bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship of variability in tumor measurement and response assessment.
Authors: Zhao Binsheng , Lee Shing Mirn , Lee Hyun-Ju , Qi Jing , Persigehl Thorsten , Tan Yongqiang , Schwartz Lawrence H. 
Published: March 2020

2541 Background: RECIST is widely used to evaluate anti-cancer therapy efficacy. This study explored variability in reporting tumor change and response to therapy due to both target lesion selection and measurement. Methods: 2256 measurements were performed in CT scans of chest, abdomen and pelvis from 30 patients retrospectively taken from a multicenter Phase II/III colorectal clinical trial. Using RECIST, three radiologists interpreted baseline, 6-wk and 12-wk scans in the following manner: (1) Radiologists independently selected and measured target lesions, (2) one radiologist’s target lesions were re-measured by the other two and (3) one radiologist re-measured the same scans in the above manner at an interval of greater than a month to prevent memory recall. Measurement variability in total tumor burden (TTB) on relative changes at 6-wk and 12-wk from baseline was analyzed for inter- and intra-reader target lesion selection, inter- and intra-reader measurement using Bland-Altman method, and agreements on RECIST categorical responses were assessed by kappa coefficient. Results: When the same target lesions were used, inter- and intra-reader variability in TTB on relative changes at 6-wk and 12-wk from baseline were similar; all had 95% limits of agreement within (-15%, 15%). Kappa coefficients for RECIST were 0.74 (6-wk) and 0.87 (12-wk) for inter-reader and 0.64 (6-wk) and 0.88 (12-wk) for intra-reader to report responses. When radiologists independently selected and measured target lesions, variability in relative changes was within (-17%, 16%) at 6-wk and (-24%, 23%) at 12-wk for inter-reader and (-16%, 16%) at 6-wk and (-14%, 18%) at 12-wk for intra-reader interpretations. Kappa coefficients were 0.66 (6-wk) and 0.75 (12-wk) for inter-reader and 0.63 (6-wk) and 0.80 (12-wk) for intra-reader to report responses. Conclusions: Differences exist in measuring tumor change. The magnitude of change in categorical RECIST response is quantifiable. The largest differences are when radiologists independently select and measure target lesions, the smallest when one radiologist repeats measurements on identical target lesions. The variability may impact the reporting of categorical responses and trial results, especially in a single arm study.
A phase Ib dose-escalation study of eribulin mesylate in combination with capecitabine in patients with advanced/metastatic cancer.
Authors: Nasim Muhammad Yaser , Plummer Ruth , Evans T.R. Jeffry , Morrison Rosemary , Anthoney David Alan , Haney Sophie , Madi Ayman , Savulsky Claudio Isaac , Johnston Claire , Carter David , Reyderman Larisa , Gopalakrishna Prashanth , Wanders Jantien , Twelves Christopher 
Published: March 2020

2552 Background: Eribulin mesylate is a microtubule dynamics inhibitor approved by FDA for patients (pts) with metastatic breast cancer after treatment with at least two prior chemotherapeutic regimens. This Phase Ib, open-label dose-escalation study determined the maximum tolerated dose (MTD) of eribulin in combination with capecitabine. Methods: Pts with advanced solid malignancies refractory to standard therapies, adequate organ function and ECOG performance status ≤2 received eribulin mesylate (2–5-min IV) by Schedule 1 (1.2, 1.6 or 2.0 mg/m2 on Day 1) or Schedule 2 (0.7, 1.1 or 1.4 mg/m2 on Days 1 and 8), in combination with twice-daily oral capecitabine 1000 mg/m2 Days 1-14 every 21 days. The MTD was defined as the highest dose in each schedule where ≤1/6 pts experienced dose-limiting toxicity (DLT). Safety and pharmacokinetics (PK) were assessed. Results: Of the 34 pts recruited, 19 (53% male; median age 62 years; 42% ECOG 0, 58% ECOG 1) and 15 (33% male; median age 61 years; 33% ECOG 0, 60% ECOG 1, 7% ECOG 2) were enrolled in Schedules 1 and 2, respectively. Most common tumor types were large intestine (20.6%), lung/bronchus (17.7%) and breast (14.7%). DLTs are shown in the table; there were no unexpected toxicities with the combination. The MTD for eribulin mesylate was 1.6 and 1.4 mg/m2 for Schedules 1 and 2, respectively, in combination with capecitabine 1000 mg/m2 twice-daily. Eribulin PK were dose proportional and independent of schedule or capecitabine co-administration. Combination with eribulin had no effect on the disposition of capecitabine and its metabolites. Although sample size was small, preliminary signs of efficacy were observed. Conclusions: The combination of eribulin and capecitabine was well tolerated with no unexpected safety findings. Schedule 2 MTD (1.4 mg/m2 Days 1 and 8) delivered a higher dose intensity of eribulin than Schedule 1 and was selected for evaluation in an ongoing Phase II breast cancer study. [Table: see text]
Phase I development of a weekly dosing schedule for the oral taxane tesetaxel.
Authors: Lang Amy , Beeram Muralidhar , Tolcher Anthony W. , Papadopoulos Kyriakos P. , Drengler Ronald , Smith Lon S. , Amaya Alex , Barnhurst Kelly , Itri Loretta , Patnaik Amita 
Published: March 2020

2555 Background: Tesetaxel (TST) has anticancer activity in patients (pts) with metastatic breast cancer (MBC) and gastric cancer when administered orally once every 3 weeks (Q3W). This drug is not a Pgp substrate, does not cause hypersensitivity reactions, and may be associated with less neurotoxicity. The maximally tolerated dose (MTD) on the Q3W schedule is 27 mg/m2, and neutropenia is dose-limiting. Since taxane activity may be schedule-dependent, we conducted a weekly, dose-ranging, and PK evaluation of TST. Methods: Eligibility: advanced solid tumors; ECOG PS 0-2; adequate organ function. TST was given once weekly for 3 weeks in a 28-day cycle, beginning at a total flat dose of 25 mg/cycle with progressive increases in total dose up to 75 mg/cycle. Subsequently, dosing was converted to a weight-based regimen at weekly doses of 12.5, 15, and 17.5 mg/m2 (i.e., total per cycle dose up to 52.5 mg/m2). Serial plasma samples were assayed by HPLC. Results: 26 pts were treated in 8 dose cohorts. The MTD was 15 mg/m2/wk (total cycle dose, 45 mg/m2). With repeated cycles, constitutional symptoms (fatigue and anorexia) rather than neutropenia proved dose-limiting at 17.5 mg/m2/wk. Only 1 pt (at 12.5 mg/m2/wk) developed grade 3 neutropenia; no other episodes of Grade 3-4 myelotoxicity were observed. One pt with MBC (who had progressed after 2 prior taxane regimens) achieved a PR; 1 pt with prostate cancer has maintained prolonged reduction of PSA (> 57%). PK analyses showed low but progressive increases in trough TST concentrations (0.4–4.6 nmol/mL) 7 days after each succeeding dose, which was consistent with the prolonged T½ of this drug (~180 hrs). There was no substantial drug accumulation over multiple cycles. Conclusions: Weekly oral TST is safe, provides long-term low-level drug exposure, and increases the total delivered dose over 12 wks by 25%. Interestingly, this regimen is not associated with significant myelosuppression. Thus, weekly TST dosing provides a highly convenient, “dose-dense”, taxane regimen that is not associated with neutropenia, which should facilitate its integration into multiple chemotherapy regimens. An ongoing study is evaluating efficacy of weekly TST dosing in MBC.
Neoadjuvant sipuleucel-T in localized prostate cancer: Effects on immune cells within the prostate tumor microenvironment.
Authors: Fong Lawrence , Weinberg Vivian K. , Chan Stephen E , Corman John M , Amling Christopher L , Stephenson Robert A , Formaker Carl , Simko Jeffrey , Sims Robert Brownell , Carroll Peter , Small Eric Jay 
Published: March 2020

2564 Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy for patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). To date, studies of sipuleucel-T in patients with mCRPC have studied immune response in peripheral blood. The effects of sipuleucel-T on prostate tumors are unknown. Methods: NeoACT (P07-1; NCT00715104) is an open-label, phase 2 study of patients with localized prostate cancer who received sipuleucel-T prior to radical prostatectomy (RP) to examine the immunologic effects of treatment on prostate tissue. Patients received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6-7 weeks prior to RP. The primary endpoint was the change in the frequency of lymphocytes between prostate biopsies (pre-treatment) and RP tissue (post-treatment), as assessed by immunohistochemistry (IHC). Results: The median age of the 42 enrolled patients was 61 years, and all had an ECOG performance status of 0. Thirty-eight patients received all 3 pre-RP sipuleucel-T infusions. To date, tissue IHC analysis has been completed on 32 patients. Treatment-related AEs were manageable and transient. Sipuleucel-T did not appear to impact surgery, as judged by operative complications, procedure time, and estimated blood loss. Frequent events that occurred ≤1 day after infusion (>10% of patients) were fatigue, headache, and myalgia. Significant increases (≥3 fold) in CD3+ and CD4+ T cell populations were observed at the tumor interface (where benign and malignant glands interface), compared with the pre-treatment biopsy, benign RP tissue, and tumor RP tissue (ANOVA post hoc Newman-Keuls test: p<0.0001 for each comparison). FoxP3+ CD4+ T cells were also increased (p=0.0005) at the tumor interface, but represented a small fraction of the observed CD4+ T cells. Conclusions: Neoadjuvant sipuleucel-T treatment is associated with an increased frequency of T cells in prostate cancer tissue at the interface of the benign and malignant glands. These data suggest that sipuleucel-T can modulate the presence of lymphocytes at the prostate tumor site. Work is ongoing to more fully characterize the immune response.
Targeting hyaluronan (HA) in tumor stroma: A phase I study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of pegylated hyaluronidase (PEGPH20) in patients with solid tumors.
Authors: Borad Mitesh J. , Ramanathan Ramesh K. , Bessudo Alberto , LoRusso Patricia , Shepard Harold Michael , Maneval Daniel C. , Jiang Ping , Zhu Joy , Frost Gregory I , Infante Jeffrey R. 
Published: March 2020

2579 Background: HA, a glycosaminoglycan, accumulates in ~25% of solid tumors and is associated with poor prognosis. Tumors that accumulate HA develop high interstitial fluid pressure (IFP) and become resistant to chemotherapy. In animal models, PEGPH20 reduced tumor-associated HA and increased efficacy of chemotherapy. Methods: This ongoing phase 1 study was designed to assess safety, tolerability, PK, PD, and the maximum tolerated dose (MTD) of PEGPH20 as a single agent in patients with treatment-refractory solid tumors. IV PEGPH20 was administered in a twice weekly or a once weekly dosing schedule with oral dexamethasone (dex) pre-and post dose. Biomarkers included tumor histochemistry to detect HA depletion, plasma HA catabolites, and DCE-MRI or FDG-PET. Results: Fifteen patients have been enrolled into the study. Dose administration ranged from 0.5 µg/kg to 5 µg/kg. Musculoskeletal events (MSEs) were the most common and dose limiting toxicities. To date, up to 3 µg/kg twice weekly IV infusions of PEGPH20 were well tolerated with manageable Grade 1 MSEs in most patients. MTD has not been reached. Plasma concentrations of PEGPH20 showed dose proportional exposure with a terminal half life of ~2 days. Enzymatic activity of PEGPH20 was reflected by dose-dependent HA catabolites in plasma. Pre- and post-dose tumor biopsies from 2 colon patients demonstrated 23-60% reduction in tumor HA after 4 weeks of dosing. Serial DCE-MRI and FDG-PET demonstrated increased tumor perfusion (Ktrans) and decreased metabolic activity 8 and 24hrs post-PEGPH20 in one patient each. Doses of ≤3 µg/kg were tolerated with intermittent Grade 1-2 MSE. Enrollment at dose levels > 3 µg/kg is ongoing. Conclusions: Repeated IV PEGPH20 infusion resulted in dose-dependent systemic exposure and is tolerated with concomitant dex treatment. HA catabolites in plasma demonstrated the in vivo enzymatic activity of PEGPH20. Reduced HA in tumor biopsies and serial DCE-MRI and FDG-PET images confirmed PD activity. Increased tumor perfusion by PEGPH20 may enhance drug delivery to tumor. Combination studies of PEGPH20 with cytotoxic chemotherapy are planned.
Phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) trial of NGR-hTNF given at high doses in patients with refractory solid tumors.
Authors: Zucali Paolo Andrea , Simonelli Matteo , De Vincenzo Fabio , Lorenzi Elena , Perrino Matteo , Bertossi Monica , Balzarini Luca , Bonifacio Cristina , Lambiase Antonio , Bordignon Claudio , Santoro Armando 
Published: March 2020

2580 Background: NGR-hTNF exploits the asparagine-glycine-arginine (NGR) peptide for selectively targeting tumor necrosis factor (TNF) to a CD13 overexpressed by tumor vasculature. Maximum tolerated dose (MTD) of NGR-hTNF was previously established at 45 µg/m2, when given as 1-h infusion every 3 weeks (q3w), with dose limiting toxicities (DLT) being grade 3 infusion-related reactions (IRRs). We explored further dose escalation by prolonging infusion time (2-h) and using premedication (paracetamol). Methods: DLTs were defined as drug-related grade 3/4 adverse events (AEs). PK and soluble TNF receptors (sR1-sR2) were tested in 46 pts. The volume transfer coefficient (Ktrans) and initial area under gadolinium concentration (IAUGC) were assessed before and 2 hours after dosing by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in 37 pts. Results: 12 dose levels (DLs) from 60 to 325 μg/m² q3w were evaluated. 48 pts (PS 0/1: 21/27; M/F: 37/11; median age: 61 years) received a total of 117 cycles (range 1-6). Prior regimens ranged from 1 to 7 (median 3). No DLT occurred and MTD was not reached. Study-emergent grade 3 and 4 AEs were reported in 12 (25%) and 5 (10%) pts, respectively. Grade 1/2 IRRs included chills (58%) and pyrexia (56%). Both Cmax (p<.0001) and AUC (p=.0001) increased with dose. Post-treatment peaks of sR2 were higher than sR1 (9.6 v 4.9 ng/mL; p<.0001). However, changes in sRs did not differ across DLs, with a plateau in shedding kinetics. By DCE-MRI assessment, median pre- and post-first cycle values declined from 0.15 to 0.09 min-1 for Ktrans (p=.02) and from 10.2 to 7.2 mM/L/sec for IAUGC (p =.0005). Over treatment, 28 pts (76%) showed decreases in IAUGC (-47%, p<.0001) and Ktrans (-59%; p<.0001) that were inversely correlated with baseline Ktrans values (p<.0001) and NGR-hTNF Cmax (p=.03). Of 41 evaluable pts, 12 (29%) had stable disease for a median time of 2.9 months. Survival at 1 year was 34%, with improved survival observed in pts with lower sTNF-R2 levels (p=.01) and greater Ktrans reductions (p=.05) after 1st cycle. Conclusions: NGR-hTNF can be safely escalated at doses higher than MTD and induces low shedding of receptors and early antivascular effects.
A phase II, single arm clinical trial involving an alternative cancer treatment psorinum therapy in patients with unresectable metastatic colorectal carcinoma.
Authors: Chatterjee Aradeep , Chakraborty Amitava , Bhattacharya Sudin , Bhakta Radhe S. , Chatterjee Ashim Kumar , Biswas Jaydip 
Published: March 2020

2581 Background: We prospectively studied the clinical efficacy of an alternative cancer treatment “psorinum therapy” in treating unresectable metastatic colorectal carcinoma (UMCRC). Methods: Our study was phase-II, open level, single arm and single stage. Participants eligibility criteria included (1) histopathology confirmation of the malignancy (2) metastatic and unresectable disease status (3) No prior conventional cancer treatments (4) Karnofsky performance status between 40 – 70%. The primary outcome measures of the study were (1) to assess the radiological tumor response rate (using CT scanning procedure and following the RECIST criteria); (2) to assess how many participants survived at least 1 yr, 2 yrs, 3 yrs, 4 yrs and finally, after 5 yrs of the study. The secondary outcome measure was to assess the side effects of the investigational anti- cancer drug (psorinum) if any. Psorinum (an alcoholic extract of scabies slough and pus cells) was administered orally at a dose of 0.02ml / kg body weight / day as a single dose on an empty stomach for a complete course duration of 2 yrs to all the participants along with allopathic and homeopathic supportive cares. Results: 105 participants included in the final analysis at the end of the study. According to the RECIST criteria, complete response occurred in 12 (11.43%) cases and partial response occurred in 38 (36.19%) cases. 76 (72.38%) of them survived at least 1 yr, 58 (55.24%) survived at least 2 yrs, 51 (48.57%) survived at least 3 yrs, 43 (40.95%) survived at least 4 yrs and 37 (35.24%) of them survived at least 5 yrs. These participants didn’t receive conventional or any other investigational cancer treatments. Conclusions: The results of the study show clinical efficacy of psorinum therapy in treating patients with UMCRC. The investigational drug psorinum is non- toxic. Randomized controlled clinical trial should be conducted for further investigation of this alternative cancer treatment in treating unresectable metastatic colorectal carcinoma to integrate it into the mainstream of oncology treatments.
Phase I/II, two-part, open-label, multiple-dose, dose-escalation study of siltuximab in patients with solid tumors.
Authors: Angevin Eric , Elez Elena , Cohen Steven J. , Van Laethem Jean-Luc , Ottensmeier Christian , Joly Florence , Ray-Coquard Isabelle , Lopez-Martin Jose A. , Dirix Luc , Machiels Jean-Pascal , Clive Sally , Steven Neil Matthew , Reddy Manjula , Hall Brett , Puchalski Thomas , Bandekar Rajesh , Van De Velde Helgi , Tromp Brenda J. , Vermeulen Jessica , Kurzrock Razelle 
Published: March 2020

2583 Background: Siltuximab (S) is a chimeric mAb with high affinity for soluble IL-6. This Ph 1/2 study evaluated safety, efficacy and PK of escalating, multiple IV doses of S from a new cell line in patients (pts) with advanced refractory solid tumors. Methods: In Ph 1, S was given to 20 pts with advanced solid tumors at escalating dose levels (2.8 or 5.5 mg/kg q2w or 11 or 15 mg/kg q3w) and to 24 pts with taxane and platinum resistant ovarian cancer (OVC) or KRAS mutant (KRASmt) tumors at 15 mg/kg q3w. In Ph 2, 17 OVC pts and 23 KRASmt pts received the Ph 1 selected dose of 15 mg/kg q3w. The Ph 2 primary efficacy endpoint was clinical benefit rate (CBR: CR + PR + SD of > 6 wk). Results: In Ph 1-2, 84 pts (35 colorectal, 29 OVC, 9 pancreatic, 11 other) pretreated with a median of 4 prior tx regimens received a median of 3 (range 1, 45) cycles. 1 DLT occurred at 5.5 mg/kg; MTD was not reached. 62% pts had AEs gr ≥ 3 in Ph 1-2, most common were hepatic function abnormalities (15%), PS deterioration (12%), fatigue (11%). 10% pts had possibly S-related AEs gr ≥ 3; only neutropenia (4%) was reported in >1 pt. 42% pts had SAEs, most were related to underlying disease, 2% were possibly S-related. 18 deaths occurred on study, 17 due to PD, 1 due to AE. No pt had antibodies to S. The PK profile was bi-exponential with a t1/2 ranging 15 − 20 d. PK profile of S from the new Chinese hamster ovary cell line appears similar to the previous murine Sp2/0 myeloma cell line. CBR in Ph 2 was 5%. ORR by RECIST was 26% SD in Ph 1, 9% SD in Ph 2. 1 OVC pt had CA 125 response. In Ph 2 the median PFS was ~ 2 mo in both cohorts; the median OS was 4.2 mo in KRAMSmt and 11 mo in OVC. Hb increased by a max of ≥10 g/L in 73% pts given 15 mg/kg in Ph 2, with 94% showing a median decrease of 68% at d 8 after dose 1 in hepcidin, a regulator of iron homeostasis. CRP was suppressed in all pts during tx, with median decrease 93% at 11 mg/kg and 88 − 93% at 15 mg/kg as early as d 8 after dose 1. Other biomarkers will be presented. Conclusions: S appears to be well tolerated; doses of 11 − 15 mg/kg q3-4w can be used in future studies. No CR/PR was observed, although some pts with advanced solid tumors had durable SD and CRP suppression. Improvement in Hb was observed in a large proportion of pts, indicating a role of IL-6 in anemia that needs to be further explored.
Effect of the novel therapeutic cancer vaccine formulation DPX-0907 on multifunctional T-cell responses in ovarian, breast, and prostate cancer patients.
Authors: Berinstein Neil Lorne , Karkada Mohan , Nigam Rita , Morse Michael , Nemunaitis John J. , Chatta Gurkamal S. , Kaufman Howard , Odunsi Kunle , Weir Genevieve , MacDonald Lisa , Stanford Marianne , Mansour Marc 
Published: March 2020

2588 Background: To increase the efficacy of peptide cancer vaccines, we developed a novel vaccine platform called DepoVax, an adjuvanted water-free depot formulation with the ability to generate enhanced immune responses. Naturally processed HLA-A2 restricted peptides that are selectively presented by breast, ovarian and prostate cancer cell lines, but not by normal HLA-A2+ cells, were used as antigens with a proprietary adjuvant and a T helper peptide epitope to create a therapeutic cancer vaccine, DPX-0907. Methods: A phase I clinical study was designed to examine the safety and immune activating potential of DPX-0907 in advanced stage breast, ovarian and prostate cancer patients. A total of 23 late stage cancer patients were recruited and were divided into two dose volume cohorts in a three immunization clinical protocol. Results: DPX-0907 proved to be safe with no serious adverse effects related to the vaccine reported. Of those evaluable for immunogenicity, all breast cancer patients (3/3), most of ovarian (5/6) and one third of prostate (3/9) cancer patients demonstrated immune response to one or more of seven antigenic peptides, resulting in a 61% response rate. Immune responses correlated with achievement of CR, PR or SD to last treatment. No difference in immune response rate or magnitude was seen between the two dose groups. DPX-0907 displayed strong immune induction potential, with 73% of immune responders showing responses with just one dose of vaccine. In 83% of responders, immune responses were detected at ≥2 time points post vaccination and 64% had a persistent immune response at one month post last vaccination. Immune monitoring showed peptide-specific CD8 T cells, and these T cells were able to secrete multiple Th1 cytokines indicating their multifunctionality, a feature attributable to cells that mediate protective responses. Conclusions: These data support the ability of DPX-0907 to elicit Th1 dominated, specific immunity and support the rationale for further testing in immunologically competent cancer patients. The novel DepoVax formulation may promote multifunctional memory responses with peptides from other tumor associated antigens.