bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anatomic response correlation with biological response
Authors: Kasymjanova G. , MacDonald N. , Roseman M. , Kreisman H. , Pepe C. , Agulnik J. S. , Gagnon B. , Small D. 
Published: August 2020

8092 Background: Chronic systemic inflammation is a well recognized strong adverse prognostic factor in advanced NSCLC. We have previously identified that in stage IIIB/IV NSCLC the presence of elevated C-reactive protein is associated with early progression of the disease and reduction in median survival. Little is known, however, about CRP behavior over time and its correlation with response to chemotherapy and survival. Methods: Newly diagnosed NSCLC with IIIB/IV disease had CRP measured prior to 1st treatment and after 2 cycles of chemotherapy between February 2005 and September 2008. For each measure CRP level was categorized as < 10mg/L or ≥10mg/L. Response was evaluated by chest CT following two cycles of CTX and rated as progression (PD) or freedom from progression (FFP). We investigated the association between change in CRP and response to 2 cycles of CTX, as well as survival. Results: 143 pts were enrolled. Of those, 62 patients had a CRP level <10mg/L and 81 patients ≥10mg/L at the time of diagnosis. After 2 cycles 70% and 72% of pts in each category remained in the same category and 30% and 28% of patients changed category: in 24/81 pts CRP decreased below 10mg/L and in 17/62 pts CRP increased above 10mg/L. Thus, after two cycles 69 pts had CRP <10mg/L and 74 pts ≥10mg/L. The rate of progression after 2 cycles was significantly lower among pts with CRP <10mg/L after 2 cycles of chemo ( Table ). Median survival was 19 (16–22) mo for those with CRP <10mg/L and 9.3 (7.1–11.4) mo for those with CRP ≥10mg/L after 2 cycles (P<0.001). The hazard increased by 66% (HR 1.7) for those pts with CRP increased above cut-off point of 10 mg/L and decreased by 60% (HR 1.6) for pts whose CRP decreased below cutoff point. Conclusions: The presence of an inflammatory state expressed by high levels of CRP either prior to treatment or following 2 cycles of chemotherapy correlates significantly with both first-line chemotherapy response and survival. Normalization of CRP might improve the prognosis of patients in terms of survival and response to chemotherapy. [Table: see text] No significant financial relationships to disclose.
Correlation of polymorphisms of genes involved in platinum/gemcitabine (P/G)-based metabolism with toxicity and clinical response in patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Tonato M. , Ludovini V. , Pistola L. , Floriani I. , Meacci M. , Chiari R. , Garavaglia D. , Tofanetti F. R. , Flacco A. , Ferraldeschi M. , Crinò L. 
Published: August 2020

8093 Background: Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in NSCLC. Genetic variations in drugs metabolism may affect the clinical response, toxicity and prognosis of NSCLC pts treated with P/G-based therapy. Methods: We evaluated 8 single nucleotide polymorphisms (SNPs) of 6 genes (P53 Arg72Pro (G/C); XRCC3 Thr241Met (C/T); XPD Lys751Gln (A/C); ERCC1 Asn118Asn (C/T); CDA Lys27Gln (A/C), Ala70Thr (G/A), Thr145Thr (C/T) and RRM1 C524T) involved in P/G-based metabolism in a homogeneous population of pts with advanced NSCLC treated with this regime. Genomic DNA was extracted from whole blood samples using the QIAamp DNA estraction kit on Biorobot EZ1 (Qiagen). Polymorphisms were detected with TaqMan-probe based assays using the 7300 Real-Time PCR System (Applied Biosystems, Foster City, CA). Association between SNPs and response, toxicity, progression free survival and overall survival was estimated using logistic regression model, the Kaplan-Meier method, the long-rank test and the Cox proportional hazard model. Results: We performed a retrospective analysis in 192 chemotherapy-naive pts (median age 63 years), including M/F:74/26%; stage IIIb/IV:24/76%; Adeno/Squa/other Ca:42/27/31%; ECOG PS:0–1/2–3:94/6%. Overall response rate was 32.3%, stable disease 25% and disease progression 42.7%. The CDA Thr145Thr T/T genotype significantly correlated with poorer response (partial response in 23.1% of pts versus 42.3% and 34.6% in C/T and C/C genotypes, respectively; p=0.03). The ERCC1 T/T genotype was significantly associated with haematological toxicity (G1–4) (p=0.05) compared to ERCC1 C/C allele. The CDA Thr145Thr C/T genotype was significantly associated with non-haematological toxicity (G3–4) (p=0.02) compared to CDA Thr145Thr C/C allele. The median overall survival (OS) time and progression free survival (PFS) were 12.7 and 4.7 months, respectively. None of the analyzed polymorphisms was related to PFS or OS. Conclusions: These data suggest that genetic polymorphisms in the ERCC1 and CDA genes may modulate the toxicity and response to P/G-based therapy in pts with advanced NSCLC. No significant financial relationships to disclose.
An open label phase II trial of the Plk1 inhibitor BI 2536, in patients with sensitive relapse small cell lung cancer (SCLC)
Authors: Gandhi L. , Chu Q. S. , Stephenson J. , Johnson B. E. , Govindan R. , Bonomi P. , Eaton K. , Fritsch H. , Munzert G. , Socinski M. 
Published: August 2020

8108 Background: BI 2536 is a potent, selective inhibitor of polo-like kinase 1 (Plk1), a regulator of mitotic progression. BI 2536 demonstrated favorable tolerability and antitumor activity in phase I trials. We investigated the antitumor efficacy, safety and PK of BI 2536 in patients (pts) with sensitive relapse SCLC. Methods: This open label single arm phase II study followed a Gehan two-stage design. Primary objective was to determine the antitumor efficacy of BI 2536 in SCLC pts with disease recurrence ≥60 days after completion of first-line chemotherapy. 18 pts had to complete 2 courses to be evaluable for stage 1 analysis. In case of ≥2 partial or complete antitumor responses (RECIST criteria), stage 2 accrual would continue until 40 pts were entered. Patients received 200 mg BI 2536 as a 1h i.v. infusion on Day 1 every 3 weeks. Dose escalation to 250 mg (cycle 3 onwards) was encouraged in pts with <Grade 2 drug related non-hematologic and <Grade 3 hematologic toxicity. Results: 23 pts (14 female, 9 male, 21 extensive disease, 2 limited disease), median age 60 yrs (range: 35–77) were treated. All patients had disease recurrence >60 days after completion of first-line therapy. Of 23 pts, no objective antitumor responses were observed, 7 had stable disease as best response, 14 had progression, 2 were not evaluable. A median of 2 courses were given, up to a maximum of 12 in 1 pt. The PFS rate at 3 months was 25%. Due to the lack of antitumor responses, trial accrual was terminated after stage 1. Overall, BI 2536 was well tolerated. Frequent AEs were neutropenia (48%), fatigue (39%), nausea (30%), anemia, vomiting, constipation (26% each), and thrombocytopenia (22%). Drug related grade 3/4 AEs were neutropenia (13%/26%), grade 3/4 thrombocytopenia (1 pt each), grade 3/4 anemia (1 pt each), grade 4 sepsis (1 pt), Grade 4 ARDS (1 pt) and Grade 3 fatigue (1 pt). PK analyses indicate that BI 2536 has high clearance (>1,000 mL/min) and quickly distributes in multiple compartments in a large volume of distribution (>1,000 L). Estimated elimination half-life was >25 h. Conclusions: BI 2536 was well tolerated in relapsed SCLC pts, but demonstrated no convincing antitumor efficacy after stage I of the study. Therefore, BI 2536 will not be assessed further as a single agent in SCLC. [Table: see text]
Final results of PX-171–003-A0, part 1 of an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM)
Authors: Jagannath S. , Vij R. , Stewart K. , Somlo G. , Jakubowiak A. , Trudel S. , Schwartz R. , Siegel D. , Kunkel L. 
Published: August 2020

8504 Background: CFZ is a novel proteasome inhibitor of the epoxyketone class that exhibits a high level of proteasome selectivityand demonstrates antitumor activity in bortezomib (BTZ)-resistant MM pts in phase I studies. Methods: PX-171–003-A0 was an open-label, multicenter study that enrolled MM pts who relapsed from >2 prior therapies, failed BTZ and at least 1 immunomodulatory agent [thalidomide (THAL) or lenalidomide (LEN)], and were refractory to last treatment [progressing on or within 60 d of last therapy or <25% response to last therapy]. Pts received CFZ 20 mg/m2 IV d 1, 2, 8, 9, 15 and 16 every 28 d for up to 12 cycles (C). Clinical benefit response (CBR) was defined as MR or better. Results: 46 pts were enrolled, including 78% with progression on or within 60 d of last therapy and 22% with no response to last therapy. 39 pts completed at least 1 C of CFZ, had measurable M-protein, and were evaluable for response. Median prior therapies was 5 (range 2–15). 100% of pts received prior BTZ, 91% prior THAL, 89% prior LEN, and 83% prior stem cell transplant (SCT) and all had failed combinations including anthracyclines (80%) and/or alkylating agents (94%). Pts received a median of 3 C (range 1–12); 13 pts completed ≥6 C. CBR was 26% (10/39 eval pts), including 5 pts achieving PR and 5 pts achieving MR. 5 BTZ-refractory pts achieved MR or PR. Median TTP was 6.2 mo, the median DOR for the MR + PR was 7.4 mo. 8/10 pts achieved response during C1. 16 additional pts achieved SD for at least 6 wks. The most common adverse events were fatigue, anemia, thrombocytopenia, nausea, upper respiratory infection, increased creatinine and diarrhea. Peripheral neuropathy occured in < 10% of pts with 1 Gr 3 in a pt with pre-existing Gr 2. Conclusions: Single-agent CFZ achieved a TTP of > 6 mo in relapsed and refractory MM pts who failed available therapies. 26% of patients had at least an MR and median duration of >7 mo with this steroid- and anthracycline-sparing regimen. CFZ toxicities were manageable and importantly, exacerbation of pre-existing PN was rare. The study has been expanded to enroll an additional 250 pts in this unmet medical need population at an escalated dose, and treatment has been extended beyond a year. [Table: see text]
Clinical trial of the novel structure proteasome inhibitor NPI-0052 in patients with relapsed and relapsed/refractory multiple myeloma (r/r MM)
Authors: Hofmeister C. C. , Richardson P. , Zimmerman T. , Spear M. A. , Palladino M. A. , Longenecker A. M. , Cropp G. F. , Lloyd G. K. , Hannah A. L. , Anderson K. 
Published: August 2020

8505 Background: NPI-0052 produces rapid, broad and prolonged inhibition of all 3 catalytic activities of the 20S proteasome. NPI-0052 has a non-peptide based structure that appears to result in a unique proteasome inhibition (PI), signal transduction and safety profile. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with significant activity in hematologic and solid tumor malignancies including MM resistant to bortezomib (BZ) and other agents. Methods: This phase I dose escalation study of NPI-0052 was conducted in patients (pts) with r/r MM, including after BZ and/or lenalidomide. Pts were treated with NPI-0052 IV weekly for 3 weeks in 4-week cycles. The dose of NPI-0052 was escalated utilizing a combination of accelerated titration and 3+3 designs. PI and PK were assayed after the 1st and 3rd doses. Results: 17 patients have been treated at doses ranging from 0.025 mg/m2 to 0.6 mg/m2 without reaching a MTD. One patient experienced reversible creatinine elevation associated with progression of light chain nephropathy at 0.075 mg/m2. Drug- related adverse events have consisted principally of mild-to-moderate fatigue, nausea and diarrhea. In this study at dose levels 0.75 and 0.15 mg/m2, the half-life = 0.5 - 5.0 min; clearance = 4.8 ± 5.2 L/min and Vz = 22.6 ± 44.2 L. PI in whole blood demonstrates dose-dependent chymotrypsin-like inhibition up to 26% at 0.075 mg/m2. Of note, 2 patients remained on study for over 6 months and one year with stable disease and no significant toxicity. Importantly, NPI-0052 does not appear to induce peripheral neuropathy or myelosuppression. Conclusions: NPI-0052 was well tolerated in this study with escalation continuing to a recommended phase II dose (RP2D) for r/r MM. The RP2D (0.7 - 0.8 mg/m2), PI and safety profiles of NPI-0052 have been defined in other diagnoses, and appear unique from BZ in spite of up to 100% proteasome inhibition. In this study, NPI-0052 has effects on PD, PK and may potentially confer clinical benefit at doses which are well below the MTD determined in the other trials. Additional trials in MM are being initiated, including with lenalidomide. [Table: see text]
Activity of lenalidomide in a phase II trial for T-cell lymphoma: Report on the first 24 cases
Authors: Dueck G. S. , Chua N. , Prasad A. , Stewart D. , White D. , vanderJagt R. , Johnston J. B. , Belch A. , Reiman T. 
Published: August 2020

8524 Background: Novel therapies are needed to improve outcomes in T-cell lymphomas. We report the interim results of a prospective multicenter trial evaluating lenalidomide in T-cell lymphomas. Methods: Patients with relapsed and refractory T-cell lymphomas other than mycosis fungoides were prescribed oral lenalidomide (25mg daily) on days 1 to 21 of each 28 day cycle, with standardized dose reductions for toxicity. Treatment continued until disease progression, death or unacceptable toxicity. The primary endpoint was overall response rate, and secondary endpoints were complete and partial response rates, progression-free and overall survival (PFS, OS), and safety. The two-stage design allows for up to 40 patients. Results: At the time of this interim analysis, 24 patients were enrolled in this study and 23 were evaluable for response. The median age was 65 years. ECOG PS was 0–1 (n=15), 2 (n=7), 3 (n=2). The histology was peripheral T-cell unspecified (PTCL-u, n=10), angioimmunoblastic (n=7), anaplastic large cell (n=5), enteropathic T-cell (n=1) and hepatosplenic gamma/delta (n=1). Median number of prior therapies was 1 (range, 0–4), and three had prior autologous stem cell transplant. Four patients were previously untreated and not candidates for combination chemotherapy. Median time from completion of prior therapy to the start of lenalidomide was 8 months (range, 1–48 months). The overall response rate was 7/23 (30%); all were partial responses. Two patients had stable disease (SD) for ≥3 cycles. Responses were seen in anaplastic, angioimmunoblastic, and PTCL-u histologies. Median PFS was 96 days (range, 8–696 days). Median OS was 241 days (range, 8–696+ days). Among the 9 patients with SD or better, median PFS was 168 days and median OS has not yet been reached with 241–696 days of follow-up. The most common grade 4 adverse event was thrombocytopenia (33.3%). The most common grade 3 adverse events were neutropenia (20.8%), febrile neutropenia (16.7%), and pain NOS (16.7%). Conclusions: In relapsed and refractory T-cell lymphomas, oral lenalidomide monotherapy has clinical activity and toxicity is consistent with the known profile of lenalidomide. Further study of lenalidomide in these diseases is warranted. [Table: see text]
FDG PET/CT (FDG PET) in evaluation of response in patients with multiple myeloma (MM) treated with bortezomib, pegylated liposomal doxorubicin, and dexamethasone
Authors: Pandit-Taskar N. , Comenzo R. L. , Hassoun H. , Hoover E. , Borkar S. , Reidel E. , Cohen A. , Surti C. , Nimer S. D. , Landau H. J. 
Published: August 2020

8533 Background: In a high risk population of pts with newly diagnosed or primary refractory MM, we prospectively studied FDG PET imaging to determine the value of PET/CT in assessing therapeutic response. Methods: Forty pts with high-risk MM defined as ISS II, ISS III or presence of extramedullary plasmacytoma have been enrolled on study and treated using a combination of bortezomib, pegylated liposomal doxorubicin hydrochloride (Doxil), and dexamethasone (BDD) for 3 cycles followed by 2 cycles of thalidomide and dexamethasone for patients achieving at least PR. Pts were assessed using serial FDG PET imaging: at baseline (BL), after 3 cycles of BDD and at end of study (EOS). FDG PET response was determined using European Organization for research and treatment of cancer (EORTC) recommendations. MM disease response was assessed according to the International Myeloma Working Group (IMWG) criteria. Results: Median age of pts enrolled was 59 yrs (range 41–80), 62% male, 38% ISS II, 47% ISS III, and 15% ISS I with soft-tissue disease. Thirty-five percent (14/40) had soft-tissue involvement with MM. At completion of protocol therapy, the ORR was 79%, with 44% of pts achieving CR/nCR and 59% ≥ VGPR. Ninety FDG PET scans were performed in 40 pts; 25 pts were evaluable for FDG PET response. The other pts are as follows: 2 had negative FDG PET at BL, 6 were taken off study (5 for toxicity and 1 with CR), 1 FDG PET was unable to be compared due to technical differences and 6 pts have not completed treatment. Seventeen of the 25 pts had PR by FDG PET, 5 had SD and 3 PD; none of the pts had CR. There was little agreement between MM disease response and FDG PET responses (Kappa statistic, 0.05). Three pts with PD by FDG PET, had PR (n=2) or CR (n=1) by IMWG criteria. One had granulomatous disease rather than MM at biopsy. In 1 pt with progression of disease with a progressive skull-based plasmacytoma, FDG PET was scored as PR by EORTC criteria. Conclusions: There was poor agreement between FDG PET response and MM disease response by IMWG criteria. Serial FDG PET did not provide additional information for therapeutic response assessment in pts with newly diagnosed or primary refractory MM. [Table: see text]
Randomized phase II trial on primary chemotherapy with high-dose methotrexate (HD-MTX) alone or associated with high-dose cytarabine (HD-araC) for patients with primary CNS lymphoma (I.E.L.S.G. #20 Trial): Tolerability, activity, and survival analyses
Authors: Ferreri A. J. , Reni M. , Martelli M. , Pangalis G. , Frezzato M. , Cabras G. , Fabbri A. , Corazzelli G. , Zucca E. , Cavalli F. 
Published: August 2020

8545 Background: HD-MTX-based chemotherapy (cht) is the conventional approach to primary CNS lymphoma (PCNSL), but superiority of polycht over HD-MTX alone is unproven. A benefit of adding HD-araC to MTX has been suggested. This is a randomized phase II trial comparing HD-MTX monocht versus HD-MTX plus HD-araC as primary cht in immunocompetent patients (pts) with PCNSL. Methods: 79 HIV- pts with newly diagnosed PCNSL, age 18–75 ys, ECOG-PS≤3, and measurable disease were randomly assigned to receive 4 courses (interval 3 weeks) of MTX 3.5 g/mq (control arm; n=40) or MTX (same dose) + araC 2 g/mq × 2/d, d 2–3 (experimental arm; n=39). Cht was followed by whole-brain irradiation. Pts were stratified based on IELSG score and centre irradiation policy for pts >60 ys in complete remission (CR) after cht. CR rate (CRR) after cht was the primary endpoint; planned accrual (α=.05 β=.2) for P0 30% and P1 50% was 39 pts/arm. Results: Median age of the 79 entered pts was 58 ys (range 25–74). No differences in clinical presentation between arms were observed. Two hundred thirty-one (73%) of the 316 planned courses were actually delivered (MTX 71%; MTX+araC 76%). Causes of cht interruption were: progressive disease in 20 MTX and 8 MTX+araC pts, toxicity in 1 MTX and 7 MTX+araC pts and refusal in 2 MTX+araC pts. As expected, neutropenia, thrombocytopenia and infections were more common in MTX+araC arm. All G3–4 non-hematological toxicities were <5%. One MTX pt and 3 MTX+araC pts died of toxicity. CRR was 18% after MTX and 46% after MTX+araC (p=0.006), with an ORR of 40% and 69% (p=0.009), respectively. At a median follow-up of 30 m., 31 MTX and 22 MTX+araC pts experienced failure, with a 3-yr FFS of 21±6% and 38±8% (p=0.01), respectively. No differences in relapse sites or salvage efficacy between treatment arms were observed. Twelve MTX and 20 MTX+araC pts are alive, with a 3-yr OS of 32±8% and 46±9% (p=0.07). Conclusions: This is the first randomized trial on PCNSL with completed accrual. The addition of HD-araC to HD-MTX resulted in significantly better outcome and acceptable toxicity. MTX+araC may be the cht combination used as control arm in future randomized trials. No significant financial relationships to disclose.
A phase II study of bortezomib in combination with intensified CHOP-like regimen (ACVBP) in patients with previously untreated T-cell lymphoma: Results of the GELA LNH05–1T trial
Authors: Delmer A. , Fitoussi O. , Gaulard P. , Laurent G. , Bordessoule D. , Morschhauser F. , Ferme C. , Tilly H. , Gisselbrecht C. , Coiffier B. 
Published: August 2020

8554 Background: Patients with peripheral T/NK cell lymphomas (PTCL) still have a dismal prognosis with 5-yr survival less than 30% in most cases. No alternative regimen has been proven superior to CHOP so far. This multicenter phase II study was carried out to assess efficacy and safety of bortezomib in combination with an intensified CHOP-like regimen. Methods: Pts aged 18 to 65 yrs with previously untreated PTCL were planned to receive 4 bi-monthly cycles of ACVBP (doxorubicine 75 mg/m2 D1, cyclophosphamide 1200 mg/m2 D1, vindesine 2 mg/m2 D1 and D5, bleomycine 10 mg D1 and D5 and prednisone D1 to D5) followed by a sequential consolidation consisting of HD methotrexate (2 courses), etoposide + ifosfamide (4 courses) and cytarabine (2 courses) at 2 weeks intervals. Bortezomib 1.5 mg/m2 was administered at D1 and D5 of each ACVBP cycle, and then at D1, D8 and D15 every 4 weeks during consolidation phase for a total of 20 injections during the whole treatment. Results: 57 eligible pts (M 38, F 19, median age 52.5 yrs) with mostly AITL and PTCL NOS subtypes were enrolled between January 2006 and November 2007; 78% had stage III-IV disease and 53% had aaIPI ≥ 2. Forty six pts (81%) have completed induction treatment with ACVBP and only 28 (49%) the consolidation phase, mainly for disease progression. The CR + CRu rate was 45% after induction and 46% after consolidation. As of November 14th, 2008, 22 pts (39%) have died, mostly from lymphoma. The median percentage of planned dose of bortezomib received was 98% during ACVBP induction where the vinca alkaloid used was vindesine, and ranged from 90 to 95% during the consolidation courses. The dose intensity of bortezomib was 84.3% during induction, similar to that of doxorubicine and cyclophosphamide. Thrombocytopenia was more pronounced than previously observed with ACVBP alone but no life-threatening hemorrhagic event occurred. Conclusions: The combination of bortezomib with ACVBP is feasible without neurological or platelet unexpected toxicities. The response rate of such a regimen in PTCL does not appear higher than previously observed with ACVBP alone in our historical cohort. No significant financial relationships to disclose.