Placebo Pts Research Articles

SAT0084 Effects of different steroid doses on adverse events and radiographic progression of certolizumab pegol-treated rheumatoid arthritis patients

BackgroundUse of oral corticosteroids (CS) in rheumatoid arthritis (RA) remains controversial. While short-term use in early disease or during flares is suggested to reduce inflammation and erosion, side effects and...

THU0241 Haemoglobin Changes and Relationship between Anaemia and Fatigue or Vitality in Rheumatoid Arthritis Patients Treated with Tofacitinib

BackgroundTofacitinib is a novel, oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib inhibits JAK3 and/or JAK1 with functional selectivity over JAK2.ObjectivesTo characterise changes in haemoglobin...

FRI0176 Golimumab, a human anti-TNF monoclonal antibody, administered subcutaneously every four weeks as monotherapy in patients with active rheumatoid arthritis despite dmard therapy: 52-week results of clinical, radiographic and pharmacokinetic assessments

ObjectivesTo assess the efficacy and safety of golimumab (GLM) as monotherapy in Japanese patients (pts) with active rheumatoid arthritis (RA) despite DMARD therapy.MethodsGO-MONO is a multicenter, randomized, double-blind, placebo (PBO)-controlled...

THU0360 Rapid Improvements in Patient-Reported Outcomes with Certolizumab Pegol in Patients with Axial Spondyloarthritis, Including Ankylosing Spondylitis: 24-Week Results of Rapid-Axspa Study

BackgroundAxial spondyloarthritis (axSpA) includes both ankylosing spondylitis (AS) and axSpA with no definitive sacroiliitis on X-ray (non-radiographic axSpA, nr-axSpA). These patients (pts) subgroups have similar clinical disease burden,1 however, the...

AB0501 Efficacy and safety of certolizumab pegol (CZP) with concomitant methotrexate (MTX) in korean rheumatoid arthritis (RA) patients (PTS) with an inadequate response to MTX

BackgroundCZP as a concomitant therapy to MTX has shown rapid and sustained efficacy in RA pts in previous international clinical trials.ObjectivesTo confirm the efficacy and safety of CZP+MTX in Korean...

THU0151 Effects of tofacitinib (CP-690,550), an oral janus kinase inhibitor, or adalimumab on patient reported outcomes in a phase 3 study of active rheumatoid arthritis

BackgroundTofacitinib (CP-690,550) is a novel, oral Janus kinase (JAK) inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis (RA).ObjectivesTo compare the effects of tofacitinib 5 and...

SAT0151 Long-term safety of 4-weekly certolizumab pegol in rheumatoid arthritis: 5 year results from an open label extension study

BackgroundCertolizumab pegol (CZP) administered every 4 weeks (Q4W) for RA was shown to have an acceptable safety profile when given as monotherapy in FAST4WARD (NCT00548834) or with MTX in the...

AB0513 Safety and efficacy of golimumab, a human anti-tnf monoclonal antibody injected subcutaneously every 4 weeks, in chinese patients with active ankylosing spondylitis: one-year results of a phase 3, randomized, placebo-controlled study

BackgroundA multicenter, randomized, placebo (PBO)-controlled study of golimumab (GLM) was performed in Chinese pts with ankylosing spondylitis (AS).ObjectivesTo assess efficacy and safety of golimumab (GLM) through wk56 in Chinese pts...

PWE-025 Assessing the Percent of Days Linaclotide Improved Abdominal Symptoms and Stool Frequency in Patients with Irritable Bowel Syndrome with Constipation (IBS-C): Pooled Analysis of 2 Phase 3 Trials

IntroductionLinaclotide (LIN), a minimally absorbed guanylate cyclase C agonist (GCCA), improved abdominal symptoms and bowel movement (BM) frequency in patients (pts) with IBS-C in 2 Phase 3 trials. This post-hoc...

OP0106 Effect of Certolizumab Pegol on Signs and Symptoms of Axial Spondyloarthritis, Including Ankylosing Spondylitis and Non-Radiographic Axial Spondyloarthritis: 24-Week Results of Rapid-Axspa Study

BackgroundAxial spondyloarthritis (axSpA) includes both ankylosing spondylitis (AS) and axSpA with no definitive sacroiliitis on X-ray (non-radiographic axSpA, nr-axSpA). RAPID-axSpA (NCT01087762) is the first RCT of an anti-TNF to include...

AB0526 Sustained efficacy responses and a consistent safety profile with rituximab repeat treatment over 5 years in patients with rheumatoid arthritis and an inadequate response to tumour necrosis factor inhibitors in the reflex study

BackgroundIn the REFLEX study conducted in anti-TNF inadequate responder (TNF-IR) patients (pts) with RA, a single course of rituximab (RTX) in combination with methotrexate (MTX) significantly improved disease activity at...

PWE-027 Mediation Analysis Supports a Direct Effect of Linaclotide (LIN) on Abdominal Pain (AP) Relief Independent of Constipation Improvement

IntroductionLIN, a 14-amino-acid, minimally-absorbed guanylate cyclase C agonist (GCCA), significantly improved AP and complete spontaneous bowel movements (CSBMs) vs placebo (PBO) in 2 Phase 3 IBS-C trials. Recurrent AP in...

Outcomes in patients with liver or lung metastatic castration-resistant prostate cancer (mCRPC) treated with the androgen receptor inhibitor enzalutamide: Results from the phase III AFFIRM trial.

5065 Background: Enzalutamide (ENZA) inhibits multiple steps in the androgen receptor signaling pathway (Tran et al, Science. 2009;324:787). The phase III AFFIRM trial demonstrated that ENZA increased median overall survival (OS) by 4.8 months (P <0.001, HR 0.63) vs placebo (PBO) in post-docetaxel mCRPC patients (pts) (Scher et al, NEJM 2012; 367:1187). Here we assess the effect of ENZA on outcomes in pts with liver or lung metastases in the AFFIRM trial. Methods: The AFFIRM trial was a phase III multinational, randomized, double-blind study in post-docetaxel mCRPC pts. Randomization was 2:1 to ENZA 160 mg/day or PBO, stratified by baseline ECOG and mean pain score. The primary endpoint was overall survival (OS). Radiographic progression-free survival (rPFS) was a key secondary endpoint. PSA response defined as a decline of ≥50% compared to baseline, and soft tissue objective response per RECIST 1.1 were also assessed and reported here. Results: Pts with liver mCRPC comprised 11.5% (92/800) of ENZA pts and 8.5% (34/399) of PBO pts. Pts with lung mCRPC comprised 15.3% (122/800) of ENZA pts and 14.8% (59/399) of PBO pts. The median OS for patients with liver and/or lung mCRPC in the AFFIRM trial was 11.4 months (ENZA: 13.4 months; PBO: 9.5 months). Improved outcomes with ENZA treatment were observed in both liver and lung mCRPC pts. Conclusions: In the phase III AFFIRM trial, pts with lung mCRPC had higher median OS than pts with liver mCRPC. ENZA resulted in higher response rates in both liver and lung mCRPC pts. OS and rPFS were also improved in both pt groups treated with ENZA. Clinical trial information: NCT00974311. [Table: see text]

Correlation between baseline variables and survival in the radium-223 dichloride (Ra-223) phase III ALSYMPCA trial with attention to total ALP changes.

5080 Background: In patients (pts) with castration-resistant prostate cancer and bone metastases (mCRPC), total ALP (tALP) has been shown to be a prognostic marker for overall survival (OS) (Cook 2006). Here the prognostic value of tALP and other baseline clinical variables in Ra-223 pts is presented, along with the initial results of an exploratory analysis of changes in tALP seen with Ra-223. Methods: Study population included 921 pts (intent-to-treat population) from the ALSYMPCA trial. The Cox proportional hazards model was used to evaluate the prognostic potential of tALP and other baseline variables (albumin, Hb, LDH, ECOG performance status, PSA, and age). Log transformation was done for baseline variables (tALP, PSA, and LDH) with heavily skewed distributions. Baseline variables were assessed for interaction with treatment. To determine changes in tALP from baseline at 12 wk, 708 pts who had tALP measurements at both baseline and 12 wk were included. Results: The baseline variables in the Table were significantly associated with OS. Hb was not a significant factor when adjusting for all other covariates and was therefore removed from the final Cox regression model. No significant treatment-by-covariate interactions were detected. After controlling for other variables, higher baseline tALP was significantly associated with an increased risk of death (p < 0.0001). At 12 wk, a decline in tALP relative to baseline was seen in 87% (433/497) of Ra-223 pts, compared to 23% (49/211) of placebo pts. The mean percentage change from baseline in tALP at 12 wk was a 32% decline for Ra-223 pts, in contrast to a 37% increase for placebo pts (p< 0.001). Conclusions: In mCRPC pts, higher baseline levels of tALP were associated with an increased risk of death. With the majority of Ra-223 pts experiencing a decline in tALP at 12 wk, and the marked mean percentage tALP decline in these pts, further analysis to determine a correlation between tALP dynamics and survival is warranted. Clinical trial information: NCT00699751. [Table: see text]

Mutational analysis of plasma DNA from patients (pts) in the phase III GRID study of regorafenib (REG) versus placebo (PL) in tyrosine kinase inhibitor (TKI)-refractory GIST: Correlating genotype with clinical outcomes.

10503 Background: The phase III GRID study showed that REG provides a significant improvement in progression-free survival (PFS) compared with PL in pts with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib (IM) and sunitinib (SU; HR 0.27, p<0.0001). Determining GIST genotype in TKI-refractory disease has proven challenging due to inter-tumoral heterogeneity and pt preference to avoid serial biopsies. To overcome this, we analysed circulating DNA in plasma as a source of tumor DNA and studied the correlation between mutational status and clinical outcome. Methods: DNA was isolated from both archival tumor tissue (n=102) and plasma at baseline (n=163) and analyzed for mutations via Sanger sequencing (tissue) or BEAMing (plasma). Results: Mutational frequencies for tumor tissue samples were: KIT, 66%; PDGFRA, 3%; KRAS, 1%; BRAF, 0%. For plasma, frequencies were: KIT, 58%; PDGFRA, 1%; KRAS, 1 out of 2 samples, BRAF, 0%. Detection of primary KIT mutations showed 84% concordance between tissue and plasma. Secondary KIT mutations were more commonly detected in plasma (47%) than in tissue (12%). Subgroup analysis based on mutational status showed an improved PFS in REG-treated pts vs PL in all subgroups by both central and local review of imaging studies. The presence of a secondary KIT mutation in plasma was associated with shorter PFS in pts receiving PL (HR 1.82, p=0.05). Pts with a KIT-exon 9 mutation received IM for a shorter period of time, and SU for a longer period of time, relative to other GIST genotypes. Pts with a PDGFRA mutation showed variable clinical responses, while 1/1 KRAS-mutant GIST did not respond well to IM, SU, or REG. Conclusions: KIT mutational status correlated to IM and SU treatment duration. While consistent with prior reports using tissue sampling, this validates the utility of plasma-based circulating DNA analysis of target oncogenes. Secondary KIT mutations appear to have a negative prognostic impact in GIST, while the clinical benefit of REG vs PL was not influenced by KIT mutational status. Clinical trial information: NCT01271712.

Efficacy and safety of gemcitabine in combination with TH-302 compared with gemcitabine in combination with placebo in previously untreated patients with metastatic or locally advanced unresectable pancreatic adenocarcinoma: The MAESTRO trial.

TPS4148 Background: Tumors often consist of highly hypoxic subregions that are resistant to chemotherapy and radiotherapy. The investigational hypoxia-targeted drug TH-302 is reduced at its nitroimidazole group, and under hypoxic conditions releases the DNA alkylator bromo-isophosphoramide mustard (Br-IPM). A randomized Phase IIb trial of TH-302 in pts with metastatic or locally advanced unresectable pancreatic adenocarcinoma (PDAC) confirmed a significant PFS improvement (p=0.008) in pts treated with TH-302 at 340 mg/m2+ gemcitabine compared with gemcitabine alone (Borad et al, ESMO 2012). Skin and mucosal toxicities, mainly Grade 1/2, and myelosuppression (thrombocytopenia, neutropenia and anemia) were the most common AEs related to TH-302 and did not lead to increases in treatment discontinuation. Grade 3/4 myelosuppression was more frequent in the TH-302 + gemcitabine arm. AEs leading to treatment discontinuation as well as non-hematological serious AEs were balanced across arms. Methods: This is a Phase III, randomized, double-blind, placebo-controlled trial (NCT01746979) of gemcitabine + TH-302 compared with gemcitabine + placebo in pts with locally advanced unresectable or metastatic PDAC. The study is designed to detect a 25% risk reduction of death with 90% power and two-sided alpha of 5%. A total of 660 pts are planned to be randomized 1:1. Key eligibility criteria include histologically or cytologically confirmed disease, no prior chemotherapy or systemic therapy (except as specified in the protocol), ECOG performance status 0 – 1, and bilirubin ≤ 1.5x upper limit of normal. Randomized pts receive TH-302 + gemcitabine or gemcitabine + placebo in 4-week cycles until progressive disease, intolerable toxicity, or pt withdrawal. The primary objective is to evaluate OS. Secondary objectives include PFS, objective response, and disease control; safety and tolerability; pt-reported QoL and pain; CA 19-9 levels and PK of TH-302; exploratory pharmacogenomic markers and potential predictive biomarkers. Enrollment to the study is ongoing. Clinical trial information: NCT01746979.

Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer (SOC) and a BRCA mutation (BRCAm).

5505 Background: Previously, we reported that maintenance treatment with the oral PARP inhibitor olaparib (400 mg bid) led to a significant PFS improvement vs placebo in patients (pts) with platinum-sensitive relapsed SOC (Ledermann et al NEJM2012). A preplanned subgroup analysis from this randomized, double-blind Phase II trial (NCT00753545) suggested that olaparib may lead to a greater PFS, and an OS, benefit in pts with a known germline BRCAm (gBRCAm). Since gBRCA wild-type (gBRCAwt) pts may develop somatic tumor (t)BRCAm, efficacy analyses were performed for all pts with BRCAm. Methods: gBRCAm status was determined retrospectively for all consenting pts (n = 166) using blood samples taken before randomization. tBRCAm status was determined from archival tumor samples of 196 pts. We analyzed PFS/OS by gBRCAm and total BRCAm status. Preliminary data are reported. Results: gBRCA status was known for 218/265 pts (gBRCAm, 96; gBRCAwt, 122). Including tBRCAm, 136 pts had a BRCAm (BRCAwt, 116). gBRCAm pts had the greatest PFS benefit with olaparib maintenance vs placebo (median: 11.2 vs 4.1 months [m]; HR, 0.17; 95% CI 0.09-0.32; P<0.001) and a significant QoL improvement, as measured with Trial Outcome Index (OR, 4.08; 95% CI 1.11-19.85; p = 0.03). The PFS benefit was consistent when tBRCAm pts were included (median: 11.2 vs 4.3 m; HR, 0.19; 95% CI 0.11-0.32; p <0.0001). In an interim analysis of OS (58% maturity), a comparison of olaparib vs placebo in the overall population led to a HR of 0.88 (95% CI 0.64-1.21) with medians of 29.8 vs 27.8 m, respectively. Although HRs from the gBRCAm and gBRCAwt subgroups were similar (0.85 and 0.84, respectively), 13/37 gBRCAm placebo pts received a subsequent PARP inhibitor, confounding the OS data in this subgroup. The analysis of all BRCAm pts was less confounded and resulted in an OS HR of 0.74 (95% CI 0.46-1.19; median: 34.9 vs 31.9 m). 19 pts have received olaparib for >3 years. Olaparib tolerability was similar in BRCAm pts and the overall population. Conclusions: Olaparib maintenance treatment led to the greatest clinical benefit in pts with a BRCAm. These compelling data warrant confirmation in phase III trials. Clinical trial information: NCT00753545.

Pain analysis from the phase III randomized ALSYMPCA study with radium-223 dichloride (Ra-223) in patients with castration-resistant prostate cancer (CRPC) with bone metastases.

19 Background: Bone metastases (mets), present in >90% of patients (pts) with CRPC, may cause severe pain. In a phase II dose-response study with Ra-223 treatment, pain response (pain reduction and stable analgesic consumption) was seen in up to 71% of CRPC pts with painful bone mets (Nilsson 2012). In the phase III ALSYMPCA study, which included 921 CRPC pts with bone mets randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching placebo (Ra-223, n=614; placebo, n=307), Ra-223 significantly improved overall survival vs placebo (median 14.9 vs 11.3 mo; HR=0.695) and was well tolerated. Post hoc analyses of pain parameters in ALSYMPCA are presented. Methods: The hazard ratios for time to initial opioid use and time to external beam radiation therapy (EBRT) were analyzed using the Cox proportional hazards model. Pts with no opioid use at baseline were included in the pain analyses. Concomitant opioid use was recorded from first study drug injection to 12 weeks after last injection. Results: Baseline pain characteristics were similar between the treatment groups (approximately 55% of pts had moderate to severe pain and opioid use based on WHO ladder for cancer pain). Time to EBRT was significantly longer in the Ra-223 group vs placebo (HR=0.670, 95% CI: 0.525-0.854). Fewer Ra-223 pts reported bone pain as an AE compared to placebo pts (50% vs 62%). 269 pts in the Ra-223 group and 139 pts in the placebo group had no opioid use at baseline. Median time to initial opioid use was significantly longer in the Ra-223 group, with a risk reduction of 38% compared to placebo (HR=0.621, 95% CI: 0.456-0.846). Fewer pts in the Ra-223 group (36%) than in the placebo group (50%) required opioid use for pain relief. Conclusions: These ALSYMPCA results provide consistent evidence that, in addition to prolonging survival, Ra-223 reduces pain and opioid use in patients with CRPC and bone metastases. Clinical trial information: NCT00699751.

Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor.

6 Background: ENZA increased median overall survival (OS) by 4.8 mo (P <0.001, HR 0.63) vs placebo (PBO) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) post-docetaxel in AFFIRM (HI Scher et al, NEJM 2012). Corticosteroids (CS) can activate AR signaling in nonclinical models (J Richards, Can Res 2012). In a multivariate model of AFFIRM data baseline CS use was associated with reduced OS (HI Scher et al. ESMO 2012 abstract 899PD). The impact of CS use during study treatment in AFFIRM was evaluated to test if concomitant CS use is also associated with inferior outcomes. Methods: Pts were randomized 2:1 to ENZA 160 mg/d or PBO. Pts were allowed but not required to take CS. OS was the primary endpoint. In a post-hoc analysis On-study CS use was defined as oral CS user for ≥ 1 day on study. Results: On study CS use was 48% in ENZA and 45% in PBO pts. Prognostic factors were slightly better in the no CS group compared to the CS group. Use of CS regardless of treatment was associated median OS of 11.5 mo (95% CI: 10.5, 13.0) for CS pts vs median OS NM (NM, NM) for no CS pts (HR=0.40; 95% CI: 0.33, 0.48). ENZA was consistently superior to PBO for OS, radiographic progression free survival (rPFS) and time to PSA progression (TTPP), regardless of CS use (Table). Pts on CS had higher rates of grade 3 - 4 adverse events (AE) compared to no CS pts: 63.3% vs 34.4% respectively. Conclusions: In this post-hoc analysis, on study CS use was associated with reduced OS and higher rates of grade 3 -4 AEs in mCRPC pts post-docetaxel. While CS pts had worse outcomes, ENZA was consistently superior to PBO regardless of on study CS use. The inferior outcomes in CS pts may be due to unmeasured confounders or the biologic properties of CS use itself. Clinical trial information: NCT00974311. [Table: see text]

Outcomes in elderly patients with metastatic castration-resistant prostate cancer (mCRPC) treated with the androgen receptor inhibitor enzalutamide: Results from the phase III AFFIRM trial.

16 Background: Enzalutamide (ENZA) inhibits multiple steps in the androgen receptor signaling pathway (Tran et al, Science. 2009;324:787). The phase III AFFIRM trial demonstrated that ENZA increased median overall survival (OS) by 4.8 months with a 37% reduction in the risk of death (P <0.001, HR 0.63) vs placebo (PBO) in post-docetaxel mCRPC patients (pts) (Scher et al, NEJM 2012; 367:1187). In a post-hoc analysis, the effect of ENZA on outcomes in elderly (≥ 75 yrs) vs younger (< 75 yrs) pts in the AFFIRM trial was assessed. Methods: The AFFIRM trial was a Phase III multinational, randomized, double-blind study in post-docetaxel mCRPC pts. Randomization was 2:1 to ENZA 160 mg/day or PBO, stratified by baseline ECOG performance status and mean pain score. Statistics are presented by age group (≥75, yrs <75 yrs) for efficacy outcomes of OS, radiographic progression-free survival (rPFS), and time to prostate-specific antigen (PSA) progression. Top line safety results are also presented for both age groups. Results: Elderly pts comprised 25% (199/800) of ENZA pts and 26% (104/399) of PBO pts. Improved outcomes with ENZA treatment were observed in both elderly and younger pts, with similar safety profiles in each age group. Conclusions: ENZA significantly improved outcomes in both elderly (≥ 75yrs) and younger pts (< 75yrs). Safety and tolerability findings were comparable between the two age groups. Clinical trial information: NCT00974311. [Table: see text]