bluuebunny/crossref_metadata_2025 huggingface dataset:
FIP200 and Rb1 expression in CNS metastasis from breast cancer (CNS met): Potential predictors of patient outcome.
Authors: Hashemi Sadraei Nooshin , Ulasov Ilya , Burgett Monica , Nowacki Amy S , Prayson Richard , Weil Robert J. , Kar Niladri , Ahluwalia Manmeet Singh , Muller-Greven Ga‘lle , Shi Ting , Lesniak Maciej S. , Gladson Candece
Published: March 2020

2014

Background: Patients with CNS met have a poor outcome with significant variation in overall survival. No marker to predict survival exists. Rb1 is a negative regulator of the cell cycle, and FiP200 is an upstream signaling node that is distributed between the nucleus and cytoplasm. Nuclear FIP200 inhibits cell proliferation by promoting expression of Rb1, whereas cytoplasmic FIP200 promotes cell survival through autophagy. Previously FIP200 deletion/mutation has been reported in 20% of primary invasive breast cancer [BR ca] patients. FIP200 cellular localization and genetic alterations have not been examined in CNS met. Methods: A retrospective analysis of BR ca and CNS met was performed based on tissue availability from 2 institutions. FIP200 and Rb1 expression and localization was evaluated by immunohistochemistry. Genetic alterations were evaluated by DNA array analysis. Results: 80 patients (42 BR ca and 38 CNS met) were identified. Overall CNS met samples had significantly higher levels of cytoplasmic FIP200 as compared to BR ca (52% vs 24% respectively, p=0.0002) and increased expression of FIP200 around areas of hypoxia/necrosis, consistent with increased autophagy. There was also a significant increase in expression of nuclear FIP200 and Rb1 in the CNS met compared to BR ca (p=0.0007 and p=0.0055 respectively). Median survival from development of CNS met was longer in the group with high levels of nuclear Rb1; 14 (3-27) vs 20 (12-33) months (low expression < 20% vs high ≥ 20%, p=0.1). The same finding was observed with FIP200, longer survival was observed with high nuclear expression; 16 (7-33) vs 19 (0.4-27) months (low expression <20% vs high ≥ 20%, p=0.2). Our DNA analysis for copy number variation and LOH in CNS met revealed no deletion in Rb1 or FIP200. Conclusions: The pattern of expression of Rb1 and FIP200 in CNS met is different from BR ca. Notably, cytoplasmic FIP200 which promotes cell survival is highly expressed in CNS mets vs BR ca. This suggests metastatic breast cancer cells utilize autophagy as a survival mechanism. In addition, there is a trend to better survival of those patients with CNS met who express high nuclear FIP200 and Rb1, both of which have anti-proliferative roles in the nucleus.
Vorinostat, temozolomide, and bevacizumab for patients with recurrent glioblastoma: A phase I/II trial.
Authors: Peters Katherine B. , Vredenburgh James J. , Desjardins Annick , Friedman Henry S. , Herndon James Emmett , Coan April D. , McSherry Frances , Lipp Eric S , Brickhouse Alise , Massey Woody C , Reardon David A.
Published: March 2020

2027

Background: Prognosis for recurrent glioblastoma (GBM) remains poor with median survival between 3 to 6 months. Use of anti-vascular endothelial growth factor inhibitor, bevacizumab (BEV), has advanced this area of research, but continued studies have focused on whether the addition of other chemotherapies can improve efficacy in recurrent GBM. Vorinostat, a small molecule inhibitor of histone deactylase (HDAC), has anti-tumor activity directly through HDAC inhibition and indirectly by promoting anti-angiogenesis. Its good oral bioavailability and favorable toxicity profile make it a promising additive agent to standard therapy. Thus, we evaluated the efficacy of vorinostat in combination with BEV and daily temozolomide (TMZ) in recurrent GBM. Methods: This was a phase I/II open-label, single arm study in recurrent GBM patients. Primary endpoint was 6-month progression free survival (PFS). Secondary endpoints were safety/tolerability, radiographic response, PFS, and overall survival of recurrent GBM patients treated with BEV plus daily TMZ and vorinostat. Chief eligibility criteria included age ≥ 18 years, KPS ≥ 70, time interval ≥ four weeks from previous treatment, and maximum of 2 prior progressions. Dosing regimen was as follows: BEV 10 mg/kg IV every two weeks, TMZ 50 mg/m2 po daily, and vorinostat 400 mg po for 7 days on then 7 days off in a 28 day cycle. Results: 46 recurrent GBM patients were enrolled with 42 of those patients receiving a vorinostat dose of 400 mg. Most common grade 2 and above toxicities were leukopenia (36%), neutropenia (29%), fatigue (24%), and thrombocytopenia (19%). Serious toxicities included 4 grade 4 toxicities (grade 4 hyperglycemia, pulmonary embolism, bowel perforation and intracranial hematoma) and 1 patient expired on day of informed consent due to pulmonary embolism (grade 5). With a median follow-up of 11.3 months (95% CI: 10.1, 13.1 months), the 6-month PFS was 52.4% (95% CI: 36.4%, 66.1%). Best radiographic responses were 2 complete responses, 17 partial responses, 20 stable responses, and 1 radiographic progression. Conclusions: In summary, combination of BEV, daily TMZ, and vorinostat has promising efficacy on recurrent GBM with reasonable toxicity/safety.
Concurrent intrathecal methotrexate and liposomal cytarabine for the treatment of leptomeningeal metastasis from solid tumors.
Authors: Scott Brian J. , Feely Homira , Brown Tiffany , Van Vugt Vincent , Kim Ryan , Fanta Paul Timothy , Bazhenova Lyudmila , Kesari Santosh
Published: March 2020

2052

Background: Leptomeningeal metastasis (LM) from solid tumors is typically a late manifestation of disease with a median survival of weeks to a few months. Treatment is palliative, with no widely accepted standard of care. Options include intrathecal (IT) or systemic chemotherapy, radiation therapy or ventriculoperitoneal shunting. Randomized trials comparing single agent IT methotrexate to liposomal cytarabine have shown similar efficacy and tolerability. There is limited data, however, on the use of combination IT chemotherapy in solid tumor LM. Methods: We conducted a retrospective cohort study of 19 subjects treated for LM from solid tumors at a single institution. In addition to therapies directed at active solid tumor sites, each subject received IT liposomal cytarabine plus IT methotrexate injections every two weeks. Survival data and treatment-related toxicities were determined by systematic chart review. Results: LM was diagnosed by CSF cytology in 12/19 (63%), while the remainder were diagnosed by clinical and MRI findings. The most common cancer types were breast 7(37%), glioblastoma 6(32%) and lung 3(16%). The majority 18(95%) had active systemic or parenchymal brain disease at the time of treatment, requiring systemic chemotherapy 18(95%) or radiation therapy 13(68%). The median number of IT treatments was 4(range 1-9). Treatment was interrupted due to toxicity in 3(17%), while 7(37%) experienced ≥ CTCAE grade III toxicities, most commonly meningitis 3(16%). Treatment was stopped in 7/19(37%) following complete cytologic response 6/11(55%) or radiographic clearance 1/7(14%). The median overall survival was 96 days(n=6; range 29-158), median time to neurologic progression was 46 days (n=9; range 6-101) and the most common cause of death was progression of systemic disease 4(67%). Conclusions: Combination IT chemotherapy was reasonably well-tolerated, even in a population also receiving chemotherapy for progressive systemic disease. IT-related adverse events occurred at rates similar to previously reported single agent trials. Prospective evaluation is necessary to determine whether there is a survival benefit compared to single agent IT chemotherapy.
Correlation of large brain edema with favorable prognosis in patients with single brain metastases.
Authors: Preusser Matthias , Berghoff Anna Sophie , Dinhof Carina , Hutterer Markus , Woehrer Adelheid , Hackl Monika , Bartsch Rupert , Birner Peter , Zielinski Christoph , Widhalm Georg , Marosi Christine , Prayer Daniela , Spannberger Thomas
Published: March 2020

2053

Background: The sub-cohort of brain metastases (BM) patients (pts) with single BM has relatively favorable survival times, but novel prognostic factors are needed to individualize patient management. Methods: We retrospectively evaluated pre-operative magnetic resonance images in patients, who underwent neurosurgical resection of a single BM. The localization and largest diameter of the BM was recorded. The extent of brain edema (BE) was graded on contrast-enhanced T1, T2 and fluid-attenuated inversion recovery (FLAIR) images as follows: BE <1cm, BE >1 cm without affection of the contralateral hemisphere, BE >1cm with affection of the contralateral hemisphere. Further, immunohistochemically assessed expression of hypoxia-induced factor 1 alpha (HIF1a) was analyzed in each BM tissue specimen. Results: 159 pts were studied (81 male, 78 female; age range 24 to 80 years, median 58). The primary tumors were lung carcinoma in 74, breast cancer in 26, kidney cancer in 13, colorectal cancer in 11, melanoma in 9 and other tumor types in 26 cases. At univariate analysis, we found a significant positive correlation of overall survival time (OS) with young age, Karnofsky index >80, non-melanoma histology, and, surprisingly, large BE (p<0.05, log-rank test). At multivariate analysis, pts age, histological diagnosis and extent of BE remained independent prognostic parameters (Cox regression model, p<0.05). We found a significant positive correlation of extent of BE with expression of HIF1a (Mann-Whitney-U test, p=0.003). Conclusions: Large BE positively and independently correlates with favorable prognosis in pts operated for single BM. Peritumoral BE correlates with HIF1a expression, indicating a possible role of tumor hypoxia in its formation. [Table: see text]
Rising incidence of glioblastoma and meningioma in the United States: Projections through 2050.
Authors: Johnson Derek Richard
Published: March 2020

2065

Background: In the absence of proven environmental or behavioral risk factors, patient age and sex remain the most important predictors of primary brain tumor risk. In coming years, an increasing incidence of brain tumors in the United States can be anticipated based on shifts in the demographic structure of the population. This study provides estimates of glioblastoma and meningioma incidence through 2050. Methods: Group-specific glioblastoma and meningioma incidence rates based on age (eleven categories) and sex were calculated from National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) data for the period 2004-2008. United States Census projections based on data from the 2000 census were used to compute the size of the twenty-two demographic subpopulations of interest in 2010, 2020, 2030, 2040, and 2050. The estimated number of new glioblastoma and meningioma diagnoses for each of these years was calculated from the defined incidence rates and population size. Results: Crude annual tumor incidence rates were 3.13 per 100,000 persons for glioblastoma and 6.81 per 100,000 persons for meningioma. While the overall size of the population is expected to increase only 42% between 2010 and 2050, the number of Americans over 65 years of age, the group at highest risk of glioblastoma and meningioma, is expected to increase by 120%. We estimate that the number of new glioblastoma diagnoses will rise from 10,688 in 2010 to 18,466 in 2050, a 72% increase. Likewise, the number of new meningioma diagnoses will rise from 22,946 to 40,680 over the same period, a 77% increase. Conclusions: The number of new glioblastoma and meningioma diagnoses will increase substantially in the future. This analysis, which assumes a fixed incidence rate, may underestimate the true magnitude of the coming change given reports suggesting that incidence rates of glioblastoma and meningioma are rising over time.
The impact of bevacizumab on the occurrence and recurrence of intracranial brain metastases in non-small cell lung cancer (NSCLC) patients.
Authors: Salem Mohamed E. , Szerlip Nicholas , Pennell Nathan A. , Ali Khaled B. , Altshuler David , Taylor Stephanie , Hallock Abhirami , Sukari Ammar , Gadgeel Shirish M. , Wozniak Antoinette J.
Published: March 2020

2081

Background: Patients (pts) with brain metastases (BM) have a poor prognosis and limited treatment options. Approximately 40-50% of pts with NSCLC will develop BM during the course of their disease. A better understanding of the pathobiology of BM and the development of targeted agents hold promise for improved prophylaxis and therapy of BM which could have significant impact on disease progression and pt's survival. Vascular Endothelial Growth Factor has been implicated in setting up a metastatic niche allowing cells to seed and grow in the brain parenchyma. Inhibition of this signaling has been studied and shown to be effective in reducing BM in animal models. Methods: The objective of this retrospective study was to determine whether bevacizumab decreases the incidence and or the recurrence of BM in pts with NSCLC. We retrospectively identified NSCLC pts with and without BM treated with bevacizumab. The primary endpoint was the proportion of patients who developed BM on or after bevacizumab therapy. Secondary endpoints were rate of local or regional recurrence after stereotactic radiosurgery (SRS). Occurrence of BM was evaluated by retrospectively reviewing MRI and or CT scans. Results: A total of 30 pts with stage IV non-squamous NSCLC who had no BM at diagnosis treated with bevacizumab (Non-BM group, NBMG) and 85 pts with non-squamous NSCLC who had BM and underwent SRS (BM group, BMG) were studied (46%M; median age 60 years (range 32-84). In the NBMG, 28% of pts developed BM. Median time to development of BM was 10.5 months. In the BMG, 4 pts were treated with bevacizumab following SRS. Of these 4 pts, 3 pts (75%) had no recurrence while 1 pt (25%) developed local then regional recurrence at 7 and 9 months, respectively. Of the remaining 81 pts who underwent SRS but never received bevacizumab, 27% of pts had local recurrence and 41% had regional recurrence at median time of 4 and 4.5 months, respectively. Conclusions: Bevacizumab may have a role in the treatment of NSCLC in regards to development and recurrence of brain metastases. These results support the need for further prospective investigation in a larger patient population with matched controls.
An investigator-initiated monocentric phase I dose escalation trial of temsirolimus and irinotecan (TEMIR) in patients with relapsing glioblastoma multiforme (reGBM).
Authors: Scheulen Max E. , Richly Heike , Kalkavan Halime , Hoffmann Andreas-Claudius , Virchow Isabel , Hilger Ralf A. , Koeppen Susanne , Sure Ulrich , Schuler Martin H. , Hense Joerg
Published: March 2020

2086

Background: Deregulation of the PI3K/AKT pathway has been preclinically involved in the pathophysiology of GBM. The mammalian target of rapamycin (mTOR) is an important downstream mediator of PI3K/AKT signalling. The mTOR-inhibitor temsirolimus (Tem) achieves significant drug levels in brain. Thus, Tem may be effectively combined with irinotecan (Iri) which has shown promising results in combination with bevacizumab in patients (pts) with reGBM refractory to temozolomide (Tmz) in phase II. Exposure to Tem as well as Iri is substantially reduced in pts receiving CYP3A4 enzyme-inducing anticonvulsants (CYP3A4-Ind). Methods: TEMIR is a phase I trial of escalating doses of Tem in combination with Iri in pts with reGBM refractory to Tmz depending on the cotreatment with CYP3A4-Ind. In pts without CYP3A4-Ind dose escalation of Tem was performed according to the “3+3 protocol” from 15 via 20 to 25 mg iv wkly together with 85 mg/m2 Iri iv wkly. In pts with CYP3A4-Ind the doses of Tem were 30, 40 and 50 mg iv wkly together with 170 mg/m2 Iri iv wkly, respectively. The determination of the pharmacokinetics (PK) of Tem and its influence on the PK of Iri and its active metabolite SN38 was performed by validated RP-HPLC methods with fluorescence detection. Results: Up to now, 14 pts [4 female and 10 male, median age 47 yrs (range 41-65 yrs), 9 without and 5 with CYP3A4-Ind] have been treated. All 9 pts without CYP3A4-Ind (3 pts on 15, 20 and 25 mg Tem each) are evaluable for safety with only mild toxicity [highest CTC-grade ≥2 (gr) per pt]: diarrhea 4 (gr2) and 1 (gr3), neutropenia 1 (gr3), thrombopenia 1 (gr2), anemia 1 (gr2), pneumonia 2 (gr2), rash 1 (gr2). PK parameters of Iri and SN38 were in agreement with previously published studies and there was no significant effect of 15 to 25 mg Tem combined with 85 mg/m2 Iri on the PK of Iri and SN38. In 7 pts evaluable for efficacy there was no remission (RECIST) and median time to symptomatic and/or MRT progression was 10 wks (7, 9+, 10, 10+, 11, 15, 20 wks). Conclusions: The combination of Tem in standard dose of 25 mg iv wkly with 85 mg/m2 Iri wkly is safe in pts with reGBM without CYP3A4-Ind. Tem has no significant effect on the PK of Iri and SN38.
Anaplastic oligodendroglial tumors: The Cleveland Clinic experience.
Authors: Hashemi-Sadraei Neda , Robles Irizarry Lizbeth , Patel Mital , Tekautz Tanya M. , Murphy Erin Sennett , Recinos Violette , Chao Samuel T. , Suh John H. , Peereboom David M. , Stevens Glen , Weil Robert J. , Vogelbaum Michael A. , Barnett Gene H. , Ahluwalia Manmeet Singh
Published: March 2020

2100

Background: Anaplastic oligodendroglial tumors include both anaplastic oligodendroglioma (AO), and anaplastic oligoastrocytoma (AOA), histological categories of WHO grade 3 gliomas. There is limited data on specific prognostic factors for patients with these tumors. Methods: After obtaining IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify patients with histologically confirmed AO and AOA at the time of diagnosis. Multivariable analysis was conducted with use of a Cox proportional hazards model and a stepwise selection algorithm that used p<0.05 both as the criteria for entry and retention in the model to identify independent predictors of survival. Results: Chart records of 139 patients, 52% of whom were male, diagnosed between 1992 and 2009 were included for analysis. Median age at presentation was 47 years (range, 18-83 years). 22% of patients had biopsy only, 35% had gross total resection, 43% had near total resection or subtotal resection. Following surgery, 30% of patients were treated with chemotherapy (CT) alone, 14% were treated with radiotherapy (RT) and 47% received both CT and RT. Median progression free survival and median overall survival (OS) were 29.0 and 58.7 months respectively. On multivariate analysis, four factors were identified as independent predictors of OS: age at diagnosis (≥50 vs. <50, p=0.004), Hypothyroidism (p=0.009), multifocal disease (p=0.005) and 1p 19q co-deletion (p<0.001). Choice of initial therapy did not impact survival in this cohort of patients. Conclusions: Older age, hypothyroidism and multifocal disease were associated with higher mortality. 1p, 19q co-deletion was associated with lower mortality. [Table: see text]
Correlation between CD4 lymphocytes count and the opportunistic infections in treated glioblastoma.
Authors: Begin Marie Josee , Belanger Karl , Florescu Marie
Published: March 2020

2102

Background: Less than 200 CD4 lymphocytopenia happens frequently with temozolomide treatment of glioblastoma. This immunosuppression is associated with many opportunistic infections and antibiotic prophylaxis is given in some centers to prevent Pneumocystis pneumonia. Methods: We analyzed the association between documented culture-proved infections and CD4 lymphocytes level in 140 patients treated with temozolomide in first-line glioblastoma in Notre-Dame Hospital from 2006 to 2009. Demographic and treatment data were collected and analyzed with Kaplan-Meier survival plots and Log Rank tests. Results: The cohort of infected patients was represented by 31 patients who developed 49 culture-proved infections: 21 urinary origin, 8 pulmonary (1 Pneumocytis and 2 Aspergillosis), 5 brain, 5 bacteremia and 2 other. The infected cohort (n=31) had similar demographs, but also similar outcome compared to our control non infected glioblastoma treated patients cohort (n=109) with a 2 year survival of 40.8% vs 50.2% (p=). The median CD4 lymphocytes level was 260, but clearly infections were associated with less than 200 CD4 lymphocytes. During their infection, 20 patients had a CD4 level less than 200, compared with 11 patients with more than 200 CD4 lymphocytes count. Conclusions: CD4 lymphocytopenia less than 200 is associated with increase in number of documented culture-proven infections in patients treated with temozolomide, but the survival is not altered by the infection.
Anti-CD3 immunotoxin to induce remissions in cutaneous T-cell lymphoma patients.
Authors: Frankel Arthur E.
Published: March 2020

2505

Background: The anti-CD3 immunotoxin, AdmDT390bisFv(UCHT1), composed of the catalytic and translocation domains of diphtheria toxin (DT390) fused to two anti-CD3 sFvs showed selective cytotoxicity to normal and malignant human T cells in vitro and in vivo and was prepared for a phase I clinical study (Woo, Protein Exp Purif 58, 1, 2008). FDA approval (BB IND#100712), and IRB approval was obtained. Methods: Nineteen T cell lymphoma patients were screened, and 12 patients treated. Median age was 62 years (range, 39-84 years) with 6 males and 6 females. Disease was previously treated with one (6), two (3), three (1) or four (2) systemic therapies. One patient had stage IV PTCL and the other patients had CTCL (stage IB in 5, IIB in 4, IIIB in 1, and IV in 1). Six patients were treated with 2.5µg/kg x 8; five patients were treated with 5µg/kg x 5 - 8 and one patient treated with 7.5µg/kg x 8. Results: Drug-related toxicities were mild in 11/12 patients and were not dose dependent with transient fevers, chills, lymphopenia, transaminasemia, CMV and/or EBV viremia, and hypoalbuminemia. One 69 year old male with pre-existing heart failure treated at the 5µg/kg x 5 suffered severe vascular leak syndrome and heart failure. Immunotoxin Cmax was 1 – 60ng/mL, and mean half-life was 42min. Four patients had pre-treatment anti-immunotoxin titers >10µg/mL, and the others had lower pre-treatment antibody levels. All evaluable patients except two had increases of antibody titer between day 12 to 30 of 4 – 2000-fold. Among 10 evaluable patients, there were 2 complete remissions (CRs) of 17 and 41+ months durations and 4 partial remissions (PRs) of 1+ - 32+ months. Conclusions: The immunotoxin has exciting clinical efficacy in this heavily pretreated group of patients. Dose escalation is proceeding.
WT1-targeted dendritic cell vaccination as a postremission treatment to prevent or delay relapse in acute myeloid leukemia.
Authors: Berneman Zwi N. , Van de Velde Ann , Anguille Sebastien , Cools Nathalie , Van Driessche Ann , Nijs Griet , Stein Barbara , Vrelust Inge , Gadisseur Alain P. , Schroyens Wilfried A. , Van Tendeloo Viggo F. , Smits Evelien L.
Published: March 2020

2506

Background: Vaccination with tumor antigen-loaded dendritic cells (DC) holds promise for the adjuvant treatment of cancer. Methods: In a phase I/II trial, we investigated the effect of autologous DC vaccination in 17 patients with acute myeloid leukemia (AML) in remission but at very high risk of full relapse. Wilms’ tumor 1 protein (WT1) was chosen as immunotherapeutic target and introduced into the DC by mRNA electroporation. We are continuing a phase II trial, which is still recruiting. Results: Two out of 3 patients, who were in partial remission with chemotherapy-refractory disease, were brought into complete remission following 4 biweekly intradermal injections of WT1 mRNA-electroporated DC. In those 2 patients as well as in 6 other patients who were in complete remission but who had molecularly demonstrable residual disease, there was a return to normal of the AML-associated WT1 mRNA tumor marker following DC vaccination, compatible with reaching clinical and molecular remission in 8/17 patients. Among the 8 responders, there have been 2 relapses and 2 deaths. Of the 9 non-responders, 8 have relapsed and 7 have died. Of the 2 patients in partial remission who were brought into complete remission by DC vaccination, 1 has died following relapse. Median overall survival was 6 months in non-responders and 52 months in responders (p=0.0007). Median relapse-free survival was 3 months in non-responders as compared to 47 months in responders (p<0.0001). Clinical responses overall were correlated with elevated levels of activated natural killer (NK) cells post-vaccination. Long-term clinical responses, lasting for at least 3 years, were significantly correlated with an increase in polyepitope WT1-specific tetramer+ CD8+ T-cell frequencies. Conclusions: DC-based immunotherapy elicits both innate (NK) and adaptive (T cells) cellular responses correlated with clinical benefit. WT1 mRNA-transfected DC emerge as a feasible and effective strategy to control residual disease in AML, in particular as a post-remission treatment to prevent full relapse.
Costimulatory effect of agonistic 4-1BB antibody on proliferation and effector phenotype of tumor-infiltrating lymphocytes in melanoma.
Authors: Sarnaik Amod , Bilotto Anthony , Jure-Kunkel Maria , Hall MacLean S , Wang Wenshi , Younos Ibrahim , Pilon-Thomas Shari , Weber Jeffrey S.
Published: March 2020

2511

Background: Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) is a promising form of immunotherapy with a 20-30% durable response rate. Its widespread implementation is limited by the relatively long time needed to establish TIL in vitro and the lack of effective tumor reactivity. Our objective was to incorporate co-stimulation with 4-1BB agonism to optimize TIL growth preparation time and tumor reactivity to improve outcomes. Methods: 7 metastatic melanoma patients were consented to an IRB-approved tissue procurement protocol. For each specimen, TIL were propagated in vitro from 4 melanoma tumor fragments per condition with standard 6000 IU/mL of IL-2 and either 10 ug/mL of 4-1BB agonistic antibody (BMS-663513) or its isotype control. After 3 weeks, TIL were counted and phenotyped using flow cytometry. TIL were re-stimulated with HLA-matched melanomas and assessed for interferon-γ (IFNγ) release by ELISA. Statistical comparisons involved the 2-tailed, paired t test using GraphPad Prism software. Results: 4-1BB treatment yielded a median 4.3x107 TIL (range 1.1x107-8.4x107) compared to a median 2.3x107 cells in the control (range 1.5x106-5.3x107, p = 0.009). This is clinically significant as the initial minimum target number for TIL generation is 3x107. On phenotypic analysis compared to control, 4-1BB treatment resulted in a 1.5X higher CD8+ cell numbers (p=0.02), a 6X lower CD4+ cell numbers (p=0.02), and 5.5X lower CD4+CD25+FoxP3+ Treg cell numbers (p=0.09). A paired sample was re-stimulated in triplicate with HLA-matched tumor target, and ELISA of the supernatant treated with 4-1BB yielded 1.6 fold higher IFNγ (p=0.05). A paired sample was then assayed for known markers of T cell cytolytic activity: EOMES and perforin. 4-1BB treatment resulted in 34.5% EOMES and perforin double positive TIL compared to 18.8% in the control group. Conclusions: 4-1BB agonism is associated with enhanced kinetics of TIL proliferation, increased yield of CD8+ TIL, lower Treg numbers, increased markers of cytolysis, and enhanced IFNγ release upon tumor re-stimulation. 4-1BB agonism may be a useful adjuvant in the generation of TIL in future clinical trials.
Radiotherapy plus the anti-EGFR mAb nimotuzumab or placebo for the treatment of high-grade glioma patients.
Authors: Solomon Maria Teresa , Selva Julio Cesar , Figueredo Javier , Vaquer Jose , Toledo Carolina , Quintanal Nelson , Salva Silvia , Dominguez Rafael , Alert Jose , Marinello Jorge Juan , Catala Mauricio , Gonzalez Griego Martha , Luaces Patrcia Lorenzo , Iznaga Normando , Bach Ferdinand , Crombet Ramos Tania
Published: March 2020

2515

Background: Despite remarkable advances in multimodal therapy, high grade glioma (HGG) patients still face a poor prognosis. EGFR is well validated as a primary contributor of HGG initiation and progression. Nimotuzumab is a humanized monoclonal antibody (mAbs) that recognizes the EGFR extracellular domain. While it has similar preclinical and clinical activity when compared to other anti-EGFR mAbs, it does not induce skin toxicity or hypomagnesemia. Methods: A randomized, double blind, multicentric clinical trial was conducted in 70 anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) patients that received radiotherapy (RT) plus nimotuzumab or placebo. Patients received 6 weekly doses of nimotuzumab or placebo together with radiotherapy. Treatment was maintained every 3 weeks, until completing 1 year of treatment. GBM patients did not receive temozolomide since the drug cannot be sold to Cuba. The objectives of this study were to assess the overall survival, progression free survival (PFS), response rate, immunogenicity and safety in both treatment groups. Results: Seventy patients were included in the study: 41 AA and 29 GBM. The median cumulative dose was 3600 mg of nimotuzumab and the median antibody number of doses was 16. The combination of nimotuzumab and radiotherapy was very safe. The most prevalent related adverse events included grade 1-2 nausea, fever, tremors and anorexia. There was no increasing toxicity with repeated drug exposure. No anti-idyotipic response was detected. The mean and median survival time for subjects treated with nimotuzumab and RT was 31.06 and 17.76 months while the mean and median survival time for controls was 21.07 and 12.63 months, respectively. For the evaluable patients of the AA stratum, the median survival time was 44.56 months (active drug) vs. 14.6 months (control). For the evaluable patients in the GBM cohort, the median survival time was 16.06 months (nimotuzumab arm) vs. 8.36 months (placebo arm). Median PFS was 18.23 vs. 6.25 months. Conclusions: In this randomized trial, nimotuzumab continues showing an excellent safety profile and positive efficacy results in patients with high grade glioma in combination with irradiation.
Assessment of a novel immunological biomarker SNP panel from a phase III trial of Bacillus Calmette-Guérin (BCG) adjuvant treatment in stage III melanoma patients.
Authors: Chiu Connie Ging Ting , Morton Donald L. , Chong Kelly , Hoshino Mirei , Huang Sharon , Nicholl Michael Bruce , Elashoff David , Hoon Dave S. B.
Published: March 2020

2519

Background: Melanoma is an immunogenic cancer, whereby immunotherapy in stage III patients has shown some success. However, there are no effective immune biomarker tests to identify patients most likely to benefit from immunotherapy. BCG (Bacillus Calmette-Guérin) therapy is a form of immunomodulation. The objective was to assess the predictive clinical effect of a single nucleotide polymorphism(SNP) immune biomarker panel in stage III resected melanoma patients treated with BCG. Methods: MMAIT-III was a phase III prospective randomized international multicenter trial of BCG+melanoma vaccine vs BCG+placebo after complete resection of stage III melanoma patients (NIH #NCT00052130). 120/292 patients with palpable disease treated with resection and BCG+placebo had lymphocytes(PBL) from USA sites available for analysis. Endpoints were overall survival(OS) and disease-free survival(DFS), with a 10-yr follow-up. PBL DNA was assessed by MassARRAY MALDI-TOF for 28 SNPs associated with macrophage/monocyte-related immune response pathways to BCG/tuberculosis. A pilot study(n=34) from phase II BCG trial confirmed presence of the SNPs. A logistic regression determined a SNP score, and a cutoff was identified by ROC and used as a predictor in a Cox proportional hazard model in a verification study(n=120). Results: 9 SNPs in 6 genes had prognostic value: NRAMP1 and CD14, 18, 195, 209, 282. The 9-SNP panel distinguished patients in 2 survival groups(OS median 4.9-yrs vs 1.5-yrs, p=0.0008), AUC=0.77. SNP biomarker positivity demonstrates significant association with 10-yr OS (59.7% vs 15.7%; HR 1.97, CI 1.11-3.50, p=0.018) and DFS (47.2% vs 12.3%; HR 2.35, CI 1.43-3.92, p=0.0007). In Cox model, the SNP panel was a significant predictor of OS(HR 2.69, CI 1.56-9.00, p=0.0052) and DFS(HR 2.33, CI 1.49-5.16, p=0.0003) independent of known melanoma prognostic factors. Conclusions: The 9-SNP panel identified patients with an exceptionally favourable disease outcome, and may represent a stratifying predictive SNP panel for identifying patients that are inherently responsive to BCG therapy and potentially other immunomodulating agents in melanoma.
Adjuvant dendritic cell (DC)-based vaccine therapy of melanoma patients.
Authors: Petenko Natalia N. , Mikhaylova Irina N. , Chkadua George Z. , Baryshnikov Anatoly Y. , Demidov Lev V.
Published: March 2020

2524

Background: Earlier DC vaccine therapy demonstrated clinical benefit in some patients (pts) with advanced melanoma although the effect was seen only in pts with minimal tumor burden (ASCO2007 abstract No: 3077). As there is no effective treatment for high risk resected melanoma we conducted an exploratory trial to assess the effectiveness of DC vaccine in stage III and IV melanoma pts after radical surgery in comparison with observation. Methods: 108 stage III and IV melanoma pts were enrolled in two comparative arms. The arms were well balanced in respect with demographic and prognostic factors. The vaccine was based on mature autologous monocyte-derived DC primed with autologous tumor lysate, administered intradermally every 2-6 weeks until the disease progression. Disease free survival (DFS) and overall survival (OS) were evaluated with Kaplan-Meier method and compared between the two arms using the log rank test. Safety of DC vaccine was also monitored. Results: The vaccine arm included 56 pts (stage III – 46, stage IV – 10 pts) who were surgically rendered free of disease and treated with DC vaccine. 52 pts were enrolled in the control arm (stage III – 47, stage IV – 5 pts), they were treated surgically and observed afterwards. At a median follow-up of 22 months, the HR (DC vs observation) for DFS was 0.45 (p < 0.05; 95%CI 0.29-0.69) and for OS was 0.71 (p=0.23; 95%CI 0.40-1.25). 60% of pts in the DC arm remained alive at this time point. Risk reduction significantly correlated with the strong delayed type hypersensitivity reaction induced by vaccine in 31 (55%) out of 56 vaccinated pts. The vaccine was safe and well tolerated although vitiligo was registered in 4 cases which was associated with more durable time to progression and OS. Conclusions: The immunotherapy with DC vaccine is safe and significantly improves DFS compared with observation in the adjuvant treatment of stage III and IV melanoma.
A mismatch between methods and objectives in phase I drug development: Statistical limitations and personalized medicine—A California Cancer Consortium (CCC) study.
Authors: Frankel Paul Henry , Shibata Stephen , Groshen Susan G. , Longmate Jeff , Pal Sumanta Kumar , Khoo Stella , Newman Edward M.
Published: March 2020

2538

Background: Patient variation in drug response and toxicity impacts all phases of drug development. While detailed sample-size calculations and analysis based on statistical methodology are critical for addressing variation in late stage trials, phase I studies pose unique and largely unsolved challenges related to variability. Changes in patient selection during the study, small sample-sizes and large patient variation in toxicity are exactly the kind of problems that statistical methods cannot address in small, isolated phase I studies, regardless of apparent mathematical rigor. We have documented these problems via a physician survey. Methods: A 10-question anonymous survey was sent to 670 oncologists at National Comprehensive Cancer Network (NCCN) and CCC institutions via an online survey. 19 % (126/670) of the oncologists polled responded. 78/126 (62%) specialized in Medical Oncology. The number of years in practice varied from 2-45 yrs with a median of 17 yrs. Results: a) 66% of all respondents stated that non-DLT toxicities on one dose level would impact their patient selection on the following dose level, conflicting with the assumption of random patient selection implicit in simulations used in evaluating statistical designs. b) Only 13% stated a desire to target a non-heme toxicity as high as 20% grade 3, while 87% desired a 10% or less grade 3 rate; c) More than half the respondents would prefer not to escalate if 3/3 patients experienced grade 2 LFTs; d) 82% of the respondents thought the appropriate target toxicity differed for patients depending on their potential for becoming a surgical candidate, furthering the need for personalized dosing. Conclusions: Statistical methods in phase I trials are unable to address many of the salient features of phase I study conduct and investigator goals. We will present several approaches we have initiated to address these limitations, and present future plans to help produce a more reliable estimate of a recommended dose. Supported in part by NCI grants U01CA062505, N01-CM-62209, and NCCN data collection assistance.
Prediction of early death among patients (pts) enrolled in phase I trials: Development and validation of a new model based on platelet count and albumin level.
Authors: Ploquin Anne , Olmos David , Lacombe Denis A. , A'Hern Roger , Duhamel Alain , Twelves Christopher , Marsoni Silvia , Morales Rafael , Soria Jean-Charles , Verweij Jaap , Voest Emile E. , Schoffski Patrick , Schellens Jan H. M. , Kramar Andrew , Arkenau Hendrik-Tobias , Kaye Stanley B. , Penel Nicolas
Published: March 2020

2540

Background: Selecting pts with “sufficient life expectancy” for phase I oncology trials remains challenging. The Royal Marsden Model (RMM; Arkenau, JCO 2009) identified high-risk pts as those with ≥2 of: albumin (ALB) <35g/l; LDH >ULN; more than 2 metastatic sites. The RMM was assessed in 1845 pts treated in phase I trials by members of the European New Drug Development Network (ENDDN). The present study aimed to develop an alternative prognostic model using a different methodology and to compare its performance with the RMM. Methods: The primary endpoint was 90-day mortality rate (90-DMR). The new model was developed from the ENDDN database using CHAID, an exploratory non-parametric data analysis method evaluating the relationship between a dependent variable (90-DMR) and possible predictive variables through a decision-tree analysis. The ROC characteristics and calibration of both methods were then validated in the independent EORTC Database (n=341 pts). Results: The CHAID method identified low and high-risk groups with 90-DMR of 9.5% vs 37.5%. High-risk pts had ALB<33g/L or ALB≥33g/L but platelet count ≥400.000/mm3. Applying both models to the validation dataset; the rates of correctly-classified pts were 0.86 [CI-95% 0.82-0.90] vs. 0.67 [CI-95% 0.60-0.74], with the CHAID model and RMM respectively. The CHAID model had higher specificity (0.90 vs. 0.65), but lower sensitivity (0.36 vs. 0.93) than the RMM. Discriminative slopes were similar for the CHAID model and RMM (19.4% and 19.3%, respectively). The negative predictive value (NPV; correct identification of pts surviving 90 days) was similar for the CHAID model and RMM (0.94 [0.91-0.97] and 0.99 [0.94-1.00] respectively). Calibration, assessed by the Brier score, was slightly better with the CHAID model (0.001 and 0.098, respectively). Conclusions: In selecting pts for phase I trials arguably an important criterion is NPV; the CHAID model and RMM provided a similar high level of NPV but the CHAID model gave a better rate of correctly-classified patients. Both models improved the screening process and reduce the attrition rate in phase I trials.
How to run survival-endpoint phase II trials with 25% to 40% fewer patients.
Authors: Schell Michael J. , Haura Eric B. , Kim Jongphil , Han Gang , Simon George R.
Published: March 2020

2544

Background: New molecular information, whether arising from expression profiling, identification of key mutations, or proteomic analyses is making the personalization of therapy increasingly feasible. This leads to the fragmentation of common disease entities into multiple molecular subtypes. Having sufficient numbers of patients to demonstrate the effectiveness of novel targeted therapies for each subtype has therefore become challenging, essentially impeding progress. Methods: Use of sample size determination software allows for comparison of phase II trials with a target survival proportion at a given time T based upon Kaplan-Meier versus exponential survival methods. Results: The use of exponential survival fitting methods, in lieu of the currently implemented trial designs, to single arm phase II studies can routinely reduce patient numbers by 25-40% (Table) without compromising the statistical power. The biggest advantage is that survival information both before and after time T reduces the variability for the exponential fit estimate. This approach will lead to the saving of financial and patient resources for researchers. Moreover, the time saved will accelerate the approval of agents making the proposed trial designs ethically attractive. However, this approach is only applicable if the exponential distribution assumption behind the approach is valid. Conclusions: The exponential survival fitting method should replace the current standard approach in all instances unless the exponential distribution assumption is known to be false. Detailed examples and analysis will be presented. [Table: see text]
First-in-human phase I and pharmacokinetic study of DTS-108 in patients with advanced carcinomas.
Authors: Coriat Romain , Faivre Sandrine J. , Dreyer Chantal , Mir Olivier , Bouattour Mohamed , Goldwasser Francois , Raymond Eric
Published: March 2020

2557

Background: DTS-108 is a soluble pro-drug of SN38, the active metabolite of irinotecan, where the SN38 moiety is covalently linked to a 20AA peptide through a specific cross-linker that releases SN38 by esterase bond cleavage. DTS-108 was designed to achieve therapeutic levels of SN38, while reducing diarrhea. Methods: This trial identified the pharmacokinetics, the adverse event (AE) profile (NCI-CTCv3 criteria), the dose limiting toxicities (DLT) at cycle 1, the maximum tolerated dose (MTD), and the recommended phase II dose (RD) of intravenous DTS-108 (1-2 hours) every two weeks (q2w) in patients (pts) with advanced/metastatic carcinomas, ECOG:0-1, and adequate hepatic, marrow, and kidney functions. Results: Forty-Two pts received DTS-108 across 14 dosing cohorts (range: 3-416 mg/m2). All grade AEs were asthenia (43%), nausea (43%), diarrhea (41%), vomiting (33%), anemia (31%), rash (21%), anorexia (21%), alopecia (19%), abdominal pain (19%), and neutropenia (19%). Grade 3 diarrhea was only reported in two pts with either partial bowel obstruction or recent history of a total colectomy. Neutropenia was the dose limiting toxicity of DTS-108. Neutropenia started to be observed at doses >56 mg/m2. At 416 mg/m2, 3/6 pts had grade 4 neutropenia. Infusion related reactions (itching urticaria) were observed with increasing frequency and severity at doses >75 mg/m2 and required antihistamine premedications. At 313 mg/m2 and 416 mg/m2, infusion skin reactions were 2/6 pts and 6/6 pts, respectively. Fluorescence HPLC was initially used to quantify DTS-108 and its metabolites (SN-38 and SN-38G). Sample stability analysis of this method showed that SN38 values were inaccurate as DTS-108 degraded forming ex-vivo SN-38 during the blood collection, plasma storage, and/or sample extraction. New processes and analytical LC/MS/MS methods for testing SN-38 were implemented. At the dose of 313 mg/m2, mean DTS-108, SN38, and SN38G AUCINF (CV%) were 439293 (24%), 1992 (34%), and 4538 (46%) h*ng/mL. Tumor stabilization (RECIST) was observed in 9 pts and confirmed in 6 pts. Conclusions: DTS induced neutropenia and infusion skin reactions but no dose-limiting diarrhea. The MTD was 416 mg/m2 and the RD was 313 mg/m2 q2w.
Phase II trial of a GM-CSF-producing and CD40L-expressing cell line combined with allogeneic tumor antigen as a novel vaccine for metastatic lung adenocarcinoma.
Authors: Creelan Ben C. , Antonia Scott , Noyes David , Hunter Terri B. , Simon George R. , Bepler Gerold , Williams Charles C. , Tanvetyanon Tawee , Haura Eric B. , Schell Michael J. , Dessureault Sophie , Chiappori Alberto
Published: March 2020

2559

Background: We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Methods: Intradermal vaccine was given every 14 days x3, followed by monthly x3. Cyclophosphamide (300 mg/m2 IV) was administered before 1st and 4th vaccines to deplete regulatory T-cells. All-trans retinoic acid was given (150/mg/m2/day) after 1st and 4th vaccines to enhance dendritic differentiation. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and after each vaccination. T-cell activation profiles were analyzed by ELISpot assay and tested by generalized Wilcoxon for correlation to survival. Results: 24 participants were accrued at a single center from 10/2006 to 6/2008, with median age 64 and median of 3 previous lines of chemotherapy prior to entry. 20 were former smokers and 4 had brain metastases. A total of 101 vaccines were administered. Common toxicities of any grade were joint pain (79%) and fatigue (75%). Significant adverse events included a grade 3 hypotension and a grade 3 acute respiratory distress. No confirmed complete or partial radiologic responses were observed. Median overall survival (OS) was 8.0 mo (95% CI 3.5 – 12.5) and median time-to-progression was 2.4 mo (95% CI 0.3 – 4.6). Presence of HLA-A2 conferred reduced risk of progression (HR 0.37, 95% CI 0.14 -0.89, p=0.02) and trend to improved OS (HR 0.59, p = 0.06). Of 14 participants with evaluable PBMCs, 5 demonstrated sustained tumor peptide-specific T-cell activation after vaccination. Ex vivo peptide immune response correlated with improved OS compared to non-responders (23 vs. 7 mo, HR 0.48, p = 0.04). Conclusions: Vaccine administration was feasible and tolerable in a heavily pretreated population of metastatic lung cancer. These data suggest the vaccine has clinical activity in the subset with peptide-induced T-cell immune responses and warrants further investigation. A randomized trial of the vaccine is currently in development.