bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome for metastatic (M+) medulloblastoma (MB) treated with carboplatin during craniospinal radiotherapy (CSRT) followed by cyclophosphamide (CPM) and vincristine (VCR): Preliminary results of COG 99701
Authors: Jakacki R. , Burger P. , Zhou T. , Holmes E. , Packer R. , Goldwein J. , Mehta M. , Pollack I. 
Published: March 2020

2017 Background: The outcome for patients with metastatic medulloblastoma has historically been poor. Carboplatin is both a potent radiosensitizer and has activity against medulloblastoma. In this study, we evaluated the feasibility of administering carboplatin during CSRT and the impact of anaplasia as an independent predictor of outcome. Methods: All patients underwent surgical debulking followed by 36 Gy CSRT with boosts to the posterior fossa and sites of bulk disease. During CSRT, patients received weekly VCR as well as carboplatin doses ranging from 30 mg/m2/dose x 15 to 45 mg/m2/dose x 30 given 1–4 hours prior to each RT fraction, using a Phase I design. G-CSF was given for neutropenia during CSRT. Six weeks after completing chemoradiotherapy, patients received six courses of monthly CPM (2 gm/m2) and VCR. Central pathology review was performed to confirm the diagnosis and assess for anaplasia. Results: 57 patients (median age 7.3 yrs, range 3.1–18.1 years, M/F ratio of 2.6:1) with centrally reviewed M+ MB were enrolled. Thrombocytopenia was dose limiting and 35 mg/m2/dose x 30 was selected as the maximum tolerated carboplatin dose. 20 patients (35%) had severe anaplasia. There was no difference in age, M/F ratio or distribution of M-stage between those with or without anaplasia. Median follow-up for surviving patients is 4.5 yrs. Four-year overall survival (OS) and event-free survival (EFS) for the entire group is 81 ± 5% and 66 ± 6%. Four-year OS is 89 ± 5% for patients without anaplasia vs. 65 ± 11% for those with anaplasia (log-rank p=0.002). Four-year EFS is 76 ± 7% for patients without anaplasia vs. 48 ± 12% for those with anaplasia (log-rank p=0.02). There was no difference in survival based on M-stage. Conclusions: The use of daily carboplatin as a radiosensitizer appears to be a promising strategy for patients with metastatic MB. The presence of anaplasia is a significant negative predictor of outcome. No significant financial relationships to disclose.
Prospective monitoring of circulating tumor cells in breast cancer patients treated with primary systemic therapy—A translational project of the German Breast Group study GeparQuattro
Authors: Mueller V. , Riethdorf S. , Loibl S. , Komor M. , Houber J. , Schrader I. , Conrad U. , Untch M. , vMinckwitz G. , Pantel K. 
Published: March 2020

21085 Background: The impact of circulating tumor cells (CTC) in patients with primary breast cancer is still unclear. Primary systemic treatment (PST) allows the assessment of therapeutic efficacy in breast cancer patients without long follow-up periods. Here we present first results on the presence of CTC in peripheral blood of patients enrolled in the “GeparQuattro” study. Methods: This study incorporates three different chemotherapy approaches and additional Trastuzumab (Herceptin®) treatment for patients with HER-2/neu-positive tumors. Recruitment finished in November 2006 and not all patients have completed therapy yet. We used the CellSearch™ system to evaluate CTC before PST from 245 patients and after PST from 67 patients. CTC from 45 samples were also examined for HER-2/neu expression by immunocytochemistry in the CellSearch™ system. Results: Before PST we detected CTC in 54/245 patients (22%). CTC numbers in 7.5 mL blood ranged between 1 and 200 (mean 6.5). In 8 CTC-positive samples (3.3%) = 5 CTC were found. Her-2/neu-positive CTC were observed in 25/45 cases (55.6%). CTC could be detected in 7/67 patients (10.4%) after PST (1 or 2 CTC). Before and after PST blood was analyzed from 43 patients, 27 of them were CTC-negative at both time points. Ten initially CTC-positive cases were CTC-negative after PST whereas 6 cases were detected CTC-positive after PST although no CTC could be found before PST. Conclusions: With the CellSearch™ system CTC can be detected in non-metastatic breast cancer patients at primary diagnosis and also after PST. To our knowledge, this is the largest study evaluating the presence of CTC in this context. With the availability of response information from more patients, it will be possible to examine the correlation between the incidence of CTC and response as well as kinetics of HER-2/neu expression during Trastuzumab treatment. [Table: see text]
Results of a phase II clinical trial of 2 doses and schedules of CP-675,206, an anti-CTLA4 monoclonal antibody, in patients (pts) with advanced melanoma
Authors: Ribas A. , Antonia S. , Sosman J. , Kirkwood J. M. , Redman B. , Gajewski T. F. , Pavlov D. , Bulanhagui C. , Gomez- Navarro J. , Camacho L. H. 
Published: March 2020

3000 Background: CP-675,206 has antitumor activity in pts with metastatic melanoma. A 2-stage, 2-arm phase II trial was conducted to choose the optimal dosing regimen for pivotal clinical trial testing. Methods: Eligible pts had measurable melanoma (stage IIIc or IV) progressing on or after prior therapy with ECOG PS = 1. In stage 1, 18 pts per arm were randomized to either 10 mg/kg monthly (10 Q1M) or 15 mg/kg every 3 months (15 Q3M). If 3 or more pts in either arm had CR or PR, then 25 more pts were entered to that arm. Primary endpoint was objective tumor response, and secondary endpoints were safety and survival. Results: 89 pts received at least 1 dose (44 at 10 Q1M, 45 at 15 Q3M), with both study arms moving to stage 2. 96% of pts had stage IV disease, and 57% had elevated LDH. There were no significant differences in age, sex, stage, or baseline LDH levels between study groups. A median of 3 doses (range, 1 to 26) at 10 Q1M and 1 dose (range, 1 to 9) at 15 Q3M were administered with 100% compliance. Dose delays occurred in 30% of pts treated at 10 Q1M and 16% at 15 Q3M. 2 pts at 10 Q1M and 5 pts at 15 Q3M continued on study beyond 12 months (mo). To date, 6 pts at 10 Q1M have been discontinued due to toxicity (3 diarrhea/colitis [1 requiring colectomy], Grave’s ophthalmopathy, pancreatitis, hypersensitivity reaction) and 2 pts at 15 Q3M (colitis and pancreatitis, diarrhea) (P = 0.14). There were no toxic deaths. 15 Q3M was associated with lower incidence of grade 3 or 4 AEs (31% vs 41% at 10 Q1M; P = 0.42). Responses by investigator assessment were 1 CR and 3 PRs at 10 Q1M, and 1 CR and 2 PRs at 15 mg/kg Q3M, including responses in skin, LN, bone, liver, lung, and adrenal glands. To date, only 1 pt with PR at 10 Q1M has relapsed, and the remaining responses are ongoing (18+ to 28+ mo). Median survival is 10.3 mo at 10 Q1M and 11.0 mo at 15 Q3M (P = NS). Conclusions: The 15 mg/kg Q3M regimen was chosen for further clinical testing based on comparable antitumor efficacy and a trend to improved feasibility and safety compared with 10 mg/kg Q1M. CP-675,206 at this dose and schedule is being examined in pivotal phase II and III clinical trials for pts with melanoma, and in early phase II trials in pts with CRC and NSCLC. No significant financial relationships to disclose.
Phase I study of intraperitoneal MHC unrestricted adoptive cell therapy with TALL-104 cells in patients with peritoneal carcinosis
Authors: Bengala C. , Rasini V. , Sternieri R. , Dominici M. , Andreotti A. , Gelmini R. , Cafarelli L. , Bevini P. , Berti A. , Conte P. 
Published: March 2020

3054 Background: TALL-104 is an irradiated human leukemic T cell line (CD3+, CD4- CD8+, CD56+, CD16-) grown in IL-2- containing medium, that has the ability to kill tumor cells in preclinical models in a MHC unrestricted way. A phase I trial in metastatic breast cancer patients, has shown that multiple i.v. infusions (infs) of TALL-104 cells can be given safely. In order to optimise the tumor:effector cell ratio, we have designed a phase I study of intraperitoneal infs of γ-irradiated TALL-104 cells. Methods: Patients (pts) with peritoneal carcinosis from ovarian or gastrointestinal tumors not responding to at least 2 lines of chemotherapy were eligible for study entry. The treatment included 5 i.p. infs (day 1, 3, 5, 15, 30) and the study aimed to test three cell dose levels: 1 x 108, 5 x 108, 2.5 x 109. End points of the study were: safety, kinetic of TALL-104 cells on ascites (if present) and peripheral blood (PB) by PCR, levels of cytokines (TGF-β, GM-CSF, IL-2, IL-4, IL-10, IFN-γ, TNF-a and -β, HGF, sIL-2R, sICAM-1) on ascites and serum, and cytotoxicity of autologous PB mononuclear cells (MNC) against K562 cells. Results: So far 10 pts have been treated: 6 with GI and 4 with ovarian cancer; 7 patients had ascites. Five pts have been treated at the 1st and 5 pts at the 2nd dose level. No treatment-related adverse events were observed. TALL-104 cells were detected in ascites (100 % of the pts) and PB (43 % of the pts) up to 48 hrs after the infs. Cytotoxicity of MNC showed a mean 5-fold increase at day 3 through 7 and it was still evident at day 30 in both dose levels. Cytokine levels are available for the first 5 pts. In one pt 18-fold increase of TNF-a was observed in ascites after the first infusion with a peak of 40-fold at day 15. sIL-2R and sICAM-1 showed both a mean 1.2-fold and 1.5-fold increase in serum in ascites respectively up to day 45. TGF-β1 level increased in average 3.3-fold in serum and 1.5-fold in ascites during the same observation period. HGF showed a mean 1.2-fold increase both in serum and ascites. Conclusions: These preliminary results show that the i.p. infusion of TALL-104 is safe. Moreover, the increased autologous cell-mediated cytotoxicity and the levels of soluble cytokines after i.p. infs indicate that TALL-104 cells may elicit potential antitumor activity. No significant financial relationships to disclose.
Phase I trial of a sequence-specific combination of the HDAC inhibitor, vorinostat (SAHA) followed by doxorubicin in advanced solid tumor malignancies
Authors: Daud A. , Schmitt M. , Marchion D. , Bicaku E. , Minton S. , Egorin M. , Zwiebel J. , Chiappori A. , Sullivan D. , Munster P. 
Published: March 2020

3502 Background: Preclinical cell culture and xenograft studies suggest that pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) may potentiate topoisomerase (topo) inhibitors. The HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. Methods: This Phase I trial explores the safety, tolerability and maximum tolerated dose (MTD) of a weekly schedule of escalating vorinostat doses (twice daily days 1–3) followed by doxorubicin (20 mg/m2) on day 3 (3 out of 4 weeks). Histone acetylation and topo II expression are evaluated in pre-and post-vorinostat peripheral blood mononuclear cells and in tumor cells of the 30 patients treated at the MTD. Results: To date, 15 patients [median age 54 (38–73)] have been treated in 4 vorinostat cohorts: 200, 300, 400, 500 mg bid. Tumor types included: breast (3), melanoma (3), pancreatic (2) and one each of SCLC, sarcoma, endometrial, colon, prostate, renal cell and bladder cancer. Dose-limiting toxicities included a grade 3 thrombocytopenia (1/6) at the 400 mg bid dose. Non-dose limiting Grade 3 and 4 toxicities include neutropenia, thrombocytopenia, fatigue, pulmonary embolus, and anemia (1 pt each). Currently, vorinostat doses of 500 mg bid are being evaluated. One confirmed partial response in a breast cancer patient, as well as minor responses in a melanoma and a prostate cancer patient were seen in 10 evaluable patients. Patients received a median number of 2 (1–9+) treatment cycles. Doxorubicin is stopped after 6 cycles and patients continue on vorinostat alone. H3 and H4 histone acetylation and topo II expression will be correlated with vorinostat dose, plasma concentration and response. Conclusion: A sequence-specific combination of vorinostat and doxorubicin is active without exacerbation of doxorubicin toxicity. The tolerated vorinostat dose exceeds the proposed single agent dose for vorinostat derived from patients with hematological malignancies. Histone hyperacetylation occurs in peripheral blood mononuclear cells at all levels. The anti-tumor activity in breast cancer and melanoma will be further explored. No significant financial relationships to disclose.
Phase I experience with c-MET inhibitor XL880 administered orally to patients (pts) with solid tumors
Authors: Eder J. P. , Heath E. , Appleman L. , Shapiro G. , Wang D. , Malburg L. , Zhu A. x. , Leader T. , Wolanski A. , LoRusso P. 
Published: March 2020

3526 Background: XL880 is a sub-nM inhibitor of the hepatocyte growth factor receptor (Met) and VEGF receptor family with low in vitro nM inhibition of PDGFRβ, KIT, FLT3, Tie-2 and Ron. Methods: The safety of XL880 was evaluated in two phase 1 studies. XL880 was administered mass-based on a 5 days on / 9 days off schedule (study 1) or as a fixed daily dose (study 2). Inclusion criteria include ECOG performance status = 2, adequate liver, cardiac, and renal function and no brain metastases. Tumor response is assessed every 8 wks by RECIST criteria. Pharmacokinetics, pre and post treatment tumor biopsies and plasma markers of angiogenesis (VEGF, sVEGFR and Ang2) were collected. Results: To date, 51 pts have been dosed in studies 1 & 2. In study 1, dose limiting toxicities (DLT) included reversible Gr3 elevations of lipase, hepatic transaminases and proteinuria. The maximum tolerated dose (MTD) was 3.6 mg/kg. In study 2, the MTD has not been defined. Common adverse events include hypertension and fatigue with loss of concentration. In study 1, 5 of 40 pts had partial responses (2+ -12+ months[m]), 3 pts had minimal responses and 8 pts had stable disease (SD) > 3 m. In study 2, 5 of 8 evaluable pts had SD > 3 m (4 ongoing) and 3 are too early to evaluate. Correlative studies in tumor biopsies show marked inhibition of phospho (p)-met, p-RON, p- ERK, p-AKT and increased apoptosis at less than the MTD. Patients in study 2 pts showed lower XL880 Cmax values with consistent mean concentrations (Css)compared with study 1 MTD pts. Css levels are reached in 15 d. Conclusions: XL880 as daily oral or 5 day on / 9 day off administration is generally well tolerated for > 1 year, although hypertension is nearly universal but manageable. XL880 has demonstrated substantial phase I antitumor activity with both dosing regimens. Correlative studies indicate significant activity against Met and Ron signaling. Enrollment continues on study 2. Phase II trials in gastric cancer and head and neck cancer will begin soon. No significant financial relationships to disclose.
Interim results from a first-in-human study with AMG102, a fully human monoclonal antibody that neutralizes hepatocyte growth factor (HGF), the ligand to c-Met receptor, in patients (pts) with advanced solid tumors
Authors: Gordon M. S. , Mendelson D. S. , Sweeney C. , Erbeck N. , Patel R. , Kakkar T. , Yan L. , Eckhardt S. G. , Gore L. 
Published: March 2020

3551 Background: AMG102 is a fully human IgG2 monoclonal antibody against HGF that prevents tumorigenesis in preclinical models through blockade of the HGF/c-Met receptor tyrosine kinase pathway. We describe interim results from the first-in-human study of AMG102. Methods: This ongoing phase 1, open-label, dose-escalation study is evaluating safety, pharmacokinetics (PK), and preliminary pharmacodynamics (PD) of AMG102 after single and multiple intravenous doses in pts with advanced solid tumors. Sequential dose cohorts of 4–6 pts were administered AMG102 at 0.5, 1, 3, 5, 10, or 20 mg/kg. Pts received a single dose, followed by a 4-wk treatment- free period during which safety and PK were assessed. If no dose-limiting toxicity (DLT) was observed, treatment was resumed every 2 wks at the same dose until pts exhibited drug intolerance or disease progression. Results: As of 10 August 2006, 31 pts have been treated with AMG102 at doses up to 20 mg/kg ( Table ). AMG102 appears to be well tolerated. One pt with non-small cell lung cancer had a grade 3 DLT of dyspnea/hypoxia after the first dose (0.5 mg/kg); a second pt with pancreatic cancer had a grade 3 DLT/serious adverse event of gastrointestinal hemorrhage after the first dose (1 mg/kg). The most frequently reported, treatment-related adverse events (AEs) have been fatigue (13%), constipation (10%), anorexia (6%), nausea (6%), and vomiting (6%). No anti-AMG102 antibodies have been detected. Initial PK analysis indicates approximately linear PK in the dose range of 0.5 to 20 mg/kg. The overall mean (SD) [median] clearance and half-life estimates based on day-1 dosing were 12.1 (5.21) [10.7] mL/hr and 15.4 (5.84) [15.5] days, respectively. Tumor response is described ( Table ). Conclusions: In this study, interim results suggest that AMG102 at doses up to 20 mg/kg appears to be well-tolerated, with preliminary PK data supporting every-2-wk administration. [Table: see text] No significant financial relationships to disclose.
A phase I dose escalation and pharmacokinetic study of BIBF 1120 in combination with paclitaxel and carboplatin in patients with advanced gynecological malignancies
Authors: Harter P. , Huober J. , Pfisterer J. , Wimberger P. , Loibl S. , Stopfer P. , Kaiser R. , Reichardt V. , du Bois A. 
Published: March 2020

3561 Background: BIBF 1120 is an oral triple angiokinase inhibitor targeting VEGFR, PDGFR, FGFR kinases which might be interesting targets for gynecologic tumor therapy. Therefore, we performed a phase I study to evaluate maximal tolerated dose (MTD), safety, and pharmacokinetics (PK) of twice daily BIBF 1120 in combination with carboplatin AUC 5 and paclitaxel 175 mg/m2 q21 (CP) in patients with advanced or recurrent gynecological malignancies. Methods: 6 courses of CP and escalating bid doses of BIBF 1120 (2x100 mg to 2x250 mg) on the days without i.v. chemotherapy were administered. A 3 + 3 dose escalation design was followed. An additional cohort of 6 pts was treated on the MTD level. Results: Twenty-three pts were enrolled and 21 pts were treated with at least one cycle of CP and BIBF 1120. At 2x250 mg of BIBF 1120, two pts developed reversible CTCAE °3 and °4 elevations of AST and ALT in the first treatment course. MTD was determined as 200 mg BIBF 1120 bid for the combination with CP. Within the other dose cohorts (2x100 mg, n= 3, 2x150 mg, n= 4, 2x200 mg, n= 13) no dose limiting toxicities were observed. There was no increase in hematological toxicity with the addition of BIBF 1120 compared to standard CP. Further non-hematological °3 toxicities were: diarrhea (n=4), ascites (n=1), dyspnoe (n=1), nausea (n=3).Thus far, the PK profiles of carboplatin, paclitaxel, and BIBF 1120 have been evaluated in seven pts (2x100 mg, n=3 and 2x150 mg, n=4). There was no significant change of the individual and geometric mean plasma concentrations of C and P before and after 3 weeks of continuous daily bid dosing with BIBF 1120. Conclusions: BIBF 1120 can be given safely at a dose of 200 mg bid together with standard doses of CP in pts with advanced gynecological malignancies. Preliminary PK analyses did not reveal any interaction of CP and BIBF 1120. [Table: see text]
Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) administered twice weekly
Authors: Murgo A. J. , Kummar S. , Gardner E. R. , Figg W. , Chen X. , Yancey M. , Ivy P. , Conley B. , Doroshow J. H. , Gutierrez M. E. 
Published: March 2020

3566 Background: 17-DMAG binds to heat-shock protein 90, leading to degradation of oncogene client proteins, inhibiting tumor growth. Preclinically, 17-DMAG has potent antitumor activity. Methods: 17-DMAG was given by 1–2 hour infusion twice weekly for 4 weeks/28-day cycle. Starting dose: 1mg/m2/dose. Eligibility: ECOG = 2, adequate organ function. Exclusions: prolonged QTc/uncontrolled illness. An accelerated titration escalation design was used; one patient (pt)/dose level was entered until a single pt experienced dose-limiting toxicity (DLT) or 2 pts have grade (gr) = 2 toxicity during the first cycle. Ending the accelerated phase, it converts to a standard 3–6 pt/cohort design. Objectives: To determine the toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD) and MTD of twice weekly 17-DMAG. Plasma samples collected before and up to 48 hours after 17-DMAG infusion were analyzed by LC-MS. Results: 23 pts were accrued and treated; Diagnosis: renal cell-1, pancreatic-2, medullary thyroid-1, NSCLC-3, colorectal -5, peritoneal mesotelioma-1 adrenocortical carcinoma-1, pheochromocytoma-2, malignant thymoma-1, melanoma-2, sarcoma-1, hepatocarcinoma-1 and head & neck -1 and ovary-1. 2 DLTs (gr 3 peripheral neuropathy and renal failure) were observed at 27 mg/m2/dose. Toxicities at the MTD dose (21 mg/m2/dose) have been acceptable: Myalgias/arthralgias being the most common. Other gr 1–2 toxicities included: diarrhea, weight loss, fatigue, elevated transaminases, hair loss, electrolyte abnormalities (hyponatremia and hypo/hyper-magnesemia) and leukocytopenia. PK is linear, with AUC and Cmax increasing as dose was escalated. Drug clearance is independent of dose, but highly variable (10.75 ± 5.56 L/hr/m2). Half-life: 10.0 to 31.7 h, with a median of 17.2 h. At the MTD: Cmax was 523.6 ± 265.3 ng/mL; Very high interindividual variability (CV = 70.3%) and a mean AUCinf of 2467.5 ± 1733.8 hr*ng/mL. Disease stabilization was achieved in a pt with mesothelioma (19 mos +) and another with head and neck cancer (8 mos +). Conclusions: We recommend 21mg/m2/dose twice weekly as the Phase II dose. The study continues to accrue at the MTD to collect paired biopsies for proteomic evaluation on Hsp90 client proteins analysis. No significant financial relationships to disclose.
Integrated report of the phase 2 experience with XL999 administered IV to patients (pts) with NSCLC, renal cell CA (RCC), metastatic colorectal CA (CRC), recurrent ovarian CA, acute myelogenous leaukemia (AML), and multiple myeloma (MM)
Authors: Cripe L. , McGuire W. , Wertheim M. , Eisenberg P. , Stadler W. , Paquette R. , Logan T. , Zimmerman T. , Matei D. , Matulonis U. 
Published: March 2020

3591 Background: XL999 is a potent spectrum-selective inhibitor of tyrosine kinases including VEGFR2/KDR, FGFR1/3, PDGFR-β, FLT3, RET, KIT, & SRC. A Ph 1 study in pts w/advanced malignancies has shown anti-tumor activity (3 PRs &10 SD lasting 3–26+ months) DLTs were cardiac failure & transaminase elevation. Methods: XL999 is being investigated in 6 Ph 2 trials. Pts w/histologically confirmed NSCLC, RCC, CRC, recurrent ovarian CA, AML, & MM were enrolled. The primary objectives of these independent studies are to determine response rate and further evaluate safety and tolerability of XL999. The secondary objectives are to assess PFS, duration of response & OS. Pts receive a once wkly 4hr IV administration of XL999 (2.4 mg/kg). Tumor response is assessed every 8 wks. Results: A total of 79 pts were treated. A confirmed PR was reported in 1/ 9 pts w/NSCLC. An additional 2 pts have SD at 2 & 3 months w/1 showing tumor shrinkage (24%). Two of 11 pts w/RCC have SD at 2 & 4 months. Of 14 pts enrolled w/AML, 1 of 3 with an activating FLT3 mutation had a PR, and 8 of 10 w/circulating myeloblasts had >50% reduction in myeloblasts. AEs = Grade 2 in =10% of pts related to XL999 included N/V, constipation, diarrhea, dry mouth, oral hypoesthesia, fatigue, pyrexia, dizziness, dysguesia, & hypertension. Cardiovascular (CV) events considered SAEs were reported in 11 pts (14%), and all but 1 occurred with the 1st dose of XL999.These events were characterized by ST /T wave changes in ECG,LVEF decreases and /or troponin elevation. Most pts with CV SAEs recovered to baseline within 2–3 wks upon withdrawl of further XL999. Conclusions: XL999 administered IV at a dose of 2.4mg/kg wkly was associated w/CV AEs, the majority of which were associated w/the 1st dose and were generally reversible upon XL999 discontinuation. XL999 shows preliminary evidence of anti- tumor activity in pts w/NSCLC & AML. [Table: see text]