Placebo Plus Research Articles

Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer.

In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680). Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis. As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups. First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.

SCT-I10A or Placebo Plus Docetaxel With Previously Treated Squamous Cell Non-small Cell Lung Cancer

SCT-I10A or Placebo Plus Docetaxel With Previously Treated Squamous Cell Non-small Cell Lung Cancer

Quality of Life Was Not Negatively Impacted By the Addition of Lenalidomide to R-CHOP Chemotherapy (R2-CHOP) Compared with Placebo Plus R-CHOP Chemotherapy in Patients with Previously Untreated Activated B-Cell (ABC)-Type Diffuse Large B-Cell Lymphoma (DLBCL): Health-Related Quality of Life (HRQoL) Analysis of the International Robust Study

Quality of Life Was Not Negatively Impacted By the Addition of Lenalidomide to R-CHOP Chemotherapy (R2-CHOP) Compared with Placebo Plus R-CHOP Chemotherapy in Patients with Previously Untreated Activated B-Cell (ABC)-Type Diffuse Large B-Cell Lymphoma (DLBCL): Health-Related Quality of Life (HRQoL) Analysis of the International Robust Study

A Study of Toripalimab or Placebo Plus Chemotherapy as Treatment in Early Stage NSCLC

A Study of Toripalimab or Placebo Plus Chemotherapy as Treatment in Early Stage NSCLC

PC02.03 IO Should Be Given as a Single Agent

PC02.03 IO Should Be Given as a Single Agent

An Efficacy and Safety Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Chinese Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC)

An Efficacy and Safety Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Chinese Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC) - Full Text View.

Ratify (Alliance 10603): Prognostic Impact of FLT3 tyrosine Kinase Domain (TKD) and NPM1 Mutation Status in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Treated with Midostaurin or Placebo Plus Standard Chemotherapy

Ratify (Alliance 10603): Prognostic Impact of FLT3 tyrosine Kinase Domain (TKD) and NPM1 Mutation Status in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Treated with Midostaurin or Placebo Plus Standard Chemotherapy

LBA10_PR - Primary results of LORELEI: A phase II randomized, double-blind study of neoadjuvant letrozole (LET) plus taselisib versus LET plus placebo (PLA) in postmenopausal patients (pts) with ER+/HER2-negative early breast cancer (EBC)

LBA10_PR - Primary results of LORELEI: A phase II randomized, double-blind study of neoadjuvant letrozole (LET) plus taselisib versus LET plus placebo (PLA) in postmenopausal patients (pts) with ER+/HER2-negative early breast cancer (EBC)

A phase II multicenter, randomized, placebo-controlled, double-blind study of CC-486 plus pembrolizumab (pembro) vs pembro plus placebo (PBO) in previously treated patients (pts) with locally advanced/metastatic non-small cell lung cancer (NSCLC).

TPS9107Background: Effective second-line chemotherapeutic treatment options for pts with NSCLC are limited. Pembro, a PD-1–blocking antibody, has demonstrated antitumor activity and proven second-l...

Abstract P4-13-03: Updated safety from a double-blind phase 3 trial (PALOMA-3) of fulvestrant with placebo or with palbociclib in pre- and postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy

Abstract Background: Endocrine therapy (ET) resistance remains a major clinical problem for patients (pts) with hormone receptor (HR+) breast cancer (BC). In PALOMA-3, palbociclib (P) combined with fulvestrant (F) demonstrated significant prolongation of progression-free survival (PFS) vs F plus placebo (PLB) in pre/peri and postmenopausal women with HR+/HER2– metastatic BC (MBC) whose disease progressed on prior ET (median PFS 9.2 vs 3.8 m; HR=0.422, P=0.0001). Methods: In this double-blind phase 3 study, 521 pts with HR+/HER2– MBC were randomized 2:1 to receive P (125 mg/d orally for 3 weeks followed by 1 week off) and F (500 mg given per standard of care) or PLB plus F. Pre- and perimenopausal women also received goserelin. One previous line of chemotherapy (CT) for MBC was allowed. Safety assessments occurred at baseline and D1 of each cycle; blood counts occurred every 2 wks for the first 2 cycles and on D1 of subsequent cycles. As pts may have experienced multiple episodes of neutropenia during treatment, we analyzed all episodes in aggregate based on laboratory data per CTCAE4.0. Results: The results reported here are from the data cutoff of Dec 2014, with a median follow-up of 5.6 m. Overall rate of any grade (G) and G3/4 AEs was 98/70% of pts in P+F vs 89/18% in PLB+F. The most commonly reported AEs in P+F (≥20%) were hematologic toxicities, fatigue, nausea, and headache. Per lab data, G3/G4 neutropenia occurred in 52.2/8.2%, G3/G4 leukopenia in 39.5/1.2%, G3/G4 anemia in 20.8/2.9% and G3/G4 thrombocytopenia in 2.1/1.2% of pts on P+F. Neutropenia occurred early, with a median onset time for first episode of ≥G3 neutropenia of 15 d (13–197) and median time from first dose to the lowest absolute neutrophil count (ANC) of 29 d (13–334). The median duration of ≥G3 episode was 7 d (1–35), suggesting that most pts can resume treatment after a 1-week cycle delay. A comparable proportion of any grade neutropenia was observed in pts with or without prior CT (prior CT 88.4% vs no prior CT 85.4%). There was no difference in the rate of G3/G4 neutropenia in the older pts (>65 yrs, 51% vs ≤65 yrs, 57%) in P+F arm. Concurrent G≥3 infections occurred in 1% of pts with G≥3 neutropenia (2/192 pts). Febrile neutropenia occurred in 0.6% of pts in both arms. 21% of pts had dose reductions and 45% had dose interruption due to neutropenia. Dose intensity was maintained at 89.7% for P. Serious adverse events (SAEs) were reported in 9.6% of pts on P+F and in 14% of pts on PLB+F. The most common SAEs on P+F were pulmonary embolism (0.9%) and pyrexia (0.9%). Safety analyses with longer follow-up (data cut off, March 2015) are ongoing and will be presented. Conclusions: Findings suggest P+F has a favorable safety profile characterized mainly by asymptomatic hematologic toxicity. Overall SAE rates were low and comparable between the 2 arms. Palbociclib-related neutropenia differs from that seen with CT, consistent with proposed mechanism of action, in that it is not commonly associated with fever, and can be effectively managed by a dose interruption or cycle delay. Funding: Pfizer, Inc. Citation Format: Verma S, DeMichele AM, Loi S, Ro J, Colleoni M, Iwata H, Harbeck N, Stearns V, Cristofanilli M, Huang Bartlett C, Schnell P, Zhang K, Thiele A, Turner NC, Rugo HS. Updated safety from a double-blind phase 3 trial (PALOMA-3) of fulvestrant with placebo or with palbociclib in pre- and postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-03.

Baseline Predictors of Mortality in Patients with Relapsed or Refractory Acute Myeloid Leukemia Treated with Vosaroxin Plus Cytarabine or Placebo Plus Cytarabine in the Phase 3 VALOR Study

Baseline Predictors of Mortality in Patients with Relapsed or Refractory Acute Myeloid Leukemia Treated with Vosaroxin Plus Cytarabine or Placebo Plus Cytarabine in the Phase 3 VALOR Study

Improvement of Quality of Response with Ibrutinib Plus Bendamustine/Rituximab Vs Placebo Plus Bendamustine/Rituximab for Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Introduction Recent results from the HELIOS phase 3 study in relapsed/refractory CLL/SLL demonstrated that the addition of ibrutinib to chemoimmunotherapy with bendamustine/rituximab (BR) leads to an 80% reduction in risk of progression or death compared with placebo + BR (Chanan-Khan et al. ASCO 2015). In addition to prolongation of progression-free survival (PFS; median not reached vs 13.3 months; hazard ratio: 0.203, 95% confidence interval: 0.150-0.276, p Methods In total, 578 patients (pts) with relapsed/refractory CLL/SLL requiring treatment were randomized 1:1 (289 per arm) to receive BR (≤ 6 cycles) with either ibrutinib (420 mg daily) or placebo. Purine analog refractoriness (yes vs no) and number of prior therapies (1 vs > 1) were stratification factors. Pts with deletion 17p (del17p; > 20% of cells) were excluded. All pts were required to have ≥ 1 abnormal lymph node (LN; defined as a measurable lesion > 1.5 cm). The primary end point was independent review committee (IRC)-assessed PFS. In this analysis, individual parameters of response (LN, spleen, overall radiology, absolute lymphocyte count [ALC], complete blood count [CBC], and bone marrow [BM]) were evaluated. Minimal residual disease (MRD) was assessed by flow cytometry using an 8-color panel (Rawstron AC, et al. Leukemia. 2007;21:956-964); MRD samples were collected at confirmation of suspected CR (bone marrow) and every 3 months thereafter (peripheral blood). Rate of MRD-negative response was defined as the proportion of pts who reached negative disease status ( Results The ORR assessed by the IRC was 82.7% with ibrutinib + BR vs 67.8% with placebo + BR (p At baseline, similar proportions of pts in each arm had bulky disease defined as LN > 5 cm (54%-58%) or abnormal spleen (~40%) as assessed by IRC. Complete resolution of previous CLL/SLL manifestations as assessed by the IRC was achieved more often in the ibrutinib + BR arm in comparison with placebo + BR for LN (34.6% vs 15.2%), spleen (56.7% vs 37.0%), overall radiology (21.1% vs 9.0%), and BM (19.7% vs 5.9%). Rates of normalization of ALC (> 90%) and CBC (> 70%) were high and similar in the 2 arms. MRD was assessed in 120 pts treated with ibrutinib + BR and 57 pts treated with placebo + BR and was negative in 37 pts and 14 pts, respectively, which corresponds with an MRD-negative response rate of 12.8% vs 4.8% for ibrutinib + BR vs placebo + BR (p = 0.0011). Investigator-determined responses by different levels of MRD are shown in Table 1. The percentage of pts with an MRD level Conclusions Pts treated with ibrutinib + BR showed not only a higher ORR, but also a greater depth of response, with more CRs and a higher rate of resolution of LN, spleen, and BM involvement. Furthermore, the rate and depth of MRD negativity was improved, and appeared to last longer in pts treated with ibrutinib + BR compared with pts receiving placebo + BR. With a median follow up of 17 months in the ibrutinib + BR arm, no MRD-negative pts and few MRD-positive pts had progressed, thus evaluating a trend in PFS with MRD negativity is currently limited in this arm. Disclosures Cramer:Gilead: Other: Travel grant, Research Funding; Glaxo Smith Klein/Novartis: Research Funding; Astellas: Other: Travel grant; Mundipharma: Other: Travel grant; Janssen: Other: Travel grant, Research Funding, Speakers Bureau; Hoffman LaRoche: Other: Travel grant, Research Funding, Speakers Bureau. Off Label Use: Combination of bendamustine, obinutuzumab and ibrutinib for treatment of CLL. Fraser:Hoffman LaRoche: Consultancy, Honoraria; Janssen: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding. Demirkan:Amgen: Consultancy; Celgene: Other: Travel reimbursement. Santucci Silva:Merck: Research Funding; Celgene: Research Funding; GSK: Research Funding; Janssen: Other: Travel reimbursement, Research Funding; Hoffman LaRoche: Other: Travel reimbursement, Research Funding; Novartis: Other: Travel reimbursement. Janssens:Mundipharma: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy. Goy:Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Mayer:Janssen: Research Funding. Dilhuydy:Roche: Honoraria, Other: Travel reimbursement; Janssen: Honoraria, Other: Travel reimbursement; Mundipharma: Honoraria. Bartlett:Millenium: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; ImaginAB: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Gilead: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celgene: Research Funding. Rule:Roche: Consultancy, Other: Travel reimbursement; JJ Celgene: Consultancy, Other: Travel reimbursement; Gilead: Research Funding. Sun:Janssen/JJ Janssen: Employment, Equity Ownership. Howes:Janssen/JJ Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding.

Rationale and Design for the LUME-Colon 1 Study: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Nintedanib Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in Patients With Advanced Colorectal Cancer Refractory to Standard Treatment

BackgroundClinical studies of antivascular endothelial growth factor (anti-VEGF) agents have demonstrated that angiogenesis is critical to colorectal cancer (CRC) tumor growth and metastasis. Nintedanib is a triple angiokinase inhibitor of VEGF, platelet-derived growth factor, and fibroblast growth factor signaling. Nintedanib, combined with docetaxel, has been approved in the European Union for the treatment of patients with non-small-cell lung cancer with adenocarcinoma tumor histologic type after first-line chemotherapy. The objective of the present study (1199.52; clinicaltrials.gov identifier NCT02149108; LUME-Colon 1) is to evaluate the efficacy and safety of nintedanib plus best supportive care (BSC) in patients with advanced colorectal cancer refractory to standard chemotherapy regimens and biologic agents. Patients and MethodsA total of 764 patients worldwide will be randomized 1:1 to receive either nintedanib 200 mg twice daily plus BSC or placebo plus BSC in 21-day courses until disease progression, undue toxicity, or withdrawal of informed consent. The primary endpoints are progression-free survival (PFS) and overall survival (OS). The secondary endpoints are the objective tumor response and disease control. PFS and OS will be evaluated using a log-rank test to determine the effect of nintedanib independently at the 2-sided α-level of 0.05. Other assessments will include the frequency and severity of adverse events and changes in laboratory parameters to measure the safety, health-related quality of life, and pharmacogenomic analyses, focusing on exploring the predictive biomarkers and drug-resistance mechanisms. The results are expected in 2016.

Improved Survival in Patients with First Relapsed or Refractory Acute Myeloid Leukemia (AML) Treated with Vosaroxin Plus Cytarabine Versus Placebo Plus Cytarabine: Results of a Phase 3 Double-Blind Randomized Controlled Multinational Study (VALOR)

Introduction: Despite 40 years of intense clinical research, there remain no new approved treatments or standard of care for patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). New safe and effective salvage treatments are urgently needed. Vosaroxin is a first-in-class anticancer quinolone derivative that is active in AML. Vosaroxin is minimally metabolized, evades P glycoprotein receptor–mediated efflux and has activity independent of p53 status. VALOR is a rigorously designed and conducted phase 3, adaptive design, randomized, double-blind, placebo-controlled trial evaluating vosaroxin plus cytarabine (vos/cyt) vs placebo plus cytarabine (pla/cyt) in patients with R/R AML (NCT01191801). Methods: Patients were randomized 1:1 to receive cytarabine (1 g/m2 IV over 2 hr, d 1-5) plus either vosaroxin (90 mg/m2 IV over 10 min d 1 and 4; 70 mg/m2 in subsequent cycles) or placebo. Up to 2 induction and 2 consolidation cycles were administered. Eligible patients had refractory disease (persistent disease after induction, or first complete remission [CR1] Results: Between Dec 2010 and Sept 2013, 711 patients were randomized to receive vos/cyt (n = 356) or pla/cyt (n = 355) at 124 sites; per the adaptive design, a prespecified 1-time sample size increase of 225 patients was implemented after the interim analysis. At the final analysis, median OS was 7.5 mo (95% CI: 6.4-8.5) with vos/cyt vs 6.1 mo (95% CI: 5.2-7.1) with pla/cyt (HR = 0.866 [95% CI: 0.73-1.02]; 2-sided unstratified log-rank P = 0.06) (Figure). The OS difference was statistically significant in a preplanned analysis accounting for the stratification factors at randomization (2-sided stratified log-rank P = 0.02). Overall, 29.5% of patients underwent allogeneic stem cell transplant (ASCT), including 45.8% of patients Thirty-day and 60-day all-cause mortality was similar in the 2 arms (30-day: 7.9% vs 6.6%; 60-day: 19.7% vs 19.4% with vos/cyt vs pla/cyt, respectively). Most common serious AEs were febrile neutropenia (11.3% with vos/cyt vs 7.4% with pla/cyt), sepsis (8.7% vs 4.3%), pneumonia (7.6% vs 4.9%), bacteremia (8.5% vs 2.9%), and stomatitis (3.4% vs 1.4%). Serious and non-serious cardiac, renal, neurologic, and hepatic AEs were comparable between treatment groups. Conclusion: Vos/cyt demonstrated improved OS and higher CR rates in patients with R/R AML without increased early mortality. In the primary OS analysis, the overall clinical benefit associated with vosaroxin may be underestimated, particularly in younger patients, due to the confounding effect of high transplant rates, a methodological limitation of AML trials. Vosaroxin-containing therapy had acceptable tolerability. VALOR results represent one of the largest datasets available in this setting, and the OS benefit was confirmed by a robust sensitivity analysis. These data support the use of this combination as a new option for salvage therapy in patients with R/R AML. Disclosures Ravandi:Sunesis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Sayar:Sunesis: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Strickland:Sunesis: Membership on an entity9s Board of Directors or advisory committees. Schiller:Sunesis: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Erba:Sunesis: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Pigneux:Sunesis: Consultancy. Horst:Sunesis: Research Funding. Recher:Sunesis: Consultancy; Celgene: Consultancy, Research Funding; Chugai: Research Funding. Klimek:Sunesis: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Craig:Sunesis: Equity Ownership. Fox:Sunesis: Consultancy, Equity Ownership. Ward:Sunesis: Employment, Equity Ownership. Smith:Sunesis: Employment, Equity Ownership. Acton:Sunesis: Consultancy. Mehta:Sunesis: Consultancy. Stuart:Sunesis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding.

Long-Term and Low-Grade Safety Results of a Phase III Study (PARAMOUNT): Maintenance Pemetrexed Plus Best Supportive Care Versus Placebo Plus Best Supportive Care Immediately After Induction Treatment With Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non–Small-Cell Lung Cancer

IntroductionIn the PARAMOUNT (“A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed plus Best Supportive Care vs. Best Supportive Care Immediately Following Induction Treatment with Pemetrexed Plus Cisplatin for Advanced Non-Squamous Non–Small-Cell Lung Cancer”) trial, patients with advanced nonsquamous non–small-cell lung cancer (NS-NSCLC) benefited from pemetrexed maintenance therapy after induction therapy with pemetrexed and cisplatin by extending survival, delaying disease progression, and maintaining quality of life (QoL). However, low-grade 1 or 2 toxicities during long-term maintenance treatment may become burdensome and impact QoL. Materials and MethodsPatients in this double-blind study (n = 539), who had completed 4 induction cycles (pemetrexed with cisplatin) without progressive disease (PD) and had an ECOG performance status of 0/1, were randomized 2:1 to pemetrexed maintenance (500 mg/m2, day 1) plus best supportive care (BSC) or placebo plus BSC until PD. Adverse events (by maximum Common Terminology Criteria for Adverse Events [CTCAE] grade) and QoL (EuroQol 5-dimensional [EQ-5D] scale) were assessed. ResultsA median of 4 maintenance cycles was administered (range, pemetrexed 1-44; mean ± SD 7.9 ± 8.3; placebo 1-38; mean ± SD 5.0 ± 5.2), with 28% of pemetrexed and 12% of placebo patients receiving ≥ 10 maintenance cycles. The pemetrexed dose intensity was 94%. More patients receiving pemetrexed (12%) than placebo discontinued because of possible drug-related CTCAEs (4%; P = .005). Overall, pemetrexed was associated with significantly more (P < .05) low-grade events (grade 1/2 nausea, grade 2 anemia, edema, and neutropenia) than placebo. Overall, the incidence of low-grade fatigue, anemia, and neutropenia decreased with long-term pemetrexed exposure; however, renal events increased across treatment arms. EQ-5D analyses demonstrated no treatment-by-time interaction or overall treatment differences between the 2 arms. ConclusionPARAMOUNT demonstrated a low incidence of low-grade toxicities with long-term pemetrexed exposure without compromising QoL in patients with NS-NSCLC.

Cediranib Plus FOLFOX/CAPOX Versus Placebo Plus FOLFOX/CAPOX in Patients With Previously Untreated Metastatic Colorectal Cancer: A Randomized, Double-Blind, Phase III Study (HORIZON II)

Cediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) signaling with activity against all three VEGF receptors. HORIZON II [Cediranib (AZD2171, RECENTIN) in Addition to Chemotherapy Versus Placebo Plus Chemotherapy in Patients With Untreated Metastatic Colorectal Cancer] assessed infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (FOLFOX/CAPOX) with or without cediranib in patients with previously untreated metastatic colorectal cancer (mCRC). Eligible patients were initially randomly assigned 1:1:1 to receive cediranib (20 or 30 mg per day) or placebo plus FOLFOX/CAPOX. In an early analysis of this and two other cediranib studies (HORIZON I [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Previously Treated Metastatic Colorectal Cancer] and HORIZON III [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer]), the 20-mg dose met the predefined criteria for continuation. Subsequent patients were randomly assigned 2:1 to the cediranib 20 mg or placebo arms. Progression-free survival (PFS) and overall survival (OS) were coprimary end points. In all, 860 patients received cediranib 20 mg (n = 502) or placebo (n = 358). The addition of cediranib to FOLFOX/CAPOX resulted in PFS prolongation (hazard ratio [HR], 0.84; 95% CI, 0.73 to 0.98; P = .0121; median PFS, 8.6 months for cediranib v 8.3 months for placebo) but had no impact on OS (HR, 0.94; 95% CI, 0.79 to 1.12; P = .5707; median OS, 19.7 months for cediranib v 18.9 months for placebo). There were no significant differences in the secondary end points of objective response rate, duration of response, or liver resection rate. Median chemotherapy dose-intensity was decreased by approximately 10% in patients treated with cediranib. Adverse events (AEs) associated with cediranib were manageable. CONCLUSION Addition of cediranib 20 mg to FOLFOX/CAPOX resulted in a modest PFS prolongation, but no significant difference in OS. The cediranib AE profile was consistent with those from previous studies. Because of the lack of improvement in OS, cediranib plus an oxaliplatin-based regimen cannot be recommended as a treatment for patients with mCRC.

PLS-4 - Results of a Phase III Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial (CORRECT) of Regorafenib Plus Best Supportive Care (BSC) Versus Placebo Plus BSC in Patients with Metastatic Colorectal Cancer (MCRC) who have Progressed after Standard Therapies

ABSTRACT Regorafenib (BAY 73-4506) is an oral multikinase inhibitor of a broad range of angiogenic, oncogenic, and stromal kinases. The phase III CORRECT trial was conducted to evaluate efficacy and safety of regorafenib in patients with mCRC who had progressed after all approved standard therapies. Methods Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Patients were randomized 2:1 to receive regorafenib (160 mg od po, 3 weeks on/1 week off) plus BSC, or placebo (PL) plus BSC. Patients continued on treatment until progression, death, or unacceptable toxic effect. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), safety, and quality of life. Results From May 2010 to March 2011, 760 patients were randomized (regorafenib: 505; PL: 255). Baseline characteristics were balanced between the two arms. Results are available from a pre-planned formal interim analysis. The estimated hazard ratio (HR) for OS was 0.77 (95% CI: 0.64, 0.94; 1-sided P = 0.0052). Median OS was 6.4 months (95% CI: 5.9, 7.3) for regorafenib and 5.0 months (95% CI: 4.4, 5.8) for PL. The estimated HR for PFS was 0.49 (95% CI: 0.42, 0.58; one-sided P Conclusions Statistically significant benefit in OS and PFS was observed for regorafenib over PL in patients with mCRC who have failed all approved standard therapies. No new or unexpected safety signal was found.

776TiP - Gamma (Gemcitabine and Amg 479 for Metastatic Adenocarcinoma of the Pancreas): a Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Ganitumab Plus Gemcitabine (G) or Placebo Plus G as First-Line Therapy for Metastatic Pancreatic Cancer

776TiP - Gamma (Gemcitabine and Amg 479 for Metastatic Adenocarcinoma of the Pancreas): a Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Ganitumab Plus Gemcitabine (G) or Placebo Plus G as First-Line Therapy for Metastatic Pancreatic Cancer

1249P - Final Results of a Randomized, Double-Blind Phase II Study to Compare Nitroglycerin (N) Plus Oral Vinorelbine (NVBO) Plus Cisplatin (C) with Placebo (P) Plus NVBO Plus C in Patients (Pts) with Stage IIIB/IV Non-Small Cell Lung Cancer (NSCLC)

ABSTRACT Background Yasuda (JCO 2006) reported increased ORR, TTP and OS when adding N to the combination of i.v. vinorelbine (NVBiv) + C in pts with stage IIIB/IV NSCLC probably due to better drug delivery based on changed vascular tonus. NVBo and NVBiv have comparable efficacy with a more convenient administration of the oral form. Main study objective was the confirmation of the Asian results in a Caucasian population. Methods In the experimental arm pts received N 25 mg D-3 to D2 + NVBo (60) 80 mg/m2 D1, D8 + C 80 mg/m2 D1, q3w; in the control arm pts received P D-3 to D2 + NVBo (60) 80 mg/m2 D1, D8 + C 80 mg/m2 D1, q3w. Treatment continued until PD, unacceptable toxicity (tox) or pts wish to discontinue treatment. The primary endpoint was ORR, secondary endpoints included OS, PFS and safety. To show an ORR-increase from 40 to 70% with a power of 0.80 and a two-side alpha of 0.05 the planned sample size was 100 pts. Results From 10/07 to 05/10, 68 pts were randomised to the N-arm (35 pts) or P-arm (33 pts). 66 pts were treated (N-arm: 34 pts, P-arm: 32 pts). The study was stopped prematurely due to lack of recruitment. N-arm n = 34 P-arm n = 32 All n = 66 Male (%) 76.5 68.8 72.7 Median age (y, range) 63.0 (36-82) 62.5 (33-73) 62.5 (33-82) Median Karnofsky (%, range) 90 (70-100) 90 (70-100) 90 (70-100) Smoker (%) non/former/current 8.8/41.2/50.0 15.6/40.6/43.8 12.1/40.9/47.0 Squamous/adeno (%) 55.9/44.1 46.9/34.4 51.5/39.4 IIIB/IV/local relapse (%) 32.4/64.7/2.7 34.4/65.6/0 33.3/65.2/1.5 Median N cycles (n, range) 4.5 (1-8) 4.0 (1-6) 4.0 (1-8) ORR ITT (%) 95%CI 35.3 (19.7-53.5) 18.8 (7.2-36.4) 27.3 p = 0.171 ORR eval (%) 95%CI (n = 32/27/59) 37.5 (21.1-56.3) 22.2 (8.6-42.3) 30.5 p = 0.262 DCR ITT (%) 61.8 53.1 57.6 Median TTP (mo) 4.7 5.0 4.8 Median OS (mo) 11.0 12.1 11.5 Tox G3-4 >5% (%pts): N-arm: neutropenia 32.3, leucopenia 20.6, anemia 14.7, nausea 8.8 (G3), fatigue 5.9 (G3), pneumonia 5.9 (G3). P-arm: neutropenia 43.8, leucopenia 25.0, fatigue 9.4 (G3), nausea 9.4 (G3), anemia 6.3, vomiting 6.3. 1 case of febrile neutropenia G3 (N-arm). 2 deaths potentially related to chemotherapy (1 per arm). Conclusions The oral formulation of Vinorelbine + C achieved in both arms a high level of efficacy (all pts: ORR 27.3, DCR 57.6, TTP 4.8, OS 11.5). Despite the premature discontinuation and low sample size per group, the results seem to confirm previous data reported in Asian patients, with an ORR numerically higher in the N-arm but without significance. Disclosure M. Reck: Honoraria for lectures: Lilly, Roche, AstraZeneca, Daiichi-Sankyo Advisory Board: Lilly, Roche, AstraZeneca, Daiichi-Sankyo, BMS, Pfizer, Genentech. C. Rose: Employed by Pierre Fabre Pharma GmbH. All other authors have declared no conflicts of interest.

1275P - Updated Safety and Quality of Life (QOL) Results of Paramount Study: Maintenance Pemetrexed (PEM) Plus Best Supportive Care (BSC) vs Placebo (PBO) Plus Bsc Immediately Following Induction Treatment with Pem Plus Cisplatin (CP) for Advanced Nonsquamous Non-Small Cell Lung Cancer (NS-NSCLC)

ABSTRACT Objectives The PARAMOUNT trial showed that continuation maintenance therapy with pem after induction therapy with pem plus CP significantly reduced the risk of disease progression (HR = 0.62) and death (HR = 0.78) in patients (pts) with advanced NS-NSCLC. The purpose of this abstract is to present the updated safety and patients' QoL results from the continuation maintenance treatment of the PARAMOUNT trial. Methods In this phase III, randomized, double-blind, PBO-controlled study, 939 pts were treated with pem (500 mg/m2) plus CP (75 mg/m2) on day 1 of four 21-day cycles. Patients (n = 539) who had not progressed and had an Eastern Cooperative Oncology Group performance status (PS) of 0/1, were randomized (2:1; stratified for PS, induction response, and disease stage) to maintenance pem (500 mg/m2, day 1) plus BSC (n = 359) or PBO plus BSC (n = 180) until disease progression. All pts received vitamin B12, folic acid, and dexamethasone. All randomized pts were qualified for the maintenance phase safety analyses, which included summaries of the incidence of adverse events by maximum Common Terminology Criteria Adverse Events, version 3, grade. All enrolled patients that had provided baseline and at least 1 subsequent measurement for EuroQol 5-dimensional (EQ-5D) scale were included in the analysis of patient-reported outcomes. Results Safety and the QoL analyses in the continuation maintenance therapy will be presented. Conclusions The long-term and low-grade toxicities of continuation maintenance therapy with pem will be discussed. Disclosure C.M. Visseren-Grul: Employed by and own stock in Eli Lilly and Company. L. Paz-Ares: I have advisory board relationship and honararia to disclose with Eli Lilly and Company, Bayer, Roche, Pfizer. I. M. Dediu: Advisory Board - Eli Lilly and Company. M. Thomas: Advisory Board - Eli Lilly and Company Corporate Sponsored Trial - Eli Lilly and Company. N. Chouaki: Employed by and own stock in Eli Lilly and Company. A. Zimmermann: Employed by and own stock in Eli Lilly and Company. J. Pujol: Advisory Board - Eli Lilly and Company. C. Gridelli: Advisory Board, corporate-sponsored research, and honoraria/speaker bureau with Eli Lilly and Company. All other authors have declared no conflicts of interest.