bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bevacizumab plus irinotecan therapy in relapsed, heavily pre-treated malignant glioma: A case series
Authors: Friedland D. M. , Ali S. A. , Ahmad A. , Rahman M. , Bejjani G. , Braffet M. 
Published: March 2020

12500 Background: Endothelial proliferation has been recognized as a marker of high grade or aggressive glioma in several grading classifications and it has been demonstrated that the degree of microvascularity as assessed by the endothelial cell/capillary density correlates well with the biologic aggressiveness of these tumors. These features suggest that high grade gliomas are a suitable target for angiogenesis inhibiting therapies. Bevacizumab (B) is a humanized IgG1 monoclonal antibody to VEGF that has been shown to have activity in malignant gliomas when combined with irinotecan (CPT-11), a topoisomerase 1 inhibitor. Methods: We report a case series of 10 patients with recurrent, heavily pre-treated malignant glioma who were treated with the combination of B and CPT-11. Nine patients had WHO grade 4 tumors while one had a grade 3 lesion. All patients had failed standard therapy with primary resection followed by adjuvant chemotherapy and radiation. Most had also failed additional resection, chemotherapy and radiation after their initial relapse. The mean number of failed therapies in addition to adjuvant therapy prior to starting B and CPT-11 was 3 (range 1–6) and the median ECOG performance status was 2 (range 1–3). Nine patients were started on B at a dose of 5 mg/kg every 2 weeks and were given CPT-11 at a dose of 125 mg/m2 every week for 3 weeks with 1 week off. The tenth patient received B at a dose of 10 mg/kg but with CPT-11 at 125 mg/m2 every 2 weeks. Results: This regimen was well tolerated with no CNS hemorrhages or >grade 1 bleeding. One patient had treatment held for repair of an anal fissure but then had it restarted. One patient had a DVT while on therapy. The objective response rate was 80% (8 PR and 2 SD).The median progression- free interval on treatment is 25 weeks with 5 patients still having a response at the time of this report. In patients with progressive disease, the median time to progression is 25 weeks. The median overall survival has not been reached, and exceeds 6 months. There has been one death due to disease progression. Conclusion: The combination of B and CPT-11 is safe and has excellent activity even in this relapsed, heavily pre-treated population of patients with high grade malignant glioma, most of whom would not be candidates for clinical trials. No significant financial relationships to disclose.
Phase I/II study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme (GBM) or gliosarcoma
Authors: Butowski N. A. , Lamborn K. , Chang S. , Thornton D. , DeBoer R. , Page M. , Rabbitt J. , Parvanateni R. , Kivett V. , Nicol S. , Prados M. 
Published: March 2020

12511 Background: Enzastaurin is a potent, selective, oral serine/threonine kinase inhibitor of PKCβ, an enzyme activated by vascular endothelial growth factor (VEGF). VEGF is upregulated in most cases of GBM, producing significant angiogenesis. This study combines the anti-angiogenic properties of enzastaurin with the current standard treatment of radiation therapy (RT) and cytotoxic chemotherapy (temozolomide; TMZ). Methods: A Phase 1/2 study of enzastaurin with TMZ during and following RT is ongoing in patients with newly diagnosed GBM. Two doses of enzastaurin will be evaluated during Phase 1. The first 6 patients will received 250 mg of enzastaurin daily. If no more than one patient experiences a dose-limiting toxicity (DLT) during RT and the first adjuvant cycle, an additional 6 patients will receive an escalated dose of 500 mg daily. The dose established in Phase 1 will be administered to 60 patients in Phase 2. The primary objective of Phase 2 is to determine the efficacy of enzastaurin as measured by overall survival. Multiple pharmacokinetic (PK) and pharmacodynamic (PD) endpoints will be evaluated using perfusion imaging and plasma biomarkers. Relevant growth factors and pathways will be analyzed in primary tumor tissue from each patient. Results: Since September 06, 6 patients have completed RT with concurrent enzastaurin (250 mg) and TMZ. None of these patients has experienced a DLT to date. It is expected that an additional 6 patients will be enrolled in January 07 and Phase 2 will start in May 2007. Conclusions: Enzastaurin with concurrent RT and TMZ appears safe. Final Phase 1 safety results and preliminary PK and PD data will be presented. [Table: see text]
CVX-045: A novel thrombospondin-1 (TSP-1) mimetic CovX-Body that potentiates chemotherapy in preclinical colon cancer models
Authors: Levin N. J. , Leedom T. A. , Doppalapudi V. R. , Li L. , Lai J. , Johnson K. , Rizzo J. D. , Lappe R. W. , Bradshaw C. W. , Woodnutt G. 
Published: March 2020

14011 Background: TSP-1 reduces angiogenesis and tumor growth in vivo, and induces endothelial cell apoptosis in vitro. CVX-045 was produced by fusing a peptide derived from TSP-1, known to have anti-vascular activity, to a proprietary monoclonal antibody. CVX-045 possesses the potency and specificity of the TSP-1 mimetic peptide, along with the advantageous PK of an antibody. Methods: Anti-tumor activity of CVX-045 was evaluated in A549, A431, and HT-29 human adenocarcinoma xenograft models. Cells were implanted SC in female nu/nu mice, and tumors were staged to 300–400 mm3 prior to initiation of weekly treatments: CVX-045 IV 10–30 mg/kg; 5-FU or CPT-11 IP 100 mg/kg. Results: CVX-045 (10 mg/kg) significantly reduced A549 and A431 tumor growth 73% (day 49) and 51% (day 22), respectively, but was not effective in the HT-29 xenograft (10 or 30 mg/kg). CVX-045 demonstrated significant anti-vascular activity, reducing tumor microvessel density 51% in A549, 49% in A431, and 36% in HT-29 xenografts. CVX-045 (30 mg/kg) plus 5- FU significantly decreased HT-29 tumor growth 70% and microvessel density 61.2% on day 30 (both P<0.01), effects significantly greater than either agent alone. Co-treatment with CVX-045 (30 mg/kg) plus CPT-11 decreased HT-29 tumor volume 91% on day 28 (P<0.001), also significantly greater than either agent alone. As a surrogate measurement of survival, mice remained on treatment until tumors reached 2000 mm3. CPT-11 alone extended the time to reach tumor load from day 28 to day 39, while the combination of CPT-11 with CVX-045 extended this further to day 60. Conclusions: CVX-045 exhibits significant anti-angiogenic activity in several tumor models and enhances anti-tumor activity in combination with standard chemotherapies in a highly aggressive colon tumor model. No significant financial relationships to disclose.
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of LBH589, a novel deacetylase (DAC) inhibitor given intravenously on a new once weekly schedule
Authors: Sharma S. , Vogelzang N. J. , Beck J. , Patnaik A. , Mita M. , Dugan M. , Hwang A. , Masson E. , Culver K. W. , Prince H. 
Published: March 2020

14019 Background: LBH589 is a novel deacetylase inhibitor that inhibits proliferation of tumor cells at nanomolar levels. This phase I study tested the safety and tolerability of IV LBH589 once each week for 3 of 4 wks in pts with advanced solid tumors or lymphoma. Methods: LBH589 was administered IV over 30 min. on days 1, 8 and 15 of a 28-day cycle. Western blots on peripheral blood lymphocytes were used to study histone acetylation (HA). Plasma PK profiles were analyzed on Days 1 and 8. Results: Thirty five pts (median age: 70 yrs; 23M, 12F) have been treated on 3 dose levels [10 mg/m2 (8pts), 15 mg/m2 (8 pts), 20 mg/m2 (19 pts)] with the following tumor types: Cutaneous and peripheral T cell lymphoma (7 pts), prostate (6 pts), mesothelioma (4 pts), colon (3 pts) and other (15 pts). There was one dose-limiting toxicity (transient grade 4 thrombocytopenia) at 20 mg/m2, none at the lower doses. Other G3/G4 toxicities (all cycles) include: transient thrombocytopenia (G4–5 pts, G3–5 pts), neutropenia (G3–2 pts), anemia (G3–5 pts), G3 hypophosphatemia (1 pt), G3 hypokalemia (1 pt), G3 nausea (1 pt) and G3 pruritus (1 pt). Thrombocytopenia was transient. Of 2,042 ECGs, 1 pt had an increase in QTcF from baseline of > 60 msec another with a QTcF >500 msec, both at 20 mg/m2. There was a dose-dependent increase in HA 7 days after one dose with 43% (10 mg/m2), 50% (15 mg/m2) and 60% (20 mg/m2) of pts with increased acetylation. The LBH589 plasma conc. peaked at the end of the 0.5 hr infusion with a mean terminal half-life of 16 hr. Median Cmax achieved with 20 mg/m2 was 1,000 ng/mL (2.86 μM). The AUC0-inf increased linearly with IV doses of 10–20 mg/m2. One pt with CTCL achieved a complete response (CR) on cycle 3, Day 1; this pt had previously received oral LBH589 at 20 mg MWF, achieving a CR on cycle 6, Day 28 that lasted for 7 months. One peripheral T-Cell lymphoma pt achieved a partial response that has persisted for >7 months. One pt with prostate cancer has had a 26% reduction in nodal disease and > 50% drop in PSA in the first 2 cycles. Conclusions: The maximum tolerated dose of LBH589 given IV wkly on a 3 of 4 wk schedule is 20 mg/m2. This dose produced sustained PD effects and higher systemic exposure compared to oral LBH589. Preliminary evidence of antitumor activity has been observed. No significant financial relationships to disclose.
AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, in combination with chemotherapy in adult patients with advanced solid tumors
Authors: Mita A. C. , Wang D. , Takimoto C. H. , Malseed E. , Nguyen L. , Rasmussen E. , Storgard C. , LoRusso P. 
Published: March 2020

14033 Introduction: AMG 386 is a selective angiopoietin 1 /2-neutralizing peptibody that inhibits angiogenesis by preventing interaction between angiopoietins and Tie2 receptors. This open-label study evaluated the safety, pharmacokinetics (PK), and antitumor activity of AMG 386 in combination with FOLFOX-4 (F), carboplatin + paclitaxel (CP), or docetaxel (D) in adult patients (pts) with advanced solid tumors. Methods: Three cohorts of 6–9 pts received 1 full cycle of chemotherapy (2 weeks of F or 3 weeks of D 75 mg/m2 or CP). Administration of AMG 386 10 mg/kg IV weekly was started on day 1 of cycle 2 for patients who did not experience a dose-limiting toxicity (DLT) to chemotherapy during cycle 1, and continued until disease progression or intolerance. Safety and tolerability, tumor response (RECIST every 8 weeks), PK profiles of AMG 386 and chemotherapy agents, and formation of antibodies to AMG 386 were assessed. Results: As of October 2, 2006, 16 pts have received AMG 386: 6 pts in the F cohort, 5 in CP, and 5 in D; 7 pts were men, median age 59.5 years (range, 44- 75 years). No AMG 386-related serious AEs or DLTs were reported. AEs related to chemotherapy + AMG 386 in = 2 pts were neutropenia (n = 3), thrombocytopenia (n=2), diarrhea (n=2), and vomiting (n=2). No neutralizing antibodies were observed. F, CP, and D coadministered with AMG 386 did not appear to affect the PK profile of AMG 386, and AMG 386 had no apparent effect on the PK profile of 5 FU, leucovorin, C, P, or D. Tumor response data are available for 6 pts. One pt receiving CP+ AMG 386 for bladder cancer refractory to gemcitabine/cisplatin had a complete response (CR) at week 8, confirmed at week 16. Stable disease in 4 pts and progressive disease in 1 pt were also observed. Conclusions: Weekly administration of AMG 386 in combination with F, CP, or D appears to be safe and well tolerated. A CR in bladder cancer suggests promising antitumor activity of AMG 386 in combination with chemotherapy. Further clinical studies of AMG 386 in combination with chemotherapy and other targeted agents are warranted. [Table: see text]
A phase I study of oral belinostat (PXD101) in patients with advanced solid tumors
Authors: Kelly W. K. , Yap T. , Lee J. , Lassen U. , Crowley E. , Clarke A. , Hawthorne T. , Buhl-Jensen P. , de Bono J. 
Published: March 2020

14092 Background: Belinostat (PXD101) is a hydroxamate HDAC inhibitor which demonstrates broad anti-neoplastic activity in vitro and in vivo. In Phase I studies in patients (pts) with advanced cancer, IV belinostat is well-tolerated up to 1000 mg/m2 daily x5. Preliminary results of an oral formulation of belinostat showed that the oral bioavailability was 20 - 50%. This Phase I trial of oral belinostat will determine the maximal tolerated dose (MTD) of once and twice daily dosing, tolerability and pharmacokinetics (PK) in pts with advanced solid tumors. Methods: Sequential cohorts of 3–6 pts with advanced solid tumors refractory to standard therapy or for which no standard therapy exists were administered belinostat 250–500mg once or twice daily in 4 week cycles. Fasting (day 1) and non-fasting (day 7) pharmacokinetic studies were performed on all patients along with serial ECGs to evaluate any potential effects on QTc prolongation. Patients were evaluated with routine blood work weekly and tumor imaging at the end of cycle 1 then every other cycle. Results: Sixteen pts have been treated in 3 dose levels at 250mg QD (6 pts), 500mg QD (6 pts) and 250mg BID (4 pts). The median number of cycles of therapy is 1 (range 1–5), nine pts continue to be treated. The most common reasons for discontinuation were adverse event (3 pts) and PD (3 pts). No DLTs were identified at 250mg QD or 250mg BID. DLTs of grade 3 dehydration and grade 3 fatigue were reported at 500mg QD. In pts from the first 3 dose cohorts, there were no grade 4/5 events reported. Other Grade 3 toxicities were fatigue (2 pts), abdominal pain (1 pt), ataxia (1 pt), prolonged INR (1 pt), prolonged PTT (1 pt) and confusion (1 pt). Symptoms were transient and usually resolved after drug was held. In > 500 ECG’s collected, there were no QTcF > 500 ms, and no QTcF increase > 60 ms above baseline. To date, the best clinical response observed has been SD in 7 patients. Conclusions: Oral belinostat at doses of 250mg QD and 250mg BID given on a continuous schedule appears to be well tolerated. Alternative dosing schedules are being explored to further dose escalate the belinostat. Updated safety, activity and pharmacokinetic data will be presented on these and alternate dose schedules. [Table: see text]
The Hsp32/HO-1-targeted drug SMA-ZnPP counteracts the proliferation and viability of neoplastic cells in solid tumors and hematologic neoplasms
Authors: Gleixner K. V. , Mayerhofer M. , Vales A. , Gruze A. , Pickl W. F. , Lackner E. , Sillaber C. , Zielinski C. C. , Maeda H. , Valent P. 
Published: March 2020

14122 Background: Heat shock protein 32 (Hsp32) is a stress-related survival factor that is overexpressed in various neoplastic cells. Recently, specific Hsp32- targeting drugs such as styrene maleic acid encapsulated zinc protoporphyrin (SMA-ZnPP) have been developed. Methods: We examined the effects of SMA-ZnPP on proliferation and survival of various tumor cell-lines, including U97MG (glioblastoma), A549 (lung cancer), MDA-MB-231 (breast cancer), BxPC-3 (pancreatic), HepG2 (hepatocellular), Colo201, Colo320DM, DLD-1 (colon), OvCar3 (ovarian carcinoma), KG1, U937, HL60, K562 (myeloid leukemias), RAJI, NALM-6 (lymphatic leukemias), RPMI 8226, U266 (multiple myeloma) as well as on primary neoplastic cells. Moreover, Ba/F3 cells with doxycycline-inducible expression of oncoproteins (RAS-G12V, BCR/ABL, KIT-D816V) were analyzed. Expression of Hsp32 mRNA was examined by RT-PCR and Northern blotting, and expression of the Hsp32 protein by Western blotting. To silence Hsp32 in neoplastic cells, we used specific siRNA as well as SMA-ZnPP. Proliferation was analyzed by 3H-thymidine uptake and apoptosis by light microscopy. Results: All neoplastic cells tested were found to express Hsp32 mRNA and the Hsp32 protein in a constitutive manner. In Ba/F3 cells, induction of RAS-G12V, BCR/ABL, or KIT D816V enhanced the expression of Hsp32. The Hsp32 siRNA was found to lead to a reduced viability and induction of apoptosis. Treatment of malignant cells with SMA-ZnPP resulted in a significant decrease in proliferation and induction of apoptosis. The effects of SMA- ZnPP on primary neoplastic cells and cell lines were dose-dependent and occurred at pharmacologic concentrations (IC50 1–30 μM). Moreover, SMA-ZnPP was found to synergize with various anti-neoplastic drugs (cisplatin, cytarabine, tyrosine kinase inhibitors, bortezomib) in producing growth-inhibition in neoplastic cells. Conclusions: The Hsp32-targeting drug SMA-ZnPP counteracts malignant cell growth and sensitizes neoplastic cells against various other targeted or conventional antineoplastic drugs. Hsp32-targeting drugs may represent an interesting new aproach to inhibit malignant cell growth in solid tumors and leukemias. No significant financial relationships to disclose.
Cetuximab and irinotecan-based chemotherapy as an active and safe treatment option for elderly patients with extensively pre-treated metastatic colorectal cancer
Authors: Bouchahda M. , Macarulla T. , Spano J. P. , Bachet J. B. , Liedo G. , Andre T. , Landi B. , Tabernero J. , Levi F. , Rougier P. 
Published: March 2020

14528 Background: Cetuximab ( C ) has demonstrated activity both as a single agent and in combination with irinotecan (CPT11) in patients (pts) with metastatic colorectal cancer (mCRC) expressing epidermal growth factor receptor (EGFR) refractory to CPT 11 and oxaliplatin based chemotherapy. This European retrospective study explored the tolerability and activity of C combined with CPT 11 in an unselected population of elderly pts with CPT11- refractory mCRC Methods: 67 pts with mCRC aged = 70 yrs were treated with C (400 mg/m2 loading dose over 2 hours, then 250 mg/m2 over 1 hour weekly). C was given alone (2 pts), combined with CPT11 (56 pts) or CPT11 + 5FU-LV as conventional (4 pts) or chronomodulated delivery (5 pts). Treatment was administered as 2nd to 6th line. Primary endpoint was time to tumor progression (TTP). Secondary endpoints were toxicity, objective response rate (RR) (with RECIST Criteria) and overall survival (OS). Results: Median age was 77 yrs (70–84); M/F: 44/23; WHO performance status 0/1/2/unknown: 12/40/11/4; EGFR expression: + in 55 pts, - in 2 pts and unknown in 10 pts; colon/rectum/unknown: 49/14 /4. More frequent toxicities included acneiform skin rash, which occurred in 33 pts (Grade (G) 2: 24 pts, 35%; G3: 9 pts, 13%), diarrhea (G3, 11 pts, 16%; G4, 2 pts, 3%) and neutropenia (G3: 4 pts, 6%; G4: 5 pts, 7%). RR was 23% including 1 complete and 14 partial responses. Disease control rate (RR + stable disease) was 53%. No correlation was found between skin rash and response. Median TTP (intent-to treat) was 4.5 months [95% CI: 3.2 - 5.7]. Median OS was 15 months [12.0–17.9]. Conclusions: The combination of C with CPT11-based chemotherapy resulted in good activity and acceptable tolerability in elderly patients with heavily pre-treated mCRC, comparable to that of the younger patients. This treatment option can be reasonably proposed to the elderly population. No significant financial relationships to disclose.
FDG PET predicts prognosis of patients with resectable metastatic colorectal cancer (CRC) treated with preoperative chemotherapy
Authors: Flamen P. , Huberty V. , Garcia C. , Vanderlinden B. , Muylle K. , Legendre H. , Paesmans M. , Van Den Eynde M. , Hendlisz A. 
Published: March 2020

14540 Background: Standard evaluation of response to chemotherapy in metastatic CRC is unsatisfactory. Metabolism based imaging using positron emission tomography and fluorodeoxyglucose (FDG-PET) is increasingly used to assess treatment efficacy. Aim: To evaluate the prognostic value of FDG-PET metabolic response to chemotherapy in resectable metastatic CRC. Methods: We reviewed retrospectively 382 patients with metastatic CRC between 7/2002 and 8/2006. Patients curatively operated from CRC metastases treated with preoperative chemotherapy and evaluated by FDG PET at baseline and before surgery were considered eligible for the study. Time to progression (TTP) was defined as the time between surgery and the first proof of recurrence of disease. Total Lesion Glycolysis (TLG) was used as the metabolic parameter. It represents the product of the mean standardised FDG uptake (SUV) of each lesion and its volume. The change of the sum of the TLG of all lesions was calculated. A cut-off of 30% was used to differentiate responders and non- responders. Results: 18 patients (median age 65 yrs) were included. 16 patients were operated from liver mets, and 2 from lung mets. Chemotherapy regimen was FOLFOX 4 in 10 patients, FOLFIRI in 7, and FOLFIRI-bevacizumab in 1 patient. Median number of lesions was 3 (1 to 10) before and 1 after chemotherapy. Median baseline TLG was 115.8 (6.8–841.8). Median post chemo TLG was 12.8 (0–1608.9). The distribution of the metabolic responses was CR 5, PR 9, SD 1, PD 3, with a response rate of 14/18 (78%, 95% CI : 52%-94%). Baseline TLG was not different between responders and non responders (p=0.88). Median follow-up was 422 days: 6 patients died, 15 had recurrent disease. Median TTP was 31 days for non responders, and 197 days for responders (p value not calculated because of the small number of non responding patients). After dichotomization of TLG values using their median as threshold, the post chemo TLG influenced significantly TTP (p=0.001, median TTP 86 days vs 263 days) along with the change of TLG (p=0.002, 107 days vs 263 days). Conclusions: Metabolic response assessment using PET allows a prognostic stratification after preoperative chemotherapy in resectable metastatic CRC. No significant financial relationships to disclose.
A prospective randomized trial comparing 5-fluorouracil (5-FU), mitomycin-C (MMC), and polysaccharide-K (PSK) versus UFT and PSK as adjuvant chemoimmunotherapy (CITX) for patients with locally advanced gastric cancer with curative resection
Authors: Choi J. , Kang S. , Park J. , Lee H. , Cho Y. , Han S. , Lim H. 
Published: March 2020

15074 Background: Adjuvant chemotherapy has demonstrated small but significant survival benefit in locally advanced gastric cancer in several meta-analyses, while adjuvant CITX showed improved outcome of patients (pts) compared to chemotherapy alone in a few trials. However, optimal chemotherapy regimen remains to be determined. We conducted a randomized trial comparing oral (PO) CITX with intravenous (IV) CITX in gastric cancer pts with curative resection. Methods: All enrolled pts underwent radical surgery with at least D2 dissection. After stratification for pathologic stage (IB or II vs. III) and primary tumor size (=5 cm vs. >5 cm), pts were randomized to IV CITX (5-FU 500 mg/m2 weekly for 24 weeks, MMC 8 mg/m2 every 6 weeks x 4) or PO CITX (UFT 400–600 mg/day for 12 months). Pts in both arms received PSK 3 g/day PO for 4 months. The planned target number of pts was 368 to prove the non-inferiority of PO CITX compared to IV CITX in overall survival. Results: A total of 82 pts (stage IB: 6, II: 29, IIIA: 30, IIIB: 17; 44 in IV arm, 38 in PO arm) were enrolled between May 2002 and October 2005, when the trial was closed due to poor accrual. Pts characteristics were well balanced. With a median follow-up of 39 months (14–55 months) in survivors, there were no significant differences in 3-year disease-free survival (82% vs. 61%, p=0.302) and overall survival (84% vs. 79%, p=0.838) between IV and PO arms. No grade 4 toxicity was observed in both arms. IV arm demonstrated higher incidence of grade 2 or 3 neutropenia (79% vs. 52%, p=0.025), thrombocytopenia (19% vs. 0%, p=0.008), and vomiting (36% vs. 9%, p=0.013). Conclusions: Although accrual was well below that planned, the results of this trial suggest that PO CITX with UFT might have similar efficacy with lower toxicity profile compared with 5-FU and MMC CITX in adjuvant treatment for gastric cancer. No significant financial relationships to disclose.