Final Efficacy Analysis Research Articles

359PD - Final Efficacy and Safety Analysis of the Carin Phase III Trial: Capecitabine (Cap) and Bevacizumab (Bev) with or Without Vinorelbine (Vin) in 1St Line Metastatic Breast Cancer (Mbc)

ABSTRACT Aim: Recent 1st line phase III trials in MBC demonstrated improved progression-free survival (PFS) for the combination of Cap/Bev as compared to Cap alone, but inferior efficacy when compared to paclitaxel plus Bev. Frequently used to treat MBC, Vin has few overlapping toxicities with Cap. The CARIN trial aims at further improving efficacy by adding Vin to Cap/Bev for a less toxic alternative to taxane-based 1st line therapy. Methods: CARIN was a prospective, open-label, multicenter, randomized phase III trial. Key eligibility criteria included confirmed measurable or non-measurable HER2 negative, locally advanced or MBC, ECOG ≤2, and no prior palliative chemotherapy. The 600 patients (pts) randomized (1:1) received oral Cap 1000 mg/m2 BID days 1-14 plus Bev 15 mg/kg q3w IV (Arm A) or Cap/Bev regimen combined with Vin 25 mg/m2 IV days 1 + 8 (Arm B) until progression or unacceptable toxicity. Randomization was stratified by prior adjuvant anthracycline and/or taxane therapy (yes/no) and hormone receptor status (ER/PR + /-). The primary endpoint was defined as PFS; secondary endpoints included objective response rate, overall survival (OS) and safety. Results: 297 pts in Arm A and 295 in Arm B with a median age of 62 were included in the efficacy analysis. Median follow-up was 2.4 years. 38% of pts in Arm A and 32% in Arm B were taxane pretreated; 20.8% were triple negative. The median treatment exposure was 28 weeks for both arms. Median PFS was 8.7 and 9.6 months (ms) (p = 0.03). The effect was most pronounced in pts Grade 3 were 60.6% and 76.3% in Arm A vs B, respectively, with neutropenia and leucopenia being more common in Arm B. No unexpected side effects were observed. Results of a multivariate cox regression will be presented. Conclusions: The addition of Vin to Cap/Bev is at least as effective as the combination of taxanes/Bev as reported in the RIBBON-1 trial and seems an option for taxane pretreated and TNBC pts. Disclosure: A. Welt: Advisory boards: Roche, TEVA, Eisai, Novartis Professional fee for oral presentations: P. Fabre N. Marschner: 1. Share holdings and executive employee iOMEDICO AG 2. Advisory board Roche T. Decker: Advisory Board Roche; C. Salat: Professional fee for oral presentations: Roche; S. Busies: Employee iOMEDICO AG; S. Hegewisch-Becker: Advisory Boards: Roche, Lilly, Merck. All other authors have declared no conflicts of interest.

Final Safety and Efficacy Analysis of a Phase I/II Trial with Imatinib and Vinorelbine for Patients with Metastatic Breast Cancer

Background: Imatinib is a tyrosine kinase inhibitor of BCR-ABL, ABL, PDGFR-α and -β, KIT, and DDR. In solid tumors, it inhibits proliferation and invasiveness and facilitates higher intratumoral cytotoxic drug concentrations. Vinorelbine has good tolerability and efficacy in metastatic breast cancer (MBC). This study evaluates the safety and efficacy of imatinib and vinorelbine in combination. Methods: In a prospective, open-label, phase I/II trial, 400 mg imatinib p.o. daily (corrected from 600 mg) was combined with an escalating dose of vinorelbine i.v. weekly in four dose levels of 10, 15, 20, and 25 mg/m² (each n ≥ 5) to treat patients with MBC (expressing PDGFR-α and/or -β, and/or KIT). The last patient of each level was treated for >28 days, before enrolment for the next dose level started. Study endpoints were feasibility and tolerability, incidence of hematological and nonhematological toxicity, and clinical efficacy (data cutoff: November 18, 2011). A total of 33 patients have been enrolled, and all dose levels have been fully recruited. One patient is still on study medication. A translational subprotocol is ongoing. Results: All 33 included patients are evaluable for safety (32 within the ITT population). Eleven patients were excluded early from the study (progressive disease, toxicity, and withdrawal of consent). Twenty-two patients participated in the study for >28 days (‘ITT >28'). Within the ITT population, the response rate [complete response (CR) and partial response (PR)] was 9.4% (n = 3), the clinical benefit rate (CBR; CR+PR+stable disease) 50% (n = 16), and the median time to progression (TTP) 155 days. A total of 21.3% of the patients were on study medication for >6 months, and 15.2% for >12 months (mean 140 days, range 15-643). Within ‘ITT >28', the response rate was 13.6%, CBR 72.7%, and median TTP 176 days. The response was independent of the receptor status (PDGFR-α, -β, and KIT). Toxicities were as follows (safety population): 21.6% severe leukopenia, 9.1% severe neutropenia (with 1 febrile neutropenia), 1 case of bowel perforation, 36% diarrhea (3% severe), 84.8% nausea (severe 15.2%), 48.5% vomiting (severe 9.1%), 27.3% infections (severe 6.1%), 12.1% peripheral neuropathy (severe 9.1%), and 36.4% dyspnea (3% severe). Four patients on trial died (nondrug-related). Conclusion: The combination of imatinib and vinorelbine in MBC appeared to be feasible and tolerable. A CBR of 50% (ITT) in pretreated patients suggests that this combination may be active. Although toxicities were frequent, they appeared to be manageable.

Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial

The role of adjuvant bisphosphonates in early breast cancer is uncertain. We therefore did a large randomised trial to investigate the effect of the adjuvant use of zoledronic acid on disease-free survival (DFS) in high-risk patients with early breast cancer. In the AZURE trial, an open-label, international, multicentre, randomised, controlled, parallel-group phase 3 trial, women (age ≥18 years) with stage II or III breast cancer were randomly assigned (1:1) by a central automated 24-h computer-generated telephone minimisation system (balanced for number of involved axillary lymph nodes, tumour stage, oestrogen receptor status, type and timing of systemic therapy, menopausal status, statin use, and treatment centre) to receive standard adjuvant systemic treatment alone (control group) or with 4 mg intravenous zoledronic acid every 3-4 weeks for six doses, then every 3 months for eight doses, followed by every 6 months for five doses, for a total of 5 years of treatment. The primary endpoint was disease-free survival (DFS). Secondary endpoints were invasive DFS (IDFS), overall survival, time to bone metastases, time to distant recurrence, and subgroup analyses of variables included in the randomisation. All patients have completed study treatment. Results from the intention-to-treat final analysis of this fully recruited study are presented after a median follow-up of 84 months (IQR 66-93). This final efficacy analysis was planned to take place after 940 DFS events. This trial is registered with ClinicalTrials.gov, NCT00072020. 3360 women were recruited from 174 centres in seven countries between Sept 4, 2003, and Feb 16, 2006. The number of DFS events did not differ between groups: 493 in the control group and 473 in the zoledronic acid group (adjusted hazard ratio [HR] 0·94, 95% CI 0·82-1·06; p=0·30). IDFS (HR 0·93, 95% CI 0·82-1·05; p=0·22), overall survival (0·93, 0·81-1·08; p=0·37), and distant recurrences (0·93, 0·81-1·07; p=0·29) were much the same in both groups. Zoledronic acid reduced the development of bone metastases, both as a first event (HR 0·78, 95% CI 0·63-0·96; p=0·020) and at any time during follow-up (0·81, 0·68-0·97; p=0·022). The effects of zoledronic acid on DFS were not affected by oestrogen-receptor status. However, zoledronic acid improved IDFS in those who were over 5 years since menopause at trial entry (n=1041; HR 0·77, 95% CI 0·63-0·96) but not in all other (premenopause, perimenopause, and unknown status) menopausal groups (n=2318; HR 1·03, 95% CI 0·89-1·20). 33 cases of suspected osteonecrosis of the jaw have been reported, with 26 confirmed on central review, all in the zoledronic acid group (1·7%, 95% CI 1·0-2·4). These results suggest no overall benefit from the addition of zoledronic acid to standard adjuvant treatments for early breast cancer. However, zoledronic acid does reduce the development of bone metastases and, for women with established menopause, improved disease outcomes. Novartis Global and NIHR Cancer Research Network.

Nabrax: Neoadjuvant therapy of breast cancer with weekly single-agent nab-paclitaxel—Final efficacy and biomarkers analysis of GEICAM 2011-02 trial.

1051 Background: Nanoparticle albumin bound paclitaxel (nab-P) administered weekly showed superior efficacy compared to every 3-weeks docetaxel in a randomized phase II study in first line metastat...

German Adjuvant Intergroup Node Positive (GAIN) study: A phase III trial to compare IDD-ETC versus EC-TX in patients with node-positive primary breast cancer—Final efficacy analysis.

1009 Background: Intense dose-dense (idd) epirubicin (E), paclitaxel (T), cyclophosphamide (C) (idd-ETC) resulted in a superior disease-free (DFS) and overall survival (OS) compared to conventional...

Adaptive randomized phase II design for biomarker threshold selection and independent evaluation.

Frequently a biomarker capable of defining a patient population with enhanced response to an experimental agent is not fully validated with a known threshold at the start of a phase II trial. When such candidate predictive markers are evaluated and/or validated retrospectively, over-accrual of patients less likely to benefit from the regimen may result, leading to underpowered analyses or sub-optimal patient care. We propose an adaptive randomized phase II study design incorporating prospective biomarker threshold identification (or non-identification), possible early futility stopping, potential mid-trial accrual restriction to marker-positive subjects, and final marker and treatment evaluation in the patient population identified as most likely to benefit. An interim analysis is used to determine whether an initially unselected trial should stop early for futility, continue without a promising marker, or adapt accrual and resize (up to a pre-determined maximum) according to a promising biomarker. Final efficacy analyses are performed in the target population identified at the interim as most likely to benefit from the experimental regimen. Simulation studies demonstrate control of false-positive error rates, power, reduced average sample size, and other favorable aspects. The design performs well at identifying a truly predictive biomarker at interim analysis, and subsequently restricting accrual to patients most likely to benefit from the experimental treatment. Type I and type II error rates are adequately controlled by restricting the range of marker prevalence via the candidate thresholds, and by careful consideration of the timing of interim analysis. In situations where identification and validation of a naturally continuous biomarker are desired within a randomized phase II trial, the design presented herein offers a potential solution.

Optimum duration of neoadjuvant letrozole to permit breast conserving surgery

The aim of this multicenter, prospective, longitudinal phase IV study was to establish the optimal duration of neoadjuvant letrozole that would allow breast conservation surgery (BCS) in patients with early breast cancer who were initially unsuitable. Primary, invasive, estrogen-receptor- and/or progesterone-receptor-positive breast cancer patients, with large tumors (≥T2 i.e., >20 mm) not initially suitable for BCS, received 2.5 mg letrozole p.o. daily. Patients continued treatment until they became eligible for BCS, progressed, failed to meet criteria for BCS and withdrew for scheduled mastectomy, withdrew for other reasons, or completed 12 months of letrozole treatment without a BCS decision being made. A total of 146 patients were enrolled; seven patients who did not have a valid postbaseline tumor assessment were excluded from the final efficacy analysis. At study closure, 69 % of patients (96 of 139) were eligible for BCS. The median time to achieve a tumor response sufficient to allow BCS with neoadjuvant letrozole was 7.5 months (95 % CI 6.3-8.5 months). Letrozole was well tolerated, and most adverse events were mild-to-moderate (grade 1-2). The results from this trial suggest that extended letrozole therapy in the neoadjuvant setting (7.5 months), as opposed to conventional treatment of 4 months, is optimal to achieve maximum reduction in tumor volume sufficient for BCS.

Abstract OT3-1-06: CIBOMA/2004-01_GEICAM/2003-11: A randomised phase III trial assessing adjuvant capecitabine (Cap) maintenance therapy after standard chemotherapy for triple-negative early breast cancer (EBC)

Abstract Background: The ideal adjuvant treatment of triple negative EBC remains to be defined. CIBOMA/2004-01_GEICAM/2003-11 is a multinational randomized phase III trial exploring adjuvant Cap after the conclusion of conventional chemotherapy in triple-negative EBC patients. Materials and Methods: Patients with operable, node-positive (or node-negative with tumour diameter ≥1 cm), hormone receptor-negative, HER2-negative EBC that have received 6–8 cycles of standard anthracycline and/or taxane-containing chemotherapy in the (neo)adjuvant setting (doxorubicin–cyclophosphamide x 4 allowed for node-negative disease), followed by radiotherapy (if indicated) are eligible. After central confirmation of triple negativity by immunohistochemistry, patients were randomised to either 8 cycles of Cap (1,000 mg/m2 bid, d1–14 q21d) or observation. Stratification factors: centre, prior taxane (yes vs. no), involved nodes (0 vs. 1–3 vs. ≥4) and phenotype (basal vs. non-basal). The primary endpoint is disease-free survival (DFS). Secondary endpoints include 5-year DFS, overall survival and safety. An optional pharmacogenetic sub-study will explore polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase in relation to efficacy and tolerability of Cap. Present Status: Recruitment of 876 randomized patients was completed in September 2011. Statistical assumptions: expected 30% reduction in the risk of recurrence at 5 years (64.7% to 73.7%, HR 0.701), power of 80% and 0.05 two-sided significance level. Final efficacy analysis will be triggered by 255 events. Baseline characteristics are well balanced and shown in the table below. 75.0% of the patients completed the 8 cycles of adjuvant Cap. Baseline patients characteristics Capecitabine (n = 448)Observation (n = 428)Median Age, years (range)51 (20-79)50 (24-83)Basal Phenotype,%70.772.2Histology,% Ductal87.786.1Lobular1.82.3Other9.811.4Unknown0.70.2Grade,% 13.32.8218.119.0371.969.6Not determinable6.08.4Unknown0.70.2Chemotherapy received,% Adjuvant (only)78.982.2Neoadjuvant (only)15.615.0Adjuvant + Neoadjuvant4.22.6Unknown1.30.2Postmenopausal,%69.267.3Prior Chemotherapy Agents,% Anthracyclines without taxanes32.132.2Anthracyclines and taxanes67.267.6Unknown0.70.2 Conclusions: This randomized phase III adjuvant trial in triple negative EBC patients has completed accrual and event follow up is ongoing. The trial is sponsored by CIBOMA/GEICAM. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-06.

Abstract S1-02: Final analysis of a phase II 3-arm randomized trial of neoadjuvant trastuzumab or lapatinib or the combination of trastuzumab and lapatinib, followed by six cycles of docetaxel and carboplatin with trastuzumab and/or lapatinib in patients with HER2+ breast cancer (TRIO-US B07)

Abstract BACKGROUND: The BCIRG006 study (Slamon, et al. N Engl J Med 2011) demonstrated similar efficacy and superior safety of adjuvant docetaxel, carboplatin, and trastuzumab (TCH) over an anthracycline regimen in HER2+ BC. Dual HER2-blockade with lapatinib (Ty) and H demonstrated synergism preclinically and significant activity in the metastatic and neoadjuvant settings (Blackwell, et al. J Clin Oncol 2012; Baselga, et al. Lancet 2012). This study evaluates the clinical and molecular effects of neoadjuvant TC plus H and/or Ty in HER2+ BC. METHODS: This is an open-label, randomized phase II study in which pts with stage I-III, operable BC were assigned to 1 of 3 arms: Arm 1-TCH, Arm 2-TCTy, and Arm 3-TCHTy. To test the safety of TCHTy, the first 20 pts received TCHTy. The remaining pts were randomized (1:1:1) to the 3 arms. Pts received a run-in cycle of Ty (1000 mg/d days 1-21) and/or H (8 mg/kg iv), followed by 6 cycles of q3-wkly TC (T: 75 mg/m2, C: AUC 5 or 6) plus H (6 mg/kg) and/or Ty (1000 mg/d d1-21). The first 6 pts were part of a dose-escalation evaluation of C and received AUC5. The remaining pts received C at AUC6. Biopsies were taken at baseline, post run-in cycle, and at surgery. The primary endpoint was pCR rate in each arm (defined as the absence of viable tumor cells in both the breast and axillary lymph nodes). Safety evaluation, molecular effects, and cardiac events were secondary endpoints. RESULTS: From October 2008 to December 2012, 130 pts were enrolled at 13 centers in the US. Two pts withdrew from study prior to starting any Tx (1 ineligible, 1 withdrew consent) and are excluded from analyses. As of May 2013, complete data was available for 106 pts: 32 in Arm 1, 27 in Arm 2 and 47 in Arm 3. Of these, 16 patients came off study tx prior to surgery (6 in Arm 2, 10 Arm 3) but are included in the ITT analyses. Median age was 48 years (range 27-76). Hormone receptors were both negative (HR-) in 43 pts (41%) and were ER and/or PR positive (HR+) in 63 (59%). At presentation, 5 (5%) pts had clinical stage I, 71 (67%) stage II and 30 (28%) stage III BC. The overall pCR was 42% (45/106), including 43% (13/30) in Arm 1, 25% (7/28) in Arm 2 and 52% (25/48) in Arm 3 (Chi-squared test P = 0.069). Using a pair-wise comparison, pCR is significantly lower in Arm 2 than in Arm 3 (p = 0.021) but no difference was detected between Arms 1 and 2 (p = 0.14) or 1 and 3 (p = 0.45) The pCR in HR+ and HR- tumors were 33% HR+ vs 58% HR- for Arm 1, 13% HR+ vs 42% HR- for Arm 2, and 41% HR+ vs 68% HR- for Arm 3. There were no deaths and no episodes of CHF reported. LVEF decreased >10% from baseline and below the lower limits of normal in 5 pts (1 pt in Arm 1, 3 in Arm 2, 1 in Arm 3). The most common gr >3 AEs in Arms 1/2/3 respectively were pain (10%, 25%, 17%), diarrhea (3%, 11%, 27%), neutropenia (7%, 11%, 13%), anemia (10%, 11%, 4%) hypokalemia (7%, 7%, 8%), and infection (7%, 11%, 6%). CONCLUSIONS: To our knowledge, this is the first report of this 4–drug combination in the neoadjuvant setting. Final efficacy, safety and molecular analyses from all 128 pts will be presented. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-02.

Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial

Ankylosing spondylitis is a chronic immune-mediated inflammatory disease characterised by spinal inflammation, progressive spinal rigidity, and peripheral arthritis. Interleukin 17 (IL-17) is thought to be a key inflammatory cytokine in the development of ankylosing spondylitis, the prototypical form of spondyloarthritis. We assessed the efficacy and safety of the anti-IL-17A monoclonal antibody secukinumab in treating patients with active ankylosing spondylitis. We did a randomised double-blind proof-of-concept study at eight centres in Europe (four in Germany, two in the Netherlands, and two in the UK). Patients aged 18-65 years were randomly assigned (in a 4:1 ratio) to either intravenous secukinumab (2×10 mg/kg) or placebo, given 3 weeks apart. Randomisation was done with a computer-generated block randomisation list without a stratification process. The primary efficacy endpoint was the percentage of patients with a 20% response according to the Assessment of SpondyloArthritis international Society criteria for improvement (ASAS20) at week 6 (Bayesian analysis). Safety was assessed up to week 28. This study is registered with ClinicalTrials.gov, number NCT00809159. 37 patients with moderate-to-severe ankylosing spondylitis were screened, and 30 were randomly assigned to receive either intravenous secukinumab (n=24) or placebo (n=6). The final efficacy analysis included 23 patients receiving secukinumab and six patients receiving placebo, and the safety analysis included all 30 patients. At week 6, ASAS20 response estimates were 59% on secukinumab versus 24% on placebo (99·8% probability that secukinumab is superior to placebo). One serious adverse event (subcutaneous abscess caused by Staphylococcus aureus) occurred in the secukinumab-treated group. Secukinumab rapidly reduced clinical or biological signs of active ankylosing spondylitis and was well tolerated. It is the first targeted therapy that we know of that is an alternative to tumour necrosis factor inhibition to reach its primary endpoint in a phase 2 trial. Novartis.

Treatment Efficacy with Accelerated Partial Breast Irradiation (APBI): Final Analysis of the American Society of Breast Surgeons MammoSite® Breast Brachytherapy Registry Trial

The purpose of this study was to examine data on treatment efficacy, cosmesis and toxicities for the final analysis of the American Society of Breast Surgeons MammoSite(®) breast brachytherapy registry trial. A total of 1,449 cases of early-stage breast cancer underwent breast conserving therapy. The single-lumen MammoSite(®) device was used to deliver accelerated partial breast irradiation (APBI) (34 Gy in 3.4 Gy fractions). Of these, 1,255 cases (87 %) had invasive breast cancer (IBC) and 194 cases had DCIS. Median follow-up was 63.1 months with 45 % of all patients having follow-up of 6 years or longer. There were 41 cases (2.8 %) that developed an ipsilateral breast tumor recurrence (IBTR) for a 5-year actuarial rate of 3.8 % (3.7 % for IBC and 4.1 % for DCIS). Tumor size (odds ratio [OR] = 1.1, p = 0.03) and estrogen receptor negativity (OR = 3.0, p = 0.0009) were associated with IBTR, while a trend was noted for positive margins (OR = 2.0, p = 0.06) and cautionary/unsuitable status compared with suitable status (OR = 1.8, p = 0.07). The percentage of patients with excellent/good cosmetic results at 60, 72, and 84 months was 91.3, 90.5, and 90.6 %, respectively. The overall rates of fat necrosis and infections remained low at 2.5 and 9.6 % with few late toxicity events beyond 2 years. The overall symptomatic seroma rate was 13.4 and 0.6 % beyond 2 years. The final analysis of treatment efficacy, cosmesis, and toxicity from the American Society of Breast Surgeons MammoSite(®) breast brachytherapy registry trial confirms previously noted excellent results and compares favorably with other forms of APBI with similar follow-up and to outcomes seen in selected patients treated with whole breast irradiation.

O-0007 - Adjuvant Capecitabine and Oxaliplatin (XELOX) for Gastric Cancer After D2 Gastrectomy: Final Results From the Classic Trial

2twice daily days 1–14 q3w) for 8 cycles or surgery alone. The primary endpoint was 3-year disease-free survival. The clinical cut-off date for the prospectively planned final 5-year efficacy analysis was 22 November 2012. Results: At data cut-off, 103 (20%) patients in the XELOX group and 141 (27%) patients in the surgery alone group had died. This represented a 34% reduction in the risk of death with XELOX versus surgery alone (hazard ratio 0.66, 95% CI 0.51–0.85; p = 0.0015 by stratified Cox regression analysis). The 5-year overall survival rate was 78% in the XELOX group and 69% in the surgery alone group (p = 0.0029, log-rank test unstratified). 76 (15%) patients in the XELOX group and 135 (26%) patients in the surgery alone group received subsequent, non-protocol-specified anticancer therapies after progression of disease. In the analysis of disease-free survival, 139 (26.7%) patients in the XELOX group and 203 (39.4%) patients in the surgery alone group had relapsed, developed a new gastric cancer or died. This represented a 42% reduction in the risk of an event with XELOX versus surgery alone (hazard ratio 0.58, 95% CI 0.47– 0.72; p < 0.0001 by stratified Cox regression analysis). The 5-year disease-free survival rate was 68% in the XELOX group and 53% in the surgery alone group (p < 0.0001, log-rank test unstratified). Conclusion: The final analysis of the CLASSIC trial, after a median follow-up of 5 years, supports the findings from the primary analysis performed 2 years earlier. Adjuvant XELOX after curative D2 gastrectomy improves overall survival compared with surgery alone and should be considered as a standard treatment option for patients with operable gastric cancer.

Final analysis of efficacy and safety of dose-dense chemotherapy with modified TCF regimen (TCF-dd) in elderly patients (pts) with metastatic gastric cancer (MGC).

e15086 Background: Gastric cancer is more common in elderly pts with its highest incidence around the seventh decade of life. Most oncologists are reluctant to treat this population with the most active polichemotherapy combinations because of safety concerns. Subgroup analyses of elderly pts enrolled in European studies show limited and conflicting data.We previously reported on the feasibility and high activity of a dose-dense TCF regimen (Tomasello 2010). This is a retrospective analysis of efficacy and safety of this schema in the elderly pts subgroup (≥ 65 years). Methods: From Nov 2004 to Jan 2013, 119 consecutivepts with MGC, PS 0-2, not previously treated, received Docetaxel 70 mg/m2 d1, Cisplatin 60 mg/m2 d1, l-Folinic Acid 100 mg/m2 d1-2, followed by 5-FU 400 mg/m2 bolus d1-2, and then 600 mg/m222 h c.i. d1-2, every 2 weeks, plus Pegfilgrastim 6 mg on day 3. Pts aged ≥ 65 years (60) received the same schedule with doses reducted by 30%. Results: Overall pts characteristics: 76% male, 24% female; median age: 65, range 31-81. A median of 4 cycles was administered. 102 pts were evaluable for response (86%) and all for toxicity. In pts aged ≥ 65 y, we observed 5 CR (8%), 26 PR (43%), 10 SD (17%) and 7 PD (12%); in younger pts: 3 CR (5%), 32 PR (54%), 9 SD (15%) and 10 PD (17%); ORR by ITT was 56% (95% CI 45-64). Median OS was 11,2 months (95% CI 9,4-14,1); in elderly and younger pts was 11,2 (95% CI 7,3-15,1) and 11,8 (95% CI 9,2-16,2), respectively. Out of 48 evaluable pts aged ≥ 65 years, 24 (50%) were treated at full doses without any delay. In the elderly most frequent grade 3-4 toxicities were: neutropenia (13%, p&lt;0.0001), leucopenia (7%), thrombocytopenia (18%), anemia (3%, p=0.02), febrile neutropenia (8%), asthenia (27%), diarrhea (10%), nausea/vomiting (10%) and hypokalemia (17%); in the younger: neutropenia (56%), leucopenia (31%), thrombocytopenia (22%), anemia (15%), febrile neutropenia (15%), asthenia (41%), diarrhea (15%), nausea/vomiting (22%) and hypokalemia (20%). Conclusions: This study shows that elderly pts can be safely treated with a TCF-dd regimen with a 30% dose reduction achieving similar efficacy results as younger pts with lesser toxicity.

Effect of Aliskiren on Postdischarge Mortality and Heart Failure Readmissions Among Patients Hospitalized for Heart Failure

Hospitalizations for heart failure (HHF) represent a major health burden, with high rates of early postdischarge rehospitalization and mortality. To investigate whether aliskiren, a direct renin inhibitor, when added to standard therapy, would reduce the rate of cardiovascular (CV) death or HF rehospitalization among HHF patients. International, double-blind, placebo-controlled study that randomized hemodynamically stable HHF patients a median 5 days after admission. Eligible patients were 18 years or older with left ventricular ejection fraction (LVEF) 40% or less, elevated natriuretic peptides (brain natriuretic peptide [BNP] ≥ 400 pg/mL or N -terminal pro-BNP [NT-proBNP] ≥ 1600 pg/mL), and signs and symptoms of fluid overload. Patients were recruited from 316 sites across North and South America, Europe, and Asia between May 2009 and December 2011. The follow-up period ended in July 2012. All patients received 150 mg (increased to 300 mg as tolerated) of aliskiren or placebo daily, in addition to standard therapy. The study drug was continued after discharge for a median 11.3 months. MAIN OUTCOME MEASURES Cardiovascular death or HF rehospitalization at 6 months and 12 months. In total, 1639 patients were randomized, with 1615 patients included in the final efficacy analysis cohort (808 aliskiren, 807 placebo). Mean age was 65 years; mean LVEF, 28%; 41% of patients had diabetes mellitus, mean estimated glomerular filtration rate, 67 mL/min/1.73 m2. At admission and randomization, median NT-proBNP levels were 4239 pg/mL and 2718 pg/mL, respectively. At randomization, patients were receiving diuretics (95.9%), β-blockers (82.5%), angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (84.2%), and mineralocorticoid receptor antagonists (57.0%). In total, 24.9% of patients receiving aliskiren (77 CV deaths, 153 HF rehospitalizations) and 26.5% of patients receiving placebo (85 CV deaths, 166 HF rehospitalizations) experienced the primary end point at 6 months (hazard ratio [HR], 0.92; 95% CI, 0.76-1.12; P = .41). At 12 months, the event rates were 35.0% for the aliskiren group (126 CV deaths, 212 HF rehospitalizations) and 37.3% for the placebo group (137 CV deaths, 224 HF rehospitalizations; HR, 0.93; 95% CI, 0.79-1.09; P = .36). The rates of hyperkalemia, hypotension, and renal impairment/renal failure were higher in the aliskiren group compared with placebo. Among patients hospitalized for HF with reduced LVEF, initiation of aliskiren in addition to standard therapy did not reduce CV death or HF rehospitalization at 6 months or 12 months after discharge. clinicaltrials.gov Identifier: NCT00894387.

An open, multicenter, phase II clinical trial to evaluate efficacy and safety of S-1 split cisplatin in patients with advanced gastric cancer (AGC): HGCSG0702—Safety analysis.

121 Background: From the results of SPIRITS trial, S-1 plus cisplatin has been regarded as standard first-line chemotherapy for patients with AGC in Japan. However, many facilities are forced hospitalization of hydration upon administration of high dose Cisplatin (60mg/m2). Therefore, in Hokkaido Gastrointestinal Cancer Study Group (HGCSG), to investigate the safety and efficacy, we conducted a multicenter phase II clinical trials of S-1 plus split cisplatin as a therapeutic strategy that can be administered in the outpatient. Methods: Eligibility criteria included pathologically confirmed AGC; no prior chemotherapy; Age 20 to 75, ECOG performance status (PS) of 0 to 1; adequate organ function; and written informed consent. S-1 (40-60 mg depending on patients body surface area) was given orally, twice daily for 3 consecutive weeks, and 30 mg/m2 cisplatin was given intravenously on day 1 and 15, followed by 2-week rest period, within a 5-week cycle. Primary endpoint was the response rate (RR), and secondary endpoints were progression-free survival, overall survival, safety profile, and duration of hospitalization. Results: Between Mar 2008 and Mar 2012, 40 pts were enrolled. Patients characteristics were as follows: median age 63 years (range 41-75), Male: female 30:10, PS 0:1 33:7. Median no. of cycles was 3. The most common non-hematological adverse events (AE) were anorexia (70%), nausea (60%), fatigue (60%) and diarrhea (48%) and hematological AE were anemia (88%), neutropenia (83%), leukocytopenia (68%) and thrombocytopenia (60%). The main grade 3-4 AE were neutropenia (40%), anemia (30%), anorexia (30%) and fatigue (15%). These AE were as expected. The median dose intensity of S-1 was 270mg/m2/week (relative dose intensity (RDI) 80%), and cisplatin was 10.1mg/m2/week (RDI 84%). These toxicities were tolerable and manageable. No treatment-related death was observed. Conclusions: We conclude that this S-1 plus split cisplatin regimen was well tolerated in the treatment of AGC, and most patients could be administered in the outpatient. We are planning the final efficacy analysis for February 2013.

Comparison of 0.5M gadoterate and 1.0M gadobutrol in peripheral MRA: A prospective, single‐center, randomized, crossover, double‐blind study

To evaluate the diagnostic efficacy of macrocyclic paramagnetic gadolinium (Gd) chelates gadoterate (0.5 mmol/mL) and gadobutrol (1.0 mmol/mL) for the diagnosis of clinically significant abdominal/lower limb arterial diseases at 3.0T. This study was conducted as a prospective, single-center, randomized, double-blind, intraindividual study comparing single dose (0.1 mmol/kg) gadoterate enhanced-MRA (magnetic resonance angiography) with gadobutrol enhanced-MRA at 3.0T for their diagnostic potential in patients with peripheral artery disease. A total of 20 patients were included in this trial. Fourteen patients were eligible for the final efficacy analysis. The overall image quality (excellent/more than adequate) was better rated with gadoterate than with gadobutrol (100% vs. 78.6%, 100% vs. 92.9%, 100% vs. 85.7%, 100% vs. 85.7% for readers 1, 2, 3, 4, respectively). Diagnostic confidence was rated high/excellent in 100% (readers 1, 2, and 3) and 92.9% (reader 4) with gadoterate compared to 92.9% (readers 1 and 2) and 85.7% (readers 3 and 4) with gadobutrol. Higher signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) values were obtained for gadobutrol compared to gadoterate (26.1/23.4, P = 0.01, and 22.7/20.2, P = 0.01). For the secondary criteria, no differences between groups were reported. No adverse events were reported. Gadobutrol yielded significantly higher SNR/CNR while gadoterate was better rated in terms of overall image quality and diagnostic confidence (P > 0.05).

A Cancer Research UK two-stage multicenter phase II study of imatinib in the treatment of patients with c-kit positive metastatic uveal melanoma (ITEM).

8523 Background: The median overall survival (OS) for metastatic uveal melanoma is less than 6 months with a median progression free survival(PFS) of 3 months. No systemic or regional therapy has shown a survival advantage over best supportive care. Despite pre-clinical evidence suggesting anti-tumour activity for the KIT tyrosine kinase inhibitor imatinib, there are several negative phase II trials in unselected patients. Our primary aim was to test the efficacy of imatinib in patients with prospectively-tested c-kit immunopositive metastatic uveal melanoma. Secondary aims included assessment of toxicity and patient recruitment. Methods: A phase II UK multicentre single-arm, two-stage Gehan design recruited 25 evaluable patients receiving imatinib 400mg OD until progression/unacceptable toxicity. Primary efficacy outcome was PFS at 3 months. Secondary outcomes were OS, overall PFS, disease response (RECIST) and toxicity. Prospective sample collection for putative biomarkers was included. Results: After 16.6 months 37 patients were screened, with 25 were registered and included in final efficacy analyses. The sample included PS 0-1 patients with a median age of 63 yrs and a median 9.3 months from diagnosis of metastatic disease. 82% had high LDH levels (&gt;460IU/L), 65% had no previous treatment for metastatic disease and 8% did not have liver involvement by metastasis. Preliminary final results indicate the estimated proportion of patients progression free at 3 months is 0.24 (95% CI, 0.09 to 0.45). Median PFS and OS were 12.0 weeks (95% CI,11.6 to 14.3) and 29.6 weeks (95% CI, 19.3 to 61.0) respectively. Two patients had confirmed PR with response duration of 93 and 112 weeks, respectively, despite the absence of mutations in exons 11, 13, and 17 of the c-KIT gene. Conclusions: The trial successfully recruited to target in this rare disease area failing to convincingly show improved PFS in a selected cohort of c-kit immunopositive patients. Both patients with PR experienced long periods of disease control. Response was not dependent upon the presence of activating mutations in KIT. Further translational studies are ongoing to determine putative biomarkers of response.

OT2-01-02: First-Line Bevacizumab in Combination with Capecitabine or Paclitaxel for HER2−Negative Locally Recurrent or Metastatic Breast Cancer (LR/MBC): A Randomized Phase III Trial.

Abstract Background A number of phase III studies have shown significant progression-free survival (PFS) benefits with the combination of bevacizumab (Bev) and either first-line capecitabine (X) or taxane therapy in LR/MBC. The ongoing open-label, randomized, phase III CECOG-sponsored TURANDOT study (CECOG/BC.1.3.005) is investigating the efficacy and safety of first-line Bev plus paclitaxel (P) versus Bev plus X in this setting. Materials and methods: Eligible patients (pts) are aged ≥18 years with HER2−negative, chemonaïve LR/MBC, an ECOG performance status of 0–2 and a life expectancy &amp;gt;12 weeks. Prior chemotherapy and concomitant hormonal therapy for LR/MBC are not permitted, but prior (neo)adjuvant chemotherapy is allowed if completed ≥6 months before randomization or ≥12 months if taxane based. Pts are randomized to receive Bev 10mg/kg days 1, 15 plus P 90mg/m2 days 1, 8, 15, q28d (Arm A) or Bev 15mg/kg day 1 plus X 1,000mg/m2 bid days 1–14, q21d (Arm B) until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective is to demonstrate non-inferiority in overall survival (OS) with Bev plus P versus Bev plus X (upper limit ≤1.33 for the two-sided confidence interval for hazard ratio [HR]). Secondary objectives are: comparison of overall response rate (RECIST criteria); PFS; time to response; duration of response; time to treatment failure; safety (CTCAE version 3); and quality of life (EORTC QLQ-30). The recruitment target is 560 pts. A sample size of 490 pts in the per-protocol population will be required to provide 80% power to reject the null hypothesis of inferiority at a one-sided significance level of 0.025, assuming a 24-month median OS with Bev plus P and an alternative hypothesis of HR=1. Data cut-off for adverse event reports was 12 Apr 2010. Interim and final efficacy analyses will be triggered after 175 and 389 events, respectively. Results: Recruitment to the study began in Sep 2008 and was completed in Aug 2010, with 561 pts randomized. Follow-up is ongoing. Conclusions: TURANDOT is the first study to examine the efficacy and safety of Bev plus P versus Bev plus X as first-line treatment for pts with LR/MBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-01-02.

Abraxane, temozolomide, and oblimersen (The ATG Trial): A final report of toxicity and clinical efficacy in metastatic melanoma patients with normal lactate dehydrogenase (LDH).

8545 Background: The combination (combo) of oblimersen (OBL), a bcl-2 anti-sense agent, with dacarbazine showed promise in metastatic melanoma (MM) patients (pts) with normal (nl) LDH. OBL, temozolomide (TMZ), and abraxane (ABX) were synergistic in preclinical models of A375 MM cell lines. We conducted a phase I trial of this combo in MM pts with nl LDH and will present the final analysis of toxicity (tox) and clinical efficacy. Methods: Chemo-naïve MM pts (ECOG PS≤2, nl LDH, measurable disease per RECIST) were enrolled onto a phase I protocol with 3 cohorts (ct). Treatment regimen consisted of 56-day cycles of OBL 7 mg/kg/d continuous IV infusion (CIV), d 1-7 and 22-28 in ct 1-2; OBL 900 mg fixed dose over 1 hour, twice weekly in weeks 1-2, 4-5 [d 1,4,8,11,22,25,29,32] for ct 3; TMZ 75/m2/d in ct 1-3, d 1-42, and ABX 175 mg/m2 in ct 1 and 3, 260 mg/m2 in ct 2, d 7 and 28. IHC staining for Bcl-2, Bcl-XL, BAK and caspase 3 were performed in pre- and post-therapy tumor samples. ABX and OBL PK and shed serum cryptic epitopes (SSCE) were monitored. Results: 32 pts were treated (ct 1-14; ct 2- 4; ct 3-14). Median age= 58 years (range: 34-78). Stage M1a-4; M1b-2; M1c-26. Average cycles=3. Tox, all ct: Gr III leukopenia (1), neutropenia (neut) (2), thrombocytopenia (thrombo) (1), sensory neuropathy (sens neuro) (2), OBL hypersensitivity (2); Gr IV neut (1), thrombo (1), sens neuro (4). Responses, all ct: 2-CR (48+ and 14 mos), 10-PR, 13-SD, 7-PD for a disease control rate (CR+PR+SD) of 78.1%. Survival, all ct: OS 14.7 mos; 50% survived > 1y. Correlates: No impact of combo on ABX PK. SSCE appeared to correlate with clinical response or disease progression. Alteration of the tumor biology based on phenotypic changes in Bcl-2, Bcl-xL, BAK and caspase 3 correlated with response to treatment. Conclusions: The combo of OBL, TMZ, and ABX in MM pts with nl LDH is safe and well tolerated. The disease control rate of 78.1% and the survival data are encouraging. Biomarker studies support the rationale that Bcl-2 antisense therapy specifically impacts apoptotic signaling pathways in MM cells. The twice-weekly, fixed-dose OBL schedule appears to be similar in safety and efficacy as the 7-day CIV regimen.

TBCRC009: A multicenter phase II study of cisplatin or carboplatin for metastatic triple-negative breast cancer and evaluation of p63/p73 as a biomarker of response.

1025 Background: Triple-negative breast cancer (TNBC) has a poor prognosis compared to other BC subtypes and lacks specific therapeutic targets. Platinum chemotherapy (CTx) may be active in this population. The p53 family members p63 and p73 are expressed in about 40% of TNBC and may predict response to platinum. TBCRC009 is a multicenter single arm phase II study of single agent platinum in metastatic TNBC. Methods: Eligible metastatic TNBC patients (pts) had measurable disease, available archival tumor, ≤ 1 prior metastatic therapy, and no prior platinum CTx. Pts were assigned by physician choice (limited to equal enrollment in each arm) to cisplatin 75mg/m2 or carboplatin AUC=6 every 21 days with optional extension to 28 days after cycle 1. Co-primary endpoints were: 1) Response Rate (RR) and 2) whether tumor p63/p73 expression by qRT-PCR predicts response. Results for endpoint 1 are presented. Results: 86 TNBC pts enrolled between June 2007-Oct 2010. Med age=52 (30−78), 80% White, 8% Black. 64% had ECOG PS=0, 86% had adjuvant CTx, 70% had prior anthracycline and 73% prior taxane. Mean # of disease sites = 2.4; lymph nodes (52), lung (41), bone (25), liver (24). Optional research biopsies were collected from 8 pts. Overall RR was 30.2% (95% CI 22.1%−39.4%), including 4 CR (4.7%), 22 PR (25.6%). All 4 CRs remain progression-free 156, 71, 44, and 24 weeks since study entry, and 3 stopped treatment after 6 cycles. The CBR (CR+PR+SD>6 mo) was 34%. Exploratory subgroup analysis of RR: Cis 37%, Carbo 23%; 1st line 31.7%, 2nd line 20%. Med # cycles = 4 (range 1−19), with 10 pts ≥ 10 cycles. Med PFS = 89 days and 4 pts remain on study at abstract submission. 33% of pts progressed by 6 weeks, but 33% remained on study for ≥ 6 mos. 51 treatment related grade 3/4 toxicities occurred: Gr 4 included neutropenia (1) and HTN (1); Gr3 included fatigue (8), neutropenia (6), anemia (5), hyponatremia (4). Conclusions: First or second line single agent platinum is active and well tolerated in metastatic TNBC with durable CRs and PRs. p63/p73 analysis, additional correlative studies, and BRCA mutation analysis is ongoing. Final updated efficacy analysis for primary endpoint 1 will be presented.