Phase II Trials Using Time-to-Event Endpoints

e14706 Background: Phase II trials aim to assess the anti-tumor activity of investigational therapies, and consider if they warrant further study. In some instances such as a study treatment added to standard therapy in HCC, tumor response alone may not provide a clear picture on its effectiveness (e.g. biologics and targeted therarpy). Other endpoints such as progression-free survival (PFS) in addition to conventional tumor response would increase the chance of detecting useful treatment and also be able to terminate a study earlier if the treatment was deemed ineffective. Methods: Following a similar rationale for multinomial endpoints in phase II trials by Zee (1999), we have developed a multi-stage phase II stopping rule for "mixed tumor response and time-to-event endpoints". We used a study entitled, “Randomized Phase II study of the x-linked inhibitor of apoptosis (XIAP) antisense AEG35156 in combination with sorafenib in patients with advanced HCC” as an illustration. We applied this multi-stage stopping rule for mixed endpoints in a randomized phase II setting, where the control arm was being used here as a way to set up the null hypothesis. We defined the null hypothesis by a mixture of response rate of 5% and PFS of 2.6 months versus an alternative hypothesis of response rate of 20% and PFS of 5.2 months. Results: The stopping rule was such that the null hypothesis would be rejected at a correlation of 0.5 for the mixed endpoints and conclude that the treatment is effective if we have 0-1 responders and a PFS>=4.0 months, or 2 responders and PFS>=3.8 months, or 3 responders and a PFS>=3.6 months, or 4 responders and a PFS>=3.0 months, or 5 responders with any PFS. Conclusions: In the AEG35156 study, we had 3 responders (based on Choi’s criteria), and 1 responder even if we used RECIST criteria. A PFS of 4.0 months. Therefore, we concluded that the study treatment in combination with sorafenib has a positive effect and warrants further investigation. This methodology would greatly improve the efficiency for phase II screening especially on new biologics on top of a standard or for diseases where tumor response alone does not reflect the full effectiveness of the new treatment.

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A two-stage design for phase II trials with time-to-event endpoint using restricted follow-up

Contemporary Clinical Trials Communications ◽

10.1016/j.conctc.2017.09.010 ◽

2017 ◽

Vol 8 ◽

pp. 127-134 ◽

Cited By ~ 2

Author(s):

Lisa Belin ◽

Yann De Rycke ◽

Philippe Broët

Keyword(s):

Phase Ii ◽

Time To Event ◽

Phase Ii Trials ◽

Two Stage ◽

Stage Design ◽

Two Stage Design

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Comparison of Power Between Randomized Discontinuation Design and Upfront Randomization Design on Progression-Free Survival

Journal of Clinical Oncology ◽

10.1200/jco.2008.19.6709 ◽

2009 ◽

Vol 27 (25) ◽

pp. 4135-4141 ◽

Cited By ~ 7

Author(s):

Pingfu Fu ◽

Afshin Dowlati ◽

Mark Schluchter

Keyword(s):

Tumor Growth ◽

Solid Tumors ◽

Phase Ii ◽

Treatment Effect ◽

Molecular Target ◽

Growth Characteristics ◽

Phase Iii ◽

Time To Event ◽

Phase Ii Trials ◽

End Point

Purpose Enrichment based on molecular characteristics has emerged as an important inclusion criterion in phase II trials of targeted anticancer agents. In this study, we evaluate a well-described method of population enrichment by tumor growth characteristics in the early development stage of targeted cytostatic agents. Methods For some solid tumors, such as pancreatic carcinoma, using a time-to-event end point (eg, time to disease progression) to evaluate the efficacy of a cytostatic agent in a phase II trial is more relevant than clinical response by Response Evaluation Criteria in Solid Tumors. In this setting, we compared the power of the randomized discontinuation and upfront randomization designs under two previously proposed tumor growth models for treatment effect when the end point is time-to-event. Results By selecting patients with more homogeneous tumor growth characteristics, the randomized discontinuation design is more efficient than the upfront randomization design when treatment benefit is restricted to slow-growing tumors. Under a model where only a subset of patients expressing the molecular target are sensitive to the agent, the randomized discontinuation design is more powerful than the upfront randomization design when the treatment effect is small; and vice versa when the treatment effect is moderate to large. Conclusion For selected targeted agents where a bioassay to select patients expressing the specific molecular target is not available, the randomized discontinuation design is a feasible alternative patient enrichment strategy in certain disease settings and provides a reasonable platform to evaluate drugs before phase III testing.

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A review of 565 phase II trial abstracts from ASCO 2005: Design characteristics of contemporary trials evaluating cytotoxic versus non-cytotoxic regimens

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.6569 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 6569-6569

Author(s):

C. Elser ◽

G. Pond ◽

E. Chen ◽

L. Siu

Keyword(s):

North America ◽

Phase Ii ◽

Primary Endpoint ◽

Phase Ii Trial ◽

Median Number ◽

Cytotoxic Agents ◽

Targeted Agents ◽

Time To Event ◽

Phase Ii Trials ◽

Number Of Patients

6569 Background: New phase II trial designs have been proposed to accommodate the non-cytotoxic nature of molecularly targeted agents. In particular, the use of alternative endpoints and controls has been suggested. The objectives of this survey are to review the designs of contemporary phase II trials, to compare trials of cytotoxic versus non-cytotoxic regimens, and to identify predictors of acceptance for presentation. Methods: Abstracts of phase II trials of systemic anticancer therapy published in the 2005 ASCO Proceedings were hand searched. The trial context, type of intervention, trial design, endpoints, and completeness of reporting were assessed. Results: Our search yielded 565 abstracts: 72% were multi-center, 44% North American, 25% clearly identified as industry-sponsored, the median number of patients was 44 (range 8–346). Only 83% explicitly reported the study phase, 29% the primary endpoint, 11% the number of stages, and 5% the statistical design. For design properties, 16% used multiple arms and 6% used enrichment. Of trials reporting the primary endpoint, 48% used radiological or marker response and 22% time-to-event endpoints. The median number of endpoints was 4 (range 1–8). Non- cytotoxic regimens, which included targeted agents, hormone- or immunotherapy, constituted 22% of the trials reviewed, purely cytotoxic regimens 60%, the remaining 18% contained combinations of both. Trials of non-cytotoxic and combination regimens were more likely to report the primary endpoint (p=0.02), use time-to-event endpoints (p=0.006), have multiple arms, use enrichment, be conducted in North America, be industry-sponsored, and be accepted for oral or poster presentation (all p<0.001). Other predictors of publication type in multivariate analysis were multi-centricity, higher number of patients, industry involvement, and being conducted in North America (all p<0.05). Conclusions: Design properties of contemporary phase II trials of non-cytotoxic agents differ from trials of cytotoxic chemotherapy, and are more likely to be accepted for presentation at ASCO. Proposed new trial designs start to be more widely adopted. Most abstracts incompletely report design properties. No significant financial relationships to disclose.

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