Phase I studies in non-oncology:Dosing & Designs

April 18th 2012Sharon O’ByrneSenior Medical DirectorGenentech Research & Early Development

Discovery Research(Target Candidate Profile)

• Screen molecules for activity & PK• Establish mechanism of action • Look for early safety signals (pre-clinical in vivo/in vitro)

Pre-Clinical(PK, PD, Toxicology)

• Establish PK-PD-Efficacy relationships• Projection of human PKPD and dosing (go no go)• Establish safety for move to humans (in vivo/in vitro)

File IND/CTA with appropriate Regulatory Authority – Review Tox program and Phase I protocol

Phase I/Ib(Target Product Profile)

• Safety of first in human (go no go) • Proof of mechanistic activity (go no go)• Demonstration of adequate PK & PD to meet therapeutic targets• Select Phase II doses

Submit Phase I data and proposed Phase II protocol to appropriate Regulatory Authorities

Phase II(Proof of concept)

• Meet pre-determined target for efficacy/safety (go no go) • Establish PKPD relationships• Select Phase III doses

End of Phase II (EOPII) meeting with appropriate Regulatory Authorities

Phase III(Pivotal trials)

• Meet pre-determined targets for efficacy/safety as laid out in statistical analysis plan and agreed to with Regulatory Authorities

• Confirm PKPD relationships• Understand PK variability and Drug Drug Interactions (special populations, etc)

Regulatory Authority Approval

Post-Marketing• New indications• New dosage forms• Continue monitoring safety• May have risk management plan 2

Overview of drug development process

Phase I/Ib(Target Product Profile)

• Safety of first in human (go no go) • Proof of mechanistic activity (go no go)• Demonstration of adequate PK & PD to meet therapeutic targets• Select Phase II doses

Pharmacokinetics (PK) & Pharmacodynamics (PD)

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PK: What the body does to the drug (exposure-time).PD: What the drug does to the body (response-time)PKPD: PD response as a function of drug concentration and

time (E-R)

PK: What the body does to the drug (exposure-time).PD: What the drug does to the body (response-time)PKPD: PD response as a function of drug concentration and

time (E-R)

PK PK PDPDClinical efficacyClinical efficacy

Blood

Site of action

MTC

TW

Tmax

AUC

PKPD-Anti-CD11a vs CD11a expression on T-cells

Absorption Distribution Metabolism Excretion (ADME) Differences between monoclonal antibodies & small molecules

1) IV, SC, or IM only, no oral2) Distribution limited to blood and interstitial spaces3) Large CL capacity

Non-target mediated clearance Tissue uptake endocytosis/pinocytosis Lysosomal degradation if not recycled by FcRn (all cells)

Target mediated clearance Endocytosis of receptor/antibody complex Clearance of soluble ligand/antibody complex

Slow CL and long half life (days to weeks) Low dose nonlinear, high dose linear

4) No excretion of intact mAb

1) IV, SC, or IM only, no oral2) Distribution limited to blood and interstitial spaces3) Large CL capacity

Non-target mediated clearance Tissue uptake endocytosis/pinocytosis Lysosomal degradation if not recycled by FcRn (all cells)

Target mediated clearance Endocytosis of receptor/antibody complex Clearance of soluble ligand/antibody complex

Slow CL and long half life (days to weeks) Low dose nonlinear, high dose linear

4) No excretion of intact mAb

1) Oral administration preferred2) Typically all tissues accessible3) Smaller CL capacity

Metabolism (liver; kidney) Oxidation, conjugation, others Active parent drug active metabolite Parent drug may be safe, metabolite

toxic

Fast CL and short half life (hours) Low dose linear and high dose

nonlinear4) Biliary and renal excretion (secretion)

Active or passive transporter

1) Oral administration preferred2) Typically all tissues accessible3) Smaller CL capacity

Metabolism (liver; kidney) Oxidation, conjugation, others Active parent drug active metabolite Parent drug may be safe, metabolite

toxic

Fast CL and short half life (hours) Low dose linear and high dose

nonlinear4) Biliary and renal excretion (secretion)

Active or passive transporter

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Objectives of a First-in-Human study

• To determine the acute safety profile of a study drug in man– Opportunity to detect a large safety signal

• To characterize the pharmacokinetic profile of the study drug– Half-life helps to determine future dosing interval

• To determine any pharmacodynamic effects – Is the study drug acting as expected in humans ?– Helps to determine dose levels

• Is there an opportunity to quantify clinical activity ?– Disease Activity Score in Rheumatoid Arthritis– Low Density Lipoprotein in Cardiovascular Disease– Glycosylated Hemoglobin levels in Diabetes Mellitus– Mayo Clinic Score in Ulcerative Colitis

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First-in-Human studiesGeneral considerations

• Assessment of Risk– Related to mechanism of action

• Totally novel• Target unstable (TGN1412 – anti-CD28)1

• Concern regarding the class of agent under study– May or may not apply to all therapeutics in the class

– Related to target patient population• Acute coronary syndrome• Allergy• Pregnancy

– Related to how well pre-clinical toxicology studies (in vitro & in vivo) predict toxicity in humans

– Healthy Volunteer population vs Patient population

• Focus on safety – (small n)

• Conduct some early signal seeking for proof of concept – (expanded n in some cohorts)

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1Stebbings et al Curr Opin Biotech 2009, 20:673-677

First-in-HumanCalculation of maximum recommended starting dose (MRSD)

• Starting dose based on – Pre-clinical safety studies

• Large molecules – commonly Cynomologous monkeys• Small molecules – commonly Rodent, Dog

– In vitro safety testing in a human cell-based system

• Calculation of dose based on – No observed adverse effect level (NOAEL)

• Highest dose in pre-clinical studies at which no biologically relevant safety events have occurred

– Minimum anticipated biological effect level (MABEL)• Dose at the lowest end of the dose-response curve for biological effect • Estimated from all the in vivo and in vitro data, or what is available• EMEA now recommend use of MABEL for calculation of starting dose for all

biologics*

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*http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_063117*http://www.emea.europa.eu/pdfs/human/swp/2836707enfin.pdf

Use most appropriate species

First-in-HumanCalculation of maximum recommended starting dose (MRSD) using NOAEL

1. Calculate human equivalent dose (HED) of NOAEL from most appropriate species – Human equivalent dose (HED) is calculated using appropriate scaling factors

• Based on body surface area (division factor of 3 for cynomolgus monkeys) – Dose of 1.0 mg/kg in monkeys ≅ 0.3 mg/kg in humans

2. Safety factors should be applied to the HED to ensure a safe starting dose– Safety factor applied depending on risk associated with target– In general safety factor of

• At least 10 x should be applied for large molecules

• At least 50 x should be applied for small molecules

3.Recommended starting dose– HED ÷ safety factor = maximum recommended starting dose (MRSD)

4. Safety factors may also be expressed in terms of– Exposure (AUC) or Concentration (Cmax)

• The AUC or Cmax at the NOAEL

• Using model simulation to determine dose that will provide human equivalent AUC or Cmax

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First-in-Human studiesEscalation of dose (amount of increase)

• Require sufficient dose separation between doses to determine difference, however, not too large an increase – 2 x increase may be too little– 10 x increase may be too much

• Initial dose escalation should be conservative based on knowledge of target– Molecule specific

• Commonly used rule is 3 x increase to ensure safe separation of dose levels– Semilog increment

• Depending on safety profile the degree of increment can be adjusted

• < semilog increment9

Decision making in clinical trialsTerminology used

• Adverse Event– An AE is any unfavorable and unintended sign, symptom, or disease temporally associated

with the use of an investigational medicinal product (IMP; study drug) or other protocol‑imposed intervention, regardless of attribution

• Serious Adverse Event – any AE that is any of the following:– Fatal (i.e., the AE actually causes or leads to death)

– Life threatening (i.e., the AE, in the view of the investigator, places the subject at immediate risk of death)

– Requires or prolongs inpatient hospitalization

– Results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of the subject’s ability to conduct normal life functions)

– A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s)

– Considered a significant medical event by the investigator (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above)

• Serious vs Severe– Terms not synonymous

– Severity refers to intensity of AE – maybe relatively minor but severe e.g. backache

– Seriousness is a Regulatory Authority definition• Refers to seriousness of threat to subject’s life or vital functions

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Decision making in clinical trialsClassification of severity of adverse event

Adverse Event grade of severity• National Cancer Institute Common Terminology Criteria for Adverse

Events (NCI CTCAE v.4)1

– Used in non-oncology for patients with moderate to severe disease

• Mild, moderate to severe classification used (see examples in appendix) – In patients with less severe diseases – Healthy volunteers

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1http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40

Severity Description

Mild (Grade 1) Transient or mild discomfort (< 48 hours); no interference with the patient’s daily activities; no medical intervention/therapy required

Moderate (Grade 2) Mild to moderate interference with the patient’s daily activities; no or minimal medical intervention/therapy required

Severe (Grade 3) Considerable interference with the patient’s daily activities; medical intervention/therapy required; hospitalization possible

Life-Threatening (Grade 4)

Note: Regardless of severity, some events may also meet regulatory serious criteria. Refer to definitions of an SAE

First-in-Human studiesDecision making

• Dose escalation rules• Define dose limiting toxicities (DLTs)

• Adverse events that are pre-determined and defined according to grade of severity

• Any study drug related Grade ≥ 3 adverse events occurring within 14 days of study drug administration

• Any study drug related Grade ≥ 2 adverse events occurring within 14 days of study drug administration that are considered clinically significant as judged by the Investigator or Internal Safety Monitoring Committee

• Specific related to target under study– Risk of neutropenia– Risk of infection

• Define the number of DLTs at which dose escalation will stop• Study will cease completely• There will be further evaluation of safety and study will continue• Examples – 1-2 DLTs per cohort

• Example of dose escalation rules• If 1 patient experiences a DLT, 5 additional patients will be randomized to the dose level at which the DLT was

experienced• Of these 5 additional patients, 4 will receive active drug and 1 will receive placebo in a double‑blinded fashion.

If the incidence of DLTs in the entire expanded cohort remains at 1 patient (1 of 8 patients treated with study drug), escalation will proceed to the next dose level

• If 2 or more patients experience a DLT, enrollment will be stopped for evaluation of all available safety information

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Dose Limiting ToxicitiesProbability of detection

Probability of Detecting 1 DLT at Different Event Rates

DLT event rate 1% 10% 20% 25% 33% 50%

Cohort A (n=3) Probability 2.0% 19.0% 36.0% 43.8% 55.1% 75.0%

Cohorts B–E

(n=5/cohort)

Probability 3.9% 34.4% 59.0% 68.4% 79.8% 93.8%

• The sample size is based on the dose escalation rules• The number of subjects in each cohort should be

sufficient to characterize the single‑dose safety and tolerability

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First-in-HumanSafety monitoring

• Recommend dosing of first subjects at least 24 hours apart

• First dose cohort

• First couple of subjects in each increasing dose cohort

• Starting dose route of administration– Intravenous infusion over 1-2 hours for totally novel target, or

where there are concerns for safety– Considered safer as infusion can be turned off if AE occurs during

infusion

– Subcutaneous route can be used if the target is not novel

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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078932.pdf

First-in-HumanSafety monitoring

• Timing of dose escalation (SAD/MAD)– 14 days generally considered acceptable length of time to determine

acute toxicity

– Single Ascending Dose stage – 14 days after single dose

– Multiple Ascending Dose stage – 14 days after second or third dose• Depending on likely toxicity of study drug, this time interval can be adjusted

• Duration of follow-up of patients for adverse event monitoring– ~ 5 half-lives for clearance of therapeutic under study

• Sponsor’s internal safety monitoring committee– Unblinded to treatment assignment to quickly review any SAEs etc

• Treating physician and patient – Blinded to eliminate bias

• Serious adverse events, adverse events Grade ≥ 2/3 and all events of special interest– Reported to the Sponsor within 24 hours

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Slide 16

4:1

Cohort B: 15 mg (0.2 mg/kg) SC

2:1

Cohort A: 5 mg (0.07 mg/kg) SC

d14

d14

d14

4:1

Cohort C: 50 mg (0.67 mg/kg) SC

4:1

Cohort D: 150 mg (2.0 mg/kg) SC

4:1

Cohort E: 450 mg (6.0 mg/kg) SC

d14

First-in-Human Study DesignExample 1

Assuming body weight of 75 Kg

d14

6:1

6:1

6:1

Active:Placebo

Cohort F: 30 mg FD SC (0.4 mg/kg)

Cohort G: 100 mg FD SC (1.3 mg/kg)

Cohort H: 300 mg FD SC (4.0 mg/kg)d14

Main objective of Phase I is to seek an early safety signalMain objective of Phase I is to seek an early safety signalDosing

Phase Ia – SAD Phase Ib – MADAwait full assessment of safety from SAD

Randomized, Double Blind within Cohort, Placebo-controlled, Dose Escalating StudyRandomized, Double Blind within Cohort, Placebo-controlled, Dose Escalating Study

First-in-Human Study DesignExample 2

Slide 17

• All patients dosed in Cohort A dosed on a separate day• First 2 patients in each subsequent cohort in SAD dosed on separate days

4:1

Cohort B: 15 mg (0.2 mg/kg) SC

2:1

Cohort A: 5 mg (0.07 mg/kg) SC

d14

d14

d14

4:1

Cohort C: 50 mg (0.67 mg/kg) SC

4:1

Cohort D: 150 mg (2.0 mg/kg) SC

4:1

Cohort E: 450 mg (6.0 mg/kg) SC

d14

Phase Ia – SAD

6:1

Cohort F: 30 mg FD SC (0.4 mg/kg)

Wk 0 Wk 2 Wk 4

6:1

D14 from 2nd dose

Cohort G: 100 mg FD SC (1.3 mg/kg)

6:1

Active: Placebo

Cohort H: 300 mg FD SC (4.0 mg/kg)

D14 from 2nd dose

- Real timesafety reporting

- Cohort E & F start at the same

time

- Real timesafety reporting

- Cohort E & F start at the same

time

Phase Ib – MAD

Dosing

Assuming average body weight of 75 Kg

Randomized, Double Blind within Cohort, Placebo-controlled, Dose Escalating StudyRandomized, Double Blind within Cohort, Placebo-controlled, Dose Escalating Study

First-in-Human Study DesignExample 3

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Randomized, Double Blind within Cohort, Placebo-controlled, Dose Escalating StudyRandomized, Double Blind within Cohort, Placebo-controlled, Dose Escalating Study

Time

Dos

e m

g/kg

4:1

Cohort A: 0.3 IV

Analysis of PK + clinical safetyfrom SD DE

4:1

Cohort B: 1.0 IVd14

4:1

Cohort C: 3.0 IVd14

4:1

Cohort D: 10.0 IVd14

4:1

Cohort G: 0.5 SC

4:1

Cohort H: 1.5 SC

4:1

Cohort I: 3.0 SC

4:1

Cohort J: 4.0 IV

4:1

Cohort F: 3.0 SC

= dosing; IV = intravenous; SC = subcutaneous

Dosing q4wks:

Single ascending dose stage (SAD; Phase Ia)

Multiple dose stage (MD; Phase Ib)

Active:Placebo

Appendix

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Examples of Grading for Adverse EventsSystem based

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Parameter Grade 1 (Mild) Grade 2 (Moderate) Grade 3 (Severe) Grade 4 (Life-Threatening)

SYSTEMIC

Allergic reaction Pruritus without rash Localized urticaria Generalized urticaria; angioedema Anaphylaxis

Fever: oral 37.7–38.5°C (100.0–101.5°F) 38.6–39.5°C (101.6–102.9°F) 39.6–40.5°C (103–105°F) > 40°C (> 105°F)

Fatigue Normal activity reduced < 48 hoursNormal activity decreased

25–50% > 48 hours

Normal activity decreased > 50% can’t

workUnable to care for self

GASTROINTESTINAL

NauseaMild or transient; maintains

reasonable intake

Moderate discomfort; intake

decreased significantly; some

activity limited

No significant intake; requires IV fluids Hospitalization required;

Vomiting One episode in 24 hours 2–5 episodes in 24 hours> 6 episodes in 24 hours or needing IV

fluids

Physiologic consequences requiring

hospitalization or requiring parenteral

nutrition

ConstipationRequiring stool softener or dietary

modificationRequiring laxatives

Obstipation requiring manual

evacuation or enemaObstruction or toxic megacolon

Diarrhea

Mild or transient; 3–4 loose

stools/day or mild diarrhea last < 1

week

Moderate or persistent;

5–7 loose stools/day or

diarrhea lasting > 1 week

> 7 loose stools/day or bloody diarrhea;

or orthostatic hypotension or electrolyte

imbalance or > 2L IV fluids required

Hypotensive shock or physiologic

consequences requiring hospitalization

CARDIOVASCULAR

Hypotension

Transient orthostatic hypotension

with increased heart rate of < 20

bpm or decreased systolic BP of

< 10 mm Hg; no treatment required

Symptoms due to orthostatic

hypotension or decreased

systolic BP of < 20 mm Hg;

correctable with oral fluid

treatment

Requires IV fluids; no hospitalization

required

Mean arterial pressure < 60 mm Hg or end

organ damage or shock;

requires hospitalization and vasopressor

treatment

 

RESPIRATORY

Bronchospasm (acute – within

48 hours of dosing)

Transient; no treatment;

70–80% FEV1 of peak flow

Requires treatment;

normalizes with

bronchodilator;FEV1 50–70% of peak flow

No normalization with bronchodilator;FEV1 25–50% of peak flow; or

retractions present

Cyanosis: FEV1 < 25% of peak flow or

intubation necessary

INFECTION

Infection

Localized, no systemic

antimicrobial treatment indicated

AND

symptoms causing no or minimal

interference with usual social and

functional activities

Systemic antimicrobial

treatment indicated OR

symptoms causing greater

than minimal interference

with usual social and

functional activities

Systemic antimicrobial treatment

indicated AND symptoms causing

inability to perform usual social and

functional activities OR operative

intervention (other than simple incision

and drainage) indicated

Life-threatening consequences (e.g., septic

shock)

SKIN – DERMATOLOGICAL

Mucocutaneous Erythema; pruritusDiffuse, maculopapular rash,

dry desquamation

Vesiculation or moist desquamation or

ulceration

Exfoliative dermatitis, mucous membrane

involvement, erythema multiforme, Stevens-

Johnson, or necrosis requiring surgery

Pruritus (itching – no skin

lesions)Slight itching at injection site

Moderate itching at injection

extremityItching over entire body NA

Rash at Injection Site < 15 mm 15–30 mm > 30 mm  

FcRn Recycles IgG Via pH Dependent Binding & Release

V. Ghetie & E.S. Ward, Ann. Rev. Immunol. 2000

pH 6

pH 7.4

Neonatal Fc receptor for IgG (FcRn)