bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of topotecan (T) with weekly 5-fluorouracil (5FU)/leucorin (LV) in patients with advanced malignancies
Authors: Axelrod R. S. , Rose L. , Biermann W. 
Published: March 2020

13018 Background: Topotecan (T) is a semi-synthetic camptothecin analog with a broad spectrum of activity targeting the nuclear enzyme topoisomerase I. Daily iv schedules (up to 5) can result in dose limiting neutropenia. Reported synergy in vitro between topoisomerase I inhibitor and 5 FU/LV led us to explore a weekly schedule of 5FU, LV, and T in refractory tumors. Methods: Entry criteria: metastatic or locally advanced solid tumors; up to two prior chemotherapy regimens; prior adjuvant regimen admissible; no chemotherapy or radiation therapy within 4 weeks; adequate hepatic, hematologic, renal function. Exclusion: active second malignancy; CNS metastases; prior topotecan; allergy to related agents; active uncontrolled infection or conditions that would interfere with the study. Treatment was administered days 1, 8, 15, 22 of a 42 day cycle as LV 20 mg/meter (m)2 over 15 minutes intravenously (iv), 5 FU 400mg/m2 bolus, iv, and T at the specified dose (1.5mg/m2, 1.75, 2.0, up to 4 mg) over 30 minutes iv. Cohorts were advanced after at least three pts had completed 42 d. Study is reported through cohort 9: 5 FU 400/m2, LV 20/m2, topotecan 4 mg/m2. Results: Pt characteristics: 19 F, 25 M; ages 29–80, median 62. Tumor types: Pancreas (9), colorectal (6), lung (6), liver (3), salivary gland (5), sinus (2), nasopharynx (2) esophagus (2), and tongue, larynx, ovary granulosa cell tumor (gct), endometrium, mixed mullerian, mesothelioma, sarcoma, gastric (1 each). Related toxicities: gr 3/4 neutropenia 9%/2%, Hb 11%/0, platelets 4.5%/0, fatigue 4.5%/0. Stable disease of ≥ 4 cycles was observed in 18%: pancreas (2), ovarian (1), endometrium (1), salivary gland (3) (2 adenoid cystic, 1 adenocarcinoma). Conclusions: 5 FU, LV and T is well tolerated as a weekly out patient schedule (4 of 6 wks). It achieved minor response in one patient with gct for 8+ cycles and stable disease for ≥ 4 cycles in 6 pts. It is worthy of further exploration for gynecologic, salivary gland and pancreatic cancers. No significant financial relationships to disclose.
The primary clinical trial of dendritic cell vaccine pulsed with apoptosis tumor cell in patients with malignant cancers
Authors: Qian K. , Wang Y. , Shi H. , Yajun Wang G. , Ye Heng , Min Haiyan , Lu Xiao , Ning Yongling 
Published: March 2020

13509 Background: We evaluated the feasibility, safety, and immunogenicity of mature, apoptosis tumor cells-pulsed dendritic cell (DC) vaccines administered by intradermal injection. Methods: We performed a randomized study in 16 patients with malignant tumors, including 4 cases for gastric cancer, 3 cases for prostate cancer, 2 cases for breast cancers, one case for lung cancer, esophageal carcinoma, liver cancer , colorectal cancer, kidney cancer, ovarian cancer, endometrial cancer respectively.The vaccine used mature DCs (CD11c++, HLA-DR++, CD83+, and CD86+++) generated from peripheral blood monocytes in the presence of GM-CSF and IL-4. After 5 days, DCs were matured with a defined cocktail of cytokines (IL-1+ TNF-a+PGE2) and simultaneously pulsed with apoptosis autologous tumor cells or heterologous tumor cell lines, for 2 days.Patients were administrated four DC vaccinations (5×106 per time) at 7th day, 14th day, 21st day and 42nd day by intradermal injection(ID). Toxicity effect, life quality, immune function and clinical efficacy were monitored during the whole therapy. Results: Fourteen (82.4%) of 17 patients completed all four vaccinations. Vaccinations were well tolerated; a few patients exhibited less than grade 1 toxicities including rash, transient fever, transient debilitation and injection site reaction. The life quality of most patients had improved to certain degree, including sleep, appetite, mental status, and a good recovery from surgery and chemotherapy. Moreover, the serum level of IL-2 of 10/14 patients increased more than several times to twenty times, and 6/10 patients had a long increase for more than forty days. Serum level of IL-12 were increase in 11/14(9/11 patients increased for more than forty days) patients, Serum level of IFN-? were increase in 11/14(5/11 patients increased for more than forty days ) patients. Conclusions: Administration of this apoptosis tumor cell-pulsed mature DC vaccine by ID routes is feasible and safe. This administration seems to result in superior immunological sensitization as measured by in vitro serum level of immune cell factor such as IL-2, IL-12 and IFN-?. No significant financial relationships to disclose.
Therapeutic monoclonal antibodies target phenotypically-differing human breast cancer
Authors: Hahn S. E. , da Cruz L. A. , Sayegh D. , Ferry A. , O’Reilly K. , Pereira D. S. , Rubinstein D. B. , Findlay H. , Young D. S. 
Published: March 2020

13510 Background: CD44 (an adhesion molecule and stem cell antigen), CD59 (a complement-inhibitory molecule), MCSP (an adhesion and cell-cell interactions), and Trop-2 (EpCam a related signaling molecule) represent a group of biologically-significant cancer proteins acting through distinct mechanisms. We have described Abs with in vitro and in vivo cancer suppressive activity to this group of targets. However, their effectiveness depends on the phenotype of malignant cells; cell response should correlate with expression of its Ag, and tumor cells represent a heterogeneous group of non-synchronous cells. The present study describes the efficacy of those antibodies in breast cancer models and the prevalence of their antigen targets in a survey of human breast cancer tissues. Methods: In vivo activity of antibodies ARH460–16–2 (anti-CD44), AR36A36.11.1 (anti-CD59), AR11BD-2E11–2 (anti-MCSP), and AR47A6.4.2 (anti-Trop-2) in estrogen-dependent and hormone sensitive xenograft models of human breast cancer was examined. In addition, distribution of the antigens in breast cancer was determined by immunohistochemistry using tumor tissue arrays of breast cancer sections from distinct patients. Results: Treatment of an established breast cancer model with ARH460–16–2 resulted in 51% median tumor xenograft suppression (p<0.05), as well as increased survival in an MDA-MB-231 (breast cancer) grafted model. 63% of human breast cancer sections expressed the CD44 antigen. Treatment with anti-CD59 antibody AR36A36.11.1 resulted in 68% xenograft tumor suppression (p<0.005). AR47A6.4.2 anti-Trop-2 antibody bound to 100% of human breast cancer sections tested, and showed efficacy in the estrogen- dependent MCF-7 breast cancer model. Anti-MCSP antibody AR11BD-2E11–2 demonstrated 80% tumor growth inhibition (p<0.001), increased survival in an estrogen-dependent model of breast cancer, and was found to stain 62% of breast cancer tissues examined. Conclusions: The heterogeneity of breast cancer cell phenotypes in in vitro and in vivo studies and variable composite cellular antigen targets is the basis for the therapeutic use of multiple antibodies, each with independent mechanisms of action, and offers a rationale for combined antibody therapy in selected patients. [Table: see text]
A phase I dose escalation trial of the VEGFR tyrosine kinase inhibitor, PTK787/ ZK222584 (PTK/ZK), used in combination with paclitaxel in patients with advanced solid tumors with pharmacokinetic (PK) analysis
Authors: Malireddy S. R. , Chiorean E. , Foster A. , Jones D. , Waddell M. , Margol M. , Hall S. , Schneider B. , Sweeney C. J. 
Published: March 2020

14012 Background: The aim of this study was to define the maximum tolerated dose (MTD) for weekly paclitaxel administered in combination with daily PTK/ZK and assess for a potential PK drug interaction. Methods: 17 patients (pts) with refractory metastatic solid tumors, were enrolled. During cycle 1 (C1) paclitaxel was given on days 1 and 15 in combination with PTK/ZK on days 3 to 28. PTK/ZK was administered once daily each night. During cycle 2 (C2) and beyond, paclitaxel was given on days 1, 8 and 15 every 28 days. PTK/ZK was taken orally each night. A “3+3” design was used. In addition to the standard definitions of dose limiting toxicity (DLT) occurring in C1 and C2, the inability to give day 8 or 15 of paclitaxel or > 7 days of missed PTK/ZK due to toxicity was also deemed dose limiting. Therapy was given until disease progression. Results: 60 cycles (range: 1 to 8) have been administered to 16 evaluable pts. No DLTs were observed when 75 mg/m2 of paclitaxel was combined with PTK/ZK doses of 250 mg, 500 mg and 750 mg. Two of 5 pts treated with paclitaxel 85 mg/m2 and PTK/ZK 1,000 mg had Grade 3 transaminase elevation (defined DLT) in C1 after day 15. The MTD was therefore 75 mg/m2 paclitaxel and 750 mg PTK/ZK. Paclitaxel PK was obtained in 14 patients: 13 of 14 patients had a faster clearance (L/hr) of paclitaxel on C1 day 15 versus day 1 (average % increase: 79%, range 14–256%, SD: 69). Only one patient had a slower clearance: 26% decrease. Activity included 2 partial responses (prostate and esophageal cancer), and 8 pts had stable disease lasting 2–9+ months, including ovarian cancer pts previously treated with paclitaxel. Conclusion: The MTD for weekly paclitaxel plus daily PTK/ZK is 75 mg/m2 and 750 mg. DLTs were liver transaminase elevation. This combination was well tolerated, and responses and prolonged disease stabilization were seen. PK analysis revealed an increase in rate of paclitaxel clearance in most patients. No significant financial relationships to disclose.
Targeting the human double minute (HDM)-2 ubiquitin ligase as a strategy against non-Hodgkin’s lymphoma
Authors: Jones R. J. , Leopold L. , Yang D. , Orlowski R. Z. 
Published: March 2020

14016 Background: The ubiquitin-proteasome pathway has been validated as a target for non-Hodgkin lymphoma (NHL) with the recent approval of bortezomib for mantle cell lymphoma (MCL). In addition to anti-tumor activity, however, proteasome inhibitors have pleiotropic effects, including activation of an anti-apoptotic heat shock protein response, and their use clinically is complicated by toxicities such as peripheral neuropathy. By targeting E3 ubiquitin ligases, which are involved in ubiquitination of only a small subset of cellular proteins, it may be possible to achieve more specific anti-tumor effects with a better therapeutic index. One attractive target is HDM-2, which is responsible for ubiquitination of the p53 tumor suppressor. Methods: To evaluate the therapeutic potential of agents targeting HDM-2, we studied the impact of the small molecule MI-63, an inhibitor of the HDM-2-p53 interaction, in both p53 wild-type and -mutant cell line models. Results: Treatment of wild-type p53 MCL, NHL, and acute lymphocytic leukemia (ALL) cell lines with MI-63 induced a dose- and time- dependent inhibition of proliferation, with an IC50 in the 1.0–5.0 μM range. This was associated with G1/S cell cycle arrest , and apoptosis mediated by caspase-3. MI-63 induced accumulation and phopshorylation of p53 and also enhanced MDM-2 levels. Multiple p53 target genes were induced, including p21Cip1 and p53-upregulated modulator of apoptosis (PUMA), resulting in cleavage of poly-ADP-ribose-polymerase (PARP). Cell lines expressing certain p53 mutants were sensitive to the effects of MI-63, resulting in activation of caspases 3, 8, 9 and apoptosis. Cells without p53 expression were resistant to MI-63, but at higher drug concentrations proliferation was still inhibited, indicating a possible impact on HDM-2-mediated but p53-independent cell death pathways. Combinations of MI-63 with other anti-tumor agents showed enhanced anti-proliferative effects that met the criteria for synergistic interactions. Conclusions: Inhibition of the HDM-2-p53 interaction is a promising approach both by itself, and in combination with currently used chemotherapeutics, against lymphoid malignancies, providing a rational for translation of this agent into the clinic. No significant financial relationships to disclose.
Real-time ultrasound elastography for monitoring tumor response to neoadjuvant chemotherapy in primary breast cancer
Authors: Bando H. , Ishii M. , Tohno E. , Ueno E. 
Published: March 2020

14023 Background: Response to neoadjuvant treatment is vital to predict a patient’s long-term survival. Precise detection of residual tumor cells after neoadjuvant chemotherapy would allow a better cosmetic results avoiding over surgery and reduce second operation due to positive margin status. Moreover, accurate prediction of pathological CR will yield no surgical intervention in certain population. Recently, a new generation of ultrasound platforms with real-time freehand elastography that enables the imaging of elasticity of the lesion by using the extended combined autocorrelation method (CAM) has become available. We are currently applying this technology to our patients with primary breast cancer in an attempt to assess response to neoadjuvant chemotherapy in comparison with MRI, conventional ultrasound and pathological findings. Methods: A total of 38 patients with primary breast cancer who underwent neoadjuvant chemotherapy and following surgical resection From May 2005 to Dec 2006 were included in this study. Board certified radiologists assessed the tumor response by MRI, US and US Elastography prior to surgery. Positive predictive value (PPV), and negative predictive value (NPV) for pathological CR (pCR) was assessed. Tsukuba Elastography score was applied for the assessment of Elastography. Results: 11/38 patients (28.9%) achieved a pCR in breast to neoadjuvant chemotherapy while no patients demonstrated progressive disease. The PPV for pCR of MRI and US was 54.5% and 36.3% respectively. The NPV of MRI and US was both 90.9%. None of the residual tumor mass with score 4 or 5 cases diagnosed by Elastography achieved pCR. When residual tumor image was detected by US, pCR was present in all 4 cases with score 1 or 2 Elatography. If the cut-off line is determined between score 3 and 4, the PPV and NPV for pCR by Elastography was 100% and 66.6% respectively. Conclusions: Elastography is easy to perform and it can provide an inexpensive, non-invasive, real-time tool for assessment of response to neoadjuvant chemotherapy among patients with primary breast cancer. In particular, Elastography might more effectively diagnose pathological CR. More patients are needed to evaluate the sensitivity and specificity of this new technology. No significant financial relationships to disclose.
Responses to the combination of the glycolytic inhibitor 2-deoxy-glucose (2DG) and docetaxel (DC) in patients with lung and head and neck (H/N) carcinomas
Authors: Raez L. E. , Langmuir V. , Tolba K. , Rocha-Lima C. M. , Papadopoulos K. , Kroll S. , Brawer M. , Rosenblatt J. , Ricart A. , Lampidis T. 
Published: March 2020

14025 Background: We demonstrated in mouse xenografts that the combination of docetaxel chemotherapy with 2DG is feasible and increases responses against tumors (CancerRes; 2004 64:31–4). Methods: To determine the maximum tolerated dose (MTD) of daily oral doses of 2DG given alone and in combination with weekly docetaxel (DC) in patients (pts) with advanced malignancies who had relapsed after chemotherapy, and to evaluate the pharmacokinetics (PK) of 2DG alone and in combination with weekly DC. 2DG was initially administered orally once daily for 7 days every other week starting at a dose of 2 mg/kg, and DC was administered at 30mg/m2 for 3 of every 4 weeks. A modified accelerated titration design was used. Following completion of the every other week (EOW) 2DG dosing regimen, 3 weeks on and 1 week off (3–1W) dosing; and then continuous (CW) 2DG dosing were investigated. Results: 21 pts were enrolled in the EOW dosing at 2DG doses up to 88 mg/kg/day; another 10 pts were enrolled in the other dosing regimens. 5 pts had lung cancer (4 NSCLC + 1 SCLC); and another 6 pts had H/N cancers. One pt discontinued for DC-related sensory neuropathy. Single cases of DLT occurred - asymptomatic (64mg/kg) and symptomatic (88 mg/kg) Grade 3 hyperglycemia. The MTD was not reached with the EOW regimen. 2DG is rapidly absorbed (Tmax 0.5–1h) with a half-life of 5–10h. 2DG exhibits linear PK following single and multiple doses with minimal accumulation after multiple doses at 63 and 88 mg/kg. 2DG PK and DC PK do not alter each other. One of 18 evaluable pts in the EOW dosing with breast cancer had a partial response (PR). Another 8 pts achieved disease stabilization (SD) among them: 2 of 4 pts with NSCLC, 2 of 6 pts with H/N cancers, 1 pt with thyroid cancer, and 1 of 3 pts with adenoidcystic carcinoma. The others were unknown primary and a breast lymphoma. Also the MTD was not reached at 63mg/kg (3–1W) dosing where one patient with H/N cancer achieved stabilization of his disease. Enrollment of pts in the CW regimen is ongoing now. Conclusions: The combination of 2DG and DC appears to be feasible and safe with no evidence of PK interactions. Evidence of anti-tumor activity was observed in patients with NSCLC and H/N cancers. No significant financial relationships to disclose.
Phase I and pharmacokinetic (PK) study of 17-allylamino-17 demethoxygeldanamycin (17-AAG) in combination with weekly paclitaxel for advanced solid malignancies
Authors: Musquire L. A. , Ramalingam S. , Egorin M. J. , Sikorski R. P. , Chatta G. S. , Ramanathan R. K. , Friedland D. , Potter D. , Ivy S. P. , Belani C. P. 
Published: March 2020

14028 Background: 17-AAG inhibits heat shock protein 90, promotes degradation of oncoproteins & exhibits synergy with paclitaxel in vitro. We conducted a phase I study in patients (pts) with advanced malignancies to determine the recommended phase II dose (RP2D) of the combination of 17-AAG & paclitaxel. Methods: Key eligibility criteria were: histologically confirmed malignancy; lack of standard or proven treatment options; age > 18 years; ECOG PS 0–2; adequate hepatic, renal & bone marrow function & willingness to sign informed consent. Patients with neuropathy > grade 1 and those on therapeutic anticoagulation were excluded. 17-AAG (80–225 mg/m2) was given on days 1, 4, 8, 11, 15 & 18 of each 4-week cycle to sequential cohorts of patients. Paclitaxel (80–100 mg/m2) was administered on days 1, 8 & 15. PK sampling was done on days 1, 4 & 8 of cycle 1. Dose-limiting toxicity (DLT) was assessed during cycle 1. 17-AAG & paclitaxel were quantitated with validated HPLC and LC/MS assays, respectively. Results: 25 pts were accrued to 5 dose levels. Patient demographics were: male 18; median age 61; PS 0–14 pts, 1–10 pts, 2–1 pt. Primary tumor sites were prostate (5), lung (4), esophagus (4), ovary (2), colon (2) & others (8). The median number of cycles was 2. Chest pain (Gr 3) & fatigue (Gr 4) were dose-limiting at dose level 4 (17-AAG 225 mg/m2, paclitaxel 80 mg/m2). Other toxicities included neutropenia, fatigue, neuropathy, nausea, arthralgia and myalgia. The RP2D for the regimen is 17-AAG (175 mg/m2 administered biweekly) & paclitaxel (80 mg/m2/wk.) for 3 weeks in a 4 wk. cycle. None of the 6 patients at this dose level experienced DLT. One patient with fibrosarcoma experienced a PR & 4 (esophageal, prostate, gall bladder cancer) had SD. Paclitaxel PK were compatible with previous reports in literature and were similar on days 1 & 8. 17-AAG PK were linear and similar when given alone and in combination with paclitaxel. Conclusions: The combination of biweekly 17-AAG (175 mg/m2) and weekly paclitaxel (80 mg/m2/week) is tolerated well and was associated with anti-cancer activity. There was no evidence of drug-drug PK interactions. Support: NCI U01 CA099168–01, NIH/NCCR/GCRC grant 5M01RR 00056 No significant financial relationships to disclose.
A phase I trial of PEGylated glutaminase (PEG-PGA) in combination with 6-diazo-5-oxo-L-norleucine (DON) in advanced, refractory, solid tumors
Authors: Mueller C. , Al-Batran S. , Jaeger E. , Bausch M. , Sethuraman N. , Unger C. 
Published: March 2020

14040 Background: Tumor cells are avid glutamine consumers and highly dependent on extracellular glutamine supply. Based on a competitive mechanism, the effectiveness of the glutamine analogue DON is enhanced if the available pool of glutamine is significantly (below 10% of baseline) depleted by PEG-PGA. Methods: The study was designed to determine the maximal tolerable dose (MTD) of DON in combination with PEG-PGA. The patients received intravenous PEG-PGA 120 I.U./m2 in combination with DON twice weekly for six weeks followed by a tumor assessment according to RECIST. DON dose was escalated from 5 to 185 mg/m2 using modified Fibonacci design and traditional 3-patient cohorts. Results: Fifty-eight pts (23f/35m) received at least 1 drug administration and were evaluable for the analysis. Median age was 62 (range 43–79) and median Karnofsky PS was 90% (range 70%-100%). Median treatment duration was 29 days (range 1–106). Nausea and vomiting represented the most common non-hematological grade 3 toxicities, being observed in 6.9% and 10.3% of pts, respectively. Hematological side effects were G4 leuco- and neutropenia (1.7%) and G3 thrombocytopenia (1.7%). The treatment was very well tolerated with all other grade 3 or 4 toxicities affecting less than 5% of patients. Forty-six pts were evaluable for efficacy. Stable disease was observed in 20 (43.5%) pts, including MR (>10%) in 5 (10.8%) pts. The efficacy was dose depended. Conclusions: The combination of PEG-PGA and DON is active and has a favorable toxicity profile. The MTD is now investigated in a Phase IIa trial in patients with refractory colorectal, renal or non small cell lung cancer. The accrual will be finished by January 2007. No significant financial relationships to disclose.
A phase 1 study of MORAb-009, a monoclonal antibody against mesothelin in pancreatic cancer, mesothelioma and ovarian adenocarcinoma
Authors: Armstrong D. K. , Laheru D. , Ma W. W. , Cohen S. J. , Phillips M. , Brahmer J. , Weil S. C. , Hassan R. 
Published: March 2020

14041 Background: MORAb-009 is a monoclonal antibody that targets mesothelin, a cell surface adhesive protein overexpressed in pancreatic, ovarian, non-small cell lung carcinomas and mesothelioma and has minimal expression in normal tissue. The target is over-expressed by tumor cells. It was identified as one of the most prominent, differentially expressed cell surface antigens on pancreatic adenocarcinoma using SAGE of primary tumors vs. normal pancreatic tissue. In vitro studies show MORAb-009 to be effective in mediating cell killing by ADCC and inhibiting cell adhesion.. In xenograft models, MORAb-009 has single agent anti-tumor activity enhanced by the addition of chemotherapy. Toxicology studies show no toxicity in non-human primates and no significant binding to non-tumor tissues. Methods: Sequential cohorts of 3 patients received MORAb-009 intravenously on days 1, 8, 15 and 22 at doses of 12.5, 25, 50 and 100 mg/m2. Major inclusion criteria are the presence of a mesothelin-positive tumor with progression on primary therapy, acceptable organ function, ECOG PS 0–2, and measurable disease by CT. Safety pharmacology studies include chemistry, hematology, urinalysis and EKG. Tumors were re-imaged at day 35. Results: 11 patients have received MORAb-009 at doses up to 100 mg/m2. 6 patients had mesothelioma, 3 had pancreatic cancer and 2 had mesothelin-positive ovarian cancer. 4 patients exhibited grade 1 (3) or 2 (1) infusion reactions; no dose limiting toxicity was observed. A subject in the 50 mg/m2 cohort with pancreatic cancer who progressed on gemcitabine showed stable disease by CT and a drop in CA 19/9. Based on the response, this patient continues on extended MORAb-009 therapy. Enrollment to the final cohort of 200mgs/m2 is ongoing, as are pharmacokinetic and anti-MORAb-009 antibody analysis. Conclusion: MORAb-009, a monoclonal antibody against mesothelin is safe and well tolerated at doses up to 100 mg/m2. One subject with previously progressive pancreatic cancer had disease stabilization. In light of the positive preclinical data and safe clinical profile, this study supports further evaluation of the efficacy of MORAb-009 in mesothelin-positive tumors. No significant financial relationships to disclose.