bluuebunny/crossref_metadata_2025_split huggingface dataset:
Strategies to overcome barriers to accrual (BtA) to NCI-sponsored clinical trials: A project of the NCI-Myeloma Steering Committee Accrual Working Group (NCI-MYSC AWG).
Authors: Weiss Matthias , Gertz Morie A. , Little Richard F. , Rajkumar Vincent , Jacobus Susanna J. , Abonour Rafat , Anderson Kenneth Carl , Barlogie Bart , Callander Natalie Scott , Gorak Edward J. , Matous Jeffrey , Mills Glenn Morris , Kane Robert C. , Katz Michael S. , Jensen LeeAnn , Omel James , Orlowski Robert Z. , Richardson Paul Gerard Guy , Munshi Nikhil C. 
Published: March 2020

8592 Background: Accrual to NCI clinical trials(CT)is often slower than planned at times mandating premature closure resulting in loss of valuable resources and delay of scientific progress. Methods: The NCI-MYSC AWG identified 10 potential BtA. SWOG, ECOG and Alliance investigators were queried and agreed that these barriers impede accrual (results stratified for academic and community sites). The MYSC AWG developed in collaboration with NCI and FDA strategies to overcome these barriers. Results: Strategies listed for the 3 most often cited BtA: 1. Reimbursement for CT related expenses:increase awareness of improved reimbursement for phase II CT; tailor reimbursement according to CT complexity; request funds from industry and other sources ( http://biqsfp.cancer.gov ) for qualifying ancillary CT components. 2. Spectrum of available treatment options influences CT participation: educate patients and providers about the significance of a new CT using social media, presentations at national meetings and by adding educational material to CT protocol; encourage opinion leaders and advocacy groups not to promote a new therapy as “standard” in the absence of phase III data. 3. Requirement of CT specific therapy at NCI designated sites only: “MYSC AWG Drug Administration Table” describes NCI/FDA approved rules for CT specific drug administration; CT protocol will outline which standard treatment components of a CT can be administered at any site as long as protocol specific guidelines are followed and conduct is supervised by enrolling investigator. Examples of additional strategies to overcome identified BtA: determine feasibility, indication and insurance coverage of CT specific tests during protocol development; discourage narrow eligibility criteria; avoid competing CT; allow up to 1 cycle of commercially available therapy prior to enrollment; CIRB support for phase II CT. Conclusions: The MYSC Accrual Working Group developed in collaboration with NCI and FDA strategies to overcome barriers to myeloma clinical trial accrual. These strategies may be applicable to NCI-sponsored clinical trials evaluating interventions in other diseases.
Early mortality (EM) for newly diagnosed multiple myeloma (NDMM) in the Connect MM U.S. registry.
Authors: Terebelo Howard R. , Shah Jatin J. , Durie Brian G. , Abonour Rafat , Gasparetto Cristina , Mehta Jayesh , Narang Mohit , Thomas Sachdev P. , Toomey Kathleen , Pashos Chris L. , Swern Arlene S. , Sullivan Kristen A. , Street Thomas K. , Srinivasan Shankar , Nourbakhsh Ali , Hardin James W. , Rifkin Robert M. 
Published: March 2020

8596 Background: EM occurring ≤ 6 mos from diagnosis of MM has been reported in several NDMM studies. Incidence of EM in the pre-novel-therapy era was 10–14% of patients (pts); causes included infection/pneumonia, renal failure, refractory disease, and cardiac events. Identifying risk factors and improving response rates (RR) could lower EM. Established risk factors only have a sensitivity of 61% and specificity of 74%. Introduction of novel therapies is improving RRs and changing the profile of morbidity risk factors. Fewer indwelling catheters, better antibiotics, and bisphosphonates have reduced morbidity and mortality in MM. This analysis aims to better understand the causes of EM in this new era. Methods: Connect MM is a prospective observational registry of NDMM pts. Since 2009, 1494 pts in 228 US centers have been enrolled. Baseline characteristics were compared for pts who died ≤ 6 mos after enrollment vs pts who survived > 6 mos. Multivariate logistic analyses identified significant associations between baseline characteristics and EM. Results: Most pts received novel therapies (91%). In the entire cohort, EM occurred in 103 pts (7%), of which 93 were treated (6.5%). EM associated characteristics by multivariate analyses (P< 0.05) were: age, ISS disease stage, PS, history of hypertension, hypercalcemia, lower clonal bone marrow cells (subject to further study), and platelet count. Venous thromboembolism and cytogenetics were not risk factors. Causes of the 103 early deaths were: MM progression (38%), cardiac failure (13%), infection (7%), pneumonia (6%), renal failure (4%), sudden death (3%), vascular event, bleeding, pulmonary embolism (1% each), other (15%) and unknown (13%). Conclusions: It is important to recognize EM as a distinct entity in MM. Better understanding of the biology and pt characteristics is required to further reduce its incidence. This is the first assessment of EM in a registry where almost all pts received novel agents. Of the 103 early deaths, 38% were due to MM, representing a 2.6% incidence in the total cohort (under further review). Although the 7% EM in Connect MM is encouraging, there is still room for improvement. Additional analyses on improvements and causes of death should be performed.
Results of a phase I/II study (NCT01365559) of carfilzomib (CFZ) replacing bortezomib (BTZ) in BTZ-containing regimens for BTZ-treated patients (pts) with relapsed and refractory multiple myeloma (MM).
Authors: Berenson James R. , Hilger James D. , Dichmann Robert , Patel-Donnelly Dipti , Boccia Ralph V. , Bessudo Alberto , Stampleman Laura , Gravenor Donald , Eshaghian Shahrooz , Chamras Hilda , Nassir Youram , Swift Regina A. , Vescio Robert A. 
Published: March 2020

8599 Background: Recent data has shown that single-agent CFZ can produce responses among MM pts refractory to previous treatment regimens including those containing BTZ. We conducted an intrapatient phase I/II trial investigating the safety and efficacy of CFZ as a replacement for BTZ in BTZEcontaining regimens to which pts have progressed. Methods: Eligible pts progressed while receiving their most recent BTZEcontaining regimen after at least 4 doses of BTZ at ≥1.0 mg/m² in ≤4 weeks per cycle. CFZ replaced BTZ in each regimen via intravenous administration over 30 min on days 1, 2, 8, 9, 15, and 16 of each cycle. Treatment continued using the same dose(s) and schedule(s) of each drug administered in the BTZEcontaining regimen. CFZ doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45 mg/m² or until a maximum tolerated dose (MTD) was reached for that regimen. Results: Of 37 enrolled pts, 33 were evaluable for efficacy and 37 for safety. Pts received a median of 4 prior treatments (range, 1-23) and 2 different BTZ-containing regimens (range, 1-13). Pts were treated with CFZ and a variety of different combinations of agents, including: bendamustine, clarithromycin, cyclophosphamide, dexamethasone, melphalan, methylprednisolone, pegylated liposomal doxorubicin, thalidomide, lenalidomide, and ascorbic acid. Pts have completed a median of 3 cycles with 12 pts going on to maintenance. One of 14 combinations, CFZ + ascorbic acid + cyclophosphamide, has reached a MTD at 45 mg/m2. Clinical benefit was seen in 23 (70%) evaluable pts (complete response = 6%; very good partial response = 18%; partial response = 21%; minor response = 24%) with another 18% showing stable disease. The median time to progression is 8.8 mo. (95% CI: 6.4-11.1 mo.) with 21 pts progressing overall and 9 progressing on study treatment. The most common ≥ G3 adverse events were lymphopenia (35% of pts), thrombocytopenia (19%), neutropenia (11%), and anemia (8%). Conclusions: These results suggest that replacement of BTZ with CFZ in a BTZ-containing combination regimen to which a MM patient is failing often leads to responses and is well-tolerated. Clinical trial information: NCT01365559.
Cure candidates: Characteristics of >10yr progression-free survivors (PFS-10) and continuous CR (CCR-10) after total therapy 1 and 2 (TT1, TT2) for multiple myeloma (MM).
Authors: Waheed Sarah , Van Rhee Frits , Rosenthal Adam , Usmani Saad Zafar , Waheed Mian Adnan , Hoering Antje , Barlogie Bart 
Published: March 2020

8603 Background: Our TT studies demonstrate that long term progression free survival is achievable in MM pointing to the possible curability of MM. We report here on the base line characteristics of 33/231 TT1 patients and 109/475 TT2 patients qualifying for PFS-10, including 45/245 randomized to the control arm and 64/230 randomized to thalidomide. Methods: Baseline and response levels were compared between <10yr and >=10yr survivors and logistic regression applied to identify the critical features linked to PFS-10 status. Results: Compared to the remainder, PFS>=10yr and CCR>=10yr were characterized by lower frequencies of cytogenetic abnormalities (CA), B2M>=3.5mg/L and age >=65yr. More females and more patients with platelets >150.000/uL qualified for the >=10yr category. Finally, timely administration of 2 transplants was also over-represented in these patients. Conclusions: Long-term survival PFS-10 and CCR-10 were adversely affected by by CA and elevated B2M levels. Females more frequently attained PFS-10. Assessment of MRD by 8-color flow cytometry in these patients is in progress and will be presented at the meeting. Clinical trial information: NCT00580372, NCT 00083551. [Table: see text] [Table: see text]
HM1.24/CD317-directed immunotoxin to eliminate malignant plasma cells in vitro and in vivo.
Authors: Gramatzki Martin , Staudinger Matthias , Glorius Pia , Klausz Katja , Kellner Christian , Günther Andreas , Repp Roland , Burger Renate , Peipp Matthias 
Published: March 2020

8604 Background: Targeted immunotherapy, based on antibodies against tumor-associated antigens, is a promising approach for the treatment of multiple myeloma (MM). Recently, antibody-based strategies delivering a toxic payload have documented impressive clinical activity in hematological malignancies. In particular, surface molecules overexpressed on malignant plasma cells and efficiently internalized represent promising targets for developing myeloma-directed immunoconstructs. Here, the identification of CD317 (HM1.24) as a potent target structure and the characterization of a novel CD317-directed single-chain immunotoxin, HM1.24-ETA', is described. Methods: Using a novel screening tool, a panel of antibodies against MM-associated antigens was evaluated for their ability to mediate antigen-dependent delivery of a truncated version of Pseudomonas exotoxin A (ETA’) to MM cells. HM1.24-ETA' was generated by genetic fusion of a CD317-specific single-chain Fv antibody and ETA'. The anti-myeloma activity of the E. coli-expressed immunotoxin was evaluated in vitro and in a xenograft mouse model. Results: By screening a panel of antibodies including CD38, CS1, IL-6R, CD138 and CD317, CD317 was identified as a suitable receptor to deliver ETA’ to MM cells. The subsequently designed recombinant HM1.24-ETA' immunotoxin efficiently inhibited growth of MM cell lines with halfmaximal growth inhibition at concentrations of less than 1 nM. Antigen-specific MM cell killing occurred via induction of apoptosis. The proliferation of IL-6 dependent INA-6 cells was completely inhibited by HM1.24-ETA' even in the presence of bone marrow stromal cells that otherwise strongly support tumor cell growth. Importantly, HM1.24-ETA' strongly triggered apoptosis (up to 80%) in freshly isolated tumor cells from 7 out of 7 MM patients. In a xenograft SCID mouse model, establishment of INA-6 plasma cell tumors was efficiently abrogated by treatment with HM1.24-ETA' immunotoxin (p < 0.04). Conclusions: The HM1.24-ETA' immunotoxin in vitro and in the preclinical xenograft model in vivo demonstrates that the CD317 antigen may represent a promising target structure for immunotherapy of MM using immunoconjugates with toxic payloads.
Risk-adapted maintenance therapy (MaintRx) after ASCT in first-line therapy for multiple myeloma (MM).
Authors: Kaufman Jonathan L. , Willey Joanne , Williams Michael E. , Tiscione Brynn , Buettner Arden , Neely Douglas , Green Mark R. 
Published: March 2020

8607 Background: Maintenance lenalidomide improves survival in patients who have undergone induction therapy and then autologous stem cell transplant (ASCT) as first line management for MM. We studied how the extent of cytoreduction after induction therapy à ASCT (as measured by CR, VGPR, or PR as best response) influences MAINTRX prescribing preferences among American Hematology-Oncology physicians (AHOP). Methods: We studied 284 individual AHOPs using a proprietary, live, case-based market research tool to assess prescribing preferences. A core case scenario and variations based on extent of response to induction à ASCT was constructed. Preference data were acquired using blinded audience response technology. All responses for each scenario were obtained contemporaneously prior to any display of respondent selections. All sources of research support were double blinded. The core scenario involved a 59-year-old patient (42% plasma cells in BM, no cytogenetic abnormalities, CrCl 65ml/min, B2M 5.8, PS 1) treated with induction therapy of choice à ASCT. The same query was then posed in each of 3 settings: Following CR (or following VGPR or following PR) as best response, what, if any, further therapy would you recommend now? Results: See Table. Conclusions: Among patients with myeloma getting first-line therapy, MaintRx is almost uniformly preferred by AHOPs. Specific single or doublet therapy preferences are dependent upon best response to induction à ASCT treatment. Compared to the CR setting, preferences for 2 drug MaintRx are significantly increased in patients with VGPR (p <.0.001) or with PR (p < 0.001)] as best overall response. The potential for benefit from intensified MaintRx in these response subsets needs prospective phase III testing. [Table: see text]
Outcomes of patients with solitary plasmacytomas (SP) in the era of PET imaging and serum-free light chain (sFLC) testing: A single institution experience.
Authors: Koch Abby L. , Shain Kenneth H. , Alsina Melissa , Sullivan Daniel , Nishihori Taiga , Ochoa-Bayona Jose L. , Baz Rachid C. 
Published: March 2020

8608 Background: SP can occur in bone (SPB) or in extramedullary sites (EMP) and generally accounts for ~ 3-5% of plasma cell dyscrasias. Up to 50% of SPB and 15% of EMP will progress to multiple myeloma (MM). We evaluated the utility and prognostic significance of positron emission tomography (PET) imaging and SFLC ratio (sFLCr). Methods: We retrospectively reviewed electronic medical records of patients with SP evaluated at Moffitt Cancer Center between 1990-2012. The diagnosis of SP was per IMWG criteria (BJH 2003, 121:749) (biopsy proven single site, negative skeletal survey, bone marrow biopsy with no more than 10% plasma cells). Initial and post therapy sFLCr as well as PET findings were correlated with progression to symptomatic MM (PFS). Radiation therapy (XRT) was at the discretion of the treating physician. Results: 135 patients were identified and 91 (67%) were males. The median age was 58 years (range 20-82). Consistent with prior reports, the PFS of the entire cohort was 43 months (95% CI 17.8-70). 23 patients had PET prior to progression. All patients had uptake in the primary lesion (except 4 who had resection of the primary). 8 patients had additional PET findings in other bony structure (PET+), and 15 did not (PET-). 2 and 6 of the PET- and PET+ patients progressed (median PFS Not reached (NR) vs. 8.1 months, p=0.021) respectively. Of the 49 patients with available sFLC data, 32 had an abnormal ratio (17 progressed) and 17 patients had a normal ratio (2 progressed). Abnormal baseline sFLCr was associated with progression (median PFS 19 months vs NR, p=0.012). Post XRT, 44 patients had an available sFLCr, of which 23 had an abnormal ratio and 21 a normal ratio. A persistent serum/urine m spike after XRT was associated with progression to MM (median PFS 20.8 months vs NR, p<0.0001). However, the association between Post XRT sFLCr and progression to MM was not statistically significant (median PFS 19 vs 43 months (abnormal vs normal ratio) p=0.2). Conclusions: PET imaging and sFLC are predictors of outcomes in SP and their routine inclusion in the diagnostic work up of patients with SP will result in a stage migration where patients outcomes are improved compared to historical controls.
Adjuvant radiotherapy after lymphadenectomy in melanoma patients: Final results of an intergroup randomized trial (ANZMTG 0.1.02/TROG 02.01).
Authors: Henderson Michael A. , Burmeister Bryan , Ainslie Jill , Fisher Richard , Di Iulio Julianna , Smithers Bernard Mark , Hong Angela , Shannon Kerwin F. , Scolyer Richard A , Carruthers Scott , Coventry Brendon J , Babington Scott , Duprat Joao , Hoekstra Harald J. , Thompson John F 
Published: March 2020

9001 Background: The role of adjuvant radiotherapy following lymphadenectomy in melanoma patients identified as at high risk for further recurrence has been controversial. This final report of a multicenter randomized trial updates survival and lymph node field (LNF) control, and reports long term treatment toxicity, lymphedema and quality of life (QOL) (Lancet Oncol 2012;13:589-97). Methods: Patients at high risk of LNF relapse (≥1 parotid, ≥2 cervical or axillary or ≥3 groin positive nodes; or extra-nodal spread of tumour; or minimum metastatic node diameter of 3cm (neck or axilla) or 4cm (groin)) received adjuvant radiotherapy (ART) (48Gy in 20 fractions) or observation (OBS). LNF relapse, as a 1st relapse, was the primary endpoint; morbidity, QOL, patterns of relapse, disease free and overall survival were secondary endpoints. A target sample size of 250 enabled detection of a difference in 3 year relapse rates of 30% and 15% to be detected (2-sided logrank test, power of 80%). Results: 250 patients from 16 centres were randomized from Mar 02 to Sept 07 (123 ART; 127 OBS) with 217 fully eligible (109 ART, 108 OBS). Mean follow-up 73 months (range 21–116). LNF recurrence was reduced in the ART arm (HR=0.52 (0.31- 0.88) p=0.023) but there was no difference in survival (HR=1.13 (0.82 – 1.55) p =0.21). QOL was assessed by comparison of area under the curve from baseline to 5 years (or recurrence) with the FACT-G tool using both total score and the 4 major domains (physical, social, emotional and functional wellbeing), no difference. Regional symptoms (standardised questionnaire) were higher in the ART arm (p=0.035). Limb volumes were higher in the ART arm (leg 7.3% difference p=0.014, arm 3.4% p=0.25). Grade 2-4 RT toxicity was common for head + neck: skin (33%); axilla: skin (44%), subcutaneous tissue (41%); Groin: skin (46%), subcutaneous tissue (67%), other (38%). Conclusions: RT reduced the risk of LNF relapse by 52% but there was no impact on survival. In the ART arm loco-regional symptoms were worse, limb volumes were somewhat increased and Grade 2 - 4 long term RT toxicity was relatively common. However QOL as assessed by a validated tool (FACT-G) was similar in both groups. Clinical trial information: NCT00287196.
Clinical efficacy and safety of lambrolizumab (MK-3475, Anti-PD-1 monoclonal antibody) in patients with advanced melanoma.
Authors: Ribas Antoni , Robert Caroline , Daud Adil , Hodi F. Stephen , Wolchok Jedd D. , Kefford Richard , Patnaik Amita , Hwu Wen-Jen , Weber Jeffrey S. , Joshua Anthony , Hersey Peter , Gangadhar Tara C. , Joseph Richard Wayne , Dronca Roxana Stefania , Zarour Hassane M. , Ebbinghaus Scot , Gergich Kevin , Li Xiaoyun (Nicole) , Kang Soonmo Peter , Hamid Omid 
Published: March 2020

9009 Background: Programmed death-1 (PD-1) is an inhibitory T-cell co-receptor that may lead to suppression of antitumor immunity. Lambrolizumab is a humanized monoclonal IgG4 antibody against PD-1. This study explored the safety and clinical activity of lambrolizumab in patients (pts) with advanced melanoma (MEL). Methods: In this ongoing phase 1b expansion study of MEL pts with or without previous ipilimumab (IPI) treatment, lambrolizumab was administered IV every 2 or 3 weeks until disease progression or unacceptable toxicity. Tumor response was assessed every 12 weeks by independent, central, blinded radiographic review per immune-related response criteria and RECIST 1.1. Results: As of December 1, 2012, 294 pts with MEL were enrolled, including 179 IPI-naive and 115 IPI-pretreated. Pts received lambrolizumab 10 mg/kg (n = 183) or 2 mg/kg (n = 111). Preliminary data from the first 85 consecutive pts dosed before April 25, 2012, who had independent radiologic review available as of December 3, 2012, indicate a confirmed overall response rate per RECIST 1.1 of greater than 35%, pooled across all doses and schedules and including both IPI-naive and IPI-pretreated patients. The median duration of response has not been reached as only 2 pts who had initial response discontinued due to disease progression, but the duration of confirmed responses range from 28+ to 240+ days (up to 8+ months). Among 133 pts who were dosed with lambrolizumab before July 31, 2012, and evaluable for adverse events (AEs) as of September 28, 2012, fatigue (22%), rash (18%), and pruritus (14%) were the most common drug-related AEs (mostly grade 1/2). The incidence of drug-related grade 3/4 AEs was 10% (24% regardless of attribution). Four drug-related cases of pneumonitis were reported, all of grade 1/2. Grade 3/4 drug-related hypothyroidism (n = 1) and hyperthyroidism (n = 1) were noted. Conclusions: Preliminary data suggest that lambrolizumab has significant antitumor activity and is well tolerated with manageable side effects in both IPI-naive and IPI-pretreated MEL pts. These data have led to an ongoing, international, randomized study of lambrolizumab versus chemotherapy in IPI-pretreated MEL. Clinical trial information: NCT01295827.