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Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
1The screen versions of these slides have full details of copyright and acknowledgements
Toxicity Testing for Oncology Drugs
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Theresa ReynoldsBA, DABT
Director, ToxicologyGenentech, Inc.
Krishna AllamneniDVM, PhD, DABT
Scientist, ToxicologyGenentech, Inc.
This presentation represents the opinions of the presenters and is not intended
to reflect the policy or position of Genentech, Inc.
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Presentation objectives
1. Convey:
a) Special considerations for the development of oncology drugs and
b) How they impact the toxicology program
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2. Describe the value of a PD marker in oncology and cite examples
3. Describe the key similarities & differences in toxicity evaluation for small and large molecules
4. Present current regulatory guidance and impact on drug development for oncology
Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
2The screen versions of these slides have full details of copyright and acknowledgements
Despite new therapies, little change in overall cancer incidence
4SEER 9: National Cancer Institute, April, 2008http://seer.cancer.gov/index.html(accessed on 1/5/09)
Estimated number of cancer survivors in the United States from 1971 to 2005
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Data source: Ries LAG, Melbert D, Krapcho M, Stinchcomb DG, Howlader N, Horner MJ, Mariotto A, Miller BA, Feuer EJ, Altekruse SF, Lewis DR, Clegg L, Eisner MP, Reichman M, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2005, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2005/, based on November 2007 SEER data submission, posted to the SEER web site, 2008 (accessed 2/5/09).
5-year relative US survival rates from all cancers have improved from 35% (1950-1954) to 67.5% (1996-2004)SEER Cancer Statistics Review 1975-2005, US National Cancer Institute SEER.cancer.gov (accessed 2/5/09)
a) Why do oncology drugs have special considerations for drug development?
1.
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considerations for drug development?
b) What are they, & how do they impact the toxicology program?
Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
3The screen versions of these slides have full details of copyright and acknowledgements
Special considerations for oncology drugs - why?
• High unmet medical need
• Life-threatening & refractory nature of the disease
• Failure of standard of care; Limited therapeutic options
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p p
• Patients eligible for phase 1 & 2 trials have not responded to established therapy
Regulatory guidance for oncology drug development
Recent publication of special regulatory guidance reflects the significance of this patient population
8These will be discussed in detail later in the presentation
Special considerationsf l d
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for oncology drugs
Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
4The screen versions of these slides have full details of copyright and acknowledgements
Special considerations for oncology drugs
• Phase 1 in patients
• Treatment extension for patients that benefit
S ll th ti i d
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• Small therapeutic index
• Timing of toxicity studies
Special considerations for oncology drugs
• Phase 1 conducted in patients
– Have not responded to standard of care (SOC)
– Disease progression despite SOC
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p g p
– Early enrollment of patients → possibility of benefit
• Phase 1a typically single-dose escalation to maximum tolerable dose (MTD)
• Phase 1b typically multiple-doses for up to 3 months to assess benefit
Special considerations for oncology drugs
Treatment can be extended early in drug development for patients that benefit
– Criteria can be set as early as phase 1 to show evidence of benefit to allow treatment beyond timeframe
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evidence of benefit to allow treatment beyond timeframe supported by toxicology studies
Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
5The screen versions of these slides have full details of copyright and acknowledgements
Small therapeutic index
• Desired pharmacologic activity is often interference with life-sustaining pathways
Special considerations for oncology drugs
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• Accepted that toxicities may occur, risk of potential toxicity weighed against poor disease prognosis
Timing & duration of toxicity studies
• Reproductive toxicity studies can be conducted concurrent with phase 3 or not conducted (cytotoxics)
Special considerations for oncology drugs
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with phase 3, or not conducted (cytotoxics)
• Duration of chronic toxicity studies
– 6 months for biotherapeutics & small molecule cytotoxic
• Carcinogenicity studies not required for registration
Impact on the toxicology program
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Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
6The screen versions of these slides have full details of copyright and acknowledgements
Objectives of toxicity testing
• Identification of initial safe starting dose and dose escalation schemes for clinical trials
• Identification of potential target organs of toxicity and reversibility of effect
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• Identification of safety parameters for clinical monitoring
Impact on toxicology program• Phase 1 conducted in patients
– Disease state can make patients more sensitive to toxicities
– Impact of toxicology data on clinical risk
Identify findings
C f i h j li i l i i
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Confer with project clinical scientist
Impact of findings on phase 1 monitoring
Inclusion/exclusion criteria
Toxicology data identify hazards to be monitored and considered in risk/benefit decision making
Impact on toxicology programTreatment can be extended early in drug development for patients that benefit
– Longer phase 1-enabling toxicology studies may be needed to support early clinical trials that intend to show benefit
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Duration of clinical testing must be supported by
Toxicology studies of equivalent duration
12 weeks
Clinical assumptions, e.g.: projected therapeutic dose (10 mg/kg), route & frequency of administration (e.g. IV, weekly), treatment duration (e.g. 12 weeks)
Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
7The screen versions of these slides have full details of copyright and acknowledgements
Early extension of treatment for patients who benefit
Phase 1bToxicology
Favorable risk/benefit profilecan enable continued treatment beyond the duration supported
by toxicology
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Extension phase
Protocol-specified benefit criteria met?
Yes
NoStop
treatment
Impact on toxicology program
Small therapeutic index
• Because toxicities are expected to manifest, characterization of the toxicity profile is balanced with animal welfare
• Mortality is not a desired endpoint; Doses tested in toxicology studies should:
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studies should:
– Define the severely toxic dose in 10% of rodents (STD10) and
– The highest non-severely toxic dose (HNSTD) in non-rodents*
*JJ De George, CH Ahn, PA Andrews, ME Brower, Cancer Chemotherapy and Pharmacology, 1997
Value of a PD marker in oncology
2.
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Value of a PD marker in oncology
Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
8The screen versions of these slides have full details of copyright and acknowledgements
Activity, efficacy & toxicity, value of a PD marker
• Shows drug is active
• Can dose to effect in toxicology studies and clinical trials
• Can separate toxicity from activity
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Can separate toxicity from activity
• PD is a marker of activity not efficacy
– Must be borne out by clinical efficacy data
Value of a PD markerexample 1: Rituxan®
Rituxan® (monoclonal antibody to B-cell CD20 receptor)
PD marker: depletion of B-cells in blood; Monitorable in toxicology studies & patients
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– Demonstrates relevance of toxicology studies
– Allows separation of active vs. toxic doses
– Supports activity-based first in human (FIH) dose
– Reduces dose-escalations to attainment of active dose
Clinically validated via reduction in tumor volume
Value of a PD markerexample 2: Avastin®
Avastin® (monoclonal antibody to VEGF)
Inhibits growth of new blood vessels
No PD marker
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– Active dose extrapolated from animal tumor models
– No prospective way to separate active dose from toxic dose
– First in human (FIH) dose a fraction of safe dose determined toxicology studies
VEGF: vascular endothelial growth factor
Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
9The screen versions of these slides have full details of copyright and acknowledgements
Key similarities & differences
3.
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in nonclinical safety evaluation for small and large molecules
Key similarities & differences in toxicity evaluation for small and large molecules
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• Biologics have complex structural and biological activity compared to small molecules
• Drug development plans for small molecules are different from large molecules
Graphic Courtesy Rolf G. Werner (Boehringer Ingelheim) Apr 2008 Presentation
How do small molecules differ from biologics?
Small molecules BiologicsMolecular weight Low, e.g. <500 daltons High e.g. 10-1000 kilodaltonsDose route Oral Parenteral
Species specificity - Species-independent - Species-specificO t t t i it
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- Off-target toxicities- Species selection based
on metabolism
- On-target toxicity- Pharmacologically drivenspecies selection
Metabolism Yes Internalized and degraded
Typical toxicities Mechanism/structure-based Exaggerated pharmacology
Immunogenicity Not relevant Yes
Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
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Small molecules Biologics
Development plans Conventional Nonconventional
Regulatory environment Specific guidelines Case-by-case assessment
Drug development plans for small and large molecules are different
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Regulatory environment Specific guidelines Case by case assessment
Relevant species Toxicology program in 2 species One relevant species
Highest dose tested Maximally tolerated Multiple approaches
More conservative MABEL, NOEL, NOAEL
Basis for clinical starting dose
Less conservative MTD, NOAEL, HNSTD
MTD: maximum tolerated dose, NOEL: no observed effect level, NOAEL: no observed adverse effect level, MABEL: minimal anticipated biological effect level, HNSTD: highest non-severely toxic dose
Preclinical drivers for small molecules• Early stage discovery toxicology
– In silico, in vitro receptor binding, hERG, cell based/in vivo screens to enable lead selection
• Predictivity of models
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– In vitro/in vivo correlations
– Cross-species comparisons
• Cross functional interactions
– Lead and backup (safety, activity, PK)
• Established impurity qualification
• Appropriate formulations
Lead optimization schemeTox testing
Potency selectivity In silico genotoxicity Ames;In silico hERG
Tier 1 (solubility/chemical stability)Tier 2 (stability)
Cell assays for efficacy
5-in-1 IV PO rat PK
hERG K+In vitro hepatocytes:
Off-target receptors (Iterative)
Activity, Pharm. Sci, DMPK
30Candidate selection
PK (rodent) CYP IC50
hERG IC50; Bacterial mutagenicityhit profile screen; Hepatocyte TC50Rodent target organ Tox (Iterative)
Metabolite activity in vitroIV/PO PK non-rodent
Exploratory rodent single and repeat doseGenetox panel
In vitro safety pharmAcute toxicity/TK
Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
11The screen versions of these slides have full details of copyright and acknowledgements
Challenges specific to small molecules• Therapeutic index
• Higher attrition rates– Low translatability of nonclinical risks to clinic
– Substantial off-target activity
– Complex ADME issues
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• Identify “predictable” liabilities earlier– Therapeutic index
– Nature of toxicities (predictable, reversible, monitorable)
– Biomarkers
– Mode of toxicity
– Human relevance
Cytotoxic vs. non-cytotoxic oncology drugs• Classical anti-neoplastic agents (cytotoxic)
– Relatively non-specific MOA
– Narrow therapeutic index
– Regulatory path relatively straightforward
Genotoxicity, carcinogenicity, and reproductive toxicity i d f i i
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not required for registration
• Non-cytotoxics (cytostatics, immune modulators)– Relatively specific MOA
– Specific targeted inhibition
Relatively non-toxic
Wider therapeutic margin (??)
– Regulatory path novel
More on targeted inhibitors
• Target specific signaling alterations, e.g. kinases
– Only in presence of activating mutations in cancer cells
• Generally less toxic than cytotoxics
• Complex pathway interactions
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– E.g. feedback, crosstalk
• Emerging field
– Long term toxicities unknown
– Starting clinical dose considerations
– Translation of preclinical safety to clinic?
Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
12The screen versions of these slides have full details of copyright and acknowledgements
Toxicology plan for small molecules
Target evaluation
Lead ID
Lead optimization
Candidate selection Phase I Phase II Phase III
Post approval
IND Filing NDA Filing
In cerebro
Genotoxicity
Short-term toxicity (up to 4 wks) l d b k i
Mechanistic
In silicogenotoxicity, cardiotoxicity
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lead or backup screeningLong-term toxicity (up to 2 yrs)
In vivo SP
Reproductive toxicityLocal tolerance
Parenteral drugs only
SP – Safety Pharmacology
Impurity qualification
toxicology
minimal Indication/MOA-specific
Allergy
In vitro SPCardiotoxicity,
off-target receptor binding
Special Tox, immuno-toxicity, phototoxicity
Oncology drug failures
ntag
e of
suc
cess
35Identifying predictable preclinical safety liabilities earlier
can lead to design/selection of better drug candidates
Kola and Landis, Nature Reviews Drug Discovery 3, 711-716 (August 2004)
Per
cen
Current regulatory guidance and impact
4.
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Current regulatory guidance and impact on drug development for oncology
Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
13The screen versions of these slides have full details of copyright and acknowledgements
Regulatory guidance for oncology drug development
Recent publication of special regulatory guidance reflects the significance of this patient population
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Specific regulatory guidancefor oncology drugs
• US FDA: Regulatory Considerations for Preclinical Development of Anticancer Drugs; JJ De George, CH Ahn, PA Andrews, ME Brower, Cancer Chemotherapy and Pharmacology, 1997
• ICH M3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals
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• EMEA (1998); Note for Guidance on the Pre-Clinical Evaluation of Anticancer Medicinal Products. The European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, January 1998; (CPMP/SWP/997/96)
• MHLW is developing nonclinical guidance to address various mechanisms of anti cancer therapy excluding biologics
• ICH (2008). Preclinical Guideline on Oncology Therapeutic Development; ICH Topic S9 Step 3 has been released for comments in December 2008; ICH Topic S9 Step 3; EMEA/CHMP/ICH/646107/2008 http://www.emea.europa.eu/pdfs/human/ich/64610708en.pdf
IND-enabling toxicology program for oncology drugs
No standalone studies required
Core battery only in case of concern
Safety pharmacology
One species2 speciesRepeat dose studya
YesYesDose-ranging
yesEncouragedToxicokinetics
BiologicsSmall molecules
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Starting dose basis NOAEL Rodent STD10/non-rodent HNSTD
Yes (monoclonals) No Tissue cross-reactivity
No MaybeGenotoxicityb
a Duration to match clinical regimen b Only if testing normal volunteers or disease-free patientsPrograms should be developed case-by-case based on scientific rationale; the table above is simplified for comparison purposes only
Target evaluation Lead ID
Lead optimization
Candidate selection Phase I Phase II Phase III
Post approval
IND Filing NDA Filing
Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
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Selecting phase I starting dose:example
• Drug A resulted in 10% (2/20) mortalities in rats at 30 mg/kg in the 28 day study
– Rat STD10 = 30 mg/kg
– Human equivalent dose is 30 x 6 = 180 mg/m2
• Dogs tolerated 1/10th (10 fold safety
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• Dogs tolerated 1/10th (10-fold safety margin) of this dose = 18 mg/m2
• Phase 1 starting dose = 18 mg/m2
– mg/m2 to mg/kg in humans,
– Use 37 as the conversion factor
– 18 mg/m2 or 18/37 = 0.5 mg/kg
– =~30 mg (60 kg patient)
Source: http://www.fda.gov/cder/cancer/docs/doseflow.pdf
NoneMaybebCarcinogenicity
NoneYesbGenotoxicity
Chronic toxicity
NDA-enabling toxicology program for oncology drugs
One relevant speciesRodent and non-rodentSpecies
No longer than 6 monthsNo longer than 6 months
None13 wks for non-cytotoxicsSub chronic toxicity
BiologicsSmall molecules
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Reproductive toxicitya,b,c
yg y
NoneNoneSafety pharmacology
aICH stage C-D, or Segment II reproductive toxicity studies evaluate the period from implantation to birth (period of organogenesis); bMay be unnecessary depending on intended patient population (late stage patients); cEmbryofetal toxicity studies needed concurrent with Phase 3; Fertility studies and peri-postnatal studies needed prior to registration
Programs should be developed case-by-case based on scientific rationale; the table above is simplified for comparison purposes only
If cause for concernUseful if targetedSpecial toxicity
YesYes
Target evaluation Lead ID
Lead optimization
Candidate selection Phase I Phase II Phase III
Post approval
IND Filing NDA Filing
Non-clinical testing for drug combinations
• May not be necessary for testing in advanced cancer patients
• May exclude if:
No PK PD or metabolic interactions anticipated
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– No PK, PD, or metabolic interactions anticipated
– Drugs are not packaged as a combination
– All components well characterized individually
EMEA: guideline on the non-clinical development of fixed combinations of medicinal products (Oct 2005)
FDA: nonclinical safety evaluation of drug or biologic combinations (March 2006)
Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
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Regulatory guidance impurities
• Impurity thresholds not appropriate for oncology drugs intended to treat advanced stage patients
• Relevant for cytostatics, or drugs likely to be administered to early stage cancer patients with longer life expectancy
• Guidance documents– ICH Q3A(R) impurities in new drug substances, 2002
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ICH Q3A(R) impurities in new drug substances, 2002
– ICH Q3B(R) impurities in new drug products, 2003
– ICH Q3C impurities: guideline for residual solvents, 1997
– EMEA, guideline on the limits of genotoxic impurities, 2006
– EMEA, questions and answers on the CHMP guideline on the limits of genotoxic impurities, 2008
– Establishment of allowable concentrations of genotoxic impurities in drug substance and product, 2005, PhRMA position paper.
– FDA 2008: Genotoxic and carcinogenic impurities in drug substances and products: recommended approaches and acceptable limits
ICH S9The following is an overview of current expectations and shouldn’t
be used for designing a drug development program; original source documents and guidance should be consulted
• The current guidance addresses three key topics
– Starting dose
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– Duration of chronic studies
– Reproductive toxicity studies
• Clear guidance for “late stage or advanced cancer”
– Importance of scientific rationale
Source: ICH topic S9 step 3 released for comments in December 2008;ICH topic S9 step 3; EMEA/CHMP/ICH/646107/2008 http://www.emea.europa.eu/pdfs/human/ich/64610708en.pdf
• Approaches to setting the first in human start dose
– Pharmacologically active dose but reasonably safe
– Based on all available PK/PD, toxicity data
– Allometric scaling by body surface area
ICH S9 major topics (1 of 3) start dose
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g y yfor small molecules; Body weight basis for biologics
– Biologics with agonistic properties, consider minimally anticipated biologic effect level (MABEL)
Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
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ICH S9 major topics (2 of 3)duration of chronic toxicity studies
• Current approach – 6 month duration
• ICH S9 proposed 3 month Tox studies t b b itt d i t h 3
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to be submitted prior to phase 3
• Adequate for biologics?
ICH S9 major topics (3 of 3) reproductive toxicology
• Conducted concurrent with phase 3 and submitted for registration, or not conducted (cytotoxics) altogether
– Mechanism of action of the drug on fertility and fetal development
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• Provision to include fertility endpoints in general tox studies
Thank you for your attention
• The presenters wish to acknowledge Tonita Rios Sapinoso of Genentech for her generous technical support
• We would like to thank Kate Schofield of Henry Stewart Talks for her patience and support
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• Thank you to Jeanine Bussiere for her encouragement and the invitation to participate
Toxicity Testing for Oncology Drugs Theresa Reynolds, Krishna Allamneni
17The screen versions of these slides have full details of copyright and acknowledgements
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