14th Annual California Cancer Conference Consortium

August 10-12, 2018

JEFFREY LONGMATE, PHD CLINICAL TRIALS 101: PHASE I EXPANSION COHORTS VS

PHASE II TRIALS

NO RELEVANT FINANCIAL RELATIONSHIPS IN THE PAST TWELVE MONTHS BY PRESENTER OR SPOUSE/PARTNER.

THE SPEAKER WILL DIRECTLY DISCLOSE THE USE OF PRODUCTS WHICH ARE NOT LABELED (E.G., OFF LABEL USE)

OR IF THE PRODUCT IS STILL INVESTIGATIONAL.

FURTHER NOTICE:

• This is a talk about clinical trial design, and not about the

conclusions to be drawn from specific trials.

• Any mention of clinical trial outcomes is intended to illustrate

features of the trial designs, and is not intended to inform

medical practice.

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Recently, sample sizes of expansion cohorts in FIH trials have

surpassed 100 patients, with total sample sizes of individual

‘phase I’ trials exceeding 1,000 patients in a limited number of

cases.

Use of trial nomenclature that categorizes a 1,000 patient protocol

as a phase I trial fails to capture the complexity of the evolving

objectives of these large expansion cohort trials. This is not a

simple matter of semantics, ...

Theoret et al. 2015 Clinical Cancer Research

THE AIMS OF PHASE I TRIALS ARE BEING EXPANDED, BUT NOT ALWAYS

EXPLICITLY.

MAJOR POINTS

• Use of expansion cohorts in increasing.

• Phase II success is associated with moderate Phase I

expansions

• MTD is not well established by ordinary Phase I

• There are many reasons for expansions in Phase I

• Expansion cohorts may be part of the drug development

pathway — with caveats.

• 522 adult therapeutic phase I trials were identified during the

25 years from 1988 to 2012.

• The average sample size of a phase I study has increased from

33.8 patients to 73.1

• Sixteen of the 60 trials (27%) in 2011 enrolled patients to three

or more sub-cohorts in the expansion phase.

Evaluation of Statistical Designs in Phase I Expansion Cohorts:

The Dana-Farber/Harvard Cancer Center Experience Suzanne E. Dahlberg, Geoffrey I. Shapiro, Jeffrey W. Clark, Bruce E. Johnson

JNCI J Natl Cancer Inst (2014)

The primary intention of the expansion cohort has

evolved into an opportunity to garner efficacy data …

Trials with large expansion cohorts do not always

provide statistical justification for their sample sizes,

even though the total number of patients to be enrolled

may approximate or even exceed the number of patients

required for evaluation of the agent in a stand-alone

phase II trial testing a specified hypothesis.

— Dahlberg et al. 2014 JNCI

Evolution of Clinical Trial Design in Early Drug Development: Systematic

Review of Expansion Cohort Use in Single-Agent Phase I Cancer Trials Arif Manji, Irene Brana, Eitan Amir, George Tomlinson, Ian F. Tannock, Philippe L. Bedard,

Amit Oza, Lillian L. Siu, and Albiruni R. Abdul Razak

2013 JOURNAL OF CLINICAL ONCOLOGY

• Identified 611 unique phase I cancer trials, 149 (24%) included an expansion cohort.

• The trials more likely to use an expansion cohort were published more recently,

were multicenter, or evaluated a noncytotoxic agent.

• 26% fail to report explicit aims. Those that did cited:

• safety (80%),

• efficacy (45%),

• pharmacokinetics (28%),

• pharmacodynamics (23%),

• patient enrichment (14%).

• Among trials aimed at assessing efficacy, only 11% demonstrated antitumor activity

not previously observed during dose escalation.

• Identified 533 phase I trials evaluating 381 drugs; 112 drugs had at

least one phase I trial with an expansion cohort.

• Phase I trials with expansion cohorts of two to 20 patients were

associated with a higher rate of successful phase II trials than those

with no expansion cohort [48% vs. 27%].

• Phase II success rates were similar (48% vs. 52%) for expansion

cohorts with two to 20 and more than 20 patients.

• Drugs tested in phase I trials with expansion cohorts had a higher

rate of 5-year approval (19% vs. 5%).

Use of Expansion Cohorts in Phase I Trials and Probability of Success in

Phase II for 381Anticancer Drugs Diogo D.G. Bugano, Kenneth Hess, Denis L.F. Jardim, Alona Zer, Funda Meric-Bernstam, Lillian L. Siu,

Albiruni R.A. Razak, and David S. Hong Clin Cancer Res; 23(15) August 1, 2017

Conclusion : The better agents may be more

likely to be evaluated with expansion cohorts, or

the expansion cohorts may help with successful

progress.

Approaches to expansion-based dose adjustment:

1. Using Safety Data Alone—Retrospective Assessment

2. Prospectively Guiding Dose Expansion Using Safety

3. Prospectively Guiding Dose Expansion Using Safety and

Efficacy

4. Experimenting at More Than a Single Level

5. Taking Into Account Different Eligibility Criteria

Design Considerations for Dose-Expansion Cohorts in Phase I Trials Alexia Iasonos and John O’Quigley

2013 JOURNAL OF CLINICAL ONCOLOGY

Simulation of approach 1: 3+3 escalation, followed by

expansion, with final revision of MTD.

• The assumption that we have reached the MTD during the dose-

escalation phase and that thus patients in the expansion cohort are

receiving the right dose is not always true.

• We argue that DECs in phase I studies need to be sequentially

monitored for safety, and experimentation should be adaptively

changed if supported by the results.

• How many patients are needed depends on

A. the objective of the study,

B. the number of levels in the dose-escalation

C. whether multiple drugs, schedules, or disease groups are

involved.

D. the amount of information borrowed between groups.

• We suggest that the DEC size should be at least 50% of the pre-

expansion sample size, or a minimum of 12 to 15 patients, to obtain

some meaningful preliminary evidence for efficacy.

Involves:

1. Dose escalation by mTPI

2. Dose graduation rule based on both toxicity and efficacy.

3. Adaptive randomization in phase II

A phase I/II seamless dose escalation/expansion with adaptive

randomization scheme (SEARS) Haitao Pan, Fang Xie, Ping Liu, Jielai Xia and Yuan Ji Clinical Trials 2014

Anti-programmed-death-receptor-1 treatment with pembrolizumab in

ipilimumab-refractory advanced melanoma: a randomised dose-comparison

cohort of a phase 1 trial Caroline Robert, et al.

www.thelancet.com Vol 384 September 20, 2014

ORR was 26% at both doses

Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial Robert J. Motzer, et al. JOURNAL OF CLINICAL ONCOLOGY, 2015

CONCLUSION

Nivolumab demonstrated antitumor

activity with a manageable safety

profile across the three doses

studied in mRCC. No dose-

response relationship was detected

as measured by PFS.

Expansion Cohorts in First-in-Human Solid Tumor Oncology Trials Marc R. Theoret, Lee H. Pai-Scherf, Meredith K. Chuk, Tatiana M. Prowell, Sanjeeve Balasubramaniam, Tamy Kim,

Geoffrey Kim, Paul G. Kluetz, Patricia Keegan, and Richard Pazdur Clin Cancer Res; 21(20) October 15, 2015

Marketing approval has traditionally relied upon sequential trials

(e.g., phase I, phase II, and phase III). At a high level, there are

often multiple objectives within each phase.

FIH expansion cohorts objectives may be separate from the initial

dose-escalation portion, and may include:

• additional PK and PD endpoints,

• alternative dosage regimens,

• toxicity characterization,

• product formulation development,

• evaluation for predictive biomarkers,

• and increasingly, preliminary assessment of antitumor

activity.

The initial drug development program of pembrolizumab is a well-known example of a

breakthrough therapy–designated immunotherapeutic product evaluated in an FIH trial that

utilized multiple expansion cohorts to fulfill various drug development objectives.

CONCLUSIONS FROM DAHLBERG ET AL.

• phase I studies have changed in size and scientific scope over the last

25 years.

• We recommend that phase I studies justify their planned sample sizes

• The appropriate stakeholders should set expectations for justifications

of proposed sample sizes and designs and consider an appropriate

designation that goes beyond the designation of phase I.

• reports of phase I studies include designs and results for all expansion

cohorts of a particular study.

• Further studies of this trend’s impact on research processes, ethical

implications, and resource burden are needed.

THIS MORNING: FDA GUIDANCE (DRAFT)

Principal advantage:

• Making highly effective drugs available quickly

Challenges:

• disseminating safety information

• exposing many patients to sub-optimal or toxic

doses

• exposing more patients than required for cohort

objectives

• possibly missed interpretation of preliminary

results

FIH multiple expansion cohorts should be limited to

drugs for indications and patient populations in which

the potential benefits justify the increased risks.

Thank you