Which endpoint to choose ? (in phase II sarcoma clinical trials) (and also in other sarcoma trials!) George D. Demetri, MD Dana-Farber / Harvard Cancer Center, Boston Mass. USA for Robert Maki, MD PhD in absentia Mount Sinai School of Medicine New York, NY, USA

Tell me! What is the answer?

Well, what is the question?

Example: Is this randomized study design definitive proof of activity? Ovarian cancer xenografts in mice treated with cyclopamine or saline n = 4 {probably not good enough for FDA approval} McCann CK et al. PLoS One 2011; 6(11): e28077

Example: Is this randomized study design definitive proof of activity? Citrus fruit dietary supplementation in Sailors with Scurvy! Intervention 100% Active Disease n = 8 n = 4 {probably not good enough for FDA approval} Lind 1747 (published in summary, in posteriori)

And so it is with phase II designs. It depends on the question… Your choice of endpoint is the most important decision you make in the design of a (phase II) clinical trial

Phase I / II study general principles Treat a group of patients, typically 20-100, to obtain safety data Identify activity (or not) Got a great biomarker? YIPPEE!!!! (e.g. viral load in HIV) Radiological change typically used in solid tumors Radiological, hematological, molecular parameters for heme malignancies Perhaps the most common stage of drug development abandonment Proceed to phase III if sufficient activity Response rate often highest in phase II, lower in single center phase III, lowest in cooperative group phase III Bias is inherent in a group of highly-selected patients Often no comparison group Short term therapy: for metastatic disease, most patients often off treatment within 6-8 weeks ( How does one identify toxicity in patients treated longer? )

What is your goal? Is this a proof-of-concept study? First phase I or phase II in humans Often single agent, single arm study Phase IB or Phase IIA

Phase II Trial in “Cancer” 1972 Doxorubicin Activity Noted in Sarcomas

Phase II Trial in “Cancer” 1972 Doxorubicin Activity Noted in Sarcomas

Phase II in “Cancer” 1972 Doxorubicin and DTIC Activity Noted in Sarcomas

What is your goal? Is this a proof-of-concept study? First phase I or phase II in humans Often single agent, single arm study Phase IB or Phase IIA Are you trying to rule in or rule out activity for further development? Probably most reliable with a randomized study Can compare against other therapy or placebo Relaxed type I and type II errors (vs. phase III) Phase IIB

Endpoint options “Progression-free survival” (PFS): commonly used PFS: time from treatment initiation to tumor progression or death from any cause, with censoring of patients who are lost to follow-up “Time to tumor progression” (TTP): used much less often TTP: the only event of interest is disease progression Response rate (WHO, RECIST, modified RECIST, Choi…) Biomarker Disease marker definitely tied to outcomes [e.g. viral load in HIV] Tumor marker [e.g. PSA] Imaging [e.g. PET SUVmax] Patient-reported outcomes Aim: To test impact of study intervention on “how a patient feels, functions or survives”

How do I assess thee? Let me count the ways (…well, two) Landmark analysis Time-to-event analysis

Time to event data vs. landmark analysis More data Data are lost p>0.05 p<0.05 p>0.05

Which type of “phase II” study? One stage 2, 3, … n stage Continuous monitoring __________________________________ Response adaptive randomization Phase I-II Phase II-III “seamless” Randomized discontinuation

A brief history of clinical trials

Early Clinical Trial Phase II Investigational device study Shut down by IRB for: Consent from spouse not sufficient Failure to file annual report History of basal cell cancer 3 yrs ago made patient ineligible per entry criteria. Inscription: Meester snyt die keye ras Myne name Is Lubbert Das Master, cut away the stone; My name is Lubbert Das H Bosch. The Cure of Folly. ~ 1494

(Does your dog hunt? Art Skarin) One-stage design n patients Does this drug work? (Does your dog hunt? Art Skarin)

Rejects completely inactive treatments more rapidly 2-stage design n patients m patients Preliminary stage Follow-up stage Rejects completely inactive treatments more rapidly Gehan EA et al. J Chronic Dis 1961; 13: 346

“Optimized” 2-stage design: Simon n patients m patients Binary outcome (Response or not) Sample size minimized for given type I, type II errors Study terminated only for early lack of activity Very commonly used in oncology Simon R. 1989; Control Clin Trials 10: 1

Off to the races! 3 stages n patients Analyze after every patient: m patients p patients 3 stages n patients Analyze after every patient: continuous monitoring Enign LG et al. Stats Med 1994;13: 1727 Thall PF and Sung HG 1998; 17: 1563

To randomize & randomize not Using RECIST tumor response Monotherapy? Combination therapy? In each case randomization can help, but with IIA designs single arm studies are often used PFS Not universally validated as a validated (earlier, more direct) endpoint of clinical benefit compared to overall survival Usually requires randomization vs another therapy Key issues: time-based restaging (lead time bias) and variations in underlying disease biology (well diff liposarc…..wild type GIST…) “Mít a nemít”, 1944

Randomizations: graphically B R Other Rx Simple B A R Other Rx 2-way crossover B A R Other Rx 1-way crossover A R Other Rx nil Randomized discontinuation

Phase II: What to do? Try to randomize Sometimes not practical to randomize Very rare sarcoma subtype Can’t accrue sufficient number to show a small difference Hey, it’s O.K…. Prospective data are better than retrospective data Bayesian designs: useful to choose therapies for further study (I-SPY 2, BATTLE, etc.) May be difficult to use for regulatory approval based on very real concerns regarding patient referral bias over time Randomization as a function of drug Randomization as a function of biomarker Weigh your options, call a friend or twelve…

Phase III: Be Happy? Try to avoid expensive phase III failures! Set a high bar in Phase II before going to Phase III in order to minimize risk of phase III failure Most signals of activity are less obvious in phase III trials than they were in phase II. Decide what is truly clinically important for a patient And then be honest about whether you think you can actually achieve it based on available data… Do you really need a phase III trial to prove benefit to patients? If you think “no”, you had better have darned great data!

Conclusion : Choose your trial design with care