Z9001 trial

At the time of reported tumor recurrence, the treatment arm was unblinded after central review. Biopsy was mandatory and performed when medically feasible.

Patients were not allowed to crossover prior to an observed recurrence. The original primary endpoint was OS and an accrual of patients over 3. The trial was designed at the end of the year , when fewer than patients with metastatic GIST had been treated worldwide.

During the present trial, it became clear that the actual event death rate would be considerably lower than the putative event rate specified in the original statistical design because of the efficacy of imatinib in recurrent GIST and the crossover design that allowed patients who progressed on placebo to receive imatinib.

Consequently, the study was vastly underpowered to show a difference in OS between taking imatinib immediately after surgery versus waiting until recurrence occurred. In the revised statistical design, the putative median RFS for the placebo arm was assumed to be 3.

From the time of the amendment, the intent was to accrue more patients over 2. Interim analyses for superiority and futility were scheduled every six months beginning in December Patients and investigators were blinded to the arm that the patient was assigned.

Sixty patients were mis-randomized due to a programming error that assigned them to the placebo arm. Patients, physicians, IRBs, and health authorities were notified of the error and the patients were removed from the study. No data were collected on these patients after their removal from the study resulting in the lack of follow-up information for these patients.

RFS was defined as the time from patient registration to the development of tumor recurrence or death due to any cause. OS was defined as the time from patient registration to death from any cause. Differences in RFS and OS between the arms were analyzed with a one-sided log-rank test stratified by tumor size.

An unstratified Cox model was used for OS due to the small number of observed deaths. The placebo arm was used as the HR denominator so that HRs of less than one are in favor of imatinib. The proportionality assumption of the Cox model was tested using Schoenfeld residuals and was found to be valid for all of the analyses. For the safety analysis, all patients receiving one or more doses of their assigned treatment were included.

Chi-square tests were used to compare categorical variables between the two arms. All analyses were done with SAS version 8. Novartis employees provided input regarding the study design, but did not participate in the collection, analysis, or interpretation of data. Novartis provided imatinib and the placebo. The database was audited and updated by members of the Duke Clinical Research Institute, which received funding from Novartis.

The results were analyzed by the principal academic investigators. This article was written by the lead author and reviewed by all authors and was submitted to Novartis for comments. The decision to submit the manuscript was independent of Novartis. Between July and April , patients were accrued from institutions. The interim analysis hazard ratio was 0. The final analysis includes all data collected through April 12, The intent to treat analysis consisted of total patients Fig.

The intent to treat population included 65 9. Retrospective central pathology review was performed in Clinicopathologic features were similar between the study arms Table 2. R0 — negative microscopic margins; R1 — positive microscopic margins. Treatment was stopped prematurely in When considering just the patients who received at least one dose of either imatinib or placebo, There were Grade 3 or 4 events occurred in 63 By the final analysis of RFS, 30 8. With a median follow-up for surviving patients of The overall hazard ratio was 0.

Although the trial was not designed to assess patient subsets, we analyzed the effect of tumor size the stratification factor and found that RFS was prolonged on the imatinib arm in each size category Figs. Five 1. There were 8 2. At this time, there is no difference in OS Fig. The observed hazard ratio is 0. We found that assignment to 1 year of adjuvant imatinib compared to placebo prolonged RFS following the complete resection of primary GIST.

In addition, adjuvant imatinib was safe and well-tolerated. The adverse event rate was low and consistent with imatinib use in chronic myelogenous leukemia and metastatic GIST. We chose to stratify patients based only on tumor size. Mitotic rate and tumor site have also been reported to have prognostic importance in retrospective studies of primary GIST.

Notably, none of these tumor features has been validated prospectively. Furthermore, the method of determining mitotic rate has never been standardized and the reproducibility of measurements among different pathologists especially in a large, multicenter trial such as this has not been proven.

Patients on the placebo arm in this study provide the first large prospective cohort of patients with primary GIST in which to identify risk factors for recurrence. This is also the first large prospective evaluation of recurrence using serial radiologic imaging. Additional ad hoc analyses related to risk factors for tumor recurrence will be forthcoming as central pathologic and molecular analyses are underway.

During the year of assigned study therapy, there were 41 recurrences on the placebo arm yet only 1 on the imatinib arm. RFS was increased in each of the 3 size categories on retrospective analysis. Adjuvant therapy is especially relevant for high risk patients e. Notably, the rate of recurrence on the imatinib arm Fig.

This is consistent with a trial in metastatic GIST in which patients with responding or stable disease on imatinib developed tumor progression at a median of 6 months after randomization to discontinue therapy. The results are not expected for several years. Acquired resistance is a frequent event in patients with metastatic GIST who initially respond to imatinib.

Tumor progression occurs at a median of 18—24 months, 15 , 16 commonly from the development of a secondary mutation in KIT. Thus, the possibility to delay or prevent recurrence with adjuvant treatment is critical given that acquired resistance to tyrosine kinase inhibitors eventually occurs in most patients with measurable metastatic GIST. How cumulative exposure to imatinib i. It is not surprising that OS between the study arms is comparable given the relatively short follow-up time and the crossover design of the study, which allowed patients assigned to the placebo arm to receive imatinib upon tumor recurrence.

While imatinib is rarely curative in metastatic GIST, 15 , 16 it may eradicate residual microscopic disease in some patients following removal of the primary tumor.

Longer patient follow-up is necessary to determine whether adjuvant imatinib increases the cure rate of surgery alone for localized, primary GIST. Quality of life instruments were not used in this study. The advantage of improved RFS by taking adjuvant imatinib must be weighed against the potential toxicity of the drug, even though it was generally well-tolerated.

With the advent of tyrosine kinase inhibitors, there are now effective agents against GIST. In the first phase 3 adjuvant trial of targeted therapy following the resection of localized, primary GIST, we have found that imatinib prolongs RFS. Publications automatically indexed to this study by ClinicalTrials. J Clin Oncol. Epub Mar Erratum in: J Clin Oncol. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial.

Erratum in: Lancet. National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.

Gastrointestinal Stromal Tumor. Drug: imatinib mesylate Other: placebo Other: laboratory biomarker analysis. Phase 3. Study Type :. Interventional Clinical Trial. Actual Enrollment :. Study Start Date :. Actual Primary Completion Date :. January 27, Key Record Dates. All patients who participated will now be told whether they had been assigned to Placebo or Gleevec. Patients taking placebo as of April 1 may elect to receive one full year of imatinib without charge. The interim analysis evaluated results at the 1-year mark.

Does the study now still continue with the planned followup? The data show that at 1 year after entering the study the patients who took Gleevec had a significantly lower chance of recurrence.

The 1-year mark is the end of the period during which patients took either placebo or Gleevec. As the study matures, might it later emerge that taking 1 year of adjuvant imatinib delays recurrence but does not ultimately reduce the risk of recurrence? This is a slightly different question. What we have learned is that the rate of recurrence at 1 year is lowered by taking adjuvant Gleevec.

Whether adjuvant Gleevec prevents some patients from ever developing recurrence is unknown at this time. Is it known whether overall survival will be affected by 1 year of adjuvant imatinib?

Overall survival is not different between the 2 study arms at this time. The primary endpoint of the trial was the rate of recurrence. Will additional information be presented at the ASCO meeting about the interim analysis? Will this include a breakdown of results by tumor site, mutation status, size, risk group, or margin status R0 versus R1?