NCIC CLINICAL TRIALS GROUP DATA SAFETY MONITORING COMMITTEE Fall Conference Call 23 November 2009 SUMMARY REPORT The NCIC CTG DSMC reviewed the following trials with respect to safety, trial conduct, including accrual, and where applicable, efficacy. In addition to trial related data, where applicable, relevant data from external sources (e.g., recently published literature) were also considered. REVIEW OF PHASE III TRIALS: NCI US Affiliated Trials Open to Accrual PR.11 A phase III study of active surveillance therapy against radical treatment in patients diagnosed with favourable risk prostate cancer (START) Activation Date: June 15, 2007 RECOMMENDATION: The involvement of the Australians and Scandinavians, as the Trial Team is attempting to do, is vital for the study to be feasible. The DSMC will be recommending closure of this trial if there is no improvement in accrual by Spring Meeting 2010. The NCIC CTG is in discussion with CTEP about additional approaches to improve accrual, including any potential to alter the specifics of the feasibility stage. A full evaluation of the feasibility phase of the trial is scheduled for early April, 2010. The NCIC CTG remains committed to this trial and considers it to be of high scientific priority. NCI US Affiliated Trials Closed to Accrual BR.19 A phase III prospective randomized double blind placebo controlled trial of the epidermal growth factor receptor antagonist ZD1839 (IRESSA) in completely resected stage 1B, II, and IIIA nonsmall cell lung cancer Closing Date: April 22, 2005 RECOMMENDATION: The DSMC is expecting a final analysis report early 2010. No concerns. Review in Spring. The database for the final analysis will be locked in December 2009. DSMC Summary Report 23 November 2009 Page 1
HD.6 A phase III study of radiotherapy or ABVD plus radiotherapy versus ABVD alone in the treatment of early stage Hodgkin's disease Closing Date: April 05, 2002 RECOMMENDATION: No concerns. Review in Spring. MA.17R A double blind re randomization to letrozole or placebo for women completing five years of adjuvant letrozole in the MA.17 study Activation Date: October 14, 2004 Closing Date: May 12, 2009 RECOMMENDATION: The DSMC requests confirmation that there are no plans for an interim analysis. If there is such a plan, the DSMC wishes to be kept informed. No concerns. Review in the Spring. The trial protocol does not include a plan for an interim analysis, and no amendment to this plan is anticipated. MA.20 A phase III study of regional radiation therapy in early breast cancer Closing Date: February 2, 2007 The DSMC needs to be included in any plans to revise the plans for the interim analysis as noted in the Spring 2009 MA.20 Trial Summary provided by the Trial Team. The plans for the interim analysis are as stated in the protocol and require 156 events. This number of events has not yet been observed. As the event rate is substantially less than expected, the Trial Committee has indicated that it may consider asking the DSMC to review additional endpoints when the interim analysis is reviewed. The Trial Committee will provide this request to the DSMC prior to the conduct of the interim analysis. MA.21 A phase III adjuvant trial of sequenced EC + filgrastim + epoetin alfa followed by paclitaxel versus sequenced AC followed by paclitaxel versus CEF as therapy for premenopausal women and early postmenopausal women who have had potentially curative surgery for node positive or high risk node negative breast cancer Closing Date: April 29, 2005 DSMC Summary Report 23 November 2009 Page 2
MA.27 A randomized phase III trial of exemestane versus anastrozole in postmenopausal women with receptor positive primary breast cancer Closing Date: July 31, 2008 PR.3 Intergroup (NCIC CTG, CUOG, SWOG, MRC UK) phase III randomized trial comparing total androgen blockade versus total androgen blockade plus pelvic irradiation in clinical adenocarcinoma of the prostate Closing Date: August 31, 2005 RECOMMENDATION: Release interim analysis results to the Trial Team for publication. The DSMC requests a more detailed response to its previous concerns about the number of patients lost to follow up. The paper should include clear information about missing data (if that is still a problem when the paper is to be submitted) and discuss the caveats concerning end points, making clear that it is only a preliminary report. A specific and detailed response about the missing data / loss to follow up will be provided to the DSMC. The implications of the missing data will be indicated in the presentation / publication of the PR.3 results. The Trial Committee will review the feasibility of including a sensitivity analysis regarding the loss to follow up in a re analysis of the locked data base that will be used for publication. PR.7 A phase III randomized trial comparing intermittent versus continuous androgen suppression for patients with prostate specific antigen progression in the clinical absence of distant metastases following radiotherapy for prostate cancer Closed to accrual: November 30, 2005 Trial Team is to be commended for its toxicity summary. There appears to be a lapse between events being reached and analyses being conducted. The NCIC CTG s policy is that interim analyses should be conducted using a cleaned and locked database. The process to clean the data on this trial that includes complex, long term and international follow up has required additional Central Office resources; these have been assigned. The process to provide an interim analysis on an appropriately locked database is projected for no later than the 2010 DSMC Summary Report 23 November 2009 Page 3
NCIC CTG Spring Meeting. This database lock is thus anticipated within 9 months after observing the protocol stated event rate. The NCIC CTG Central Office is devising quality benchmarks for the timeliness of locking databases for interim analyses. It is anticipated that this benchmark will be in the range of 6 months for a trial such as PR.7 Non NCI US Affiliated Trials Open to Accrual BR.29 A double blind randomized trial of cediranib (AZD2171) versus placebo in patients receiving paclitaxel/carboplatin chemotherapy for the treatment of advanced or metastatic non small cell lung cancer Activation Date: November 6, 2008 RECOMMENDATION: A protocol mandated safety review was conducted at the 50 th patient. There are no concerns. Review in the Spring. CE.6 A randomized phase III study of temozolomide and short course radiation vs short course radiation alone in the treatment of newly diagnosed glioblastoma multiforme in elderly patients Activation Date: May 1, 2007 RECOMMENDATION: Accrual continues to be slow. Review in the Spring. CO.20 A phase III randomized study of brivanib alaninate (BMS 582664) in combination with cetuximab (erbitux) versus placebo in combination with cetuximab (erbitux) in patients previously treated with combination chemotherapy for metastatic colorectal carcinoma Activation Date: February 5, 2008 CO.21 A phase III study of the impact of a physical activity program on disease free survival in patients with high risk stage II or stage III colon cancer: A randomized controlled trial (Challenge) Activation Date: December 3, 2008 DSMC Summary Report 23 November 2009 Page 4
HN.6 A phase III study of standard fractionation radiotherapy with concurrent high dose cisplatin versus accelerated fractionation radiotherapy with panitumumab in patients with locallyadvanced stage III and IV squamous cell carcinoma of the head and neck Activation Date: December 18, 2008 LY.12 A phase III study of gemcitabine, dexamethasone, and cisplatin compared to dexamethasone, cytarabine, and cisplatin plus/minus rituximab as salvage chemotherapy for patients with relapsed or refractory aggressive histology non hodgkin's lymphoma prior to autologous stem cell transplant and followed by maintenance rituximab versus observation Activation Date: August 7, 2003 MA.29 A feasibility study of pre operative sunitinib (SU11248) with multiple pharmacodynamic endpoints in patients with T1c T3 operable carcinoma of the breast Activation Date: 12 March 2007 RECOMMENDATION: Accrual is very slow. The DSMC would like to be reassured that recruitment is forthcoming. Review in the Spring. The DSMC will be provided with details regarding accrual strategies. MA.31 A randomized, open label, phase III study of taxane based chemotherapy with lapatinib or trastuzumab as first line therapy for women with HER2/neu positive metastatic breast cancer Activation Date: 17 July 2008 RECOMMENDATION: No items were identified with respect to the material provided. The projected and actual accrual graphs and tables should be updated and provided. Since the meeting of the DSMC, a detailed toxicity assessment has been conducted. This will be provided to the DSMC for its review that should be completed in December 2009. Based on this review, The Trial Team and Trial Committee have concluded that a protocol amendment is required to permit primary DSMC Summary Report 23 November 2009 Page 5
prophylaxis with G CSF for patients allocated to the experimental (lapatinib) arm who are to receive docetaxel. This information will be provided to the DSMC. MAP.3 A phase III randomized study of exemestane versus placebo in postmenopausal women at increased risk of developing breast cancer Activation Date: February 11, 2004 The DSMC requests that a more detailed Trial Abstract be provided. A detailed Trial Abstract will be provided. PR.12 Phase III study of neoadjuvant docetaxel and androgen suppression plus radiation therapy versus androgen suppression alone plus radiation therapy for high risk localized adenocarcinoma of the prostate (DART) Activation Date: March 3, 2008 RECOMMENDATION: The trial is closed and no longer requires DSMC oversight. This trial can be removed from future DSMC agendas. SC.20 A phase III international randomized trial of single versus multiple fractions for re irradiation of painful bone metastases Activation Date: January 7, 2004 Non NCI US Affiliated Trials Closed to Accrual BR.25 A phase II study of hypofractionated 3 dimensional conformal radiotherapy (3DCRT) for inoperable stage I/II non small cell lung cancer (NSCLC) Activation Date: April 26, 2006 Closed: 18 April 2008 (accrual met) RECOMMENDATION: No concerns. Review in the Fall. DSMC Summary Report 23 November 2009 Page 6
LY.13 A multi centre phase II trial investigating the efficacy and tolerability of bortezomib added to cyclophosphamide, vincristine, prednisone and rituximab (BCVP R) for patients with advanced stage follicular non hodgkin's lymphoma requiring systemic first line treatment Activation Date: December 14, 2006 Closed: March 6, 2009 (accrual met) MA.22 A phase I/II study of increasing doses of epirubicin and docetaxel plus pegfilgrastim for locally advanced or inflammatory breast cancer Activation Date: February 25, 2003 Closed: June 8, 2009 MY.10 A randomized phase III study of thalidomide and prednisone as maintenance therapy following autologous stem cell transplant in patients with multiple myeloma Activation Date: September 16, 2002 Closed: January 30, 2009 (accrual met) DSMC Summary Report 23 November 2009 Page 7