A prognostic index for progression-free survival in malignant mesothelioma with application to the design of phase II trials: A combined analysis of 10 EORTC trials

Abstract Background This report updates the results of 3 large phase II studies of the orally available BCR-ABL tyrosine kinase inhibitor imatinib for patients (pts) in AP, BC and late chronic phase (L-CP) CML failing prior interferon therapy (Kantarjan et al, ASH 2003; Talpaz et al, ASH 2003). Methods Between August 1999 and June 2000, 1027 pts were enrolled in phase II trials for CML in L-CP (n=532), AP (n=235) or BC (n=260). Pts in L-CP were treated with 400 mg/day and pts in AP or BC with either 400 or 600 mg/day. Dose escalation up to 800 mg/d was allowed in the late-chronic phase study. Pts with a confirmed diagnosis of AP (n=181), BC (n=229) and late-chronic phase (n=454) were evaluated for efficacy. All pts were evaluated for safety. The median time from initial diagnosis to study entry was 32 months for L-CP pts. Results As of 31-Jul-03, 5% patients with BC, 25% of CML-AP and 64% of L-CP patients still remain on treatment. At the recommended dose of 600 mg, an estimated 40% (AP) and 7% (BC) of patients remained progression-free at 36 months, and an estimated 55% (AP) and 14% (BC) patients were alive at 36 months after initiation of imatinib. The 3-year survival rates for pts with AP with a major cytogenetic response at 3 months were 85% vs. 52% for pts with no response (p<0.001). In L-CP patients with a median follow-up of 40 months, 65% of patients achieved a major cytogenetic response, which was complete in 52%. The cytogenetic responses were durable with an estimated 82% of the pts in continuos major cytogenetic response at 3 years. The estimated rates of progression-free survival and overall survival at 3 years were 80% and 88%. Pts with at least a minor cytogenetic response at 6 months ≤65% Ph+ cells) had an estimated 3-year survival rate of 96% vs. 86% for pts with a ( minimal response and 81% for pts with no cytogenetic response (p<0.001). Conclusion In large phase II studies, continuous imatinib treatment is safe and has improved progression-free survival of patients at all stages of CML. Responses to imatinib are durable and are predictive of long-term outcomes. These results will be further updated at the meeting using a data base lock planned for 20-Sept-04 (using data collected up to 31-July-04, i.e. more than 4 years after the last pts enrollment).

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Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence (STOMP): Five-year results of a randomized phase II trial.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.10 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 10-10 ◽

Cited By ~ 6

Author(s):

Piet Ost ◽

Dries Reynders ◽

Karel Decaestecker ◽

Valerie Fonteyne ◽

Nicolaas Lumen ◽

...

Keyword(s):

Prostate Cancer ◽

Phase Ii ◽

Progression Free Survival ◽

Hazard Ratio ◽

Phase Ii Trials ◽

Curative Intent ◽

Free Survival ◽

Randomized Phase Ii ◽

Oligometastatic Prostate Cancer ◽

Significant Difference

10 Background: Multiple randomized phase II trials suggest that metastasis-directed therapy (MDT) for oligometastatic prostate cancer (PCa) improves progression-free survival, but the majority of trials lack longer follow-up. We present the updated 5-year results from the STOMP-trial. Methods: In this multicentre, randomised, phase II study, asymptomatic PCa patients were eligible in case of a biochemical recurrence following primary PCa treatment with curative intent and presenting with up to 3 extracranial on choline PET-CT and a serum testosterone levels > 50 ng/ml. Patients were randomly assigned (1:1) to either surveillance or MDT of all detected lesions. Randomisation was balanced dynamically on two factors: PSA doubling time (≤3 vs. > 3 months) and nodal vs non-nodal metastases. The primary endpoint was androgen deprivation therapy (ADT)-free survival. Castrate resistant prostate cancer-free survival (CRPC) was a secondary endpoint. Tests were performed two-sided; p values less than 0.20 were deemed significant. Results: The 5-year ADT-free survival was 8% for the surveillance group and 34% for the MDT group (Figure 1, hazard ratio 0.57 [80% CI: 0.38-0.84], log-rank p = 0.06). There was no significant difference in effect for the different stratification factors (interaction test). The 5-year CRPC-free survival was 53% for the surveillance group and 76% for the MDT group (hazard ratio 0.62 [80% CI: 0.35−1.09]; log−rank p = 0.27). At a median follow for survival of 5.3 years (IQR 4.3-6.3), the 5-year overall survival was 85%, with 6 out of 14 deaths attributed to prostate cancer. Conclusions: The updated STOMP trial outcomes confirm the earlier reported significant difference in ADT free survival in favor of the MDT group compared to surveillance. Prostate-cancer related mortality is low within the first 5 years of diagnosis of oligorecurrent prostate cancer. Clinical trial information: NCT01558427.

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Impact of Informative Censoring on the Kaplan-Meier Estimate of Progression-Free Survival in Phase II Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2014.55.6340 ◽

2014 ◽

Vol 32 (27) ◽

pp. 3068-3074 ◽

Cited By ~ 25

Author(s):

Federico Campigotto ◽

Edie Weller

Keyword(s):

Treatment Failure ◽

Phase Ii ◽

Progression Free Survival ◽

Informative Censoring ◽

Phase Iii ◽

Inadequate Response ◽

Phase Ii Trials ◽

Free Survival ◽

Kaplan Meier ◽

The Impact

Informative censoring in a progression-free survival (PFS) analysis arises when patients are censored for initiation of an effective anticancer treatment before the protocol-defined progression, and these patients are at a different risk for treatment failure than those who continue on therapy. This may cause bias in the estimated PFS when using the Kaplan-Meier method for analysis. Although there are several articles that discuss this issue from a theoretical perspective or in randomized phase III studies, there are little data to demonstrate the magnitude of the bias on the estimated quantities from a phase II trial. This article describes the issues by using two oncology phase II trials as examples, evaluates the impact of the bias using simulations, and provides recommendations. The two trials were selected because they demonstrate two different reasons for censoring. Simulations show that the magnitude of the bias depends primarily on the proportion of patients who are informatively censored and secondarily on the hazard ratio between the group of patients who remain on study and the group of patients who are informatively censored. Recommendations include using an alternative end point, which includes inadequate response and initial signs of clinical progression as treatment failure, and a competing risk analysis for studies in which competing events preclude or modify the probability of observing the primary event of interest. If informative censoring cannot be avoided, then all patients should be observed until progression, and sensitivity analyses should be used as appropriate.

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A Review of Perspectives on the Use of Randomization in Phase II Oncology Trials

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djz126 ◽

2019 ◽

Vol 111 (12) ◽

pp. 1255-1262 ◽

Cited By ~ 7

Author(s):

Michael J Grayling ◽

Munyaradzi Dimairo ◽

Adrian P Mander ◽

Thomas F Jaki

Keyword(s):

Phase Ii ◽

Best Practice ◽

Progression Free Survival ◽

Extensive Literature ◽

Phase Ii Trials ◽

Free Survival ◽

Current Trends ◽

Randomized Design ◽

Oncology Trial ◽

Current Design

AbstractHistorically, phase II oncology trials assessed a treatment’s efficacy by examining its tumor response rate in a single-arm trial. Then, approximately 25 years ago, certain statistical and pharmacological considerations ignited a debate around whether randomized designs should be used instead. Here, based on an extensive literature review, we review the arguments on either side of this debate. In particular, we describe the numerous factors that relate to the reliance of single-arm trials on historical control data and detail the trial scenarios in which there was general agreement on preferential utilization of single-arm or randomized design frameworks, such as the use of single-arm designs when investigating treatments for rare cancers. We then summarize the latest figures on phase II oncology trial design, contrasting current design choices against historical recommendations on best practice. Ultimately, we find several ways in which the design of recently completed phase II trials does not appear to align with said recommendations. For example, despite advice to the contrary, only 66.2% of the assessed trials that employed progression-free survival as a primary or coprimary outcome used a randomized comparative design. In addition, we identify that just 28.2% of the considered randomized comparative trials came to a positive conclusion as opposed to 72.7% of the single-arm trials. We conclude by describing a selection of important issues influencing contemporary design, framing this discourse in light of current trends in phase II, such as the increased use of biomarkers and recent interest in novel adaptive designs.

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The relationship between six-month progression-free survival and 12-month overall survival end points for phase II trials in patients with glioblastoma multiforme

Neuro-Oncology ◽

10.1215/15228517-2006-025 ◽

2007 ◽

Vol 9 (1) ◽

pp. 29-38 ◽

Cited By ~ 199

Author(s):

Karla V. Ballman ◽

Jan C. Buckner ◽

Paul D. Brown ◽

Caterina Giannini ◽

Patrick J. Flynn ◽

...

Keyword(s):

Overall Survival ◽

Glioblastoma Multiforme ◽

Phase Ii ◽

Progression Free Survival ◽

Phase Ii Trials ◽

End Points ◽

Free Survival ◽

The Relationship

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Outcome of patients with recurrent/refractory osteosarcoma enrolled in three recent phase II trials: A report from the Children’s Oncology Group.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.11530 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 11530-11530

Author(s):

Seema Rao ◽

Ruxu Han ◽

Mark D. Krailo ◽

Allen Buxton ◽

Pooja Hingorani ◽

...

Keyword(s):

Confidence Interval ◽

Phase Ii ◽

Primary Endpoint ◽

Progression Free Survival ◽

Oncology Group ◽

Phase Ii Trials ◽

Free Survival ◽

Significant Difference ◽

Measurable Disease ◽

The Impact

11530 Background: Based on seven prior Phase 2 Children’s Oncology Group (COG) trials, the 4-month event-free survival(EFS) and associated confidence interval for relapsed osteosarcoma with measurable disease according to RECIST was determined to be 12% (95% CI 6 - 19%). Three prospective clinical trials were conducted using this historical benchmark to detect activity defined by an EFS improvement of double the upper confidence interval. This report summarizes the outcome of these studies, describes whether the historical data remains an accurate baseline, and considers implications for future phase II trial study design in relapsed osteosarcoma measurable according to RECIST. Methods: We conducted an analysis of outcome for patients with recurrent/refractory osteosarcoma enrolled in three recent prospective COG phase II trials; AOST1321 (unresected cohort), AOST1322 and AOST1521 that used EFS at 4 months as the primary endpoint. Patients were eligible if they had osteosarcoma that had recurred or become refractory after standard therapy and had measurable disease according to RECIST. We assessed whether risk of an EFS event is modified by age, sex, race/ethnicity, number of prior chemotherapy regimens, or time to first relapse. Results: In each of the three phase II trials (unresected group of AOST1321, AOST1322, AOST1521), the drugs tested (denosumab, eribulin and glembatumumab) were concluded to be not effective due to a failure of the patient populations to meet the prespecified active 4-month progression free survival endpoint. The 4-month EFS for the 57 evaluable patients enrolled on these trials was 7% (95% CI 2 – 16%), similar to the 4-month EFS for 96 patients in the previous seven phase II trials of 12% (95% CI 6 - 19%). The combined EFS at 4 months for all 10 studies is 10% (95% CI 6 – 15%).There was no significant difference in EFS across trials based on age, sex, ethnicity, number of prior treatment regimens, consistent with prior analysis. Data from AOST1321 and AOST1521 were analyzed to determine the impact of time to first recurrence on EFS. Two different quantifications were applied: 1 year or less versus 2 or more years; and 2 years or less versus 3 years or more. Neither categorization was statistically significant. Conclusions: The EFS at 4 months in the three new phase II trials is similar to the previous seven phase II single arm trials. The combined analysis of 153 patients from 10 trials tightens the confidence interval, moving the upper 95% CI to 15%. Modification to future study designs could be considered based on this updated analysis. EFS at 4 months remains a robust primary endpoint. Single-arm trials using this endpoint based on the historical benchmark have accrued rapidly and allowed assessment of multiple novel agents in osteosarcoma. The negative trial results and continued poor outcome highlight the need for new approaches for relapsed osteosarcoma. Clinical trial information: NCT02097238, NCT02470091, NCT02487979.

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Progression-Free Survival Ratio As End Point for Phase II Trials in Advanced Solid Tumors

Journal of Clinical Oncology ◽

10.1200/jco.2010.34.0380 ◽

2011 ◽

Vol 29 (15) ◽

pp. e451-e452 ◽

Cited By ~ 27

Author(s):

Marc Buyse ◽

Emmanuel Quinaux ◽

Alain Hendlisz ◽

Vassilis Golfinopoulos ◽

Christophe Tournigand ◽

...

Keyword(s):

Solid Tumors ◽

Phase Ii ◽

Progression Free Survival ◽

Survival Ratio ◽

Advanced Solid Tumors ◽

Phase Ii Trials ◽

Free Survival ◽

End Point

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Prolonged Progression Free Survival Does Not Relate to Quality of Response to Treatment with Thalidomide in Patients with Relapsed Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v110.11.2718.2718 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2718-2718

Author(s):

Hang Quach ◽

Miles H. Prince ◽

Linda Mileshkin ◽

John F. Seymour ◽

David Westerman ◽

...

Keyword(s):

Phase Ii ◽

Progression Free Survival ◽

Complete Response ◽

Response To Treatment ◽

Phase Ii Trials ◽

Term Survival ◽

Free Survival ◽

Multicentre Phase

Abstract Introduction: Quality of response to treatment in relapse/refractory MM, especially complete response (CR) or near complete response (nCR), has been reported to correlate with better PFS and OS in the past (Hussein MA, et al. Mayo Clin Proc2006;81:889–95). In this report, we provide an update on long-term survival from two multicentre phase II trials using thalidomide +/- IFNα2B (MM-thal) and combination celecoxib-thalidomide (Cel-thal) in relapsed or refractory MM, and identify predictors of progression-free survival (PFS) beyond 24 months (m). Method: In 1998 and 2001, two prospective multicentre phase-II trials in relapsed or refractory MM were performed to assess the efficacy of thalidomide +/- IFNα2B (MM-thal), and combination celecoxib-thalidomide (Cel-thal), respectively. Both studies were previously reported (Blood2003;102:69; Clin Can Res2005;11:5504). The analysis of progression free survival (PFS) has been updated using the Kaplan-Meier method. Baseline characteristics were compared between patients having PFS ≥ 24m and < 24m using fisher’s exact test or the Cochran-Armitage test, to identify predictors of long-term disease control. Result: Median follow up for MM-thal (n=75) and Cel-thal (n=66) trials were 73m and 47m respectively. Median PFS in the MM-thal trial was 5.5m, with estimated PFS of 9% at 3 years (95%, CI:5-18%), and 5% at 5 years (95%, CI:2-13%). In the Cel-thal trial, median PFS was 6.8m, with estimated PFS of 21% at 3 years (95% CI: 13-33%) and 16% at 5 years (95% CI:9-27%). Overall, 27 out of 141 patients (10 from MM-thal, 17 from Cel-thal) had PFS beyond 24m. The majority of these long term responders (70%) achieved only a PR as the best response to thalidomide-based treatment;15% achieved complete response (CR), and 15% had stable disease (SD). The most significant predictors for prolonged PFS of ≥24m was β2M ≥3mg/l (p<0.0005), stage ≥2 disease (p=0.001), and non-refractory disease to previous therapy (p=0.03). Bone marrow plasma cell infiltrate following thalidomide did not predict for outcome. Conclusion: Thalidomide, and in particular combination celecoxib-thalidomide has substantial activity in relapsed MM with prolonged PFS beyond 24m in approximately 19% of patients. The strongest predictor of prolonged PFS is β2M. The depth of response to thalidomide had little influence on predicting remission duration.

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