# Presentation: 843126

## Phase 1 Clinical StudiesFirst-In-Human (FIH)<Chapter 31>Pharmacologically-GuidedDose EscalationJerry M. Collins, Ph.D.Developmental Therapeutics ProgramDivision of Cancer Treatment and Diagnosis, NCI

## Slide 2

## →

- Traditional IND

- Phase 1→ 2 → 3

- Post-Approval
- Clinical Testing

- NDA

- Phase 4

**Pre-Clinical**
_***In vitro***_
- Subcellular
- Cellular
_***In Vivo***_
- Rodents
- Non-Rodents

**and Non-Clinical**

**Clinical**

## Guidance for Industry, Investigators, Reviewers

**Exploratory IND Studies**
***January 2006***

**Categories of Studies:**
**[1] Proof-of-Concept **
**       ****(Industry; Academia)**
**[2] Selection of Lead Candidate **
**       ****from a Set of Options  (Industry)**
**[3] Imaging (parity with EMEA policy)**

## “Historical” Phases of Human Evaluation

** **
**   ****Phase 1: Safety, early signs of activity**
**   ****Phase 2: Is activity promising?**
**   ****Phase 3: Improve current therapy?**

**Phase 0: Mechanism of Action**

## What is: Proof-of-Concept?

**What is: ****Phase Zero****?**

**Can You Articulate the Key Question?**
**How Do You Answer This Question?**

## //nihroadmap.nih.gov

## Re-Engineering Phase I (FIH) Trials1.  Pipeline/Funnel Pressure:     combinatorial/HTS, new Sponsors2.  To Phase I Faster, Less Preclinical Work3.  Fewer patients, homeopathic doses4.  More patients “near-Phase 2” doses5.  “Value-Added” factors   PK only: variability, metabolism/pharmacogenetics    PD: Decisions to Drop/Continue

##   Phase 1					   714

**       ****Daniel Vasella, MD   CEO, Novartis**
**       ****Industry-Wide Trends in Clinical Trials**

**	****              ****Change****	****    # Ongoing**
** ****	****     ****	****   ****1995********2001****	****        in 2001**
**  ****Phase 1****	****	****	****	****	****   ****714**
**  ****Phase 2****	****	****+55%****	****	****1,136**
**  ****Phase 3****	****	****(none)****	****	****   488**

**+70%**

## 	Design of Phase 1 (FIH) Trial	  Starting Dose	  Escalation Scheme  For Both Elements, Conflict Between  Caution/Safety vs. Efficiency/Efficacy

## Slide 11

## 	BIBLIOGRAPHY / COLLINS / PHASE 1J.M.Collins, D.S.Zaharko, R.L.Dedrick, B.A.Chabner.  Potential roles for preclinical pharmacology in Phase I trials.Cancer Treat. Rep. 70:73‐80, 1986.** Message:  we do a lot of preclinical pharm studies;        	  - - what do we learn?        	  - - how is it used?** Initial proposal for customized dose escalation.J.M. Collins, C.K. Grieshaber, B.A. Chabner.  Pharmacologically-guided Phase I trials based upon preclinical development.   J. Natl. Cancer Inst. 82:1321-1326, 1990.	** Note that title does not say “PK”  	     Intended as an overall platform	     Summarizes mostly retrospectively

## PK-PD Hypothesis:   When Comparing Animal and Human Doses, Expect Equal Toxicity for Equal Drug Exposure

**Concentration of Drug as **
**a Biomarker or Endpoint**

## Bridges Between Preclinical

**and Clinical Development**
**Preclinical                     Clinical**
**     ****Pharm/Tox                Phase 1 Trials**
**     ****---------------****	****       -------------------**
**    ****Mouse MTD              Starting Dose**
** ********      ****	****	****  ****	****    ******
**Blood Levels              Blood Levels**
** ********	****	****	****  ******
**Escalation Strategy**

## Acute Toxicity of Anticancer DrugsHuman versus Mouse

**Dose Ratio**

**AUC Ratio**

## Conclusion:Hypothesis has merit.Follow-Up:What is underlying reason for interspecies differences?

## S.Markey, 8-Nov-01, Slide #54    Additional Effects on Drug Metabolism        Species differences• Major differences in drug metabolism in different  species have been recognized for many years  both in gut microflora and CYP proteins • Example: phenylbutazone half-life is:                   3 h in rabbit                 6 h in rat, guinea pig, dog                 3 days in humans

## Metabolism as the Principal Confounding Factor for First-in-Human Trials

## Gianni et al, JNCI (1990)AUC values in plasma for Iododeoxydoxorubicin (I-Dox) in Mouse & Humans at Equi-Toxic Doses		     Mouse    HumanI-Dox       	5.0     	 0.3I-Dox-ol       1.2      	 4.0(metabolite)

## Rule #1Always Include Some Data from the Lab

## Slide 21

## In Addition to Explaining Interspecies Differences,Other Applications for Metabolism Studies in Phase 1:Learn/Confirm Major PathwaysLearn/Confirm Active/Toxic Molecules

## In Vitro – In Vivo

*In Vitro – In Vivo*
- Metabolic Profiling

## terfenadine/SELDANE®

**fexofenadine/ALLEGRA®**

## Target-Guided Dose Escalation

**Preclinical Pharm/Tox          Clinical Phase 1 Trials**
**---------------------------------****	****    ---------------------------------**
**   **
** ****Safety Factor**
**Reference Animal Dose  ********  Starting Human Dose**

**Stop or Escalate?**

**Define Target Goal           Assess Target Impact**
**                  ********	****  ****	****   ****	****     ******

## 	Functional Imaging via PET: Biomarkers for Treatment Evaluation  Does treatment impact the desired target? What is the minimum/maximum dose?  How to select interval between courses?                             CONTEXT: Individual Patient,  or  New Agent Development

## MAO-B Inhibition by Lazabamide

**MAO-B Inhibition by Lazabamide**
**J.Fowler,BNL Neurology(93****)**

## First-In-Human Trials  Identity Crisis?

## What is Inherent in First-In-Human Trials?<surprise!>

##   

-   

**Translational Research**

## FDA

**FDA**

**NIH**

**NIEHS**

**Pittsburgh**
**Indianapolis**

**NIA/NIDA/Baltimore**

**Dartmouth**

**U**
**C**
**L**
**A**