# Presentation: 075720

## Clinical Trial Preparation for Molecularly Based Agents

- Louise B. Grochow, MD, FACP
- Chief, Investigational Drug Branch
- Cancer Therapy Evaluation Program
- National Cancer Institute

- T

**C**

**EP**

- THEORY TO THERAPY

## Changing the paradigm: targeted therapy development

- Agent Selection:

- Murine tumors
- Xenograft models

- Credentialed targets
- molecular models

- Trial design:

- Empirical

- Hypothesis driven

- Dose endpoint:

- Toxicity

- Molecular effect
- When to measure?

- Endpoint eval:

- H&P, clin. lab

- Complex assays

- Eligibililty:

- Any solid tumor

- Presence of target

- Priority:

- Log cell kill

- Growth inhibition

## Changing the paradigm: Phase II

- Ph II goal:

- Tumor shrinkage
- (cure)

- Tumor stabilization
- (eliminate progression)

- Ph II metric:
-     When?

- Anatomic imaging
- 8 weeks

- Functional probes
- Establish time points

- Dose finding

- More is better

- Molecular effect

- Combinations:

- Empiric

- Pathways and preclinical
- proof of principle

- Patient selection

- Histology

- Molecular pathology

## What experts will you need to work with?

- Basic, translational and clinical colleagues
- Preclinical experts in model design, toxicology and activity
- Clinical trials experts
- Statisticians
- Experts in molecular target assessment
- Pathologists
- Imagers
- Interventional radiologists

## So you have a good idea: Now what?

- Characterize the target
- Screen libraries against the target OR
- Synthesize based on in silico drug design
- Select lead compound based on pharmacology
- Screen for activity in engineered lines
- Validate in animal models mimicking human disease
- Develop reporters/probes to assess target effects
- Design a clinical trial

## Clinical Trial Design: dose finding (phase I) studies

- Establish disposition and safety
- Establish dose that produces target effect
- 	(_**T**_arget _**E**_ffect _**D**_ose)
- Establish relationship between
-  	dose/schedule and effect
- Agent may be non-toxic (endostatin)
- (Expensive) agent may have effects at doses that aren’t toxic
- Dose response relationship may not be monotonic (interferon)

## Slide 7

## Possible Trial Designs

- PK/target concentration-guided
- Accelerated Titration Design:
- Minimize patients treated at inactive doses
- Incorporate biological target effect
- Other designs incorporating biological effect
- O6BG: AGT suppression
- single dose before planned tumor resection
- PS 341: proteasome inhibition
- circulating normal PBM
- EGFR inhibitors: assess target presence
- bcr/abl tyrosine kinase inhibitor: response

## O6BG: Rationale for Development

- Alkylator-resistant tumors often have increased intracellular alkylguanine-DNA alkyltransferase (AGT), DNA repair enzyme
- O6BG depletes AGT
- When AGT < 10 fmol, activity of DNA alkylating agents that form adducts at the O6 guanine position increases
- O6BG and BCNU more active *in vivo* than BCNU alone

- Friedman et al JCO 16:3570, 1998

## O6-BG Phase 1 Trial Design in Malignant Glioma

- Undetectable AGT (< 10 fmol/mg protein) occurs in 20% in absence of O6-BG
- O6-BG administered 18 hr before craniotomy
- BCNU-induces interstrand cross-links by 18 hrs
- Up to 13 patients entered at each dose
- At any time, if AGT detectable in 3 patients, dose was escalated
- Biologic endpoint: undetectable AGT in _>_ 11 of 13 patients

- Friedman et al JCO 16: 3570, 1998

## Glioma AGT Activity After O6-BG

- Dose

- (mg)

- No. of

- Patients

- AGT
-  Undetectable

- 0

- 9

- 0

- 40

-  3

- 0

- 60

-  3

- 0

- 80

- 13

- 8

- 100

- 11

- 11

- Friedman et al JCO 16:3570, 1998

## O6-Benzylguanine:  Phase I Trial 

- Suppression of AGT activity in peripheral blood mononuclear cells (PBMC) did *not* predict suppression of AGT activity in tumor tissue in phase I studies
- PBMC:     36 mg/m2
- Tumor :	120 mg/m2
- Immunoreactive AGT in PBMC a poor surrogate

**Spiro TP, et al.  **_**Clin Cancer Res. **_**7:2318, 2001**

## Clinical Trial Design withBiologic endpoints 

- Evaluate for target effect as active concentration is approached
- Expand cohort when any biologic effect seen
- reproducibility of effect
- importance of well defined confidence interval
- Escalate dose
- until maximal expected effect is seen
- Until maximal effect occurs in maximal fraction of patients
- Additional steps to confirm
-  effect is maximal
-  rate of effect is maximal

## Step size and trial efficiency depend on shape of dose effect curve and reproducibility of effect reporter

## Dose Escalation Designs forTarget Effect Dose: 2 approaches

- (1)  % of patients in a cohort of 3-6 who achieve a “target effect”
- a molecular target level
- change in target level
- Stop escalation when the observed response rate is “adequate”.
- (2)  Rate of “target effect” stops increasing

## Example for Approach (1)—Identifying a Target Effect Dose (TED)

- Dose escalate in cohorts of 3 patients so long as no more than 1 “biologic response” is seen among the 3 patients.
- Expand to a cohort of 6 patients if at least 2 biologic responses are seen among the initial 3 patients.
- Stop dose escalation when at least 5 biologic responses are seen among the 6 patients, and take this TED into further testing.

## Approach (2)--Dose Escalation Until the Observed Response Rate Plateaus

- In the absence of toxicity, we may opt for continuing dose escalation so long as the observed biologic response rate continues to rise.
- If the biologic response rate appears to remain constant in the face of continued dose escalation, we may stop dose escalation despite the fact that the observed response rate continues to be low.

## Example of Approach (2)--Test the Slope for Each Successive Set of 4 Doses Using 3-Patient Cohorts / Dose (“Slope Design”)

- Dose escalate in cohorts of 3 patients.
- Stop dose escalation when 4 successive dose level cohorts (not all with 0 responses) yield non-positive (0) slope for the biologic response regression line, and take the highest dose given into further testing.

## Simulations of Dose-Response Patterns to Determine Behavior of Escalation Designs

- Dose-response patterns tested:
- Response rates rise from 30% to 90% in steps of 20%
- Response rates rise from 20% to 90% in steps of 10%
- Response rates rise from 20% to 90% in steps of 5%
- Response rates rise from 20% to 50% in steps of 10%
- Escalation designs tested:
- Targeted response rate designs: 3, 4, _or_ 5 out of 6
- Slope designs: 4 cohorts of 3 patients each _or_ 3 cohorts of 6 patients each _or_ 4 cohorts of 6 patients each
- For each dose-response pattern by escalation design combination, 10,000 trials were simulated

## Number of Patients Required for “5/6” and “4-Dose x 3-Pt/Dose Slope” DesignsBy Simulations Assuming True Response Rates Increase from 30%-90% by 20% as Dose Increases

## Number of Patients Required for “5/6” and “4-Dose x 3-Pt/Dose Slope” DesignsBy Simulations Assuming True Response Rates Increase from 20%-90% by 5% as Dose Increases

## Support for Early Clinical Trials

- CTEP support (agent supply)
- CTEP support for infrastructure
- Cooperative agreements (Dose finding)
- Contracts (Phase II)
- Other support for infrastructure
- Grant support
- Quick trials (R21)
- Clinical study section
- Cancer Center Core Grants
- General Clinical Research Centers

## Applying to CTEP for Agents

- Letter of Intent
- Form available on CTEP web site :http://ctep.info.nih.gov
**Review criteria**
- Strong scientific hypothesis
- Supporting preliminary data
- Adequate patient accrual
- Innovative correlative studies
- Ability to meet regulatory requirements
- Not duplicative
- Agent available
- Industry sponsor concurs

## Preparing a Protocol

- LOI approved after reviewed by CTEP’s Protocol Review Committee (+ extramural investigators if needed)
- Address critique in LOI approval letter
- Use available templates (supplied by CTEP)
- Include relevant details (or references) for correlative studies
- Submit electronically to CTEP PIO
- Review by CTEP PRC

## What do you need to measure drug effect on target?

- Characterized assay or probe to report effect on target relevant to therapeutic agent
- Quality assurance: calibration assays, interfering processes, sample handling
- Reproducible
- Sensitivity
- Specificity
- Economically and practically feasible
- Validate in engineered model

## Desirable Information for Design of Dose - Finding Trial

- Relevant models:
- Optimal schedule
- Optimal dose
- Concentration required for effect on target
- % change in target associated with efficacy
- Variability in dose/target and target/efficacy relationships
- Estimate of fraction of tumors that will have effect
- Normal target values, variability
- Target effect on tumor vs other tissues (eg PBM)
- Does patient’s tumor have relevant target?

## Options for Preliminary Efficacy (phase II) Trials

- Conventional and/or molecular target eligibility?
- Standard phase 2 design targeting RR, survival, PFS, clinical benefit
- Standard with biologic endpoint
- Standard targeting non-progressor rate
- Ratio of TTP for new and previous therapy
- Tumor growth before and after treatment with each patient as her own control
- Multi-arm randomized selection designs
- Randomized discontinuation design

## Clinical Trial Design: Combination Studies

- Combinations of novel agents, novel agents with cytotoxics
- Preclinical models or plausible molecular hypothesis
- Biologic target effect designs
-  	– proof of principle
- Dose escalation schemes

## Tumor Tissue Studies in Clinical Trials

- Difficulty obtaining tumor tissue
- Difficulty obtaining multiple samples
- Which time points?
- Tumor heterogeneity: results vary depending upon % tumor vs normal vs necrotic cells
- Methodological issues: sample handling, sensitivity, reproducibility, complexity, availability
- For newer targets, limited information on normal ranges, variability, magnitude of desired effect
- 192 biopsies in 107 pts; 88% success in obtaining paired biopsies

- Dowlati, Haaga et al.. Clin Cancer Res 7:2971, 2001

## Setting priorities for clinical trials

- Credentialed target
- Evidence that agent effects target
- Evidence that target effect correlates with useful therapeutic effect
- Reliable way to measure presence of target
- Probes that permit assessment of target effect in clinical trial

## Selecting and Evaluating New Agents for Cancer Treatment

- Test strategies for selecting agents for trials
- Test hypothesis of molecular diagnosis
- Evaluate novel clinical  trial designs
- Target effect is necessary but not necessarily sufficient (pathway crosstalk, downstream events, other proliferative advantages
- If proposed target is not accurately characterized, a useful agent might be discarded
- This is much simpler if the agent is non-toxic, cheap and highly selective in its effects on a critical target
- This is much harder if the agent is promiscuous in its targets, toxic, and the molecular pathology of the disease is complex

## Acknowledgements

- Trial design statistics:  Larry Rubinstein, E. Korn, J. Pluda,, S. Hunsberger
- O6BG:   H. Friedman, S. Gerson, H. Spiro, E. Dolan, J. Pluda
- Biopsy data: J. Haaga, A. Dowlati

## Our next speakers are:

**Dr. Dale Shoemaker**
**Dr. Sherry Ansher**
**Regulatory Affairs Branch**
**Cancer Therapy Evaluation Program**