Early Clinical Cancer Trials Phase I and II studies

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Early Clinical Cancer Trials Phase I and II
studies

• Ulrik Lassen, MD., PH.D.
• Head of Phase I Unit
• Dept. Of Oncology, Finsen Center
• Rigshospitalet, Copenhagen

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Research in

• New superior agents improving survival
• New agents with fewer adverse events 
• New agents against side effects
• Reducing treatment periods
• More efficacious radiotherapy
• Methods to protect normal tissue during
  radiotherapy

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Phases in drug development

• Pre-clinical studies proof of concept
• Phase 1 dose-finding
• Phase 2 activity and safety
• Phase 3 randomised trials

The whole process takes 6-12 years and costs 1
billion DKK for each approved agent
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Industry loves oncology

• Robert H. Glassman
• Merryll Lynch, N.Y.

ENA, Philadelphia, 2006
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Why?

• 1/3 of all drugs in development are cancer drugs
• Targatable physicians (few oncologists in
  relation to the number of studies)
• Cancer drugs represent the largest income
• 1300 drugs in late discovery in USA
• 600 drugs in clinical evaluation
• 95 approvals/year (FDA)
• 3-5 approved/year (FDA)

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But FDA is not quite satisfied

• The rate of success for phase III studies have
  dropped from 50 to 30 in 1990-2004
• The rate of success is higher for other
  indications- CNS 20- Oncology 30-
  CV 50- Others 70

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How come?

• Dropping response rates in phase II (low hanging
  fruits have been picked)
• To poor target validation for new drugs- 1990
  gt100 references at clinical entre- 2000 only
  8-10 references
• 200 inputs 2-3 approvals

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Phase I - background

• First in man studies
• Pre-clinical proof of principle must be achieved
• Chemical, pharmaceutical and animal
  pharmaco-logical and toxicological data must be
  available
• Purpose to describe adverse events and
  pharmacokinetic and dynamic profiles
• Identify organs at risk

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Classic phase I design

• Dose-escalation
• 3-6 patients/dose level
• MTD, DLT
• Recommended doseToxicity as surrogate endpoint

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Typical DLT definitionPatients experiencing one
of the following toxicities in cycle one are
considered as having dose-limiting toxicity (DLT)
(see NCI/CTC)

• Absolute neutrofile count lt 0,5 x 109/l lasting
  ?7 days, or absolute neutrofilte count lt 0,5 x
  109/l with septicaemia
• Absolute platelet count lt 25 x 109/l lasting ?7
  days, or platelets lt 10 x 109/l
• Any other drug-related non-haematological grade
  3-4 toxicity, except alopecia, nausea and
  vomiting, skin-rash, artralgias and myalgias, if
  appropriate prophylactic action have not been
  taken.

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What is CTCAE v3.0

• Definitions and grading
• General or organ specific
• Acute, late or chronic
• Symptomatic or asymptomatic
• Subjective or objective (radiographic or
  biochemical)
• Does not discriminate between cause or error
• CTCAE v3.0 is developed as a tool for clinical,
  scientific studies, and not for routine use or
  standard therapy

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Grading

• 0 No adverse event or within normal values
• 1 Mild adverse event
• 2 Moderate adverse event
• 3 Serious and undesired adverse event
• 4 Life-threatening or invalidating adverse
  event
• 5 Death related to adverse event

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Classic phase I design - again

• Dose-escalation
• 3-6 patients/dose level
• MTD, DLT
• Recommended doseToxicity as surrogate endpoint

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Definitions
10 of lethal dose in test animals, Expressed in
mg/m2

• LD10

DLT
Dose limiting toxicity
incl. 3 more pts.
example
Toxicity in 1/3
No toxicity
dose-escalation
More toxicity
stop dose-escalation
stop dose-escalation
Toxicity in gt 1/3
Maximal tolerable dose (tox. lt 1/3)
MTD
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Dose-escalation - fibonacci (modified)

• first dose level (most often 1/10 of LD10)
• second dose level twice first dose
• third dose level 67 greater than the second
• Fourth dose level 50 greater than the third
• Fifth dose level 40 greater than the
  fourth
• Sixth dose level 33 greater than the
  fifthNo dose escalation in the same patient

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Dose-escalation, PK-guided

• MTD - LD10 in mice
• Linear PK necessary
• Valid assays
• Caution inter-patient variability
• If necessary, wait for the results
• Continuous reassessment method
• Preferable at wide therapeutic ratios
• 1 patient per dose level
• Escalate 100 if no toxicity
• If toxicity, then include more patients
• Caution Sudden, unexpected DLT Dangerous?
  Cumulative toxicity

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Phase I - patients

• Healthy volunteers (not cytostatics)- high risk
  groups in chemoprevention
• Cancer patients without other treatment options
  (therapy)
• Life expectancy gt 12 weeks
• Different tumor types
• PS 0, 1 and possibly 2

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Phase I biological agents

• Antibodies, antisense-nucleotides, gene-therapy
• Unknown therapeutic ratios
• Unknown dose-response relations
• DLT may never be reached
• What is first dose level in case of no AE in
  animals?
• Endpoints? pharmacodynamic, biomarkers-enzyme-in
  hibition, methylation, phosphorylation,
  acethylation, biopsies (skin, tumor), PET scans

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Examples biological agents

• Anti-EGF direct from phase I to phase III
• Interferon anti-angiogenetic features seen at
  doses below MTD, but not at MTD
• Gene therapy?
• HDAC acetylation of histones in peripheral
  mononuclear blood cells
• TKI phosphorylation of downstream targets
• Apoptosis inhibitors grade of apoptosis

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Other phase I trials

• Phase Ib -Phase 1 trial in similar patients
  (one tumor type)-e.g. a distinct target
• Phase I-II -One tumor type, more
  patients-Combinations of investigational agents
  and known cytostatics-Dose-escalation of more
  agents-Determine dose and sequence of
  agents-Endpoints safety and activity

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Importance of phase 1 trials

• Drug development
• Responding tumor types of importance to phase 2
  trials
• DLT, MTD and PK not only endpoints, but also
  indicators for the optimal dose for the desired
  target
• Benefit-risk ratio high
• Imatinib had 93 OR in phase 1 for CML

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Limitations for phase 1 trials

• Many patients get homeopatic doses below the
  biologic active level
• Few patients get benefit (approx. 5-10 objective
  response, but up to 50 get stabilisation/symptom
  relief)
• Time consuming trials (observation of kohorts
  prior to dose escalation)
• Problems with inter-patient-variability
• Toxicity as a surrogate marker cannot be used if
  agent is non-toxic

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Response Rates According to Year
Horstmann, E. et al. N Engl J Med 2005352895-904
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Consequenses

• Phase 1 trials are becoming small because new
  targeted agents are less toxic
• The challenge is now phase 2 design - how to
  interpret low response rate but long-lasting
  stabilisation (e.g. erlotinib, bevacizumab,
  cetuximab)
• Can we drop phase 2?
• No, not according to the experiences from MMI,
  FTI and gefitinib

Ratain and Eckhardt, JCO 22, 2004
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Whats next?

• Phase 2 must preventive negative phase 3 trials
• Randomised phase 2 studies with cross-over,
  perhaps with more tumor types and separate
  analyses
• Valid expectations for PR and SD
• Time to progression as endpoint
• Valid biomarkers

Ratain and Eckhardt, JCO 22, 2004
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Phase II - therapeutic pilot studies

• Early phase II antitumor activity toxicity
  pharmacokinetics
• Late phase II Confirm early (more pt.)
  pharmacokinetics other study populations

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Phase II - patients, tumor types

• Based on the agent mode of action
• Phase II activity (early phase II)
• Pre-clinical antitumor activity
• ethics (age, life-expectancy, PS, risks,
  follow-up)

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Phase II - endpoints

• Response rate as a surrogate, not necessarily
  related to change of symptoms
• Time-intervals preferable time to
  progressionmedian survival and overall survival
• Safety, toxicity
• Quality of life, symptom relief
• NB. comparisons to other studies not allowed
• Phase II results always superior to phase III

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Follow up - methods

• Phase 1 Adverse events- CTCAE version 3.0
• Phase 2 Response or other surrogate markers and
  adverse events- RECIST or WHO
• Phase 3 survival, adverse events and QoL

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Only patients with measurable disease at baseline
should be included in protocols where objective
tumor response is the primary endpoint

• RECIST
• Measurable disease - the presence of at least one
  measurable lesion. If the measurable disease is
  restricted to a solitary lesion, its neoplastic
  nature should be confirmed by cytology/histology.
  
• Measurable lesions - lesions that can be
  accurately measured in at least one dimension
  with longest diameter ?20 mm using conventional
  techniques or ?10 mm with spiral CT scan.
• Non-measurable lesions - all other lesions,
  including small lesions (longest diameter lt20 mm
  with conventional techniques or lt10 mm with
  spiral CT scan), i.e., bone lesions,
  leptomeningeal disease, ascites,
  pleural/pericardial effusion, inflammatory breast
  disease, lymphangitis cutis/pulmonis, cystic
  lesions, and also abdominal masses that are not
  confirmed and followed by imaging techniques

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Evaluation of target lesions

• Complete Response (CR) - Disappearance of
  all target lesions
• Partial Response (PR) - At least a 30
  decrease in the sum of the LD of target lesions,
  taking as reference the baseline sum LD
• Progressive Disease (PD) - At least a 20
  increase in the sum of the LD of target lesions,
  taking as reference the smallest sum LD recorded
  since the treatment started or the appearance
  of one or more new lesions
• Stable Disease (SD) - Neither sufficient
  shrinkage to qualify for PR nor sufficient
  increase to qualify for PD, taking as reference
  the smallest sum LD since the treatment started

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Standard phase II

• Pro- equivocal, quick, cheap, well-defined
  endpoints/surrogate endpoints
• Contra-selection bias for endpoints (response,
  progressions-free survival and survival)

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Randomised phase II

• Two or more parallel phase II studies
• Equal patient populations
• No comparison (too few patients)
• No reference arm, only investigational arms
• Indicator for which arm to enter phase III

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Randomised phase II

• Pro- better response estimates, duration and
  DFS- some protection against selection bias,
  better statistics to evaluate toxicity
• Contra- poor power, time-consuming, expensive-
  endpoints not well accepted- cannot substitute
  phase III

Remember phase II for learning - phase III for
confirming Sheiner LB, Clin Pharmacol Ther
1997
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Phase I Unit, Dept. of OncologyRigshospitalet,
Copenhagen

• Dedicated unit for experimental cancer therapy
  and phase I trials.
• Offer complete project management and clinical
  trial management systems.
• Operating with ICH GCP to industry standards,
  including standard operating procedures (SOPs)
  covering all aspects of running clinical trials.
• Comply with all current legal requirements and
  the needs of the EU Directive on Clinical Trials
  (Directive 2001/20/EC).
• Part of a network of leading scientists and
  oncologists, including collaboration with other
  phase I units in Europe and the US.

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Pharmacokinetics and pharmacodynamics

• Detailed pharmacokinetic (PK) and pharmacodynamic
  (PD) analyses are key components of phase I and
  II clinical trials.
• This includes biological and pharmacological
  studies on the new agent to ensure that it is
  acting by its proposed mechanism in patients and
  that a potentially active drug concentration can
  be achieved and maintained.
• Our own staff of trained and GCP-examined
  research nurses obtain and handle blood samples
  for PK and PD in the laboratory facilities in the
  phase I unit.
• Tissue sampling and processing for further
  analysis including snap-freeze technique can be
  undertaken through our collaboration with the
  department of diagnostic radiology and the
  surgical departments.

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Immunological and clonogenic assays Through our
network of local academic laboratories at
Rigshospitalet, molecular biological/biochemical
analyses can be undertaken, including

• Immunohistochemistry and other immunological
  assays
• Micro-array gene analyses
• Chromosomal analyses
• Receptor expression and functional receptor
  analyses
• Proteomics
• Our clinic has a close collaboration with
  in-house laboratories for experimental basic
  research in oncology.