julilili42/papers huggingface dataset:
Predictive importance of ulceration on the efficacy of adjuvant interferon-a (IFN): An individual patient data (IPD) meta-analysis of 15 randomized trials in more than 7,500 melanoma patients (pts).
2014-05-20

9067 Background: Many randomised trials have evaluated the role of adjuvant IFN in high-risk melanoma, some suggesting benefit and others not. To assess the evidence of IFN vs. no IFN, an IPD meta-analysis of these trials was performed. Methods: Standard IPD meta-analysis methods were used to assess event-free (EFS) and overall survival (OS), with odds ratios (OR) and confidence intervals (CI) calculated. Trials were divided by dose of IFN – high (10-20MU/m2), Peg-IFN (3-6μg/Kg), intermediate (5-10MU flat), low (3MU flat) and very low (1MU). Results: IPD was provided for 11 of 15 reported trials of IFN vs. no IFN (for the other 4 trials published data were used). Over 7500 pts were included in the analysis, with over 4700 and 3800 events for EFS and OS. There was benefit for IFN for both EFS (P<0.00001) and OS (P=0.003) (Table). This translated into increased 5-year OS from 46.1% to 49.1%. There was no evidence of differences according to dose, duration of IFN, gender, Breslow thickness or disease stage, but ulceration status impacted the IFN benefit regarding EFS (interaction test: P=0.04) and OS (P=0.002) (Table). For the ulcerated melanoma, IFN increased the OS from 38.1% to 46.0%, at 5 yrs, and from 28.0% to 38.5%, at 10 yrs. Conclusions: This meta-analysis provides evidence that adjuvant IFN significantly reduces the risk of relapse and improves overall survival. This analysis does not identify the optimal dose or duration of IFN. OS benefit was confined to pts with ulcerated tumours. The biological basis of this action is incompletely defined, and being studied in the ongoing study (EORTC 18081 and ECOG-ACRIN Intergroup Trial E1609). Dose* OR (95%CI* or 99%CI**) EFS OS High (N=1196) 0.83 (0.72-0.96) 0.93 (0.80-1.08) Peg-IFN (N=1256) 0.87 (0.76-1.00) 0.96 (0.82-1.11) Intermediate (N=2243) 0.84 (0.74-0.95) 0.91 (0.79-1.04) Low (N=2732) 0.85 (0.77-0.94) 0.86 (0.77-0.96) Very low (N=484) 0.99 (0.80-1.23) 0.96 (0.76-1.21) Overall* 0.86 (0.81-0.91) 0.90 (0.85-0.97) Ulceration** Present (N=1443) 0.79 (0.66-0.94) 0.77 (0.64-0.92) Absent (N=2322) 0.95 (0.82-1.10) 1.02 (0.87-1.20) Unknown (N=2061) 0.88 (0.76-1.01) 0.91 (0.78-1.06)
Survival and quality of life in the randomized, multicenter GLARIUS trial investigating bevacizumab/irinotecan versus standard temozolomide in newly diagnosed, MGMT-non-methylated glioblastoma patients.
2014-05-20

2042^ Background: There is a need for more effective therapies in newly diagnosed glioblastoma (GBM) patients with an MGMT-non-methylated tumor. The GLARIUS trial explored the efficacy of bevacizumab (BEV) + Irinotecan (IRI) as compared to standard TMZ in the first-line therapy of MGMT-non-methylated GBM. The primary endpoint progression-free survival after 6 months (PFS-6) has already been reported as being markedly increased in the BEV/IRI arm (Herrlinger et al., ASCO 2013, LBA 2000). The present report focuses on progression-free survival, overall survival (OS) and quality of life (QoL). OS and QoL are particularly important parameters since previous randomized trials investigating BEV in primary therapy of GBM have not been able to demonstrate an OS benefit and have yielded conflicting results regarding QoL. Methods: Patients (n=170) with newly diagnosed, MGMT-non-methylated glioblastoma received local radiotherapy (RT, 30 x 2 Gy) and were randomized (2:1) for experimental therapy with BEV (10 mg/kg q2w) during RT followed by maintenance BEV (10 mg/kg q2w) + IRI (125 mg/m2 q2w) or standard therapy with daily TMZ (75 mg/m2) during RT followed by 6 courses of TMZ (150-200 mg/m2/day for 5 days q4w). For 5 prespecified domaines of the EORTC-QLQ C30 and BN20 questionnaires (global health status, physical functioning, social functioning, motor dysfunction, communication deficit as prespecified domaines), the time to deterioration by at least 10 points was analyzed using Kaplan-Meier statistics. Results: With BEV/IRI, PFS was significantly prolonged from a median of 5.9 months (95%CI 2.7-6.2 months) to 9.7 months (95%CI 8.7-10.5 months, p=0.0004; hazard ratio 0.56, 95%CI 0.4-0.79). At progression, the crossover rate was similar in both arms (60.8 and 61.9%). Final OS results will be presented. In all prespecified dimensions of QoL, the time to deterioration was not significantly different between the treatment arms. Data of post-progression QoL will be presented. Conclusions: BEV/IRI therapy was superior to TMZ regarding PFS. BEV/IRI therapy did not alter QoL as compared to TMZ therapy. Clinical trial information: No.: 2009-010390-21.
Open-label, multicenter, single-arm phase II study (DeCOG-Trial) to further evaluate the efficacy and safety of ipilimumab in patients with cutaneous melanoma and rare subgroups.
2014-05-20

9031 Background: Ipilimumab is a recently approved immunotherapy that has shown an overall survival benefit in previously treated and treatment-naïve patients with metastatic melanoma in two phase III trials. However, results of registrational trials might not address all questions regarding safety and efficacy of ipilimumab in advanced melanoma patients seen in daily routine. We performed a multicenter, phase II clinical trial of ipilimumab in patients with different subtypes of metastatic melanoma. Methods: Pretreated patients with unresectable stage III or stage IV with cutaneous, mucosal, ocular or unknown primary melanoma (MUP) were included into this study (CA184-137; supported by BMS). Treatment-naïve patients with metastatic ocular melanoma were eligible, too. Four cycles ipilimumab should be administered at a dose of 3 mg/kg 3 weeks apart. Tumor assessments according to RECIST 1.1 version were conducted at baseline, weeks 12, 24, 36 and 48. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria v.4.0. Primary endpoint was the overall survival (OS) rate at 12 months. Results: Between May 2011 to December 2013, 156 patients were enrolled in 25 German centers and received at least one dose of ipilimumab, including 83 cutaneous, 7 mucosal, 53 ocular melanomas and 13 MUP. After a median follow-up of 7 months (range 0.1-26.4), 12-month OS rates were 37% for cutaneous, 14% for mucosal, and 22% for ocular melanomas and 27% for MUP. The median OS from the first dose of ipilimumab was 6.9 months (95% CI 5.7-8.1). The overall response rates among 104 evaluable patients were 16% for cutaneous, 17% for mucosal, 9% for ocular melanomas and 11% for MUP. There were one patient with complete response (1%), 13 patients with partial response (13%), and 23 patients with stable disease (22%). Treatment-related AEs were observed in 106 patients (68%), including 39 grade 3-4 events (25%). There was a drug-related death due to pancytopenia. Conclusions: Ipilimumab is a treatment option for patients with cutaneous, ocular, mucosal and unknown primary melanoma with manageable toxicity. Clinical trial information: NCT01355120.
MM-013: An ongoing phase 2 trial of pomalidomide and low-dose dexamethasone (POM + LoDEX) in relapsed/refractory multiple myeloma (RRMM) with moderate or severe renal impairment (RI) including patients (pts) undergoing hemodialysis.
2014-05-20

TPS8626 Background: RI occurs in > 40% of MM pts and can be associated with poor prognosis (Knudsen, EJH 2000). Data from 2 pivotal trials (MM-002, MM-003) suggested comparable efficacy and tolerability for POM + LoDEX in pts with or without moderate RI (Siegel, ASH 2012; Weisel, ASCO 2013). However, pts with severe RI were excluded from these trials. Because POM is extensively metabolized, with < 5% of active substance eliminated in the urine, RI may not affect POM exposure in a clinically relevant manner. However, this has not been definitively tested in a clinical trial, and is under investigation in the US in MM-008. MM-013is a European, multicenter, open-label phase 2 study designed to assess the efficacy, safety, and pharmacokinetics (PK) of POM + LoDEX in RRMM pts with moderate or severe RI, including those undergoing dialysis (NCT02045017). Methods: The trial is enrolling RRMM pts (N = 80) across 3 cohorts: Cohort A (n = 33 with moderate RI, estimated glomerular filtration rate [eGFR] ≥ 30 and < 45 mL/min/1.73 m2), Cohort B (n = 33 with severe RI [eGFR < 30 mL/min/1.73 m2] and no dialysis), and Cohort C (n = 14 with severe RI requiring dialysis). Pts must have biopsy-confirmed MM-related RI and RRMM with ≥ 1 prior therapy (Tx; including lenalidomide). POM 4 mg is administered D1-21/28-day cycle and LoDEX 40 mg/day (20 mg for pts > 75 y) on D1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Thromboprophylaxis is required for all pts not on dialysis; pts on dialysis should receive anticoagulants as appropriate. After Tx discontinuation, pts will be followed for survival, subsequent anti-MM Tx, and second primary malignancies for 5 y after enrollment of last pt. The primary endpoint is overall response rate; secondary endpoints include assessment of renal response (≥ 2 mos improvement in eGFR from < 15 to 30-59 mL/min/1.73 m2 [partial] + improvement from < 50 to ≥ 60 mL/min/1.73m2 [complete]), time to renal response, PFS, TTP, OS, safety, and PK. Additional analyses will examine biomarkers predictive of response or resistance to POM. MM-013 is open for enrollment across Europe. Clinical trial information: NCT02045017.
Breast cancer treatment with everolimus and exemestane for ER+ women: Results of the first interim analysis of the noninterventional trial BRAWO.
2014-05-20

578 Background: BRAWO is a German non-interventional study of 3000 patients with advanced or metastatic, hormone-receptor-positive and HER2-negative breast cancer treated with Everolimus (EVE) and exemestane (EXE). Here we report the results of the first preplanned interim analysis (IA). Methods: BRAWO collects data on the routine clinical treatment with EVE 10mg/d and EXE 25mg/d at about 400 sites. Main objectives are to extend the knowledge on a) the impact of physical activity on efficiency and quality of life, b) prophylaxis and management of stomatitis in clinical routine, and c) the sequence of therapy, when EVE is used in usual daily care. This first IA focuses on objectives b) and c). Results: 866 patients (pts) at 253 active sites were analyzed, 53.2% of pts were ongoing at data cut-off. Baseline characteristics: Median age: 66 yrs; median BMI: 25.8. ECOC 0-1: 90%; visceral metastasis: 55.0%; bone only metastasis: 25.1%. 28.8% pts received EVE and EXE as first treatment (first line), 30.3% as second line, 18.0% as third line and 23.0% as forth or later line in the advanced setting. Comparing the first 200 with the most recent 200 documented pts the usage as first or second line treatment increased from 53.5% to 70.0%. Patients treated in first or second line were less likely to experience any adverse event (AE) (68.7% in first or second, 81.4% in later lines, p<0.0005). 18.1% of pts had received EXE earlier in their treatment history. Of 445 pts with at least 3 months follow-up 45.8% developed stomatitis: 26.6% grade 1, 16.9% grade 2, 2.7% grade 3. 87.2% of pts received recommendations regarding stomatitis prevention from their physician. QoL remained stable over the course of the treatment. No correlation could be seen between grade of stomatitis and QoL. Regarding global health status, pts without AEs reported better values than pts with AEs. Insights into dosing and therapy sequence will also be presented. Conclusions: This IA indicates that pts receiving EVE and EXE in earlier lines are less likely to experience AE. The majority of physicians recommend their pts to take prophylactic measures to prevent stomatitis. QoL remains stable over the course of the treatment.
G-PCNSL-SG-1 randomized phase III trial of high-dose methotrexate with or without whole brain radiotherapy for primary central nervous system lymphoma: Long-term follow-up.
2014-05-20

8527 Background: The role of whole brain radiotherapy (WBRT) in first-line therapy of primary CNS lymphoma (PCNSL) has been increasingly questioned. This is the final report of the G-PCNSL-SG-1 trial evaluating WBRT in primary therapy of PCNSL after a median follow-up (MFU) of 81.2 months. Methods: G-PCNSL-SG-1 (www.clinicaltrials.gov NCT00153530) had randomised immunocompetent patients with newly diagnosed PCNSL to high-dose methotrexate (HDMTX) - based chemotherapy (CHT) followed by WBRT or CHT alone. We hypothesized that the omission of WBRT from first-line treatment would not compromise overall survival (OS; primary endpoint), using a non-inferiority design with a margin of 0.9. Results: Of 551 patients who entered the study 524 fulfilled the eligibility criteria (primary eligibility population), 410 entered the post-HDMTX phase (intention-to-treat, ITT population), and 320 were treated per protocol (PP). OS with versuswithout WBRT was different neither in the ITT (HR 0.997, 95%CI 0.79-1.26, p=0.98) nor in the PP population (HR 1.03, 95%CI 0.79-1.35, p=0.82). In the ITT population CR patients experienced neither a progression-free survival (PFS) benefit from the last HDMTX-based CHT (PFS-2) (HR 0.84, 95% CI 0.60-1.19, p=0.33) nor an OS benefit (HR 1.13, 95% CI 0.77-1.66, p=0.53) with WBRT. In CR patients of the PP population, WBRT conferred a benefit for PFS-2 (HR 0.68, 95%CI 0.46-1.01, p=0.059), but no OS benefit (HR 1.06, 95%CI 0.69-1.63, p=0.78). In non-CR patients of the ITT population, a benefit of PFS-2 (HR 0.58, 95%CI 0.44-0.77, p<0.001), but not of OS (HR 0.86, 95%CI 0.64-1.16 p=0.32) was found with WBRT; in non-CR patients of the PP population, WBRT conferred a benefit of PFS-2 over CHT alone (HR 0.41, 95%CI 0.29-0.57, p<0.001) and a trend for OS, too (HR 0.76, 95%CI 0.54-1.08, p=0.12). Conclusions: Despite improvement in PFS, particularly in patients without CR to HDMTX-based CHT, no significant difference in OS was found when WBRT was omitted from primary therapy in this long-term follow-up. The PFS afforded by WBRT has to be balanced against its long-term toxicity. Clinical trial information: NCT00153530.
Pomalidomide plus low-dose dexamethasone (POM plus LoDEX) versus high-dose dexamethasone (HiDEX) for relapsed or refractory multiple myeloma (RRMM): Overall survival (OS) results of MM-003 after adjustment for crossover.
2014-05-20

8593 Background: The pivotal, randomized phase 3 MM-003 trial in patients (pts) with RRMM demonstrated significantly longer median progression-free survival (PFS) with POM + LoDEX (n = 302, 4 months) than with HiDEX (n = 153; 1.9 months; P < 0.0001). Unadjusted median OS was also significantly longer with POM + LoDEX than with HiDEX (HR 0.74; P = 0.0285) despite the crossover of approximately 50% of pts from the HiDEX arm to POM + LoDEX or POM monotherapy. In the presence of extensive crossover, conventional survival analysis methods are biased. Here, we used the 2-stage Weibull method for crossover adjustment to estimate the OS difference between POM + LoDEX and HiDEX. Methods: A 2-stage model was used to estimate counterfactual, adjusted survival data for the HiDEX arm, using a secondary baseline defined by the time of disease progression. To extrapolate the counterfactual data as required by health technology assessment bodies, standard model selection methods were used to identify the best fitting parametric model. Results: Unadjusted median OS in MM-003 was 12.7 and 8.1 months in the POM + LoDEX and HiDEX groups, respectively. After adjusting for crossover, the difference in median OS in the 2 groups was 7.0 months (12.7 vs 5.7 months). Median OS in the POM + LoDEX arm was therefore more than double that in the HiDEX arm. Extrapolation using a log-normal model fitted to the adjusted OS data produced an estimated difference in mean survival times of 14.6 months (28.0 vs. 13.4 months). Predicted survival at 3 years was 21% for pts on POM + LoDEX compared with 8% for pts on HiDEX. Conclusions: The MM-003 intent-to-treat analysis showed a significant increase in median PFS and OS for POM + LoDEX vs HiDEX. The present analysis suggests that OS with POM + LoDEX is double that with HiDEX after accounting for crossover. Extrapolation over a lifetime horizon predicts a mean survival difference between POM + LoDEX and HiDEX of more than 14 months. These data provide important evidence for understanding the clinical efficacy and evaluating the overall economic value of POM in the treatment of RRMM. Clinical trial information: NCT01311687.
Intralesional treatment of stage III metastatic melanoma patients with L19-IL2: Clinical and systemic immunological responses.
2014-05-20

9041^ Background: In previous studies, intralesional injection with interleukin-2 (IL2) showed efficacy for the intratumoral treatment of cutaneous/subcutaneous metastases in advanced melanoma patients. Objectives of this multicenter study (ClinicalTrials.gov Id.: NCT01253096) were to investigate whether intralesional delivery of L19-IL2, a targeted form of IL2, would yield similar results with reduced injection frequency and treatment duration and whether systemic immune responses were induced by the local treatment. L19-IL2 is a recombinant fusion protein, consisting of IL2 fused to a single-chain monoclonal antibody (L19) directed against extradomain B of fibronectin, a well-characterized marker of angiogenesis. Methods: Twenty-five patients with unresectable Stage IIIB/IIIC melanoma and cutaneous/subcutaneous injectable metastases received intratumoral injections of L19-IL2 once per week at a maximum daily dose of 10 MIU for 4 consecutive weeks. Tumor response was evaluated twelve weeks after the first treatment. Results: Twenty-four of 25 enrolled patients were evaluable. Toxicities were mild and comparable to that of free IL2. No serious adverse event was recorded. A complete response of all metastases was achieved in 6 patients (25%), which was long-lasting in most cases (5 patients ≥ 24 months). Analysis of progression rates for these patients seems to show an effect of intratumoral injection of L19-IL2 in retarding spread of the disease to distant lymph nodes or appearance of visceral metastases, as compared to historical controls. A significant temporary increase of peripheral regulatory T cells and a sustained decrease of myeloid-derived suppressor cells was observed upon treatment. Conclusions: Intratumoral L19-IL2 treatment elicited objective responses in a high percentage of lesions. The targeted form of IL2 yielded results similar to those of the untargeted cytokine, but at lower cumulative doses and more favorable schedule and treatment duration. Analysis of progression and survival rates for these patients indicates a substantial advantage, compared to historical controls, in terms of overall survival and distant metastasis-free survival. Clinical trial information: NCT01253096.
Sorafenib (SOR) plus docetaxel (DOC) as first-line therapy in patients with HER2-negative metastatic breast cancer (MBC): A randomized, placebo-controlled phase II trial.
2014-05-20

1072 Background: Anti-angiogenic therapy with the monoclonal anti-VEGF antibody Bevacizumab (Bev) in combination with chemotherapy increases overall response rates (ORR) and progression free survival (PFS) but without impact on overall survival. SOR, an anti-angiogenic multi-tyrosine kinase inhibitor (TKI) also targeting tumor growth directly, is approved for advanced renal cell and hepatocellular carcinoma. Three phase IIb trials (SOLTI-0701, NU07B1, AC01B07) have reported efficacy of SOR in combination with chemotherapy in MBC, even after prior Bev (AC01B07). As TKIs might have superior activity we conducted this trial in first-line MBC. Methods: Pts were randomized to DOC (75mg/m2 q3w) + either SOR (400 p.o. twice daily (BID)) or placebo. Following an amendment after the inclusion of 63 pts, the SOR starting dose was reduced to 400 mg/d for cycle 1 and 600 mg/d for cycle 2 with the option to increase the dose to 800 mg/d after the second cycle in the absence of > grade 1 toxicities. The planned sample size was 288, but due to slow accrual the study was closed early after 102 patients. The primary end point was progression free survival (PFS). Important secondary endpoints were overall response rate (ORR), duration of response, time to progression (TTP), overall survival (OS) and safety/tolerability. Here we report the data after 78 PFS events in 95 evaluable patients. Results: Median age was 57 years with 71.6% of patients being post-menopausal. 74.5 of patients had a positive estrogen receptor (ER) status and 47.1% and 48.0% of patients had a tumor grading 2 and 3, respectively. Overall, as of December 13th2013, the median PFS was 7.4 months with a median TTP of 7.9 months, a median duration of response of 8.9 months and an ORR of 47.1%. The corresponding median OS was 21.2 months. Grade 3 to 4 toxicities (> 5% of pts) included neutropenia (31%), lymphopenia (25%), leukopenia (25%), HFSR (19%), diarrhea (11%), febrile neutropenia (9%), and fatigue (8%). Conclusions: Final efficacy data including overall survival and detailed safety data will be presented by treatment arm. Comparative efficacy and safety data will also be presented by SOR dosing schedule. Clinical trial information: EUDRACT-Nr. 2008-001090-15.
The STRATUS trial (MM-010): A single-arm phase 3b study of pomalidomide plus low-dose dexamethasone (POM + LoDEX) in refractory or relapsed and refractory multiple myeloma.
2014-05-20

TPS8625 Background: POM is a distinct oral IMiD immunomodulatory agent with direct anti-myeloma, stromal cell support-inhibitory, and immune-modulating activities. In the phase 3 MM-003 trial, POM + LoDEX significantly extended progression-free survival (PFS) and overall survival (OS) vs. high-dose dexamethasone in patients (pts) who failed bortezomib (BORT) and lenalidomide (LEN) treatment (Tx; Dimopoulos, ASH 2013). STRATUS is a multicenter, single-arm, open-label phase 3b trial with > 85 sites across Europe to further evaluate safety and efficacy and explore cytogenetics, pharmacokinetics (PK), and biomarkers in a large pt population (target enrollment: 720 pts; NCT01712789). Methods: Eligible pts have refractory or relapsed and refractory disease, having failed BORT and LEN and received adequate prior alkylator therapy. Key exclusion criteria include absolute neutrophil count < 800/μL, platelet count < 75,000 or 30,000/μL (for pts with < 50% or > 50% of bone marrow nucleated cells as plasma cells, respectively), creatinine clearance < 45 mL/min, hemoglobin < 8 g/dL, and peripheral neuropathy > grade 2. POM is administered 4 mg D1-21/28-day cycle and LoDEX 40 mg/day (20 mg for pts aged > 75 yrs) on D1, 8, 15, and 22 until progressive disease or unacceptable toxicity. All pts receive low-dose ASA or equivalent thromboprophylaxis. Upon Tx discontinuation, follow-up will continue up to 5 yrs from enrollment of last pt for survival, second primary malignancies, and subsequent anti-MM Tx. The primary endpoint is safety. Secondary endpoints include POM exposure, PK, efficacy (overall response rate, time to response, duration of response, PFS, time to progression, OS, and cytogenetics). Cytogenetics are collected at initial diagnosis, study entry, and upon discontinuation to better understand the evolution of cytogenetics throughout the disease course and elucidate the role of POM in pts with different cytogenetic profiles. As exploratory endpoints, bone marrow and blood samples are collected for biomarker analysis to predict response or resistance to POM Tx. As of Jan 22, 2014, 400 pts have been enrolled and enrollment continues. Clinical trial information: NCT01712789.