bluuebunny/crossref_metadata_2025 huggingface dataset:
Knowledge about cancer screening among medical students and residents
Authors: Villarreal-Garza C. , Villa A. R. , Perfecto-Arroyo M. , García-Aceituno L. , Rojas-Flores M. , León-Rodríguez E.
Published: August 2020

1541

Background: Cancer is the second cause of death worldwide. In certain types of cancer, screening may detect the disease in its early stages, increasing survival. Therefore, it becomes extremely important that physicians are aware of its precise indications. We sought to explore the level of knowledge about cancer screening among Mexican medical students and residents. Methods: A questionnaire-based survey about screening in breast, cervical, colon, and prostate cancer was completed by medical students attending either public or private medical schools, and internal medicine residents from five training centers in Mexico City. The survey included 16 questions regarding tumor markers, beginning of screening, method of early detection, and frequency of screening. Knowledge scores were expressed as percentages. Statistical analysis was performed using two-tailed Fisher's exact test and Kruskal-Wallis test. Results: The survey was answered by 451 individuals, 49.22% male and 50.78% female, with a mean age of 24.3 ± 2.55 years (range 20–33). Medical students comprised 64.52% and residents 35.48%. Mean knowledge score was 63.97 ± 14.97 (range 18.75–100), increasing directly with level of training: medical students obtained a mean score of 60.46 ± 14.09 compared to residents with score of 70.35 ± 14.44 (p = 0.0001). Statistical differences were noted between third (50.00), fourth (62.62) and fifth year (60.19) (p = 0.0001) medical students; while there was no difference between sixth and seventh year students, neither between distinct years of residency. No difference was encountered between private and public schools. Comparing screening knowledge regarding tumor subgroups, residents scored higher than students in relation to tumor markers 65.24 versus 22.82, breast cancer 77.33 versus 69.19, and prostate cancer 75.00 versus 68.53 (p = 0.0001 for the three comparisons); whereas there was no difference in the education concerning cervical and colon cancer screening, 69.44 versus 70.83 (p = 0.518) and 50.61 versus 45.20 (p = 0.114), respectively. Conclusions: Knowledge of screening guidelines is suboptimal among medical students and residents, especially regarding cervical and colon cancer. Further educational efforts should be targeted to educational and training programs in this country.

No significant financial relationships to disclose.
Age and gender-related peculiarities of multiple primary cancers (MPC) in the Altai Territory
Authors: Sekerzhinskaya E. L. , Petrova V. D. , Lazarev A. F.
Published: August 2020

1552

Background: Itis known that the age-related differences in cancer incidence become distinct among males and females above 30 years of age. The share of elderly females in the general population is growing due to anomaly high non-oncological mortality of able-bodied males. Methods: The data of the Altai territory cancer registry (1995–2008 y.y.) on 3861 patients with MPC were analyzed. Results: Three thousand seven hundred forty four patients (96.97%) had 2 MPC; 114 patients (2.95 %), 3; and 3 patients (0.07 %), 4. Among all the patients with MPC there were 50.58% females and 49.42 % males. The average age of patients with double MPC was 63.1 (varied from 14.4 to 82.6). The average age of patients with triple MPC was 63.0 (varied from 39.0 to 81.0). In most of the patients. cancers were diagnosed at the ages of 60 to 69, which is considered elderly in accordance with World Health Organization gerontological classification. Females prevailed over males among the patients at the ages of 30 to 39 (71.43% to 28.57%, p < 0.05) as well as at the ages of 40 to 49 (69.34% to 30.66%, [p <0.01). However, among the patients at the ages of 60 to 69, males amounted 55.69% in comparison with 44.31% of females (p < 0.01). The was no significant difference between the number of females and males among the patients with MPC at the ages of 70 to 79. Conclusions: Thus, MPC were frequently registered in both males and females. Yet among the patients with MPC in elderly ages, there were more males than females.

No significant financial relationships to disclose.
Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of 1–3 cerebral metastases: Results of the EORTC 22952–26001 study
Authors: Mueller R. P. , Soffietti R. , Abaciouglu M. U. , Villa S. , Fauchon F. , Baumert B. G. , Fariselli L. , Tzuk-Shina T. , Collette L. , Kocher M.
Published: August 2020

2008

Background: The EORTC Radiotherapy and Brain Tumor Groups conducted a phase III trial to define the role of adjuvant whole brain irradiation (WBRT) after local treatment (surgery or radiosurgery) for brain metastases. It was hypothetized that WBRT would increase the duration of functional independence by reducing the number of intracranial relapses. Methods: Pts eligible for radiosurgery (RS) had 1–3 metastases of solid tumors (SCLC excluded) ≤ 3.0 cm in diameter (≤ 2.5 cm for 2–3 lesions). In case of surgery (S), a complete resection was mandatory. Only pts with no or stable systemic disease or with asymptomatic synchronous primary tumors, and with WHO PS 0–2 were allowed. Pts were randomized for adjuvant WBRT or observation (OBS). Primary endpoint was survival with functional independence measured by the time to WHO PS deterioration to > 3. Analysis is by intent-to-treat (Logrank, two-sided α = 0.05). Results: From 1996–2007, 359 pts were recruited. 160 surgical pts had resection of one (96%) or two (4%) metastases, and 185 (of 199 scheduled pts) had RS (marginal dose 20Gy, target dose 25Gy) of one (67%), two (23%), or three (10%) lesions. Adjuvant whole brain irradiation (30Gy/10 fractions) was given to 166/180 pts. (92%) randomized for WBRT and to 4/179 pts (2%) in the OBS arm. Median time to WHO PS > 3 was 9.8 months (95% CI 8.0 - 11.7) in the OBS arm and 9.8 months (95% CI 7.8 - 12.6) in the WBRT arm (p > 0.5). It was only significantly influenced by initial WHO PS and initial systemic disease status (p < 0.01). Overall survival was 10.9 months (95% CI 9.2 - 14.6) in both arms (p > 0.5). Cumulative incidence of intracranial progression at 6 and 24 months was 39.7% (95% CI 32.5 - 46.8) and 54.0% (95% CI 46.7 - 61.3) of the OBS pts, but only 15.2% (95% CI 9.9 - 20.5) and 31.4% (95% CI 24.5 - 38.2) of the WBRT pts (p < 0.0001). Intracranial progression was a cause of the death in 77/179 pts (43%) of the OBS group and in only 45/180 pts (25%) of the WBRT group. Conclusions: After radiosurgery or surgery of 1–3 brain metastases, adjuvant WBRT reduces the frequency of intracranial relapses and neurologic deaths but fails to prolong the time period of functional independence and overall survial time. Updated results will be presented at the Meeting.

No significant financial relationships to disclose.
NCCTG phase I trial of temsirolimus (CCI-779) and temozolomide (TMZ) in combination with radiation therapy (RT) in newly diagnosed glioblastoma multiforme (GBM) patients
Authors: Sarkaria J. N. , Galanis E. , Wu W. , Giannini C. , Jaeckle K. A. , Doyle L. , Uhm J. , Brown P. , Dietz A. B. , Buckner J.
Published: August 2020

2019

Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt signaling pathway as a critical modulator of cell survival. We previously demonstrated significant synergy of the mTOR inhibitor sirolimus with RT in glioma xenografts. Methods: The standard cohorts of 3 design was applied with dose escalation of weekly IV CCI-779 in combination with standard TMZ/RT. CCI-779 was given during both RT (60 Gy)/TMZ (75 mg/m2 daily) and adjuvant TMZ (200 mg/m2 daily x 5 every 28 days). Results: A total of 17 patients were enrolled. CCI-779 therapy during RT/TMZ was well tolerated at dose level 0 (25 mg CCI-779, n = 3) and dose level 1 (50 mg CCI-779, n = 6) with 1 of 9 patients experiencing a DLT (Gr 3 fatigue). Dose level 2 (75 mg CCI-779) exceeded the maximally tolerated dose with two of six patients with DLT (<75% CCI-779 delivered; Gr 4 dyspnea). Despite reasonable tolerance during RT/TMZ, the overall regimen was associated with a high rate of infection associated with lymphopenia. After a patient died from PCP on cycle 2 of adjuvant TMZ/CCI-779, antibiotic prophylaxis was mandated. Two other patients died of gram-negative sepsis despite prophylaxis: one after their first dose of CCI-779 and one during cycle 4 of adjuvant therapy. In contrast to our 18% grade 5 infection rate, only 4% grade 3 (no grade 4/5) infections were observed in 26 other CTEP-sponsored clinical trials involving 1,006 patients treated with CCI-779. Results from translational studies evaluating the effects of treatment on immune function will be presented. Further infections were avoided on this trial after CCI-779 therapy was limited to RT/TMZ. Conclusions: Although CCI-779 in combination with RT/TMZ was well-tolerated, adjuvant therapy with TMZ/CCI-779 was associated with an increased risk of opportunistic infections.

[Table: see text]
Phase II and pharmacogenomics study of enzastaurin plus temozolomide and radiation therapy in patients with glioblastoma multiforme or gliosarcoma
Authors: Butowski N. A. , Lamborn K. , Chang S. , Hsieh E. , Fedoroff A. , Parvataneni R. , Nicol S. , Liepa A. , Thornton D. , Prados M.
Published: August 2020

2020

Background: ENZ, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCβ and the PI3K/AKT pathways to induce apoptosis, reduce proliferation, and suppress angiogenesis. The primary endpoint of this single-arm phase II trial was overall survival (OS). Secondary objectives included progression-free survival (PFS), safety, PK/PD, and patient-reported outcomes (PROs). A concurrent PGx project assessed the value of pretreatment molecular profiles as predictive of outcome. Magnetic resonance spectroscopy (MRS) was also evaluated during treatment for its value in predicting OS. Methods: Patients enrolled with newly diagnosed GBM/GS and KPS ≥60. Treatment started <5 weeks after diagnosis with RT 60 Gy given over 6 weeks and TMZ 75 mg/m2 given daily during RT and then at 200 mg/m2 from days 1–5 of a 28-day cycle. ENZ 250 mg/day was given daily during RT and adjuvantly. Planned treatment duration was 1 year. PGx parameters were: MGMT promoter methylation, mismatch repair status, PKC isoforms, pERK, pCREB, EGFR, PTEN, GSK3B, ser9, VEGF, and pS6. MRS was performed at baseline and at scheduled intervals. Changes in molecular signatures and imaging characteristics relative to survival were estimated using Kaplan-Meier and proportional hazards models. Analyses included phase I patients at ENZ 250 mg/day. Results: From September 2007 to November 2008, 60 phase II patients enrolled; 52 completed RT and eight are receiving RT. Of these, seven patients progressed immediately after RT and 17 progressed after one or more adjuvant cycles; five discontinued due to toxicity; four withdrew from trial. Treatment was well tolerated. The only toxicities seen in more than one-third of pateints were grade 1 fatigue, grade 1 nausea, and grade 1–2 lymphopenia. Grade 1 thrombocytopenia was seen in eight patients and grade 3 lymphopenia in five patients. OS, PFS, PROs, PGx, and imaging findings will be reported. Conclusions: The combination of ENZ plus TMZ during and following RT was well tolerated and may be an active regimen in GBM. This study represents the future of neuro-oncology clinical trial design by employing a novel multi-modal therapy while concurrently studying novel imaging and molecular techniques that may predict efficacy.

[Table: see text]
Circulating cytokine and angiogenic factors as predictive biomarkers of glioblastoma response to aflibercept (VEGF Trap)
Authors: Piao Y. , Heymach J. V. , Bekele B. , Camphausen K. , Wen P. Y. , Liu J. , Yung W. K. , De Groot J.
Published: August 2020

2029

Background: Aflibercept is a recombinant fusion protein that scavenges both vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). In a single-arm phase II study (NABTC06–01; NCT00369590 ), a 22% response rate was seen in recurrent glioblastoma patients receiving aflibercept 4 mg/kg iv every 2 weeks. We performed detailed analyses of circulating and urinary cytokine and angiogenic factors to describe the modulation of markers in response to aflibercept and to identify potential predictive markers. Methods: Plasma samples were collected from 31 of 32 enrolled patients at baseline, 24 hours and every 2–4 weeks until progression. Urine samples were collected at baseline and every 4 weeks. Levels of 41 circulating factors were measured using suspension bead multiplex assays (BioRad) or ELISA. Free VEGF and PlGF levels were determined following sample immunodepletion. Baseline and changes in marker levels over time were correlated with response and progression using logistic regression and Cox proportion hazard models. Results: Treatment with aflibercept resulted in significant increases in total VEGF and PlGF at 24 hours and 28 days (p ≤ 0.001). Free VEGF was rapidly sequestered by 24 hours and remained significantly decreased at 28 days (p = 0.001). However, free PlGF levels rose over time and by 28 days were 45-fold higher than baseline (p < 0.001). Additional modulation of 4 factors at 24 hours included decreases in Groα and MIF (p = 0.001) and increases in urinary VEGF and MIP1β (p ≤ 0.001). At 28 days, levels of IL-18 were significantly decreased (p = 0.02) while SCGFβ and urinary VEGF levels increased (both p < 0.02). Comparing baseline biomarker levels between response groups (PD, SD, and PR), patients with lower levels of GROα, HGF, SCGFβ and higher levels of free VEGF were more likely to have a PR (all p < 0.05). Conclusions: In recurrent glioblastoma, aflibercept resulted in rapid and sustained decreases in free VEGF levels. Although greater than 95% of PlGF remained bound, free PlGF levels significantly increased over time. Treatment significantly modulated multiple cytokine and angiogenic factors with striking increases in MIF and SCGFβ. Potential biomarkers predictive of response to aflibercept include Groα, HGF and SCGFβ.

No significant financial relationships to disclose.
Phase I trial of vatalanib (PTK787) in combination with standard radiation and temozolomide in patients with newly diagnosed glioblastoma
Authors: Batchelor T. , Eichler A. F. , Plotkin S. R. , Drappatz J. , Wen P. , Sorensen A. G. , Gerstner E.
Published: August 2020

2035

Background: Anti-vascular endothelial growth factor (VEGF) agents are hypothesized to work synergistically with chemotherapy and radiation (RT). Vatalanib (MW 347, T1/2 4.6 h) is an oral, pan-VEGFR tyrosine kinase inhibitor that has shown activity in patients with recurrent glioblastoma. Methods: This phase I study was designed to determine the maximal tolerated dose of vatalanib in combination with RT and TMZ for patients with newly diagnosed GBM who were taking enzyme-inducing anti-epileptic drugs. RT and TMZ were administered at standard doses. Vatalanib was initiated 5 days prior to the start of RT and continued daily until tumor progression, unacceptable toxicity or a maximum of up to 12 cycles of post-RT TMZ. Cohorts of 3 patients were treated during RT and TMZ at doses of 250mg daily, 250mg BID, or 500mg BID of vatalanib. Following the completion of RT, patients were treated with vatalanib 750mg BID for the remainder of the study. Results: Nineteen patients were enrolled of which 17 took 5 or more days of vatalanib (1 patient withdrew consent prior to start of vatalanib and 1 withdrew consent after only 1 dose). The median age was 58 and the median KPS was 90. Eight patients had a diagnostic biopsy only. The MTD has not been reached. Potentially related grade 3–4 toxicities included elevated transaminases (2 patients), thrombocytopenia (1 patient), leukopenia (1 patient), neutropenia (1 patient), depressed level of consciousness (1 patient), and fatigue (1 patient). Only 1 patient suffered an asymptomatic intracerebral hemorrhage and no patient experienced wound dehiscence or infection. Five patients remain on vatalanib and the median follow-up for all patients is 6.5 months. Seven patients have died. The best responses for the 13 patients who completed combination RT/TMZ/vatalanib was 2 PR, 7 SD, and 2 PD. Two patients were clinically stable with biopsy proven pseudoprogression. Median PFS is 18.4+ months and OS has not been reached. Conclusions: Vatalanib is safe and well tolerated when added to standard RT and TMZ. The MTD has not been reached and dose escalation continues in this population of patients on enzyme inducing anti-epileptic drugs.

[Table: see text]
A phase I study of temozolomide (TMZ) and RAD001 in patients (pts) with glioblastoma multiforme (GBM)
Authors: Mason W. P. , MacNeil M. , Easaw J. , McIntosh L. , Lwin Z. , Chen E. , Eisenhauer E. E.
Published: August 2020

2036

Background: The mTOR protein kinase is a critical step in the PI3K/Akt/PKB signaling pathway. RAD001 exerts antiproliferative and antiangiogenic effects by mTOR inhibition. This phase I trial was designed to determine the maximum tolerated dose(s) (MTD) and recommended phase II dose(s) of RAD001 in combination with TMZ in patients with GBM. Patients receiving enzyme inducing anti-epileptic drugs (EIAEDs) and those not receiving EIAEDs (NEIAEDs) were studied separately. Methods: Enrollment was restricted to pts with proven GBM, either newly diagnosed following completion of radiotherapy with concurrent TMZ, or at first progression. TMZ was administered at a starting dose of 150 mg/m2/d for 5 days every 28 days, and RAD001 was administered continuously at a starting dose of 2.5 mg orally on a daily schedule starting on day 2 of cycle 1 in 28-day cycles (maximum 10 mg daily unless PK interaction shown). Response was evaluated every 2 cycles. Pharmacokinetics (PK) of TMZ and RAD001 were determined during cycle 1. Results: To date, 16 NEIAEDs and 9 EIAEDs pts have been enrolled and received 79 and 58 cycles respectively. The majority of pts (20/23) were newly diagnosed. In the NEIAEDs group at dose level 2 (RAD001 2.5 mg, TMZ 200 mg/m2) 3 of 4 pts had cycle 2 delays and dose reduction of TMZ because of myelosuppression (neutropenia 2 pts, neutropenia and thrombocytopenia, 1 pt), so further escalation of only RAD001 was undertaken, while fixing TMZ at 150 mg/m2. RAD001 at 10 mg daily with TMZ 150 mg/m2/day has been well tolerated in the NEIAEDs cohort without DLTs; RAD001 PK at this dose level have been comparable to historical single agent RAD001 PK (AUC at steady state is 602 ng*hr/mL in our study vs. 536 ng*hr/mL historical data), so no further escalation is planned. Enrollment in the EIAEDs cohort has been accelerated to 10 mg RAD001 with TMZ 150 mg/m2 because no additional DLTs have been observed in the EIAEDs cohort. Escalation beyond this dose will only take place if supported by evidence of reduced exposure of RAD001 or TMZ when PK results are available. Conclusions: RAD001 at a daily dose of 10mg can safely be combined with TMZ at 150 mg/m2/d and is the recommended dose for GBM pts receiving NEIAEDs. EIAED pts are being enrolled at this dose level; further escalation in this group will depend on PK data.

[Table: see text]
Phase II trials of erlotinib or gefitinib in patients with recurrent meningiomas
Authors: Norden A. D. , Raizer J. J. , Lamborn K. R. , Abrey L. E. , Chang S. M. , Gilbert M. R. , Cloughesy T. F. , Prados M. D. , Lieberman F. , Wen P.
Published: August 2020

2062

Background: No effective treatment is available for recurrent meningiomas when surgical and radiation options are exhausted. The epidermal growth factor receptor (EGFR) is often over-expressed in meningiomas and may promote tumor growth. In open label, single arm phase II studies of the EGFR inhibitors gefitinib (NABTC 00–01) and erlotinib (NABTC 01–03) for recurrent malignant gliomas, we included exploratory subsets of recurrent meningioma patients. We have pooled the data and report the results here. Methods: Patients with recurrent histologically confirmed meningiomas and no more than two previous chemotherapy regimens were treated with gefitinib 500 mg/day or erlotinib 150 mg/day until tumor progression or unacceptable toxicity. Results: Twenty-five eligible patients were enrolled with median age 57 years (range 29–81) and median Karnofsky performance status (KPS) score 90 (range 60–100). Sixteen patients (64%) received gefitinib and nine (36%) erlotinib. Eight patients (32%) had benign tumors, 9 (36%) atypical, and eight (32%) malignant. For benign tumors, the 6-month progression-free survival (PFS6) was 29%, 12-month PFS (PFS12) 0%, 6-month overall survival (OS6) 63%, and 12-month OS (OS12) 50%. For atypical/malignant tumors, PFS6 was 25%, PFS12 19%, OS6 81%, and OS12 68%. There were no significant PFS or OS differences by histology. Of 21 evaluable patients, there were no responses; eight patients (38%) had stable disease, and 13 (62%) had progressive disease. Treatment was well-tolerated. Rash was not a significant predictor of PFS or OS. Conclusions: Neither gefitinib nor erlotinib appear to have significant activity against recurrent meningioma. The role of EGFR inhibitors in meningiomas is unclear but evaluation of EGFR inhibitors in combination with other targeted molecular agents may be warranted.

No significant financial relationships to disclose.
Functional pathway mapping of human glioblastoma multiforme and brain metastases for patient tailored therapy
Authors: Khalil M. , Wulfkuhle J. , Fillmore H. , Deng J. , Liotta L. , Petricoin E. , Watson J. , Broaddus W.
Published: August 2020

2076

Background: Genome scanning analysis of human glioblastoma multiforme (GBM) has suggested that this form of cancer is a protein pathway disease. Since genomic analysis cannot directly predict protein activation, analysis of protein pathway activation is required. With the current focus on targeted translational therapeutic modalities, a functional understanding of the GBM signaling repertoire is critical, and yet largely unknown. Methods: Twelve tumors were included in this study: 10 GBMs (9 primary, 1 recurrent) and two brain metastases (1 breast and 1 lung). Pure tumor cell populations were obtained from fixed frozen tissue sections using Laser Capture Microdissection. Protein pathway mapping was performed using Reverse Phase Protein Microarrays (RPMA) whereby the activation of 85 key signaling proteins was quantitatively measured at once. Unsupervised and supervised analysis was used to explore pathway activation. Results: Unsupervised hierarchical clustering of all tumors in the study set revealed largely patient-specific signaling portraits yet also identified distinct pathway subsets. The two metastatic tumors clustered separately and distinctly from the GBMs. The GBM specimens clustered according to pathway activity. Statistical analysis demonstrated significant correlations between certain phosphorylated endpoints detected and overall survival. Phosphorylation of cofilin (S3) was associated with shorter survival time, while Stat1 (Y701) and Shc (Y317) phosphorylation were both positively correlated with longer overall survival. Conclusions: This study represents the most comprehensive proteomic analysis of human GBM pathway mapping to date. Since certain pathway biomarkers are themselves being targeted by current investigational therapies, the ability to map pathway activation and identify critical pathway biomarkers can lead to targeted therapeutics tailored to each patient's tumor. The ability to segregate short from long-term survivors according to protein pathway activation is promising.

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Effect of the combination of retinoic acid and rapamycin on cerebellar granule cell and medulloblastoma proliferation
Authors: Gershon T. R. , Shirazi A. , Kenney A. M.
Published: August 2020

2077

Background: Cerebellar granule cell precursors (CGCPs) are neuroblasts that proliferate in early postnatal life and may become transformed, giving rise to medulloblastoma. The proliferation of CGCPs is driven by mitogenic signals including Sonic Hedgehog (SHH), and growth factors that activate the protein mTOR. Dysregulation of these intercellular signals can promote medulloblastoma formation. We propose that microenvironmental signals that down-regulate the response of CGCPs to mitogens may inhibit medulloblastoma growth. Retinoic acid (RA) is an endogenous signaling molecule with potent anti-neoplastic effects. We investigated whether SHH, mTOR, and RA signaling pathways interact to regulate CGCP and medulloblastoma proliferation. Methods: We measured proliferation in cultured CGCP explants and the CGCP-derived murine medulloblastoma cell line PZp53 using quantitative phosphohistone-H3 immunocytochemistry. We examined the effects of adding to culture medium SHH, the mTOR inhibitor rapamycin, and all trans-RA (ATRA) in specific combinations. We compared CGCPs from wild type animals to CGCPs from mice with constitutive mTOR activation due to TSC2 mutation. Results: A minimum concentration of 1uM ATRA inhibited SHH-driven CGCP proliferation measurably but incompletely, while 10uM ATRA caused widespread necrosis. CGCPs from TSC2 mutant animals, in which mTOR was constitutively active, were 50% less effected by 1uM ATRA than wild type CGCPs. PZp53 medulloblastoma cells were relatively resistant to ATRA, tolerating 10uM ATRA with reduced but persistent proliferation. 10nM rapamycin decreased but did not eliminate PZp53 proliferation. The combination of rapamycin and ATRA, however, acted synergistically, suppressing proliferation >90%. This suppression persisted at 10-fold lower drug concentrations. Conclusions: CGCPs and CGCP-derived medulloblastoma cells integrate signals transduced by SHH, mTOR, and RA pathways. These signaling pathways can be manipulated by pharmacologic agents in combinations that confer dramatically enhanced antineoplastic effect. We are investigating the molecular basis of the synergy of rapamycin and ATRA. We plan to test the combination in xenografts and ultimately in patients with medulloblastoma.

No significant financial relationships to disclose.
A randomized, double-blind study comparing corticorelin acetate with dexamethasone in patients with primary malignant glioma who require increased dexamethasone doses to control symptoms of peritumoral brain edema
Authors: Shapiro W. R. , Mechtler L. , Cher L. , Wheeler H. , Hines V. , Milsted R. , O'Connor P. C. , Ryan R. P. , Recht L.
Published: August 2020

2080

Background: Corticorelin acetate (CrA) is a synthetic peptide of corticotropin-releasing factor, undergoing clinical trials as a treatment for peritumoral edema in patients with cerebral tumors. This study compared CrA therapy vs an increase in dexamethasone (dex) dose (+4 mg) for controlling symptoms in primary glioma patients with a subacute exacerbation. Methods: In addition to their prestudy dex dose, patients were randomized to receive CrA 1 mg bid SC or control (+4 mg dex PO) for 8 weeks. Patients were evaluated at baseline and during weeks 1 and 2 for their neurologic status, Karnofsky Performance Score (KPS), and continuing dex requirements. The primary endpoint was response, defined as no post-baseline increase in dex dose >4 mg for >1 day; stable or improved KPS; and ≥25% improvement in 10-item Neurological Examination Score during weeks 1 and 2. Dex therapy requirements were also evaluated. The study aimed to enroll 120 patients, but was terminated with only 37 patients (20 CrA, 17 control) due to slow recruitment. Results: Formal statistical analyses were not undertaken due to the small sample size. The treatment groups had similar demographic and baseline disease characteristics. Despite the small numbers, the data suggest that CrA treatment had similar efficacy to increased dex: (1) The proportions of responders were similar (CrA 3/20; control 3/17); (2) Comparable proportions of patients completed 8 weeks’ treatment (CrA 16/20; control 12/17); (3) After randomization of blinded study drug (CrA or dex 4 mg), dex dosing remained stable for most patients in each arm (CrA 12/20; control 11/17); (4) The mean daily dex dose was 3 mg in the CrA arm and 7 mg in the control arm. There was a lower incidence of cushingoid symptoms in the CrA arm (CrA 1/20, control 3/17). Patients in the CrA arm reported more injection site erythema and flushing vs. the control arm. CrA was well tolerated and no patient withdrew from the trial because of CrA side effects. Conclusions: CrA may be of value in managing patients with cerebral tumors who have subacute exacerbations of their symptoms, without needing to increase their dex dose.

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Effects of omeprazole on the pharmacokinetics and toxicities of irinotecan in cancer patients: A prospective open-label cross-over drug-interaction study
Authors: van der Bol J. M. , Verweij J. , de Jong F. A. , Loos W. J. , Lam M. H. , van Meerten E. , Mathijssen R. H.
Published: August 2020

2502

Background: The proton pump inhibitor omeprazole (Losec) is one of the most extensively prescribed medications worldwide and within its class, omeprazole is most frequently associated with drug interactions. In vitro studies have shown that omeprazole can alter the function of metabolic enzymes and efflux transporters that are involved in the metabolism of irinotecan, such as UGT1A1, CYP3A, and ABCC2. In this open-label cross-over study we investigated the effects of omeprazole on the pharmacokinetics and toxicities of irinotecan. Methods: Fourteen patients were treated with one course (C1) of single agent irinotecan (600 mg i.v., 90 min) followed three weeks later by a second course (C2) with concurrent use of omeprazole 40 mg once daily, which was started 2 weeks prior to C2. Plasma samples were obtained up to 55 hours after infusion and analyzed for irinotecan, and its metabolites SN-38, SN-38 glucuronide (SN-38G), NPC, and APC by reversed-phase high-performance liquid chromatography with fluorescence detection. Non-compartmental modelling of pharmacokinetic data was performed with WinNonLin. Toxicities were monitored during both courses and graded according to the CTCAE criteria v3.0. Paired statistical tests were performed with SPSS. Results: The mean AUCs of irinotecan and all metabolites were not significantly different between both courses (p>.151; see table). In addition, no differences were seen in Cmax and clearance of irinotecan and all metabolites between C1 and C2 (p>.072). The nadir ANC and WBC and the percentage decrease in ANC and WBC from baseline were not different between both courses (p>.529). Neither were there significant differences in the severity of neutropenia, febrile neutropenia, diarrhea, nausea, and vomiting. Conclusions: Omeprazole 40 mg did not alter the pharmacokinetics and toxicities of irinotecan. This widely used drug can therefore be safely administered during a 3-weekly single agent irinotecan schedule.

[Table: see text]

No significant financial relationships to disclose.
Pharmacokinetic and pharmacogenetic study of S-1 in Korean patients with metastatic biliary cancer
Authors: Kim K. , Jang G. D. , Lim H. S. , Kim H. S. , Shin J. G. , Lee J. L. , Ryu M. H. , Chang H. M. , Kang Y. K. , Kim T. W.
Published: August 2020

2505

Background: S-1 is an oral anticancer agent composed of tegafur (FT), CDHP, and oxonate. CYP2A6 is related to the biotransformation of FT to 5-FU. We evaluated associations of genetic variants of CYP2A6 with PK/PD of S-1 when combined with oxaliplatin in metastatic biliary cancer. Methods: This is a prospective study of patients with histologically confirmed metastatic adenocarcinoma of the biliary tract. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 14 days followed by a 7-day rest period. For PK study, S-1 was given only once at day 1 of cycle 1. From day 2, it was administered twice daily. Oxaliplatin was administered intravenously at a dose of 130 mg/m2 for 2 hours every 3 weeks. CYP2A6 polymorphism (*1, *4, *7, *9 or *10) were genotyped. Results: A total of 49 patients were enrolled. Median age was 52 years (range 23–68) and male accounted for 63%. Thirty patients (61%) had intrahepatic cholangiocarcinoma and 10 (20%) gallbladder cancer. Response rate was observed in 24.5%. The median PFS and OS were 3.7 months and 8.7 months . Grade 3–4 adverse events include vomiting (22%), diarrhea (4%) and neutropenia (14%). The allele frequencies of CYP2A6*4, *7, *9 and *10 were 10.2%, 8.2%, 19.4%, and 4.1%, respectively. AUC0–24hr of 5-FU was 1030±617.3 hr*ng/mL (range 249.5–3969, CV: 59.9%). Log- transformed AUC0–24hr were significantly different for FT and 5-FU in the *1/*1 group; metabolic ratio (AUC0- 24hr of 5-FU/AUC0–24hr of FT) of the *1/*1 group was 1.85-times higher than the other group (90% CI 1.37–2.49). AUC0–24hr of CDHP was not significantly associated with CYP2A6 genotype. Despite differences in exposure, CYP2A6 genotypes were not significantly associated with diarrhea (P=0.0740), neutropenia (P=0.396) and clinical efficacy (response rate: P=0.583, PFS: P=0.916). Conclusions: CYP2A6 genotypes was associated with transformation of FT to 5-FU; however, this association did not translate into different clinical efficacy or toxicity.

[Table: see text]

No significant financial relationships to disclose.
Validation of toxicity burden score for use in phase I clinical trials
Authors: Lee S. M. , Hershman D. , Martin P. , Leonard J. , Cheung K.
Published: August 2020

2514

Background: In phase I clinical trials, dose limiting toxicity (DLT) is defined as a binary outcome (DLT Yes/No). Concerns have been raised since this does not account for multiple non-DLTs that have a cumulative effect on drug tolerability and do not differentiate the severity of DLTs. Having a continuous toxicity burden score (TBS) as an outcome may provide more information regarding toxicity. We propose a new method for obtaining TBS. Methods: We illustrate the method using a phase I trial in lymphoma. The two main toxicities related to the experimental drug were low platelets and neuropathy with DLT defined as platelet count < 10,000/mm3 or grade 3 neuropathy. Three oncologists were asked to assign severity scores for the two main toxicities by assigning scores based on their impression of the impact of the toxicity on the patient and keeping in mind that DLT should be assigned a score of 1 and no toxicity should be assigned a score of 0. They were then given data from 25 patients along with their observed toxicities and the respective NCI toxicity grades and were asked to assign TBS to each patient. A mixed effects regression model was fit to the data. To validate the model, two of the oncologists assigned TBS to an additional list of 17 patients. Assuming the estimated TBS to be a rating, the three ratings (two oncologists and the estimated TBS) were compared using a mixed effects regression model. Results: The significant predictors of TBS are listed in the Table . Since no patient in the training data experienced grade 3 low- platelet and grade 4 neuropathy, model coefficients for these were not obtained. In the validation data, the TBS among the oncologists and the estimated TBS obtained using the fitted model were not different (P=0.18). Conclusions: A fitted model can be used to obtain TBS from maximal NCI toxicity grades suggesting the feasibility of using a continuous outcome such as TBS in dose finding studies.

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No significant financial relationships to disclose.
Phase I trial of patupilone (P) and RAD001 in patients (pts) with advanced solid tumors
Authors: Stein M. N. , Knox B. , Wesolowsky E. , Levitt M. , Moss R. , Poplin E. , Mehnert J. , Gounder M. , Goodin S. , DiPaola R.
Published: August 2020

2529

Background: P is an epothilone with activity in solid tumors including docetaxel (D) resistant prostate cancer. R is an oral mTOR inhibitor that demonstrates synergy with P in pre-clinical models, possibly by decreasing resistance to apoptosis. This on-going phase I study is assessing the tolerability of P in combination with R in pts with advanced solid tumors. Methods: Eligible patients with ECOG PS 0–2, adequate organ function and no more than 3 prior chemotherapy treatment received P every 21 days and weekly R using a standard 3+3 dose escalation schema in a 21 day(d) cycle starting at 50% of the phase II dose of P and 60% of the standard weekly dosing of R. Dosing levels are (1) P 5mg/m2 D1, R 30mg D1; (2) P 7.5mg/m2 D1, R 30mg D1 (3) P 7.5mg/m2 D1 R 30mg D1, D8 (3A) P 7.5mg/m2 D1 R 30mg D1, D8, D15 (3B) P 8mg/m2 D1 R 50mg D1, D8 (4) P 10 mg/m2 D1, D8 R 30mg D1, D8 (5) P 10 mg/m2 D1, D8 R 50mg D1, D8. Pharmacokinetic (PK) levels of R were obtained D1, D2 and PBMC were obtained to assess phospho-S6 and to assess markers of apoptosis and autophagy. Results: A total of 24 pts have been enrolled and 23 pts are evaluable for toxicity (tumor types: colon-7, prostate-6, lung-3, ampulla-3, leiomyosarcoma-2, cervical cancer-1). DLTs of grade(g) 3 diarrhea, g3 colitis and g3 fatigue were observed in dose levels 5, 4 and 1 pt in cohort 3A with a colostomy. Cohorts 1–3 were well tolerated with the common AEs of g1 diarrhea, g2 neuropathy after cycle 7, g1/g2 anemia, g1 triglycerides. In pts with prostate cancer (all previously pretreated with D) PSA declines of >50% occurred in 3/5 pts treated with >2 cycles; 1/7 pts with colon cancer had a PR and 3/7 pts with colon cancer had stable disease (SD) > 8 cycles; 1/3 pts with ampullary ca had a PR and a pt with cervical ca had SD x10 cycles. Conclusions: P 7.5mg/m2 and R 30mg D1, D8 is safe and well tolerated. Encouraging evidence of clinical activity is observed in prostate, colon and other tumor types. Enrollment to cohort 3A is ongoing.

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A phase I pharmacokinetic (PK) study of MBP-426, a novel liposome encapsulated oxaliplatin
Authors: Sankhala K. K. , Mita A. C. , Adinin R. , Wood L. , Beeram M. , Bullock S. , Yamagata N. , Matsuno K. , Fujisawa T. , Phan A.
Published: August 2020

2535

Background: MBP-426 is a novel liposome encapsulated oxaliplatin (L-OHP) formulation bound to human transferrin, developed to improve the safety and efficacy of L -OHP through the prolongation of circulation time and by targeting transferrin receptors on tumor cells. In vitro, MBP-426 is effective against various human cancer cell lines. This study assessed the toxicity and safety of intravenously (IV) administered MBP-426, including defining the maximally tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PKs). Methods: Patients (pts) with advanced/ metastatic solid tumors refractory to conventional therapy received MBP-426 as 2–4 hrs IV infusion every 3 weeks in cohorts of 3 to 6 pts. Enrollment required age > 18 yrs, ECOG Performance Status 0–2 and adequate organ functions. Tumor response was assessed by RECIST. Plasma was sampled for PK. Results: 39 pts were dosed, median age 59 (range 27–79), 25 (64%) male. The common tumor types were colorectal 23 (60%), pancreas 3 (8%), and neuroendocrine 3 (8%). Most pts were heavily pretreated with chemotherapy or chemoradiation. 77% pts had received oxaliplatin or cisplatin. Eleven dose levels ranging from 6 to 400 mg/m2 were evaluated. At 400 mg/m2, 2/3 pts had DLT as grade 4 thrombocytopenia and prolonged thrombocytopenia (1 pt each). The recommended phase II dose is 226 mg/m2 where 1/6 pts had grade 4 thrombocytopenia. Grade 3–4 toxicities included fatigue (3 pts), hypercholesterolemia (3 pts), anemia (2 pts) and constipation (1 pt). Common grade 1–2 toxicities were nausea and/or vomiting (59%), fatigue (43%), infusion reaction (15%), thrombocytopenia (15%), anemia (13%) and peripheral neuropathy (13%). 15 pts had stable disease after 2 cycles. 3 pts with colon carcinoma refractory to conventional oxaliplatin had stable disease for 4, 5 and 6 cycles respectively, one of them had 25% decrease in target lesions. PKs of MBP-426 were dose-proportional. Main PK parameters at 226 mg/m2 were AUC 2141+419 μg.hr/ml, and t½ 89+92 hr, comparing favorably with intact L-OHP. Conclusions: MBP-426 has a favorable safety profile with thrombocytopenia as main DLT. The PK target concentration of L-OHP was exceeded at higher doses. Based on PK and toxicity profiles, the recommended dose is 226 mg/m2.

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A phase I trial of sns-314, a novel and selective pan-aurora kinase inhibitor, in advanced solid tumor patients
Authors: Robert F. , Verschraegen C. , Hurwitz H. , Uronis H. , Advani R. , Chen A. , Taverna P. , Wollman M. , Fox J. , Michelson G.
Published: August 2020

2536

Background: Aurora Kinases are a family of serine/threonine kinases (Aurora Kinases (AK) A, B, and C) critical for mitosis. Elevated AKs expression occurs in a high percentage of melanoma, colon, breast, ovarian, gastric, and pancreatic tumors; in a subset of these tumors the AURKA locus (20q13) is amplified. SNS-314 is a selective pan-AK inhibitor with low nanomolar IC50s. Methods: Study design is 3+3 phase 1 dose escalation by modified Fibonacci. Patients (pts) with advanced solid tumors received SNS-314 by 3 hour infusion qweek X 3 (28 day cycle). Primary endpoints: safety, tolerability, and DLT assessment. Secondary endpoints: MTD, pharmacokinetics (PK), pharmacodynamics, and antitumor activity. Pharmacodynamic endpoint was inhibition of Histone H3 phosphorylation (pHH3) evaluated by immunohistochemistry of skin punch biopsies taken pre- and 2 hours post-infusion. Results: Thirty-two pts (16M/16F; median age = 58.5 years) were enrolled into 8 cohorts: dose range 30–1800 mg/m2. Median cycles received =2. SNS-314 was generally well tolerated with Grade 1–2 toxicities ≥ 15% incidence: nausea (31%), fatigue (28%), vomiting, constipation, and pain (16% each), and no Grade 3+ toxicities of ≥ 15% incidence. A DLT of Grade 3 neutropenia preventing administration of all 3 doses was observed at 1440 mg/m2. Plasma PK were dose proportional for exposure with no accumulation of SNS-314 following weekly administration. Clearance was moderate (5.65 L/hr/m2, CV 39.4%); Vss approximated total body water (21.5 L/m2, CV 78.1%); terminal half-life was 10.4 hours (CV 66.8%). Six patients had stable disease as their best response. Inhibition of pHH3 by SNS-314 was observed in skin biopsies of patients treated at doses of 240 mg/m2 and greater. Conclusions: SNS-314 is a novel inhibitor of AKs A, B, and C. The compound has been generally well tolerated; MTD was not established. No objective responses were observed. Pharmacodynamic activity was demonstrated by inhibition of pHH3.

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A phase I dose escalation safety and pharmacokinetic (PK) study of SSR244738 administered as a one-hour intravenous (IV) infusion twice-weekly during a 3-week cycle in patients (pts) with refractory solid tumors
Authors: Isambert N. , Spitaleri G. , Fumoleau P. , Noberasco C. , Ramazeilles C. , Chadjaa M. , Bolloni L. , De Braud F.
Published: August 2020

2539

Background: SSR244738 is a new cytotoxic agent (G2-cell cycle inhibitor). In this first in man study the original schedule of administration was an IV infusion once every 3 weeks (Q3W); and due to the high clearance variability, 1300 mg/m2 was considered the maximum administered dose (MAD). The study was amended to test the twice weekly schedule (D1-D4-D8-D11-D15, every 3 weeks). Methods: Standard escalation was used in cohorts of 3–6 pts. PK profiles (up to T48h or T96h) were obtained in each pt after the 1st and the 5th administration (D1 and D15) of Cycle 1. In the Q3W, there was a trend to lower clearance (CL) in CYP2C9 *3/*3 and *1/*3 genotype pts therefore genotype samples were analyzed at baseline to identify poor metabolizers (PM) and adjust-dosing accordingly. Results: 22 heavily pretreated patients received SSR244738 at doses of 200 (3 pts), 280 (4 pts), 400 (3 pts), 560 (3 pts), 780 (3 pt), 1000 (6 pts; one pt was a PM and received 500 mg/m2). 15 females, 7 males, median age: 60 years (29–82), ECOG: (0:12, 1:9, Unk:1). Main tumor types: ovary, lung, breast, colon and prostate. Nb cycles/pts: > 2 cycles/21 (95%), > 4 cycles/9 (41%), > 6 cycles/6 (27%), > 8 cycles/2 (9%). The most common reason for treatment discontinuation was disease progression. DLT was seen in 2 pts at 1000 mg/m2 dose level: one patient had febrile neutropenia associated with Grade 3 mucositis and the second patient had Grade 3 neutropenia, which caused a treatment delay. Both pts showed high SSR244738 plasma exposures on D15. SD was reported in 11 patients. No CRs or PRs were observed. SSR244738 exhibited an overall low plasma CL (mean [range]: 0.9 [0.3–2.1] L/h). CL slightly decreased with repeated administration. The distribution volume was low [Vss mean (CV%): 11.6 L (30%)] and the terminal half life was long [mean (CV%): 15.6 h (58%)]. No deviation from dose proportionality could be observed, despite the moderate-to-high inter-individual variability (CV<64%) in exposure. Conclusions: SSR244738 is well tolerated with PK profile similar to the Q3W schedule; by changing the schedule of administration we were able to reach the MAD dose (5000 mg/m2/cycle).

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Influence of food on the pharmacokinetics (PK) of panobinostat (LBH589), an orally active histone deacetylase inhibitor, in patients with advanced cancer
Authors: Lewis L. , Frank R. , Dandamudi U. B. , Gallagher J. , Zhao L. , Woo M. , Hirawat S. , Shapiro G. I.
Published: August 2020

2550

Background: The effect of food on the bioavailability and PK of panobinostat (PAN) are of considerable importance in allowing appropriate dosing of chronic oral cancer therapy. Methods: Patients (pts) with advanced cancer received 20 mg PAN twice a week of a 21-day cycle and were randomized to receive 1 of 6 treatment sequences where PAN PK was evaluated weekly under fasting, high fat and normal breakfast. Serial blood samples were collected for PAN PK evaluations on Days 1, 8, and 15. Plasma PAN concentrations were measured by LC-MS-MS. PK parameters were estimated by using non-compartmental analysis. Results: A total of 34 patients were evaluated. PAN was generally well tolerated with no significant lab, ECG, or other safety concerns. No residual PAN concentrations were detected in pre-dose samples on Days 8 and 15. Meal conditions and PAN PK parameters expressed as either mean (CV%) or median [range] or ratio are described in the Table . The overall exposure and inter-patient variability (CV 59%) remained unchanged with or without food, whereas Cmax was transiently reduced (<45%) by food. Although tumor response was not the main objective, a pt with recurrent RCC, following sunitinib and sorafenib treatment, has achieved a PR after ∼6 cycles of PAN and is continued on study. Conclusions: Since the overall extent of absorption and variability was not changed due to food, PAN administration with or without food is unlikely to significantly impact systemic PAN exposure in cancer patients. PAN can be administered without regards to food in future studies.

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