    interest
  • Disadvantage slow down accrual especially if
    rare/uncommon tumors

63
Phase I Trials of Agent Combinations
  • Dose escalation
  • New drug A Standard combination BC
  • Ideally keep standard combo doses and escalate
    the new drug (e.g. 1/3, 2/3, full dose)
  • Need to provide rationale why add A to BC?
  • Need to think about overlapping toxicity in your
    definition of DLT
  • Do you need PK assessment to determine if A, B
    and C interact with each other?

64
How are Phase I Studies Designed Now ?
  • 31 targeted agents representative of most common
    targets
  • Reports (papers or abstracts) of completed single
    agent phase I trials in non-hematologic
    malignancies
  • 57 phase I reports identified
  • Parulekar and Eisenhauer JNCI July 2004

65
Agents/Targets
Target Agent Trials
EGFR/HER2 ZD1839 OSI-774 C225 MAB225 EMD7200 EKB569 RG83852 trastuzumab 5 1 1 1 1 1 1 1
MMP BAY 12-9566 Marimastat COL-3 BMS-275291 3 2 1 1
Farnesyl trans- ferase BMS-214662 R115777 L778,123 SCH66336 2 3 2 3
Target Agent Trials
Angiogenesis Endostatin ZD6474 PTK787 SU6668 SU5416 Bevacizumab SU11248 3 1 1 3 3 1 1
BCL-2 G3139 2
PKC alpha ISIS 3521 2
raf kinase BAY 43-9006 ISIS 5132 3 3
DNA MTase MG98 2
MEK CI-1040 1
mTOR CCI-779 1
  • Parulekar and Eisenhauer JNCI July 2004

66
Results Reason for Halting Dose Escalation
Reason No. Trials No. Agents
Toxicity 36 20
PK 7 5
Other Design (max. planned dose) Drug Supply Other phase I results Active dose 3 4 2 1 3 2 2 1
Not stated 4 4
TOTAL 57
Parulekar and Eisenhauer JNCI July 2004
67
Basis for Recommending Phase II Dose
Recommended phase II dose? Recommended phase II dose? No. Trials No. Agents
Recommended Recommended 50 27
Basis Toxicity PK (blood levels) Other trial toxicity Clinical activity PBMC findings Tumor measures Convenience 35 9 2 1 1 1 1 19 7 2 1 1 1 1
Not stated 5 5
Not recommended Not recommended 2 1
Parulekar and Eisenhauer JNCI July 2004
68
Secondary Information to Support Dose
Recommendation
No. Trials Primary Basis No. Trials Secondary Support From No. Trials Secondary Support From No. Trials Secondary Support From No. Trials Secondary Support From No. Trials Secondary Support From
No. Trials Primary Basis Toxicity PK Tumor measures Surrogate measures Other
Toxicity 35 - 12 2 7 8
PK 9 - - 1 1 3
Tumor measures 1 - - - - -
Surrogate measures 1 - - - - -
Other 4 2 1 1 -
TOTAL 50 1 12 4 9 11
Other includes clinical effects, results other
trials, convenience, etc.
69
Laboratory and Imaging Studies
Total No. Trials Primary Basis of Dose Supportive of dose No Help
Tumor Tissue 5 1 4 -
Surrogate Tissue PMBC Skin Buccal 11 2 2 1 - - 5 2 2 5 - -
Imaging 6 - 1 5
15
Parulekar and Eisenhauer JNCI July 2004
70
Summary Review Phase I Trials Targeted Agents
  • Toxicity
  • Most common reason to halt escalation and primary
    basis for dose recommendation (35/50 trials)
  • PK (Blood levels)
  • Second most common basis for dose recommendation
    (9/50 trials)
  • Laboratory studies
  • May provide information to support dose
    recommendation

Parulekar and Eisenhauer JNCI July 2004
71
  • Phase I Study - Ethics

72
Phase I Study - Ethics
  • Patient benefit or antitumor activity is not a
    primary goal of the study, but therapeutic
    intent is an important feature
  • Desperate patients cannot make a truly informed
    decision
  • Historically low probability of response in Phase
    I trials
  • lt 5 response rate
  • Majority of responses occur within 80-120 of
    the recommended phase II dose

73
Response Rates and Toxic Deaths in Phase I
Oncology Trials (Horstman et al, NEJM 352 2005)
Trial No. of Trials of Pts Assessed for Response Overall Response Rate No. of Patients Assessed for Toxic Events Deaths from Toxic Events no.
Total First use of an agent in humans 117 3164 4.8 3498 9 (0.26)
Cytotoxic chemotherapy First use of an agent in humans 43 1298 5.0 1422 7 (0.49)
Immunomodulator First use of an agent in humans 16 404 7.4 431 1 (0.23)
Receptor or signal transduction First use of an agent in humans 27 742 3.8 853 1 (0.12)
Antiangiogenesis First use of an agent in humans 8 200 7.0 228 0
Gene transfer First use of an agent in humans 0 0 0 0 0
Vaccine First use of an agent in humans 23 520 3.1 564 0
74
Phase I Study - Ethics
  • Investigators have an inherent conflict of
    interest
  • Funding
  • Academic promotion
  • Publicity

75
Phase I Study Ethics Partial Solutions to the
Dilemma
  • Youre the patients physician 1st and a scientist
    2nd
  • Scientific goals should never take precedence
    over the patients best interest
  • Only pts for whom no life-prolonging or curative
    therapy exists are eligible for Phase I trials
  • Informed consent is obtained from every patient
  • No new agent can hit the pharmacy shelves without
    going through Phase I clinical evaluation

76
Phase I Clinical Trials - Summary
  • Most drugs tend to follow the MTD/DLT paradigm
  • Alternative designs continue to be explored. Most
    times they are more complex.
  • Correlative studies are increasingly important in
    the comprehensive evaluation of new agents
  • Patient benefit/wellbeing trumps all the science
  • Being a good phase I trialist is not as simple as
    you may think
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