Endpoints in Gynecologic Cancer Clinical Trials Keiichi Fujiwara - - PowerPoint PPT Presentation

Keiichi Fujiwara Saitama Medical University International Medical Center GOTIC

GCIG Education Symposium, November 2017, Vienna

Endpoints in Gynecologic Cancer Clinical Trials

Gynecologic Cancer InterGroup

Gynecologic Cancer InterGroup

• AGENDA

– Definition of Endpoint – Variation of Endpoint

• Primary vs Secondary
• Direct vs Surrogate

– Suitable Endpoints for Gynecologic Cancer Clinical Trials from 5th OCCC

• 1st Line
• Recurrent Setting

GCIG Education Symposium, November 2017, Vienna

Gynecologic Cancer InterGroup

• AGENDA

– Definition of Endpoint – Variation of Endpoint

• Primary vs Secondary
• Direct vs Surrogate

– Suitable Endpoints for Gynecologic Cancer Clinical Trials from 5th OCCC

• 1st Line
• Recurrent Setting

GCIG Education Symposium, November 2017, Vienna

Gynecologic Cancer InterGroup

• Endpoint

– Goal/Purpose of Clinical Trial – Depends on the Phase of Clinical Trial

• Phase 1

– Safety

• Phase 2

– Efficacy & Safety in Selective number of Patients

• Phase 3

– True Efficacy

GCIG Education Symposium, November 2017, Vienna

Gynecologic Cancer InterGroup

Endpoint of Phase I Trial

• To determine

– Maximum Tolerable Dose (MTD) for the future trial

• Whether or not the patient experiences a dose

limiting toxicities (DLT)

– Recomended Dose for Phase 2 Trials

GCIG Education Symposium, November 2017, Vienna

Gynecologic Cancer InterGroup

Endpoint of Phase I Trial

• How?

– The Traditional 3+3 Design

• Too many patients with lower doses than MTD

– Alternative Trial Designs such as Continuous Reassessment Model (CRM)

• To accelerate the process
• Good for Biologic Agents with low toxicity profiles

GCIG Education Symposium, November 2017, Vienna

Gynecologic Cancer InterGroup

Endpoint of Phase 2 Trial

• To Provide

– The testing ground for the development of definitive Phase 3 trials

• Through the screening of new agents for antitumor

activity

• By piloting new treatment combination and

schedules.

• Limitation

– Small sample size compromising in Type I and II error cannot draw definitive conclusion

GCIG Education Symposium, November 2017, Vienna

Gynecologic Cancer InterGroup

Endpoint of Phase 2 Trial

• How?

– Single-Arm Phase 2 Designs – Muli-Arm Phase 2 Designs

• Basket Trials
• Umbrella Trials
• Using Short-Term Endpoints

– Tumor Response for Cytotoxic Agents – 6-Month Survival for Target Therapies

• Little Impact on Tumor Shrinkage
• Tumor Stabilization as a Main Effect

GCIG Education Symposium, November 2017, Vienna

Gynecologic Cancer InterGroup

Endpoint of Phase 3 Trial

• To Compare the results with the Standard

Therapy for

– Superiority

• Efficacy

– OS – PFS

– Equivalence or Noninferiority

• Safety
• PRO QOL
• Cost-Benefit

GCIG Education Symposium, November 2017, Vienna

Gynecologic Cancer InterGroup

• AGENDA

– Definition of Endpoint – Variation of Endpoint

• Primary vs Secondary
• Direct vs Surrogate

– Suitable Endpoints for Gynecologic Cancer Clinical Trials from 5th OCCC

• 1st Line
• Recurrent Setting

GCIG Education Symposium, November 2017, Vienna

Gynecologic Cancer InterGroup

Primary vs Seconcary Endpoint for P3

• Primary

– OS or PFS for Superiority Trial

• Secondary

– Safety – PRO QOL – Cost-Benefit

GCIG Education Symposium, November 2017, Vienna

Gynecologic Cancer InterGroup

Surrogate Endpoints

• Although OS is the preferred primary

endpoint

–Not suitable in trials that takes longer time for diseases with good prognosis.

• Need endpoint that can surrogate OS

–Which can measure with shorter time.

• Such as PFS or Tumor Response

GCIG Education Symposium, November 2017, Vienna

0.6 0.7 0.8 0.9 1.0 1.1 1.2 0.6 0.7 0.8 0.9 1.0 1.1 1.2 PFS OS

Hazard Ratios of PFS vs. OS:

Data from Platinum-based Chemotherapy Trials in Advanced OVCA

Line of identity Linear Regression lnHRos=1.01*lnHRPFS-0.006 R2=0.91

PFS HR 0.74 (11.5 15.5 mo = gain 4 mo) OS HR 0.73 (25.8 35.6 mo = gain 11.8 mo)

Linear Regression lnHRos=0.67*lnHRPFS+0.09 R2=0.61

Hazard Ratios of PFS vs. OS:

Data from RCTs of Bevacizumab in Other Solid Tumors

0.5 0.6 0.7 0.8 0.9 1.0 1.1 0.5 0.6 0.7 0.8 0.9 1.0 1.1 PFS OS

OS improvement at least 2 months less than that for PFS

Gynecologic Cancer InterGroup

Surrogate Endpoint

• Most useful in the context of Phase 2

trials, to screen agents for further randomized testing of effects on primary true endpoints.

GCIG Education Symposium, November 2017, Vienna

Gynecologic Cancer InterGroup

• AGENDA

– Definition of Endpoint – Variation of Endpoint

• Primary vs Secondary
• Direct vs Surrogate

– Suitable Endpoints for Gynecologic Cancer Clinical Trials from 5th OCCC

• 1st Line
• Recurrent Setting

GCIG Education Symposium, November 2017, Vienna

Gynecologic Cancer InterGroup

From 5th OCCC

• Trial Endpoints for 1st line intervention trial

– OS is the preferred primary endpoint with

• r without a maintenance component.

– PFS is an alternative primary endpoint, but if PFS is chosen OS must be measured as a secondary endpoint – PFS must be supported by additional endpoints, including

• Predefined PRO
• Time to first or second subsequent therapy.

GCIG Education Symposium, November 2017, Vienna

Gynecologic Cancer InterGroup

From 5th OCCC

• Trial Endpoints for 1st line intervention

trial

– The increasing use of neoadjuvant chemotherapy provides opportunities for short-term trials to evaluate novel treatments prior to surgery – Translational endpoints in these ‘window of

• pportunity’ studies need to be better defined

and validated.

GCIG Education Symposium, November 2017, Vienna

Gynecologic Cancer InterGroup

From 5th OCCC

• Trial Endpoint in ROC

– OS is the preferred endpoint for patient cohorts with an expected median OS < 12 months. – PFS is an alternative, and it is the preferred endpoint when the expected median OS is >12 months. – However, PFS alone should not be the only endpoint and must be supported by additional endpoints

• PRO: Patient Reported Outcomes
• TSST: Time to Second Subsequent Therapy
• TUDD: time until definitive deterioration of quality of life

GCIG Education Symposium, November 2017, Vienna

Thank You !!