POTENTIAL OF PHASE II TRIALS IN DRUG DEVELOPMENT

Dr. Bhaswat S. ChakrabortySenior Vice President and Chairman,

R&D Core CommitteeCadila Pharmaceuticals Ltd.

5th Annual Clinical Trials Summit, Virtue Insight, Mumbai, June 11, 2014

CONTENTS Disease severity & Unmet medical needs:

when a well designed Phase II study is adequate for approval

Design and control issues in PoC Phase II studies: Best Phase II designs : Randomized or Single arm

End point selection

Decision to proceed to Phase III or terminate based on Phase II results

Concluding remarks

PATIENT FOCUSED DRUG DEVELOPMENT Severity of Condition Unmet Medical Need

These two provide regulators with the clinical context for weighing benefits and risks and the associated uncertainties

Benefit Risk Benefit and Risk incorporate expert judgments based on

evaluation of the efficacy and safety data Risk Management

To reduce and further characterize risks

Source: USFDA

Often disease severity & unmet need prompt fast tracking a submission with a Phase II trial only (e.g., Oncology)

DISEASE SEVERITY & UNMET MEDICAL NEED

Serious or Life threatening diseases Cancer, Autoimmune & other serious diseases

Diseases with high unmet medical need Sometimes a large market

Epratuzumab for lupus (SLE) Billion dollar market opportunity

But often not a large market (orphan) Some development so far, needs further work

Clivatuzumab for pancreatic cancer Encouraging survival benefit data from Phase I/IIb study

SUCCESS OF A [PHASE II] CLINICAL TRIAL

Right Scientific Questions

Generalizable Results

Right conduct of the trial

Adequate scope, time & budget

Proceed to higher phases

PoC of Efficacy, Safety, Dose & Frequency

Does this drug increase survivability in …cancer?

PHASE II TRIALS Ideally, a Phase II trial should

Establish the PoC Have a high benefit to risk ratio Can be generalized to a maximum number of sub-groups

and Be either adequate for approval or need just one

confirmatory Phase III trial. However, in reality the current Phase II trials rarely

show this potential > 60% oncology Phase II trials fail; other categories of Phase

II also have a high failure rate Do not represent a true screen for either success or futility Combination therapy Phase II trials are difficult to interpret

(unquantifiable effect size) Often data is not rich enough to suggest a clear “go” for

Phase III

Brown S et al: (2014) A Practical Guide to Designing Phase II Trials in Oncology, Wiley

Statistical Considerations

DESIGN & CONTROL ISSUES IN PHASE II CANCER TRIALS

One of the major issues is the use of controls One study* finds that only ~20% Phase II Cancer Trials use active

or historical control or placebo (notwithstanding a higher reporting of Onco trials)

Remember the primary objective of a phase II cancer clinical trials is to determine whether to proceed for a further Phase II or a Phase III study

This requires basically a demonstration of substantial efficacy of a new regimen

However, oncology Phase II has been limited by high rates of failure (lack of efficacy) in subsequent phase III testing

This is in part because Phase II studies which can easily discard a study with an apparent low efficacy that due to factors other than the drug itself

*Michaelis et al. (2007). Clin Cancer Res,13, 2400–5

DESIGN & CONTROL ISSUES IN PHASE II CANCER TRIALS..

Herceptin, Erbitux, and Avastin may have only modest activity as single agents and produce few clinical responses

Their effect requires more subtle trial designs e.g., delay time to progression or recurrence or enhance response rates

to standard cytotoxic agents. single arm phase II trial, with response as the end point, may lead to the

abandonment of a valuable drug Larger trials, and more complex phase II designs with TTP end

points, may be required to show effectiveness of the new agent here, concurrent controls, treated with standard agents or or other

strategies might show valuable aspects of the toxicity and effectiveness of the new agent

e.g sorafenib, [U of Chicago Researchers] randomized stable patients to continued therapy vs. drug discontinuation, with positive for patients continuing with experimental drug

Chabner B. (2007). Clin Cancer Res,13, 2307

RANDOMIZED PHASE –II (RP-II) TRIALS

At least in theory, RP-II trials are likely to give more valid and comprehensive data. By reducing selection biases By providing comparability across study arms

Inclusion of both arms in the same protocol assures similar assessment methods and supportive care measures

Valid comparison of primary and secondary end points Able to use the bio specimens from the trial to develop

predictive bio markers for therapy Without the randomized control group one cannot

determine if a bio marker is prognostic and predictive

Sargent DJ et al: (2005). J Clin Oncol 23:2020-2027Fleming TR et al: (2004). J Infect Dis 190:666-674O’Shaughnessy J et al: (2009). J Clin Oncol 27:6s

FURTHER BENEFITS OF RP-II TRIALS Able to generate robust and rich data to allow for full drug

approval A highly significant and meaningful (statistically and clinically)

endpoint in a RP-II trial would preclude a phase –III study A definitive RP-II trial is the one where a strong biological

effect of a novel therapy is observed For such studies would make phase-III trials with random

assignment to a control arm ethically questionable e.g. efficacy of VEGF inhibitors in the treatment of clear cell renal

carcinoma, the activity of imatinib in GI stromal cell tumors…….. A definitive RP-II trial may be particularly useful for a rare

malignancy in which a phase-III trial would be difficult to conduct

A strong biological effect: hazard ratio <0.60 and p < 0.0005 with quality standards similar to phase-III trials.

Sargent DJ et al: (2005). J Clin Oncol 23:2020-2027Fleming TR et al: (2004). J Infect Dis 190:666-674O’Shaughnessy J et al: (2009). J Clin Oncol 27:6s

SINGLE ARM PHASE-II (SA-II) TRIALS SA-II trials are well suited to screening drugs for further

development

Simple in design and easily executed; N is usually <50

Conservatively restrict their false-positive (α) and false-negative (β) rates to ≤0.05 and ≤0.12, respectively (found in a review of 146 SA studies)

Almost all SA-II trials can completed without any problems

During 1998-2008, on eight occasions the US FDA based their initial approval for an oncology drug solely on SA-II trials

Zia MI et al. (2005), J Clin Oncol 23:6982-6991Thezenas S et al. (2004). Eur J Cancer 40:1244-1249

Gan HK et al. (2010). J Clin Oncol 28:2641-2647

Gan HK et al. (2010). J Clin Oncol 28:2641-2647

†Capecitabine in patients with advanced breast cancer; ixabepilone monotherapy in advanced/metastatic breast cancer resistant/refractory to anthracycline, taxanes, and capecitabine; paclitaxel in AIDS-related Kaposi’s sarcoma; temozolomide in relapsed anaplastic astrocytoma.

‡Cetuximab in recurrent/metastatic squamous cell carcinoma of the head and neck;imatinib in the treatment of multiple malignancies; sunitinib in the treatment of advanced renal cell carcinoma; trastuzumab in chemotherapy-pretreated metastatic Erb2-positive breast cancer.

ONE POSSIBLE DESIGN

Endpoint RECIST objective response (PR/CR)

Simon Two-stage minimax

<30% no interest, 50% interest

If 8 or more patients show responses in the first 28, 11 additional patients are treated for a total of 39. If 15 show responses, the regimen will not be recommended for further study. If 16 patients show responses in the 39, the regimen will be studied further.

RANDOMIZED SELECTION SA-II STUDIES

A randomized phase II selection design allows conducting multiple single-arm studies in the same time frame & with same entry criteria

Advantages: Decreases the effects of patient selection bias,

population drift and stage migration, and the ability to ensure uniform evaluation

Designed to separately evaluate each arm A predetermined plan for selection of arms for future

study can be made Disadvantages

Not adequate power for formal tests if arms are compared

Gray R et al.(2006). Clin Cancer Res;12:1966-1969

RANDOMIZED SELECTION SA-II STUDIES

Gray R et al.(2006). Clin Cancer Res;12:1966-1969

ENDPOINTS IN ONCOLOGY TRIALS

Must show either direct evidence of clinical benefit or

improvement in an established surrogate for clinical benefit Clinical benefit: survival improvement

Overall survival (OS) Progress-free survival (PFS) (usually Ph III)

Improvement in a patient’s quality of life (QOL) (usually Ph III) Other endpoints on which approval has been given are:

Objective response rate (ORR) by RECIST or any radiological tests or physical examinations

Improvement in survival, improvement in a QOL, improved physical functioning, or improved tumor-related symptoms do not always be predicted by, or correlate with, ORR

Source: US FDA Guidance

OVERALL SURVIVAL (OS) OS: The time from randomization until death from any cause

Measured usually in the intent-to-treat (ITT) population

Most reliable cancer endpoint, and when studies can be conducted to adequately assess survival, it is usually the preferred endpoint

Precise and easy to measure – no influence of technicality of measurement

Bias is not a factor in endpoint measurement

Survival improvement should be analyzed as a risk-benefit analysis to assess clinical benefit

OS should be evaluated in RCTs

Historical trials are seldom reliable for time-dependent endpoints (e.g., OS, PFS).

The OS in control arm has to be compatible

Rosell et al. (2008), Annals of Oncology, 19, 362–369

ENDPOINTS BASED ON TUMOR ASSESSMENTS Disease-free survival (DFS) Objective response rate (ORR) Time to tumor progression (TTP) Progress-free survival (PFS) Time-to-treatment failure (TTF) They are all time-dependent endpoints Collection and analysis of these endpoints are based on indirect

assessments, calculations, and estimates (e.g., tumor measurements) Two critical judgments:

1. whether the endpoint will support either accelerated approval or regular approval

2. endpoint should be evaluated for the potential of bias or uncertainty in tumor endpoint assessments

Drug applications using studies that rely on tumor measurement-based endpoints as sole evidence of efficacy may need confirmatory evidence from a second trial

Rosell et al. (2008), Annals of Oncology, 19, 362–369

CONTROLEXPERIMENTAL

CAUTIONS IN TUMOR ASSESSMENTS Accuracy in measuring tumors can differ among tumor settings Imprecision can happen in locations where there is a lack of

demarcated margins (e.g., malignant mesothelioma, pancreatic cancer, brain tumors).

When the primary study endpoint is based on tumor measurements (e.g., PFS or ORR), tumor endpoint assessments generally should be verified by central reviewers blinded to study treatments This measure is especially important when the study is not blinded It may be appropriate for the FDA to audit a sample of the scans to

verify the central review process

DECISION TO PROCEED TO PHASE III

The “go or no go” decision at the end of phase II is perhaps the most difficult one to make in the drug development cycle data are limited future investment required for a phase III trial is vast success of the company may depend on the drug in question an informative phase II trial is crucial after phase II, the decision makers need to understand toxicity and

pharmacokinetics, should have strong indications of activity in a specific kind of cancer, and should have a clear sense of an approval strategy

There are often gaps in this knowledge, and the decision is guided by both fact and intuition

The decision becomes easier when the case is unmet medical needs

Chabner B. (2007). Clin Cancer Res,13, 2307

DECISION TO PROCEED TO PHASE III OR TERMINATE BASED ON SA-II

Single arm studies If properly designed and powered can be the basis for approval in S&E Sometimes, futility is better predicted than success

However, when success/failure response is used Summarize success as the proportion of number of totally included patients To proceed for Phase III, it is important to know the norm (activity of current

standard) and that the new treatment is expected to exceed this Example

The standard treatment for AML is fludarabine + ara-C (50% success) Addition of GCSF would be beneficial if Phase II shows ~70% success

In most cases, irrespective of the design of Phase II studies, a definitive Phase III would be required

Well designed, controlled, adequate study

Thall & Simon (1994). Biometrics, 50, 337-349Gan HK et al. (2010). J Clin Oncol 28:2641-2647

CONCLUDING REMARKS Phase II [cancer] clinical data can very complex (low N, mismatched

action and outcome data, censored, skewed, often fraught with missing data point), therefore, proper clinical and statistical considerations treatment of data are required

Phase II single arm (SA-II) trials can even be definitive and sometimes a basis of approval Well designed and powered There are ways to reduce bias (randomized selection)

SA-II trials are often exploratory studies

Efficient to exclude inactive therapies

Results must be interpreted cautiously, in the context of the availability of other therapies

Phase II two- or multi-arm randomized trials (RP-II) have all features of well designed studies but haven’t always been proven superior to SA-II

CONCLUDING REMARKS.. Both RP-II ans SA-II estimate clinical activity and provide further safety

information – important in the “go/no go” to Phase III decision

There are many endpoints that are scientifically valid but OS as primary end point is often preferred by regulatory agencies

PFS & Tumor assessment trials may need another confirmatory CT

Endpoints must be demonstrative (directly or indirectly) of clinical benefit

Missing data, infrequent treatment, increased type I error and other confounding factors must be addressed

Consistent ITT & PP facilitate approval

Well designed SA-II or RP II have 10-15% chance of being the basis of approval – not a bad potential!

THANK YOU VERY MUCH