Potential of phase II clinical trials in drug development


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  • The best of these drugs, such as Herceptin (Trastizumab, anti-HER2/neu receptors), Erbitux (Cetixumab, anti-EGFR), and Avastin (Bevacizumab, anti-VEGF-A), may have only modest activity as single agents and produce few clinical responses. Their value may only be obvious in more subtle trial designs, in which they delay time to progression or recurrence or enhance response rates to standard cytotoxic agents (5, 6). The traditional single-agent 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 time-to-progression end points, may be required to show effectiveness of the new agent. In this sort of trial, concurrent controls, treated with standard agents or randomized either to discontinue the experimental drug or perhaps to begin the drug after a period of placebo treatment, might show valuable aspects of the toxicity and effectiveness of the new agent. Such is the case with sorafenib, in which the University of Chicago group randomized stable patients to continued therapy versus drug discontinuation, with strikingly positive findings for patients who continued to receive the experimental drug (2). In other settings, in which a standard cytotoxic is an alternative to a new targeted drug, the choice of appropriate end points may be complicated. Although time to progression might be most appropriate for the cytostatic agent, partial or complete remission might be a clearer end point for the cytotoxic drug.
    Sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar),[1] is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma).
  • The different approaches to phase II trial design which are described in this section will be illustrated by the design
    of a single-arm phase II trial described by Thall & Simon [2]. The purpose of the trial was to assess treatment with
    ¯udarabine +ara-C+ granulocyte colony stimulating factor (GCSF) for poor prognosis acute myelogenous
    leukaemia patients. All patients in the trial receive the new treatment. The clinical endpoint is complete remission
    (CR) of the leukaemia. For patients achieving such a state,
    the treatment will be termed successful. The standard
    treatment is ¯udarabine+ara-C, for which the success rate
    is 50%. The use of GCSF would be considered bene®cial
    if it increased the success rate to 70%.
  • Potential of phase II clinical trials in drug development

    1. 1. POTENTIAL OF PHASE II TRIALS IN DRUG DEVELOPMENT Dr. Bhaswat S. Chakraborty Senior Vice President and Chairman, R&D Core Committee Cadila Pharmaceuticals Ltd. 5th Annual Clinical Trials Summit, Virtue Insight, Mumbai, June 11, 2014
    2. 2. 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
    3. 3. 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)
    4. 4. 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
    5. 5. 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?
    6. 6. 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
    7. 7. Brown S et al: (2014) A Practical Guide to Designing Phase II Trials in Oncology, Wiley Statistical Considerations
    8. 8. 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
    9. 9. 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
    10. 10. 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 23:2020-2027 Fleming TR et al: (2004). J Infect Dis 190:666-674 O’Shaughnessy J et al: (2009). J Clin Oncol 27:6s
    11. 11. 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 23:2020-2027 Fleming TR et al: (2004). J Infect Dis 190:666-674 O’Shaughnessy J et al: (2009). J Clin Oncol 27:6s
    12. 12. 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 23:6982-6991 Thezenas S et al. (2004). Eur J Cancer 40:1244-1249 Gan HK et al. (2010). J Clin Oncol 28:2641-2647
    13. 13. 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.
    14. 14. 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.
    15. 15. 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
    16. 16. RANDOMIZED SELECTION SA-II STUDIES Gray R et al.(2006). Clin Cancer Res;12:1966-1969
    17. 17. 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
    18. 18. 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
    19. 19. Rosell et al. (2008), Annals of Oncology, 19, 362–369
    20. 20. 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
    21. 21. Rosell et al. (2008), Annals of Oncology, 19, 362–369 CONTROL EXPERIMENTAL
    22. 22. 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
    23. 23. 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
    24. 24. 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, 337-349 Gan HK et al. (2010). J Clin Oncol 28:2641-2647
    25. 25. 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
    26. 26. 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!