bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of DNA repair in chronic lymphocytic leukemia: Therapeutic implications
Authors: Amrein L. , Aloyz R. , Panasci L. C. 
Published: March 2020

16513 Background: Chronic lymphocytic leukemia (CLL) is an indolent leukemia in which there is an accumulation of immature malignant B-lymphocytes. While treatment with chlorambucil, a nitrogen mustard analogue or fludarabine can control the disease, eventually all patients become resistant to chlorambucil/fludarabine. Chlorambucil’s cytotoxicity is mediated by the interstrand crosslinks (ICLs) introduced into DNA. In mammalian cells, two main pathways are known to be involved in double strand break(DSB) repair: homologous recombinational repair (HRR) and nonhomologous endjoining (NHEJ). Methods: Our laboratory has demonstrated that resistance to chlorambucil involved accelerated repair of the ICLs associated with enhanced DNA repair, specifically enhanced nonhomologous endjoining (NHEJ) and homologous recombinational repair (HRR). We also recently demonstrated that gleevec inhibition of c-abl with resulting inhibition of Rad51-related HRR sensitizes CLL lymphocytes in vitro to chlorambucil. This exciting result has stimulated the development of a clinical protocol to test this combination in CLL. Furthermore, our laboratory has demonstrated that wortmannin, a nonspecific inhibitor of DNA-PK (a key component of NHEJ) sensitizes CLL lymphocytes to chlorambucil. Results: We are actually evaluating the effect of NU7026, a relatively specific DNA-PK inhibitor, in the sensitivity of CLL cells to chlorambucil. Our results indicate that in a CLL cell line (I83) and primary CLL-lymphocytes chlorambucil plus NU7026 have a synergistic cytotoxic effect. Noteworthy, the NU7026 doses used in combination with chlorambucil were not toxic to the cells when used alone. Moreover, chlorambucil treatment induced DNA-PK nuclear foci which were inhibited by NU7026 suggesting that the synergy of both drugs is mediated by Nu7026-inhibition of DNA-PK. Conclusion: NU7026 plus chlorambucil should be a useful combination to treat CLL. No significant financial relationships to disclose.
A phase II study of DJ-927 administered orally once every three weeks as second line therapy to subjects with locally advanced or metastatic non small cell lung cancer (NSCLC) after failure of platinum-based non-taxane regimen
Authors: Szczesna A. , Milanowski E. , Juhász E. , Albert I. , Von Pawel J. , Sztancsik Z. , Oyama R. , Baas P. 
Published: March 2020

17006 Background: For the treatment of NSCLC (1st and 2nd line) effective oral formulations of drugs are currently investigated. DJ-927 is a semi-synthetic novel taxane with in vitro activity against NSCLC cells lines. Phase I studies show active plasma concentrations after oral administration with hematologic dose-limiting toxicity (DLT). This multi-centre phase II study was conducted to evaluate the safety and efficacy of the DJ-927 in patients (pts) with recurrent NSCLC. Methods: Pts with locally advanced or metastatic NSCLC who have received one prior platinum (non-taxane) containing treatment regimen, performance status 0 -2, and adequate organ function were enrolled. Pts received an initial DJ-927 dose of 27 mg/m2 on day 1 of cycle 1, orally, every 3-weeks. If < 2 DLTs occurred at this dose, the next cohort of 6 pts would start at a dose of 35 mg/m2, every 3 weeks, and all subsequent pts would be treated at that dose level. The primary endpoint was to assess the response rate. Pts were also assessed for time to disease progression (TTP), survival and safety. Results: 36 pts were enrolled, male/female 27/9; median age of 57 years (range 33–75); ECOG 0/1/2 7/21/8; stage IIIB/IV 12/24. Histology included adenocarcinoma 5; squamous cell 16; large cell 3; undifferentiated 3; other 7; unknown 2. Thirty-four pts received DJ-927; the median number of cycles was 2 (range 1–8). The optimal dosing level was confirmed at 27 mg/m2 as no dose escalation was performed based on toxicity data from parallel studies. Response in evaluable pts (completed Course 1) included CR 1, PR 1, SD 15, PD 8; for an overall response rate of 7 % and a disease control rate (CR, PR and SD) of 61%. Toxicity, ≥ grade 3, in evaluable pts (n = 32) included neutropenia (15), anaemia (6), thrombocytopenia (2), fatigue (2), nausea (2), anorexia (2), pneumonitis (1). Conclusions: In a 3-weekly setting, an oral dose 27 mg/m2 of DJ-927 shows limited efficacy in 2nd line therapy for NSCLC with neutropenia, gastrointestinal toxicity and fatigue as major side effects. [Table: see text]
Phase II study of induction docetaxel/cisplatin with rhG-CSF followed by concurrent pulsed docetaxel chemoradiation for stage III non-small cell lung cancer (NSCLC)
Authors: Chen Y. , Pandya K. J. , Smudzin T. , Qazi R. , Smith B. D. , Hyrien O. , Johnstone D. W. , Watson T. , Feins R. H. 
Published: March 2020

17034 Background: Both local and distant failures contribute to poor outcome in chemoradiation (CRT) for stage III NSCLC. Our previous study applied pulsed low-dose paclitaxel CRT for stage III NSCLC yielded 97.6% in-field tumor control and a modest survival gain. A follow-up study was designed to target distant micrometastasis up-front by one-cycle induction (IND) chemotherapy (CT) w/o further delay of local therapy. This was followed by low-dose sensitizing docetaxel (Doc) CRT. Methods: IND CT consisted of day 1 Doc 75 mg/m2 & cisplatin 75 mg/m2, and rhG-CSF (150 mg/m2 days 2–10). CRT started 3–6 wks later. Twice-weekly Doc at 12 mg/m2 was given with daily RT of 64.8 Gy to gross dz and 45–57.6 Gy to subclinical dz. Toxicity (Tox), response and survival were assessed. Results: 22 pts enrolled with 16 evaluable. 6 did not complete due to: allergy, intercurrent dz or progressive dz prior-to/during RT. Overall response was 69%. Kaplan-Meier survival was 67%, 55%, and 55% for years 1, 2, and 3. Grade (Gd) 3 Tox of IND CT included: allergy (10%), infection/nl ANC (20%), nausea (10%), HTN (5%) hyperglycemia (5%), H/A (5%), fatigue (10%), dyspnea/gd 4 hyperglycemia/fatigue (5%). No gd 3/4 hematologic Tox. Esophagitis was the main Tox of CRT. Doc was reduced after 10th pt enrolled for high incidence of gd 3 esophagitis: 4/8 (50%) at Doc dose of 12 mg/m2. Subsequent pts received reduced Doc of 10 mg/m2 and 1/8 had gd 3 esophagitis (12.5%). Other gd 3 Tox of CRT included: fatigue (14%), appetite loss (14%), flushing (7%), chest pain (7%), diarrhea (7%), and nausea (28%). No other gd 3 or 4 Tox from CRT. Conclusion: The regimen is associated with low hematologic Tox. Despite published MTD of twice-weekly Doc/RT at 15 mg/m2, 50% treated at 12 mg/m2 had gd 3 esophagitis. This was reduced to 12.5% at 10 mg/m2. Local response was 69% and survival was much better compared with our previous study of pulsed paclitaxel/RT w/o IND CT, which yielded 2 and 3-year survival of 33% and 18% for all, and 40% and 21% for pts completed protocol (Chen et al Clin Cancer Res 9:969–975,2003). Data suggest that one-cycle IND CT followed by low-dose taxane-based CRT improves survival of stage III NSCLC pts and deserves further investigation. Study partly supported by Sanofi-Aventis. No significant financial relationships to disclose.
Prospective randomised phase II study of gemcitabine and vinorelbine versus gemcitabine and docetaxel combination in patients with previously untreated advanced non-small cell lung cancer
Authors: Fernández Y. , Esteban E. , Villanueva N. , Fra J. , Muñiz I. , Jimenez P. , Luque M. , Vieitez J. , Estrada E. , Lacave A. , Buesa J. M. 
Published: March 2020

17052 Background: Previous comparative studies have shown similar efficacy and less toxicity with either the Gemcitabine(G)/Vinorelbine(V) or Gemcitabine/Docetaxel(D) combination with respect to platinum-based chemotherapies in patients with advanced NSCLC. This trial was designed to test the efficacy and safety of both GV and GD combination in non-selected patients with advanced NSCLC. Methods: Patients (n = 39) with ≤75 years of age, KPS ≥ 60% and adequate haematological, renal and hepatic function were randomly assigned to: G 1250 mg/m2 i.v. d1 and d8 plus either V 25 mg/m2 i.v. d1 and d8 or D 35 mg/m2 i.v. d1 and d8 every 3 weeks. Prophylactic i.v. ranitidine (50 mg), diphenhydramine (25 mg) and dexamethasone (8 mg) were prescribed just prior to the administration of taxane that was given over 30 minutes immediately before gemcitabine. Results: Baseline characteristics were comparable in GV (n = 20) and GD (n = 19) arms: median age (67 years) and KPS (70%), most patients were male (79%), had metastatic disease (85%) and adenocarcinoma histology (55%). Treatment indicated objective response of 7 (35%) versus 6 (31%) patients, median time-to-treatment failure of 120 versus 90 days, and overall survival of 209 versus 177 days in GV and GD arms respectively. The most common non-haematological toxicities were (GV versus GD; No. of patients): grade 2–4 pulmonary toxicity in 1 versus 7 (37%); grade 2–3 diarrhoea in 0 versus 4 (21%) and oedemas 1 versus 3. Grade 2–4 haematological toxicities in 5 versus 2 patients. All side effects were reversible phenomena since resolution was achieved by suspending the treatment and in the case of the pulmonary toxicity, by the prescription of additional corticoids. Conclusion: The combination of Gemcitabine/Docetaxel does not have a favourable safety profile with this schedule of administration, particularly in terms of pulmonary toxicity. Further patients’ enrolment was stopped and the study has been terminated. This kind of toxicity and alternative schedules of GD combination warrant further investigation. No significant financial relationships to disclose.
Preliminary results of G versus GViElC: A phase III trial of gemcitabine associated to vindesine or gemcitabine alone in elderly or poor performance patients with advanced non-small cell lung cancer (NSCLC)
Authors: Santo A. , Genestreti G. , Terzi A. , Azzoni P. , Caffo O. , Galligioni E. , Cipriani A. , Binato E. , Cartei G. , Cetto G. 
Published: March 2020

17083 Background: Monochemotherapy with gemcitabine (GEM) or vinorelbine is considered the standard treatment in elderly or poor performance (PS) patients (pts) with advanced NSCLC. Many topics report a synergic enhancement of antitumor effect of GEM if associated to Vindesine (VDS). The aim of this study is to evaluate if GEM combined to VDS produces an advantage in terms of overall survival (OS) compared to GEM alone without enhancement of toxicity. Methods: Chemonaive pts with stage IIIB/IV NSCLC, aged ≥ 70 years with PS < 2 or aged < 70 years with PS > 2 were enrolled. Pts were randomized to receive either GEM 1200 mg/m2 day 1 and 8 every 21 days for three cycles (arm 1) or GEM 1000 mg/m2 and VDS 3 mg/m2 (max dose 5 mg) both drugs infused on day 1 and 8 every 21 days for three cycles (arm 2). Pts of both arms received other three cycles in case of responsive or stable disease. Overall survival (OS) was the primary end-point, secondary end-points were time-to-progression and toxicity. First interim analysis was planned at 120 pts enrolled. Results: From May 2002 to December 2005, 107 pts from 13 Italian institutions were enrolled. Their characteristics are: 24 stage IIIB and 83 stage IV, 79 pts with ≥ 70 years (ECOG PS 0–1) and 28 pts with < 70 years (ECOG PS > 2). In arm 1 there were enrolled 55 pts while 52 pts in arm 2: both arms were well balanced with pts characteristics. Conclusions: The enrollment of this phase III trial is ongoing: we are achieving first step for an interim analysis to assess if GEM associated to VDS produces an advantage in terms of OS compared to standard treatment as GEM in monochemotherapy without toxicity enhancement. (Supported by GIVOP: Gruppo Interdisciplinare Veronese di Oncologia Polmonare). No significant financial relationships to disclose.
Phase II study of weekly chemotherapy with paclitaxel and gemcitabine as second-line treatment for advanced non-small cell lung cancer
Authors: Mori K. , Kamiyama Y. , Kondo T. , Kodama T. 
Published: March 2020

17096 Background: Second-line chemotherapy has become almost routine in non-small cell lung cancer (NSCLC) patients (pts) with good performance status (PS). The availability of the new pharmacological agents opens up new possibilities for their use in pts who have retained a good PS following relapse or progression after first-line chemotherapy. Paclitaxel (PTX) and Gemcitabine (GEM) are among the most active new agents in NSCLC and are worth considering for second-line chemotherapy. In phase II study, we evaluated the tolerability and activity of the combination of weekly PTX and GEM in second-line treatment of NSCLC. Methods: PTX (100mg/m2) and GEM (1000 mg/m2) were administered on days 1 and 8 at every 3–4 weeks. A total of 40 pts (M/F, 27/13 pts; median age 59.3 years [33–75]; PS 0/1/2, 7/27/6 pts) were enrolled between October 2000 and July 2003. Results: The number of cycles conducted was 1 in 5 pts, 2 in 8 pts, 3 in 10 pts, and 4 in 17 pts (mean: 4). The final efficacy was PR in 13, NC in 26 and PD in 1 for a response rate of 32.5 % (95% CI: 18.0–47.0%). The median survival time was 41.7 weeks (95% CI: 28.5–54.7 weeks). The median time to progressive disease was 19 weeks. Hematologic toxicities observed included Grade 3 or 4 neutropenia in 60%, Grade 3 or 4 anemia in 20%, and Grade 3 or 4 thrombocytepenia in 10%. Non-hematologic toxicities were mild except Grade 3 diarrhea in 3 pts and Grade 3 pneumonitis in 2 pts. There were no toxic deaths. Conclusions: The combination of weekly PTX and GEM is a feasible, well-tolerated, and active scheme for second-line treatment of advanced NSCLC. No significant financial relationships to disclose.
Gemcitabine/docetaxel (GD) versus gemcitabine/cisplatin (GC) in stage III/IV non-small cell lung cancer (NSCLC): Preliminary results
Authors: Gamaz M. , Makhloufi T. , Taright S. , Baba-Ahmed R. , Amrane R. , Bouzid K. 
Published: March 2020

17116 Background: This study was designed to compare the response rates and toxicities of the standard GC regimen versus GD, a non-platin regimen, in locally advanced and metastatic NSCLC. Methods: In both arms, gemcitabine 1250 mg/m2 was administered on days 1 and 8. In the GD arm, docetaxel 75 mg/m2 was given on day 8. In the GC arm, cisplatin 70 mg/m2 was given on day 1. Both regimens were repeated every 3 weeks. Results: From September 2004 to September 2005, 47 patients were enrolled In the GD arm (N = 25), the median age was 54.6 years (range, 45–70), and 22 (88.0%) were male. The majority of patients had either squamous cell (52.0%) or adenocarcinoma (44.0%), and stage IIIB disease (64.0%). In the GC arm (N = 22), the median age was 60.9 years (range, 42–74), and 20 (90.9%) were male. Most patients also had either squamous cell (50.0%) or adenocarcinoma (31.8%), and stage IIIB disease (59.1%). The difference in age between arms was significant (p = 0.046), but the differences in the remaining baseline characteristics and demographics were not significant. Toxicity and response results are in the table below. Conclusions: Overall response rate was numerically higher in the GC arm than the GD arm, but the difference was not significant because of the small sample size in each arm. The toxicity profile was significantly better in the GC arm for fatigue and nausea/vomiting. We think that GC regimen will remain the standard in treatment for advanced and metastatic NSCLC; however, we will confirm these findings in a randomized phase II study. [Table: see text] No significant financial relationships to disclose.
Simplified gemcitabine and platin regimen for NSCLC to be used in the neoadjuvant setting
Authors: Cartei G. , Binato S. , Sacco C. , Scalone S. , Ceravolo R. , Fantoni U. , Cingarlini S. , Palamidese A. , Iop A. , Colombrino E. 
Published: March 2020

17155 Background: Platin (P) salts and Gemcitabine (G) are used for NSCLC. GP regimens frequently included G on day 1, 8 and 15; P on day 2; every 28 days. However, the third G dose often is omitted because of myelo-toxicity, with a consistent no respect of the intended drugs’ doses. We devised a simplified regimen, based on two Day-Hospital admissions per cycle (c), with G on day 1 and 8; P after G on day 8; every 21 days. Aim of study: a high RR within the first 3 c.s for a GP regimen for neoadjuvant therapy. Methods: This prospective, multi-centre investigation included G (1500 mg/m2) on day 1 and 8, and P (100 mg/m2) on day 8 immediately following G, on a 3-weeks-c. Eligible criteria: age 18 to 75 years, NSCLC histologically, no previous chemotherapy, KPS 50%, WBC ≥ 4.0 × 109/L, platelet ≥100 × 109/L and normal kidney-liver function. QoL evaluation: 46 out of 95 valuable patients. Restaging procedures: repeated 3 and 6 c.s. Results: Out of 105 patients, 95 had at least 3 c.s and 59 of them had further 3 c.s. Myelo-toxicity ≥ G3 was mainly neuthropoenia, easily amenable with symptomatic and GCSF therapies; PNS toxicity occurred in 17.9% of patients. QoL was ameliorated (p < 0.05). Therapy was tolerable; gave RR was 52.3% after 3 c.s (Intention-to-treat analysis) and 57.9% in 95 valuable patients after at least 3 therapy c.s. In the 95 valuable patients over the first 42 days, i.e. after 2 c.s and just before the third c., 10 c.s out of 190 were delayed by one week, with a dose intensity reduction of 5.29%. Conclusions: This two Day-Hospital admissions regimen is at least as good as more complex GP regimens, with an appreciable RR after 3c.s; it may be proponed in the neoadjuvant setting. Acknowledgments: Present work was part of studies program of, and partly supported by, AOI (Associazione Oncologia Italiana, Padova, Italy). No significant financial relationships to disclose.
A phase II study of combination of bortezomib, liposomal doxorubin, and dexamethasone (VDD) as first line therapy for multiple myeloma
Authors: Jakubowiak A. J. , Friedman J. , Kendall T. , Al-Zoubi A. , Kaminski M. S. 
Published: March 2020

17504 Background: We have recently reported that a combination of bortezomib (Velcade), liposomal doxorubicin (Doxil), and dexamethasone (VDD) is very active and well tolerated in relapsed/refractory myeloma (MM) producing 83% overall response rate and 33% of complete (CR) or near complete (nCR) response rate. In the current study, we evaluated the activity of VDD as first line therapy in newly diagnosed patients with MM. The primary objective of this study was to determine the efficacy of this regimen. Methods: This is a phase II, single institution trial which opened in July 2005 with target accrual of 30 patients. EBMT criteria were used for evaluation of responses. The regimen was given as follows: Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and Dexamethasone for a total of 160 mg per cycle, initially at 40 mg on days 1–4 and then 20 mg on days of Velcade and the day after. VDD was repeated every 3 weeks for a total of 6 cycles. Results: To date, 19 pts have been enrolled, 18 of whom are presently evaluable for response after receiving a mean of 4.7 cycles (range 1–6). The characteristics of the evaluable patients included the following: median age 58 (range 39–83), chromosome 13 deletion in 4 patients, beta2-microglobulin 4.4 (61% > 4.0). CR + nCR have been observed in 2 patients (11%), very good partial response (VGPR) in 5 patients (28%), partial response (PR) in 9 patients (50%) and minor response (MR) in 1 patients (5%) for an overall response (≥ MR) of 94%, ≥ PR of 89% and ≥ VGPR of 39%. All patients who proceeded to stem cell transplant collected without any problems. The regimen was very well tolerated. Most surprisingly, only 1 patient developed peripheral neuropathy grade 1. One patient developed pneumonia and PE and one patient grade 3 diarrhea, which was found to be secondary to cryptosporidium. Grade 3 or 4 neutropenia was observed in 6 patients and grade 3 thrombocytopenia in 1 patient. The most common grade 1 and 2 toxicities were thrombocytopenia and fatigue, both significantly less common than in relapsed patients treated with the same regimen. One patient developed grade 2 DVT and 1 grade 2 PPE. Conclusions: VDD combination shows high overall activity of 94% and ≥ 90% disease reduction of 39%. The regimen is very well tolerated and has a surprisingly low incidence of peripheral neuropathy. [Table: see text]
Phase II study of rituximab and cladribine (2-CDA) in newly diagnosed mantle cell lymphoma (MCL) (N0189)
Authors: Inwards D. J. , Hillman D. W. , Fishkin P. A. , White W. L. , Morton R. F. , Dakhil S. R. , Nikcevich D. A. , Wender D. B. , Fitch T. R. , Kurtin P. J. 
Published: March 2020

17505 Background: A previous trial of 2-CDA as a single agent for therapy of mantle cell lymphoma demonstrated this agent to be efficacious with an overall response rate of 81% (31% complete responses) (Blood 1999 Nov 15; 94:660a). A phase II study of the addition of rituximab to 2-CDA was conducted by the North Central Cancer Treatment Group based on improved outcomes achieved by the addition of rituximab to other regimens active in MCL. Methods: This one-stage phase II study was designed to determine the complete response (CR) or complete response/unconfirmed (CRu) rate. Central pathology confirmation of cyclin D1 positive mantle cell lymphoma was required. No previous therapy for lymphoma was allowed, with the exception of splenectomy. The shedule was rituximab 375 mg/m2 IV day 1; 2-CDA 5 mg/m2/d IV days 1–5 of a 4-week cycle. After 2 of the first 6 patients developed grade 4 neutropenia, subsequent patients received either pegfilgrastim or filgrastim support. Patients received 2–6 cycles of therapy, depending on response. Patients were required to achieve at least a PR after 2 cycles of therapy to continue on protocol therapy. Results: Patient characteristics of all 29 eligible pts: median age: 70 (range: 41–86); 21 male, 8 female; PS 0 (55.2%), PS 1 (41.4%), PS 2 (3.5%); stage II (6.9%), stage III (3.5%), stage IV (89.7%); prior splenectomy (20.7%). The only grade 4 adverse event occurring more than once was neutropenia (20.7%). One patient died of cerebral ischemia in the setting of pneumonia without neutropenia. Response has been determined in 26 pts with 50.0% (95% CI: 30.0–70.0%) achieving a CR, none of whom have relapsed to date. Three patients progressed early at 17, 45, and 46 days, two of whom have died, and a fourth relapsed day 222. 10 pts (34.0%) went on to receive further therapy off study, 5 in less than a PR after 2 cycles, 2 in PR after study therapy, and 1 who went off study for a rash. At last contact, 26 (89.7%) were alive (median follow-up 10.7 months; range: 1–28). Conclusions: Rituximab and cladribine were well tolerated for the treatment of MCL in a group including elderly patients. The response rate may have been underestimated due to the study design, which required at least a PR after 2 cycles to continue therapy. Despite this, 50% achieved a complete remission. [Table: see text]