Author's response to reviews

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1 Author's response to reviews Title:A randomized phase II study of weekly nab-paclitaxel plus gemcitabine or simplified LV5FU2 as first-line therapy in patients with metastatic pancreatic cancer: The AFUGEM GERCOR Trial Authors: Jean-Baptiste Bachet Benoist Chibaudel Franck Bonnetain Pierre Validire Pascal Hammel Thierry André Christophe Louvet Version:3Date:26 August 2015 Author's response to reviews: see over

2 30 July, 2015 Manuscript: MS Title: Randomized Phase II Study of Weekly nab-paclitaxel plus Gemcitabine or Simplified LV5FU2 as First-line Therapy in Patients with Metastatic Pancreatic Cancer. Authors: Jean-Baptiste Bachet, Benoist Chibaudel, Franck Bonnetain, Pierre Validire, Pascal Hammel, Thierry André, Christophe Louvet Journal: BMC Cancer Dear Editors, We would like to thank you and the Reviewers for in-depth reading of this manuscript and very relevant comments and suggestions. We submit a revised version of the manuscript with tracked changes (underline in the manuscript) taking into account all of these comments. We hope that this revision improve the paper such that you and the Reviewers now deem it worthy of publication in BMC Cancer. Please find below the point-by-point responses to yours and the Reviewers concerns: Response to editorial office 1) Rephrase the Competing Interests section to indicate that some authors do have competing interests; We rephrased the competing interests section as requested. 2) List sources of funding in the Acknowledgments section; In the revision, we added the source of funding in the acknowledgments section: The GERCOR cooperative group received grants from Celgene for this investigator initiative survey project. 3) Clarify in the Methods section that Ethical approval has been obtained and include the full names of the Ethics committees that approved the study. Per your suggestion, we included the full names of the Ethic committee and the National health agency in the Methods section.

3 Response to Reviewer 1: Andrew Ko Major Compulsory Revisions - Much of the background describes predictive biomarkers and the translational research component of the study; yet in the proposed trial, collection of tumor tissue seems like it is optional. It sounds like the investigators will be relying on archived specimens rather than mandating prospective study-associated tumor biopsies (meaning, realistically, only a fraction of study patients will have sufficient tumor material available for analysis). It is difficult to believe that enough data will be obtained from the framework to assess the redictive value of the biomarkers in question. Along these same lines, there is also no description of the planned statistical analysis of the biomarker work. We agree with this comment. In France, a translational research component is an optional part of a clinical study with a specific consent form. Thus, patients at any time can refuse to participate in any or all of the study s activities. We also agree that tumor samples were not available for all pancreatic adenocarcinoma patients due to the well-known difficulty to obtain tissue using fine-needle aspiration. For these reasons and because the final number of tumor samples was uncertain, it was not possible to plan a statistical analysis for the translational part of the study. This is an exploratory analysis and will need further validation in a largest series. We highlight now this fact in the revised manuscript. Given the discordant results of the predictive value of hent1reported at the 2013 and 2014 ASCO meetings and the fact that the theoritical interest of the LV5FU2 plus nab-paclitaxel combination was largely based on the translational data of predictive biomarkers of gemcitabine, it was intentional to stress this concern in the background. - As written, SPARC expression will be measured in both arms, while hent1 and dck only will be looked at for the gem-containing arm and TS for the 5-FU-containing arm. To sort out predictive vs prognostic value of these respective biomarkers, all of them really should be analyzed in both arms. Per the Reviewer suggestion, all the biomarkers: hent1, dck, and TS will be analyzed in both arms. In the revision, we add a sentence that states: To assess the prognostic and predictive value of SPARC, hent1, dck and TS expressions when feasible in both arms. - Provide some justification for use of 4-month PFS rate as primary objective; this is a somewhat unusual choice. We agree with the Reviewer that the 4-month PFS rate is unusual endpoint for a phase II study. However, objective response rate did not appear to be a right endpoint for treatment comparisons while overall survival should be used for phase III studies rather than phase II study focusing on detection of an early signal of efficacy, like ours. Therefore, after much discussion and reflection with our statisticians team, we have decided to take this early endpoint given the observed 4-month PFS rate of 40% in previous phase III studies of: GEMOX vs gemcitabine (Louvet C et al, JCO 2005) and FOLFIRINOX (Conroy T et al, NEJM 2011). The 6-month PFS is not suitable in metastatic pancreatic adenocarcinoma due to the aggressiveness of the disease and rapid tumor growth. We add a

4 new reference in the manuscript: Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials). Bonnetain F et al, Eur J Cancer Has the combination to be used in arm 2 (nab-paclitaxel+slv5fu2) previously been formally evaluated in a phase I study in terms of safety and dosing? I can't tell from the background description. No, the combination slv5fu2 plus nab-paclitaxel has not been formally evaluated in a phase I study. However, as discussed in the background section, data on the combination of nabpaclitaxel with capecitabine in breast cancer and with FOLFOX in pancreatic adenocarcinoma showed acceptable safety profiles. Moreover, the Fleming 2-stage design allowed to perform an intermediate analysis after inclusion of the first 15 patients and to confirm that the combination LV5FU2 plus nabpaclitaxel dose not lead to increase toxicities. Minor Essential Revisions - In Statistics section, reference [40] is incorrect We apologize for this mistake. We corrected the reference 40, now reference 43 in the revised manuscript. Discretionary Revisions - Even though this is a two-stage design, the stopping rules for stage I (only 2 of the first 15 patients in arm 2 need to be free from progression at 4 months) are very lax. The number of patients (n=2) is defined by the Fleming 2-stage design. We decided to perform an early interim analysis (i.e. amongst the first 15 randomized patients in arm 2) to check for futility and to prevent patient from inefficient treatment (lack of non-progressive patients) while aiming at a large cohort for the efficacy analysis. Based on the Fleming decision rules we at least two alive patients free of progression are required in order to pursue randomization. - Consider inclusion of CA19-9 marker response (e.g. >50%) as a secondary endpoint CEA and Ca 19-9 are collected at inclusion, at each evaluation, and every 2 months thereafter. These data will be provided in the final analysis. Level of interest: An article whose findings are important to those with closely related research interests Thank you very much for your kind words about our work. Quality of written English: Needs some language corrections before being published

5 We amended the mistakes, we clarified the unclear parts and we accepted the Reviewers suggestions. Finally, to accommodate all potential editing problems, a medical writer checked the paper before resubmission. Because many parts of the manuscript have been corrected, these corrections are not highlighted in the revised version. Response to Reviewer 2: Andrea Wang-Gillam The manuscript is well written. There is no major concerns. Just a couple of discretionary revisions. Thank you for the kind words. 1. Under abstract section- methods/design-please correct progression free survival to be progression-free survival. Thank you for this point. We corrected this throughout the indicated sections. 2. Suggest to change ABO-007 to nab-paclitaxel As suggested, we changed ABI-007 into nab-paclitaxel throughout the revised manuscript. 3. Eligibility- 8 ANC> 1.5 x 10 9 should be g/l. platelets 9 change to g We apologize for this typing error. This was corrected in the revision. 4. Discussion- the last sentence of the first paragraph- suggest to change oxaliplatin/cisplatin to oxaliplatin as there is no phase III trial to support the OS benefit of cisplatin. Thank you for this suggestion. We changed it as suggested. Response to Reviewer 3: Roberto Passera From a biostatistical point of view, the manuscript is well written, presenting a new chemotherapy protocol for pancreatic adenocarcinoma (NCT ). The sample size determination is correct and fully described, the Fleming 2-stages methodology is adequate and commonly used in clinical oncology. The choosen endpoint are quite classical and completely described. Thank you very much for your kind words about our paper. My suggestion is to improve the subchapter "statistical analysis", which is now very short, giving some details concerning data analyses (KM curves, Cox regression, time-dependent covariates and so on) Per suggestion, we added a subchapter "statistical analysis" including description of the planned statistical analyses.