bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of single agent mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in patients with diffuse large cell B-cell (DLBCL) and follicular (FL) lymphomas.
Authors: Crump Michael , Andreadis Charalambos , Assouline Sarit E. , Rizzieri David , Copeland Amanda , Van Der Jagt Richard H. C. , Fox Susan , Reid Gregory K. , Besterman Jeffrey M. , Martell Robert E. , Younes Anas 
Published: March 2020

8535 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single-agent activity in Hodgkin’s lymphoma and in AML and MDS (in combination with 5-azacitidine). More than 430 patients have been treated to date. Methods: This open-label, phase II trial enrolled patients with DLBCL and FL. Patients received mocetinostat at doses ranging from 70-110 mg 3x/wk every 28 days. Anticancer activity, safety, pharmacokinetics and pharmacodynamics were evaluated. Results: Sixty-nine patients with DLBCL (n=41) and FL (n=28) were enrolled for treatment at starting doses of 85-110 mg. Median age was 62 years (range: 32 to 81). Median duration of treatment was ~3 months (range: <1 to 24). Objective response rate in DLBCL and FL, respectively, was 7/41 (17%; including 2 unconfirmed PRs) and 3/28 (11%; including 1 CR). Median time to response was 2.0 mos (range 1.7-21.0) and 5.3 mos (range 4.3-6.0) respectively. Stable disease was achieved by 13/41 (32%) and 14/28 (50%), respectively, for a disease control rate of 49% and 61%, respectively. Mean duration of SD in patients with DBLCL was ~4.5 mos (range 2-12 mos), with 10 patients remaining stable for ≥3 mos. Among FL patients, mean duration of SD was approximately 4.1 mos (range 1.7-13 mos), with 9 patients remaining stable for ≥3 mos. The FL CR occurred in a 62-year-old female with paratracheal, subcarinal and portal target lesions who achieved a PR after 4 cycles and CR after 12 cycles that persisted through the remaining 4 mos on study. Study drug was discontinued for adverse events in 19/69 (28%). Fatigue, weight loss or anorexia were most common (n=4 each). A total of 26 drug-related SAEs were reported among 12 patients (17%; 1-6 events per pt). There were no drug related deaths. Enrollment is complete and final data will be presented. Conclusions: Single-agent mocetinostat has activity in DLBCL and FL. Fatigue, gastrointestinal, and cardiac symptoms are the most common adverse events resulting in discontinuation of dosing. Based on the acceptable tolerability and clinical activity further development is warranted. Clinical trial information: NCT00359086.
Impact of time from diagnosis to initiation of curative chemotherapy on survival of patients with diffuse large B-cell lymphoma (DLBCL).
Authors: Hay Kevin A. , Lee Benny , Goktepe Ozge , Connors Joseph M. , Sehn Laurie Helen , Savage Kerry J. , Shenkier Tamara Nina , Klasa Richard John , Villa Diego 
Published: March 2020

8552 Background: DLBCL is potentially curable with combination chemotherapy such as CHOP-R. Although it is generally regarded appropriate to start chemotherapy promptly after diagnosis, the impact of the time from diagnosis to treatment initiation on treatment outcome is unknown. Methods: Patients diagnosed with DLBCL and treated with at least one cycle of CHOP-R with curative intent during 2003 – 2008 in British Columbia were identified in the Lymphoid Cancer Database. Additional demographic data were obtained from the BC Cancer Registry. The BC Cancer Agency provincial pharmacy database was used to obtain dates of chemotherapy administration. The impact of the time interval from the date of pathologic diagnosis to treatment on overall survival (OS) and progression-free survival (PFS) was evaluated. Results: A total of 793 patients were identified: 199 (25%) received CHOP-R <2 weeks after diagnosis, 244 (31%) at 2-4 weeks, 293 (37%) at 5-8 weeks, and 57 (7%) at >8 weeks. High international prognostic index, primary mediastinal DLBCL, and hospitalization at the time of CHOP-R start were associated with earlier initiation of chemotherapy (p<0.001 for all factors). Distance to chemotherapy from home (p=0.237), rural vs. urban location (p=0.952), geographic region (p=0.458), and median household income (p=0.127) were not associated to treatment start. Five-year PFS and OS respectively were 54% (SD 4%) and 61% (SD 4%) for treatment <2 weeks, 63% (SD 3%) and 66% (SD 3%) for 2-4 weeks, 70% (SD 3%) and 74% (SD 3%) for 5-8 weeks, and 60% (SD 7%) and for 61% (SD 8%) >8 weeks, p=0.006 (PFS) and p=0.024 (OS). A multivariate analysis demonstrated no significant difference between the groups. Conclusions: In a publicly funded healthcare system, earlier initiation of chemotherapy was strongly associated with poor prognostic factors, as well as inferior PFS and OS. The timing of chemotherapy initiation appears to be related to clinical factors instead of system or socioeconomic barriers. Notwithstanding the lack of detrimental outcomes in those commencing CHOP-R after 8 weeks, clinicians should endeavor to initiate curative chemotherapy as soon as possible after a diagnosis of DLBCL is established.
MM-005: A phase I trial of pomalidomide, bortezomib, and low-dose dexamethasone (PVD) in relapsed and/or refractory multiple myeloma (RRMM).
Authors: Richardson Paul Gerard Guy , Hofmeister Craig C. , Siegel David Samuel DiCapua , Lonial Sagar , Laubach Jacob , Efebera Yvonne Adeduni , Vesole David H. , Nooka Ajay K. , Rosenblatt Jacalyn , Raje Noopur S. , Zaki Mohamed H. , Hua Ye , Shah Sheetal , Wang Jianming , Anderson Kenneth Carl 
Published: March 2020

8584 Background: Combinations of lenalidomide (LEN), bortezomib (BORT), and dexamethasone (DEX) have demonstrated preclinical and clinical activity in patients (pts) with multiple myeloma. Pomalidomide with low-dose DEX (LoDEX) has demonstrated efficacy in RRMM pts treated with prior LEN and BORT. MM-005 was designed to identify the optimal PVD dose for a phase 3 trial comparing PVD vs BORT + LoDEX (VD) in RRMM (MM-007). Methods: Eligible pts had RRMM with 1-4 prior therapies including ≥ 2 consecutive cycles of LEN and a proteasome inhibitor. Pts must have been refractory to LEN (progressive disease [PD] during or within 60 days of LEN treatment), but not refractory to BORT (at 1.3 mg/m2 twice-weekly). The maximum tolerated dose (MTD) was determined using a 3 + 3 design in 5 cohorts. Each cohort received 21-day cycles of POM 1-4mg/day on D1-14; BORT 1-1.3mg/m2on D1, 4, 8, 11; and LoDEX 20mg/day on D1-2, 4-5, 8-9, 11-12. An expansion cohort was enrolled at the MTD. Treatment was continued until PD or unacceptable toxicity. Dose-limiting toxicities (DLTs) were assessed during cycle 1. The primary endpoint was MTD; secondary endpoints were safety, overall response rate (ORR; ≥ partial response), duration of response, and time to response (TTR). Results: As of Dec 31, 2012, 21 pts were enrolled (3 pts per escalating dose cohort; 6 in the expansion cohort). Median age was 57 years (36-75). All were LEN-refractory and had prior BORT. No DLTs were observed at any dose level. The most common grade 3/4 adverse events (AEs) were neutropenia (32%) and thrombocytopenia (21%). With thromboprophylaxis, no deep vein thrombosis was observed. 17 pts remain on study and no pts have discontinued treatment due to AE. Thus far, the ORR was 72% (n = 18 evaluable) and responses were rapid (median TTR, 2 cycles). Conclusions: PVD was well-tolerated in RRMM with no DLTs and no discontinuations due to AE to date. PVD has promising activity with a current ORR of 72%. The maximum planned dose of POM 4mg/day on D1-14; BORT 1.3mg/m2 on D1, 4, 8, and 11; and DEX 20mg on D1-2, 4-5, 8-9, 11-12 of a 21-day cycle has now been incorporated into the MM-007 phase III trial comparing PVD with VD in RRMM pts (N = 782 planned). Clinical trial information: NCT01497093.
Evaluating results from the multiple myeloma subset of patients treated with denosumab or zoledronic acid (ZA) in a randomized phase III study.
Authors: Raje Noopur S. , Willenbacher Wolfgang , Hungria Vania , Spencer Andrew , Alexeeva Yulia , Facon Thierry , Stewart A. Keith , Roodman David , Terpos Evangelos , Feng Amy , Braun Ada , Balakumaran Arun 
Published: March 2020

8589 Background: Denosumab (dmab) is a fully human monoclonal antibody against RANKL and is superior to ZA in preventing skeletal-related events (SREs) as shown in 3 identically designed phase 3 trials (N=5723). Overall survival (OS) was balanced between treatment groups in the overall study populations of these trials. In the trial of patients (pts) with solid tumors (excluding breast and prostate) and multiple myeloma (MM), OS was longer for dmab pts with lung cancer, shorter for pts with MM, and balanced for pts with other solid tumors. This analysis further characterizes the results from the MM subset of this trial. Methods: Pts with solid tumors or MM were randomized (1:1) to receive 120 mg of SC dmab or 4 mg of IV ZA Q4W. Daily calcium and vit D supplements were strongly recommended. The primary endpoint was the time to first on-study SRE; results from the primary endpoint and lung cancer subset were previously reported. Results: Of 1776 randomized pts, 10% had MM (93 ZA, 87 dmab). OS favored ZA (hazard ratio: 2.26; 10 subject difference in deaths). 1-year OS was 83% dmab, 97% ZA. Imbalances in baseline prognostic characteristics were observed. More pts in the dmab arm had low baseline renal function (CrCl < 40 mL/min) (ZA 2 [2%], dmab 9 [10%]) and more ZA pts underwent stem cell transplant (ZA 23 [25%], dmab 15 [17%]). Additionally, more ZA pts had stage I tumors at diagnosis (ZA 13 [14%], dmab 9 [10%]) and better performance status (ECOG = 0; ZA 30 [32%], dmab 21 [24%]). Study discontinuations due to consent withdrawal or lost to follow-up were also higher in the ZA group (ZA 17 [18%], dmab 11 [13%]) and occurred earlier in the ZA arm (ZA 59%, dmab 45% within 9 months of randomization). Conclusions: In this SRE study of dmab vs ZA, pts were stratified by baseline characteristics known to affect SRE outcomes, but not by prognostic factors or concurrent anticancer therapy that may impact survival in MM. OS results in the MM cohort are difficult to interpret due to small sample size and imbalances in baseline disease characteristics, stem cell transplant therapy, and consent withdrawal or loss of follow-up that favored ZA. A phase 3 trial is currently underway, which controls for these factors in pts with MM. Clinical trial information: NCT00330759.
A phase I/II study (NCT01541332) of pomalidomide (POM), dexamethasone (DEX), and pegylated liposomal doxorubicin (PLD) for patients with relapsed/refractory (R/R) multiple myeloma (MM).
Authors: Hilger James D. , Berenson James R. , Klein Leonard M. , Bessudo Alberto , Rosen Peter J. , Eshaghian Shahrooz , Chamras Hilda , Nassir Youram , Swift Regina A. , Vescio Robert A. 
Published: March 2020

8598 Background: POM is a newer IMiD immunomodulatory compound with high in vitro potency that has shown promise in combination with DEX as an effective treatment option for R/R MM patients (pts), even those refractory to bortezomib and lenalidomide (LEN). We conducted a phase I/II trial investigating the safety and efficacy of POM in combination with IV DEX and PLD using a modified dose and longer 28-day schedule in R/R MM pts. Methods: Phase I pts had progressive MM at the time of enrollment that was R/R to at least one anti-MM regimen. Phase II pts had to be refractory to LEN (singe-agent or in combination) demonstrated by progressive disease while receiving LEN or relapse within 8 weeks of its last dose. During phase I, POM was administered orally at 2, 3, or 4 mg daily in 3 successive cohorts of 3 pts each on days 1-21 of each 28-day cycle. DEX was administered IV at 40 mg over 30 min and PLD was administered at 5 mg/m2as an IV infusion over 30-90 min on days 1, 4, 8, and 11 of each cycle. POM doses were escalated until maximum tolerated dose (MTD) was reached. Once MTD was reached, all subsequent pts were enrolled at that dose. Results: To date, 27 pts have been enrolled, with 18 evaluable for efficacy and 19 for safety. Pts received a median of 5 prior treatments (range, 1-18) with a median of 1 prior PLD regimens (range, 0-2). Pts have completed a median of 1 cycle (range: 0-8) with a median of 1.4 months of follow up (range: 0-7.1). No DLTs were seen during phase I, which established the MTD at 4 mg. Phase II has enrolled 16 pts at 4 mg so far. Clinical benefit was seen in 7 (39%) of evaluable pts (partial response = 22%; minor response = 17%) with another 44% showing stable disease. Common ≥ G3 adverse events included leukopenia (32% of pts), neutropenia (32%), lymphopenia (26%), and hyponatremia (16%). Neutropenia at ≥ G3 occurred in more than half of patients on the phase II trial (4 mg POM). Conclusions: The combination of pomalidomide with dexamethasone and PLD on a 28-day cycle shows efficacy for R/R MM pts. However, because of excessive ≥ G3 neutropenia, POM is being reduced to 3 mg for newly enrolled patients. Clinical trial information: NCT01541332.
Coexistence of multiple escape mechanisms in a BRAFV600E-mutated cutaneous melanoma treated with vemurafenib.
Authors: Michielin Olivier , Romano Emanuela , Peters Solange , Paillusson Alexandra , Weber Johann , Muehlethaler Katia , Harshman Keith , Speiser Daniel E , Pradervand Sylvain , Rimoldi Donata 
Published: March 2020

9014 Background: Mechanisms of acquired resistance to vemurafenib are the subject of intense research. Here we report, for the first time, two coexisting yet mutually exclusive mechanisms of escape in a melanoma patient who presented an excellent clinical response following reintroduction of vemurafenib. Methods: To investigate the mechanisms of resistance to vemurafenib, we performed whole-exome sequencing using the Illumina technology of a pre-treatment paraffin-embedded lymph node metastasis (Pre) and of two progressing subcutaneous snap-frozen metastases of the right arm (PV1 and PV2). The tumor samples, along with germline controls, were sequenced at high coverage (mean range 268x-356x). Results: We identified 107 exonic somatic Single Nucleotide Variants (SNVs) in Pre, 139 SNVs in PV1, and 127 SNVs in PV2, generating a set of 202 different SNVs, 82 of which were common to all 3 samples. The non-synonymous to synonymous ratios were higher for PV1 (1.82) than for PV2 (1.46), and lower for Pre (1.31). C>T transitions, largely predominated in the samples, indicating light-induced damage. Two independent NRAS escape mutations (Q61K and Q61R) where observed in PV1, whereas appearance of a BRAF splice variant (lack of exon 4-10) was present in PV2. Most importantly, these 2 escape mechanisms were mutually exclusive, i.e. no BRAF splice variant was observed by PCR in PV1 and no NRAS mutation found in PV2. Conclusions: Our results clearly demonstrate that multiple molecular escape mechanisms can be both coexistent and mutually exclusive. These findings have clinical implications: firstly, local treatment of isolated progressing lesions and continuation of vemurafenib could be supported by the fact that the resistance mechanisms are not necessarily shared. This approach is currently being tested within clinical trials with preliminary results that seem to support this hypothesis. Secondly, the coexistence of divergent escapes within the same patient strongly argues that single biopsy analysis at progression might not reflect the molecular complexity of tumor progression, and therefore might not be sufficient to guide selection of second-line optimal combination therapy.
Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: Data from the Italian cohort of ipilimumab expanded access programme (EAP).
Authors: Ascierto Paolo Antonio , Simeone Ester , Chiarion-Sileni Vanna , Queirolo Paola , Del Vecchio Michele , Di Guardo Lorenza , Guidoboni Massimo , Marchetti Paolo , Antonini Cappellini Gian Carlo , Ferrucci Pier Francesco , Cognetti Francesco , Bernengo Maria Grazia , Guida Michele , Marconcini Riccardo , Mandala Mario , Parmiani Giorgio , Rinaldi Gaetana , Aglietta Massimo , Calabro Luana , Maio Michele 
Published: March 2020

9035 Background: Ipilimumab and vemurafenib have recently been approved as single agents for the treatment of unresectable or metastatic melanoma. Currently, limited data exist on the sequential treatment with these agents in patients (pts) with the BRAF mutation; here we evaluate the efficacy outcomes of pts enrolled in the EAP in Italy who sequentially received a BRAF-inhibitor and ipilimumab, or vice versa. Methods: Ipilimumab was available upon physician request for pts aged ≥16 years with unresectable stage III/stage IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at baseline and after completion of induction therapy using immune-related response criteria. Patients were considered for this analysis if they tested positive for the BRAF mutation and had received a BRAF-inhibitor before or after ipilimumab treatment. Results: In total, 855 Italian pts participated in the EAP from June 2010 to January 2012 across 55 centres. Out of 173 BRAF positive pts, 93 (53.7%) were treated sequentially with both treatments: 48 pts received a BRAF inhibitor upon disease progression with ipilimumab and 45 pts received ipilimumab upon disease progression with a BRAF inhibitor. As of December 2012, median overall survival was 14.5 months (11.1-17.9) and 9.7 months (4.6-14.9) for the two groups, respectively (p=0.01). Among the 45 BRAF inhibitors pretreated pts, 18 (40%) had rapid disease progression (median overall survival: 5.8 months) and were unable to complete all four induction doses of ipilimumab, while the remaining 27 (60%) pts had slower disease progression (median overall survival: 19.3 months) and were able to complete the therapy with ipilimumab. Conclusions: These preliminary results suggest that, in BRAF-mutated pts, to start the sequential treatment with ipilimumab can provide a better survival than the reverse sequence. These findings deserve confirmation in a prospective study.
Adjusting for treatment crossover in the METRIC metastatic melanoma (MM) trial for trametinib: Preliminary analysis.
Authors: Abrams Keith R. , Latimer Nicholas , Amonkar Mayur , Stapelkamp Ceilidh , Casey Michelle ,   test group
Published: March 2020

9040 Background: In METRIC, a randomized phase III study, trametinib significantly improved PFS (hazard ratio [HR]=0.44 [95% CI 0.31–0.64; p<0.001]) vs chemotherapy (chemo) in patients (pts) with BRAF V600E+ MM and no brain metastases. Median overall survival (OS), a secondary endpoint, has not yet been reached. OS results are likely to underestimate the effect of trametinib as pts progressing on chemo could cross over to experimental treatment (trt). This analysis attempts to adjust for confounding effects of trt crossover on OS in the overall population and first line (1L) subgroup using current METRIC results. Methods: Randomization-based crossover adjustment methods – Rank Preserving Structural Failure Time Models (RPSFTM) and the Iterative Parameter Estimation (IPE) algorithm – were used. We conducted two sets of analyses testing different assumptions regarding the durability of the trt effect. “Trt group” analyses adjusted for crossover under the assumption that the trt effect is maintained until death regardless of trt duration; “On trt – observed” analyses adjusted for crossover under the assumption that the trt effect disappears upon trt discontinuation. Results are presented as HRs. Results: 178 and 95 MM pts were randomized to trametinib and chemo, respectively; 49.5% of chemo pts crossed over to trametinib as of data cut off (Oct. 2011). Median follow-up was 4.9 months and 19.8% deaths occurred across both arms. Crossover adjustment results are presented in the Table. Conclusions: RPSFTM and IPE “trt group” analyses resulted in OS HR point estimates that represented greater trt effects in the overall population and 1L subgroup compared to the unadjusted HRs. Results are exploratory because few deaths have been observed in the current dataset. Future analyses on a mature dataset should produce more robust estimates of the OS trt effect after crossover adjustment. [Table: see text]
Impact of complete lymphadenectomy in stage I melanoma: SEER analysis, 2004-2009.
Authors: Stager Victoria , Arena Elizabeth Anne , Albright Joslyn , Faries Mark B. 
Published: March 2020

9101 Background: Stage I melanoma has excellent prognosis, yet it remains a treacherous entity leading to fatal disease progression in a small and ill-defined population of patients. Role of complete lymphadenectomy in early melanoma is not determined. Methods: We used the Surveillance Epidemiology and End Results (SEER) database from 2004 to 2009 to identify patients who underwent wide local excision (WLE) with or without nodal surgery for management of AJCC Stage I primary cutaneous melanoma. Patients with complete data on age, race, sex, and primary tumor histology and anatomic site were categorized by type of surgical treatment into WLE, WLE+sentinel node biopsy (SNB), or WLE+complete lymphadenectomy (CLND) groups. Five-year disease-specific survival (DSS) was determined by treatment group and by sentinel node status. Specific risk factors were identified using multivariate analysis. Results: During the selected time period, 51,573 patients were diagnosed with AJCC Stage I cutaneous melanoma. Rate of SNB was 22%, and out of this group, 2% of patients had metastases to the regional lymph nodes. Five-year DSS was decreased in the node-positive group compared to the patients who had a negative SNB or WLE only (HR=4.95). Rate of CLND was 67%, and it did not improve survival of the patients with positive SNB (5-year DSS 83% vs. 79%, p=0.29). Performance of CLND did not correlate with age, histological type, presence of ulceration, or Breslow depth. Conclusions: SEER database suggests that a clinical equipoise regarding the utility of CLND in patients with positive SLN remains. These findings justify ongoing MSLT II.
Phase II study of selumetinib (sel) versus temozolomide (TMZ) in gnaq/Gna11 (Gq/11) mutant (mut) uveal melanoma (UM).
Authors: Carvajal Richard D. , Sosman Jeffrey Alan , Quevedo Fernando , Milhem Mohammed M. , Joshua Anthony Michael , Kudchadkar Ragini Reiney , Linette Gerald P. , Gajewski Thomas , Lutzky Jose , Lawson David H. , Lao Christopher D. , Flynn Patrick J. , Albertini Mark R. , Sato Takami , Paucar Daniel , Panageas Katherine S. , Dickson Mark Andrew , Wolchok Jedd D. , Chapman Paul B. , Schwartz Gary K. 
Published: March 2020

CRA9003 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June, 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.