Challenges in Clinical Trials in Oncology

1. Challenges in Clinical Trials in Oncology

2. Learning Outcomes This presentation covers some aspects of the key learnings required for Module 3 as follows: • Early studies in patients: dose-finding / proof of concept studies and their impact on drug development plan. • Clinical trial design (practical aspects) • Principles and application of statistics in clinical trials. • Various types of clinical studies in oncology and the challenges in choosing the appropriate design and in conducting trials. • Impact of emerging results on the drug development plan. • Evaluation of the outcome of drug development: final therapeutic profile / usage of a medicine.

3. AGENDA • Background • General principles • Phase I oncology studies • Phase II oncology studies • Late Phase/ Registration oncology studies • Regulatory issues • New technologies

4. GENERAL PRINCIPLES Oncology is different • Oncology means > 100 types of tumour • Each tumour is an ‘independent disease entirely’ • Each tumour requires a different, specific treatment • Approaches to treatments continuously changing • Different lines of treatment (1st/2nd line) different modalities (adjuvant / neo-adjuvant), combination with radiotherapy

5. Oncology Treatment Definitions: Neo-adjuvant treatment: Given before primary modality. Role to treat potential systemic metastases or shrink a tumour so easier to resect / irradiate Adjuvant treatment: Given after primary modality. Role to treat microscopic residual disease and potential systemic metastases. Concurrent regimens When more than one modality is used simultaneously e.g. chemoradiation Sequential When chemotherapy or other agents are given in a sequential manner.

6. Chemotherapy Chemotherapy introduced 1960’s Hormonal agents (tamoxifen) 1970’s Breakthorugh Platinum agents 1978 Anti-emetics 1980s Monoclonal antibodies 1990’s Human Genome Project 2000 Cytotoxics Mainstay of cancer theapy but poorly selective. Basic mechanism is to target rapidly dividing cells. The therapeutic index (also known as therapeutic ratio), is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic effects. Commonly induces chemotherapy drug resistance

7. New Approach • Oral agents with predictable milder toxicity • OBED optimum biological effective dose • Tumour targeted signal transduction Antibody specific Biochemical targets • Monotherapy development is challenging as cancer is heterogenous • Still using cytotoxics but often in conjunction with above agents-example: • Some cytotoxics in development but aimed at specific groups e.g. Overcome mechanisms of resistance

8. Clinical Development - Oncology First indication – Breast Cancer Refractory Patients (3rd line/4th line) MARKET Phase I 1st line/2nd line Metastatic Disease MARKET Phase III Adjuvant treatment MARKET Additional indications Eg. NSCLC, Ovary, Bladder, etc

9. Trial Challenges • Defining trial population • Trial design • Endpoints – TTP/OS • Use of validated surrogate endpoints • Trial completion • Complexity of newer technologies

10. Oncology CDP Monotherapy Combination therapy Phase I Different tumour types Phase II Phase III Treatment setting Line of therapy Phase IV External environment

11. Dose of investigational agent in monotherapy Dose of investigational agent in combination therapy Dose of each combination agent Dose of each agent in different tumour types Performance status ADME (including differential tissue penetration) Hepatic function Renal function Political environment Social environment Variables

12. Phase I Studies • Determine the MTD (max tolerated dose) • Determine DLT (dose limiting toxicity) • Recommend dose for Phase II • Characterise the most frequent side effects and organs of toxicity- as regards relationship to dose and schedule • Response evaluation where possible- direct tumour measurements / biomarkers • Orally administered drug- food interactions studies required Objectives

13. Phase I Studies Subject selection • Any confirmed malignancy with no effective therapy available • Have a performance status (0-2), life expectancy of > 3 months • Have reasonably normal hepatic and renal function • Have reasonable bone marrow function • For non- cytotoxics- healthy volunteer studies maybe appropriate based on preclinical findings and pharmacology of drug

14. Phase I Studies Specific Consent Issues • Drug is experimental and has not been used in humans before this study • Side effects to be expected • Effects/benefits on tumour are uncertain • Objective of study to provide data necessary to progress cancer therapy • Subject who refuses or drops out will receive the best possible treatment

15. Phase I Studies Study Design • Starting dose based on NOAEL or LOEL in most sensitive pre-clinical species and apply safety factor > 10 fold • Cohorts (3 - 6 pts) at predefined dose levels • Escalate quickly at low doses, slowly at high doses • If not life threatening toxicity seen  increase the dose and repeat • If possible toxicity  same dose and repeat group size • When pre defined level of toxicity seen  STOP

16. Toxicity Assessments • Treatment continued until: • Non- acceptable side effects • Patient request • Disease progression • Evaluation of toxicity: • Physical examination • Blood and urine tests • Radiological assessments • WHO toxicity criteria / NCI Common Toxicity Criteria • Severity, relationship to study drug, reversibility, dose, symptomatic measures required

17. Study Design • Choice of starting dose (SD) is critical • Dose escalation (e.g. modified Fibonacci)

18. Phase I Studies • Alternative study designs:- • PK guided escalation • Within patient dose escalation Benefits: few patients quicker all subjects may get an active dose Disadvantages: cannot distinguish between acute and cumulative toxicity all subjects may get a toxic dose

19. OLD Determine MTD Recommend Phase II dose Describe toxicities Examine PK NEW Determine MTD Recommend Phase II dose Describe toxicities Examine PK Demonstrate mechanism Devise assay in patients Stratify by molecular pathology Phase I Cancer Drug Development

20. Phase 1 Proof of Mechanism Pre-gefitinib On gefitinib Baselga et al 2002

21. Phase II Studies Efficacy screening:- • Review efficacy in different tumour types • Further define toxicities • Treat enough patients with each tumour • False positive results are better than false negative • Go/no go decisions before Phase III Basic Principles

22. Phase II Study Design • Dose usually ~80% of MTD from Phase I • 25-50 pts per dosing schedule per tumour type • Sequential measurements of specified lesions using Response Evaluation Criteria in Solid Tumours (RECIST) / WHO criteria • Standardisation of imaging techniques required • Independent review of tumour response adds to validity of data • Analysis should be based on intention to treat population • RCT 2 are increasing used and highly informative

23. Endpoints for Phase II Studies Cytotoxic • Response rate Targeted Agent • Tumour shrinkage / response rate? • Inhibition of target pathway • TTP or proportion of patients without progression at a specified time • Historical control versus randomised comparison

24. Any Questions?