Clinical Trials and Cooperative Group Studies

Sam J. Lubner MD, FACPUniversity of Wisconsin Carbone Cancer Center

Objectives

• Understand the concept of clinical trials and the differences across the phases

• Understand why cooperative groups are necessary for many/any disease type

• Bemoan why it takes so much time and money to answer a relatively simple question

Why it matters

• It currently costs around $1.2B to successfully bring a compound through trials to market.

• Most drugs fail.– Enormous cost/risk for failure

• It takes about 8 years to go from phase 1 testing to approval (with some exceptions).

How do we decide what works?

• Pre-clinical data gives us a hint.• In vitro as a start• High-throughput screening– Expose a ton of compounds to a series of cancers all at

once• Animal models better– Gives a sense of tolerability

• Tons of improvements in this area right now• Tons more to do…

A story…

Ripped from the headlines

• Epidermal growth factor receptor (EGFR) was found to be important in tumor growth in cancer cells grown in culture

• Inhibition of EGFR was found to be possible in 1988.

• IMC-225 was created in the late 1990’s out of a lab in Israel, and a company called ImClone was started

Phase 1 clinical trials

• Dose-finding and toxicity finding, ‘first in human’ studies

• Take a drug that has been through in vitro and animal testing

• Start at the LD10 (the dose at which 10% of animals died)

Traditional phase 1 studies

• Patients with refractory malignancies• Already treated with ‘everything’• Still feeling ok• Truly altruistic• High risk/high reward (for patients)• Endpoints: toxicity, “Maximum Tolerated Dose”

(MTD)• All open label, no randomization or placebo

How do they work?

• Classical 3+3 design– Challenges

• Underdosing first few cohorts

• Overdosing second-to-last cohort

• Modified designs– Targeting a “biologically

effective dose”

What does success look like?

• Dose found that is both biologically plausible and tolerable to patients

• Responses achieved in a subset of patients– Why did they respond?– Were there similarities between the responders?– Historical response rates: 5%

• Dose expansion cohorts in some subsets of patients

Next chapter

• In a phase 1 study, IMC-225 showed 2 partial responses out of 13 treated patients.

• Data published in 2000 in the Journal of Clinical Oncology. (our big journal)

• Based on those responses, phase II studies were proposed in colorectal and head and neck cancers that overexpressed EGFR.

Phase II studies

• After the dose and schedule are worked out, how do we determine success?

• Patients for whom there is biological plausibility of effectiveness, or demonstrable effectiveness in phase 1 studies

• More patients, looking for a signal of effectiveness that can be more broadly applied

Phase II• Typically still pretty small– 40-100 patients

• Open-label• Occasionally randomized– Can test two drugs at once, or one drug against what is

already out there• Typically still late-line, heavily pretreated• Endpoints would be some endpoint to serve as a

surrogate for helping people live longer– Response rate– Progression-free survival– Disease control rate

Home run

• In a heavily pretreated population, a response rate or stable disease rate of anything more than a few percent is an important finding

• Start thinking about further clinical trials and ways to adopt this into practice

• Sometimes, FDA approval happens after a great phase II study.

Back to the story

• IMC-225, now called ‘cetuximab’, produced response rate of 9% (5/57 patients) with EGFR-overexpressing colon cancer

• Tons of excitement• 60 Minutes did a piece on it, advocated for

expanded access through “compassionate use” • Heralded as a breakthrough, thought to get

FDA approval on a fast-track basis

A good thing…

• Expected FDA approval was held up because an initial study in colorectal cancer failed to show a survival benefit.– This drug is why Martha Stewart went to jail…

• However, in a subset of patients, it generated remarkable responses…

What happens now?

• In those 5 patients, what was unique? • Is there a reason the others did not respond?• Better understanding of disease biology led to

improved targeting.• Data reanalysis suggested that the drug could

be saved…

Tempered enthusiasm

• With more study into the pathway, we learned more about how the drugs work and how cancer might have primary resistance/develop secondary resistance to the drugs

Back to the drawing board

• Further studies showed its effectiveness in the treatment of colon cancer, both as a single agent and combined with other chemotherapies.

• FDA approval came based on a phase III study showing a survival benefit in heavily pretreated patients in February of 2004.

Next phase, USE IT FOR EVERYTHING!!!

• Trials using cetuximab in every line, every combination, and every setting were undertaken

Phase III studies

• After showing safety (phase I) and a hint of efficacy (phase II), a comparison against existing treatments is necessary

• Much more costly• Much more time-consuming• Requires blinding, randomization to avoid bias

Phase III studies

• High-risk/High-reward (for companies)• Requires a ton of regulatory oversight– IRB– Data safety monitoring– Entirely protocol driven

• Typically sponsored by companies, best run by governments/neutral parties

Design options

• How do we randomize?• What is the effect size

we are looking for?• Is randomization

ethical?• Do we offer crossover?• Unblinding at study

conclusion?

Phase III studies

• Really brass-tacks as far as endpoints– Do patients live longer as a result of drug x when

compared to the standard• Safety reporting– Talk to your doctor about…

• “Registration trial”

Phase III trial • In each clinical scenario, a phase III trial needs to be conducted to

show efficacy compared to what is already out there.• CRYSTAL study (First line): response rates 59.3%, overall survival

improved in in KRAS WT patients compared to FOLFIRI alone– 1198 patients

• COIN (First line): Response rates improved, OS not changed when added to FOLFOX– 1630 patients

• BOND-2 Outcomes worse with avastin and cetuximab combined– More adverse events, worse PFS results– 755 patients

• PETACC-8 (adjuvant): The addition of cetuximab did NOT improve DFS compared with FOLFOX alone in resected stage III colon cancer• 2559 patients, 340 sites.

Phase III trials

• Generally, cost per patient on a clinical trial is between $25-40K.

• 6142 patients just on those four studies.– $153,550,000-$245,680,000

• There were many more studies looking at the same thing.

Competition in the marketplace

• Similar compound developed and tested by Amgen

• Similarly confusing results were seen. – Why did it work really well in some patients, and

so poorly in others?– Why didn’t it work as adjuvant therapy?

After all that…

• Thousands of patients• Billions of dollars– 2008, ImClone (sole product was cetuximab) was

sold to Eli Lilly for $6.5 B… • Hypotheses proven– Targeting EGFR is possible, safe, and improves

overall survival for patients with metastatic colon cancer

• Surprising findings

What else have we learned?• Response rates are better with cetuximab in the first

line setting• Overall survival not really changed when you start with

cetuximab or avastin in WT patients• There are other mutations besides KRAS that mean that

the drug won’t work– HRAS, NRAS, BRAF

• Responses are great but don’t last forever.• Cetuximab and panitumumab work about the same– Fewer infusion reactions with pan, less rash overall with cet

Why does any of that matter to you guys?

• As a group interested in maximizing efforts to improve clinical trials for patients with colorectal cancer, it is important to be mindful of the process.

• When reviewing the study ask yourself:– Is the question valid?– Will the study answer the question?– Is the study worth the risk?

• To the patient• To society

• These questions are critically important

How can we do this?

• It takes hundreds/thousands of patients to sort these questions out.

• Cooperative group studies critical to drug development.

What are cooperative groups?

• Groups of doctors willing to work together to answer important questions.

• Examples– Eastern Cooperative Oncology Group/ACRIN– Southwestern Oncology Group– Big Ten Cancer Research Consortium– National Cancer Clinical Trials Group– Gynecologic Oncology Group

Cooperative groups

• Advantages– Can get tons of patients– Can be quick to accrue

once all sites are open– Well-respected studies– Leverage strengths of

different institutions– Can ensure protocol

adherence

• Disadvantages– Slow

• To design• To open

– Practice sometimes not uniform

– Different techniques at different places

– Takes a ton of staffing to get it right

How do they work?

• Ideas from investigators in the group go to the steering committee. – Usually esteemed investigators/thought leaders

• The steering committee decides yay/nay• Idea needs a sponsor– Industry?

• Who provides drug?– Private donations?

• Who pays for science?– Government (gold standard)

Once the go-ahead is achieved

• Members of the cooperative group decide whether or not to open at their sites– Seems like a no-brainer– But…

• Accrual is complete• Findings are presented/published• Sam/Dusty/Nataliya get promoted.

What about this moonshot thing?

• Goal is to make discoveries faster, at lower cost

• Is it the science that is so hard, or the infrastructure?

I mean, how hard can it be?