bluuebunny/crossref_metadata_2025 huggingface dataset:
Tegwondo-CCNU: A novel combination of protracted, near-continuous temozolomide and CCNU with activity in recurrent malignant gliomas.
Authors: Strik Herwig Matthias , Rock Hans , Kallenberg Kai
Published: March 2020

2079

Background: Recent data have been raising doubt if dose-dense temozolomide is more efficient against malignant gliomas than with conventional dosing. We report here updated results of combined near-continuous temozolomide, aimed at depleting anti-alkylating MGMT, with once weekly application of low-dose lomustine (CCNU) at first or second relapse of malignant gliomas. Methods: 25 consecutive patients with recurrent malignant gliomas (12 anaplastic gliomas WHO III, 13 glioblastomas or gliosarkomas WHO IV) were treated: 15 males (60%), 10 females (40%); mean age at start of chemotherapy was 52 (20-78) years; Eight patients were treated at first, 15 at second and two at third recurrence. All patients were pretreated with temozolomide. Four patients received fractionated, stereotactically guided re-irradiation (FSRT). The treatment regimen consisted of near-continuous temozolomide 50mg/m2 day 1‑5/7 and low-dose CCNU 40mg absolute dose day 6/7. In cases of bone-marrow depression, temozolomide was reduced in steps of 20mg total dose or – in more severe cases – chemotherapy was interrupted until normalization of blood counts. Results: In total, 89 cycles (months) of chemotherapy were applied. The combination was well tolerated in terms of nausea and fatigue. Blood counts usually decreased continuously, enabling a gradual dose adaptation. Hematological WHO grade 3+4 toxicity occurred in 5/25 patients (20%), two of them were symptomatic. Three patients had prolonged elevation of liver enzymes. Best responses after ≥ 3 months (23 patients) were: 2 complete and 1 partial remissions (13%, ), 13 stable diseases (57%), and 7 progressive diseases (30%). Progression-free survival at six months from start of chemotherapy of the 16 patients treated > 6 months or deceased (PFS 6) was 37%, median overall survival 6.3 months. Conclusions: Although some hematotoxicity was observed, the regimen presented here is well tolerated and safe if carefully controlled. The objective responses and considerable rate of stable diseases indicate that this combination is active in malignant gliomas after pretreatment with temozolomide alone. The results have to be controlled in a prospective trial.
The role of fluorescence-guided surgical resection in the combined treatment of malignant glioma.
Authors: Carapella Carmine Maria , Oppido Piero Andrea , Vidiri Antonello , Cattani Fabio , Telera Stefano Maria , Pompili Alfredo , Pace Andrea
Published: March 2020

2085

Background: Malignant glioma represents a relevant therapeutic issue and the value of extensive surgical resection remains debated; recent evidence suggests that radical removal is associated with better survival. An interesting tool for identifying tumor tissue and increasing the extent of surgery is represented by fluorescence-guided resection, taking advantage of metabolic and structural changes induced by a natural precursor of heme biosynthetic pathway, 5-amino-levulinic acid (ALA). Methods: The present experience is related to 32 patients affected by malignant glioma (18 newly diagnosed: 16 glioblastoma (GBM), 2 anaplastic oligodendroglioma; and 14 recurrent GBM) eligible for fluorescence-guided resection, operated on in our Institute since fall of 2009. All patients underwent preoperative and early postoperative MRI, showing contrast enhancing lesions. An oral dose of 20 mg 5-ALA /kg bw was administered to each patient. Microsurgical resection was performed by an operating microscope enabled to visualize the fluorescence. All the patients, as first line treatment, have been submitted to radiotherapy and chemotherapy; second and in some cases third line treatments were utilized in recurrent cases. The patients follow-up ranged from 2 years to 6 months. Results: In more than 90% of patients tumor tissue showed intraoperative red fluorescence; mainly in recurrent GBM, when MRI documented heterogeneous lesions with enhancing areas mixed with non enhancing gliotic scars, fluorescence-guided surgery allowed a better definition of active tumor, with net margins from perilesional “healthy” brain. Early postoperative MRI confirmed gross total resection without contrast enhancement in 80 % of patients. In the present experience the procedure did not determine any relevant additional neurological deficit. Considering overall survival of recurrent patients we obtained a median extension of at least 9.0 months (3 – 16+ months). Conclusions: Fluorescence-guided surgery improves tumor detection and allows extended resection of malignant glioma, without any relevant impact on neurological status, resulting helpful mainly in the recurrent setting with a consistent effect on overall survival.
Correlation of survival with tumor antigen expression in patients with newly diagnosed glioblastoma receiving a multi-epitope pulsed dendritic cell vaccine.
Authors: Phuphanich Surasak , Wheeler Christopher Jay , Rudnick Jeremy , Mazer Mia , Wang Hong Qiang , Nuno Miriam , Richardson Jaime , Fan Xuemo , Ji Jianfei , Chu Ray M , Bender James , Hawkins Elma S. , Patil Chirag , Black Keith L. , Yu John
Published: March 2020

2087

Background: This study evaluated the safety and immune responses to an autologous dendritic cell vaccine pulsed with class I peptides from tumor associated antigens (TAA) expressed on gliomas and overexpressed in their cancer stem cell population (ICT-107). These TAA epitodes AIM-2. TRP-2, HER2 and AIM-2, are also overexpressed on glioblastoma multiforme (GBM) cancer stem cells. Methods: TAA epitopes included HER2, TRP-2, gp100, MAGE-1, IL13Rα2, and AIM-2. HLA-A1 and/or HLA-A2 positive glioblastoma (GBM) patients with gross total resection were eligible. Mononuclear cells from leukapheresis were differentiated into dendritic cells, pulsed with TAA peptides, and administered intradermally three times at two-week intervals in the axilla region after a standard treatment with concurrent temozolomide (TMZ) and radiation therapy for newly diagnosed (ND-GBM). Results: Twenty-one patients were enrolled with 17 ND-GBM and three recurrent GBM patients and one brainstem glioma. Immune response data on 15 newly diagnosed patients showed 33% responders. TAA expression by qRT-PCR showed all patient tumors expressed at least three TAA with 75% expressing all six. Correlations of increased PFS and quantitative expression of MAGE1, AIM-2, gp100 and HER2 were observed. A decrease or absence of CD133 expression was seen in five patients who underwent a second resection. As of February 1, 2012, six of 16 ND-GBM patients showed no evidence of tumor recurrence (44-63 months). Median progressive free survival (PFS) in newly diagnosed patients was 16.9 months with a two-year PFS rate was 43.8% (95%CI,19.8-66.0 ). The median overall survival rate (OS) was 38.4 months and a two-year OS was 80.3% (95%CI,58.6-96.7). Conclusions: Expression of four ICT-107 targeted antigens in the pre-vaccine tumors correlated with prolonged overall survival and PFS in ND-GBM patients. The goal of targeting tumor antigens highly expressed on glioblastoma cancer stem cells is supported by the observation of decreased or absent CD133 expression in the recurrent areas of gadolinium-enhanced tumor.
The addition of bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide, and oral topotecan for newly diagnosed glioblastoma multiforme (GBM).
Authors: Friedman Henry S. , Desjardins Annick , Peters Katherine B. , Reardon David A. , Kirkpatrick John , Herndon James Emmett , Coan April D. , Bailey Leighann , Sampson John Howard , Friedman Allan H. , Vredenburgh James J
Published: March 2020

2090^

Background: The prognosis for newly-diagnosed GBM is dismal. The addition of temozolomide to radiation therapy improved the median overall survival (OS) to 14.6 months (mos). GBM’s have the highest levels of vascular endothelial growth factor (VEGF). Hypoxia inducing factor-1 alpha (HIF-1 alpha) is an important regulator of VEGF, and topotecan may inhibit HIF-1 alpha. Methods: We performed a phase II trial in newly diagnosed GBM by adding bevacizumab and topotecan to standard therapy. 80 newly diagnosed GBM patients were enrolled between January 2010 and January 2011. Patients received standard radiation therapy and temozolomide. Bevacizumab at 10 mg/kg every 14 days was added a minimum of 4 weeks post-op. Two weeks after radiation therapy was completed, 12 monthly cycles of temozolomide at 150 mg/m2 /d days 1-5, oral topotecan at 1.5 mg/m2 for patients not on an enzyme inducing anti-epileptic drug (EIAED) and 2.0 mg/m2 for patients on an EIAED days 2-6, and bevacizumab at 10 mg/kg on days 1 and 15. Results: The addition of bevacizumab to standard radiation therapy and daily temozolomide was safe. Of the 80 patients, 76 completed radiation therapy. Four patients did not complete radiation, two with clinical decline, one each with a bone flap infection, and a pulmonary embolus. Fifteen patients came off study for toxicity, five with recurrent grade IV thrombocytopenia, three with grade III fatigue, two each with grade 2 CNS hemorrhage, and wound dehiscence requiring surgery and one each with GI perforation, pulmonary embolism and an aortic thrombus. Of the 80 patients, 56 have progressed and 37 have died. The median progression-free survival (PFS) and OS are 11.1 mos (95% CI: 9.4-13.6) and 17.2 mos (95% CI: 15.2) at a median follow-up of 18.4 months. The two year OS is 45.3%. Conclusions: The addition of bevacizumab to temozolomide and radiation followed by temozolomide, bevacizumab and oral topotecan is tolerable. The median PFS and OS are encouraging. The randomized phase III trials with bevacizumab for newly diagnosed GBM patients are essential.
CD40 ligand/interferon-γ matured DC immunization with gp100 antigen HLA class I A *0201 restricted peptides in patients with newly diagnosed metastatic melanoma.
Authors: Linette Gerald P. , Becker-Hapak Michelle , Huang Alexander , Alyasiry Amer , Chan Megan , Lie Wen-rong , Cornelius Lynn , Moley Jeffrey F. , Aft Rebecca , Tan Benjamin R. , Trinkaus Kathryn , Carreno Beatriz M
Published: March 2020

2525

Background: CD40L/IFN-γ matured Dendritic Cells (DCs) produce IL-12 and are potent antigen-presenting cells for naïve resting T cells. We sought to determine the magnitude and kinetics of CD8+ T cell growth in patients receiving autologous CD40L/IFN-γ matured DC and identify biomarkers associated with clinical outcome. Methods: A phase I clinical trial (NCT00683670) incorporating CD40L/IFN-γ for the ex vivo maturation of autologous DCs pulsed with three well characterized gp100 melanoma antigen derived peptides (G154, G209-2M, G280-9V) was initiated with enrollment from 2008-11 at a single center. HLA-A*0201+ individuals with treatment naïve metastatic melanoma were immunized every 3 weeks by intravenous infusion for six doses after a single dose of cyclophosphamide (300 mg/m2 iv). CT imaging was performed at baseline, week 9 and 18 for clinical assessment using RECIST. Responding patients were eligible for maintenance doses every 2-4 months. PBMC were taken weekly for immune monitoring by tetramer analysis and functional assays. DC preparations were characterized to assess for biomarkers of response. Results: 10 patients were screened. Among the 7 treated patients, there were 3 confirmed responses (independently verified), including one durable CR >3 years and 2 PR. Three patients had rapid disease progression and received only 3 doses. Four patients (1 CR, 2 PR, 1 PD) received 6 or more vaccine doses. No SAEs were noted. There was no correlation between tumor volume and response. Using pre-specified immune response criteria, 6 (86%) treated patients developed CD8+ T cell immunity to all three peptides as assessed by tetramer analysis. The vaccine-induced T cells from all 6 individuals were polyfunctional and killed gp100+, HLA-A2+ human melanoma targets in a standard 51Cr release assay. IL-12 production by DCs correlated with TTP (p=0.0198, likelihood ratio test) but not OS (p=0.08). Conclusions: Weekly immune monitoring reveals the rapid onset of CD8+ T cell immunity against gp100 among the responder patients. This is the first DC vaccine clinical trial in melanoma to demonstrate a correlation of IL-12 production and TTP.
Association of idiotype vaccine-induced T-cell response with improved survival and time-to-next treatment (TTNT) in untreated mantle cell lymphoma (MCL).
Authors: Dunleavy Kieron , Neelapu Sattva Swarup , Kwak Larry W. , Grant Cliona , Santos Carlos F. , Popa Mihaela A. , White Therese , Miller Barry , Jaffe Elaine S. , Steinberg Seth M. , Wilson Wyndham Hopkins
Published: March 2020

2528

Background: Murine models show Id-vaccines induce antitumor responses, possibly through Th1/Tc1 cytokines. We report an 11-year follow-up of Id-vaccine following DA-EPOCH-Rituximab in 26 untreated MCL patients. Methods: DA-EPOCH-R was administered q3 weeks × 6, followed 12 weeks later by 5 cycles of Id-vaccine. Id protein was made by hybridoma technology, conjugated to keyhole limpet hemocyanin (KLH) and administered with GM-CSF. Pre- and post-vaccine immune responses (IR) were tested in parallel: anti-Id and anti-KLH humoral responses (ELISA); anti-KLH cellular responses (intracellular cytokine assay); and anti-tumor cellular responses (cytokine induction, IFNγ ELISPOT). Results: Characteristics: median age 57 (r 22-73), blastoid variant 15%, and MIPI (low-65%; intermediate-16%; high-19%). With 122 mo median follow-up (r 111-132), the median PFS is 24 mo and OS is 104 mo. MIPI was associated with OS (p=0.0002); median OS: low (not reached), intermediate (84 mo) and high (44 mo). We found no association between OS and anti-KLH IR, anti-Id humoral response, IFNγ ELISPOT, or antitumor TNFα or IFNγ responses. Normalized antitumor T-cell GM-CSF response (median <4.3 vs. >4.3) was associated with OS of 79 mo vs. not reached, respectively (p=0.015 (unadj.) and p=0.045 (adj.)). MIPI (p=0.02) and GM-CSF (p=0.057) were independently associated with OS. TTNT (based on disease activity), correlated with antitumor GM-CSF response (p=0.018) but not MIPI and was independent of MIPI (GM-CSF; p=0.041). Correlation of pre-and post-treatment GM-CSF production suggested a priming effect. Tumor proliferation by GEP did not correlate with OS (n=14). Conclusions: Antitumor GM-CSF response was significantly associated with OS and TTNT, suggesting antitumor cellular immune response significantly delayed tumor growth. Antitumor GM-CSF response may serve as a surrogate biomarker for vaccine efficacy. Our results are consistent with recent data that T-cell GM-CSF production is required for breaking tolerance against self-antigens. Id vaccines may prolong survival of MCL following rituximab-based chemotherapy and should be further evaluated.
Feasibility and safety of sequential research-related tumor core biopsies in clinical trials with anti-angiogenic and targeted therapies.
Authors: Lee Jung-min , Hays John L. , Noonan Anne M. , Squires Jennifer , Annunziata Christina M. , Wood Bradford J , Yu Minshu , Houston Nicole D. , Azad Nilofer Saba , Kohn Elise C.
Published: March 2020

2545

Background: There has been increasing interest in serial/paired research biopsies (bx) in studies of molecularly targeted therapies. Definition of optimal target tissue and patient characteristics for safe and feasible research tumor bx in the era of anti-angiogenic and targeted therapies is needed. Methods: IRB-approved review of retrospective clinical data including patient demographics, pre-and post-procedure and recovery notes, and radiographic bx images. The cohort consisted of 142 pts scheduled for serial bx enrolled in phase 1 (5) and phase 2 (1) studies. Tumor core bx were obtained percutaneously under local anesthesia using a 16 or 18g needles under US or CT visualization by interventional radiologists. Results: Paired tumor core bx were collected in 96 pts (68%) and baseline only in 42 pts (32%). Bx were aborted in 4 pts due to cystic mass (3) and safety (1). 132 pts were female and 10 pts were male, median age 56 yrs (27-78), median BMI 25.8 (14.4-46.2), ECOG PS 0-2, and normal end-organ function. All pts had recurrent metastatic cancers (gynecologic 121, breast 6, sarcoma 5, melanoma 4, colon 2, adrenal 1, mesothelioma 1, RCC 1, papillary thyroid ca 1). 67 pts (51%) were on bevacizumab (bev)-based therapy at the time of their 2nd/3rd bx (bev + sorafenib; bev + dasatinib); others received gefitinib (27), imatinib (23), vandetinib (9), or olaparib + carboplatin (16). Median tumor size was 2.7cm (1-14.5cm). Bx sites were abd/pelvic masses 42, liver 40, lymph nodes 42, abd/chest wall 12, lung 4 (3 pleural, 1 parenchymal), and psoas muscle 1. Minor complications were observed in four pts (3%; uncomplicated liver subcapsular hematoma [1]; vasovagal syncope responding to fluids [2]; uncomplicated pneumothorax without intervention [1]) and there were no major complications. The median number of tumor cores was 3 (1-6) at the baseline, 2nd (during or at the end of the first cycle) and 3rd time point (during cycle 2). Conclusions: Core needle bx of deep internal lesions such as intra-abdominal masses and retroperitoneal lymph nodes can be obtained percutaneously under imaging guidance. Sequential tumor bx are feasible and safe for pts on anti-angiogenic and chemotherapeutic agents.
Phase I immunotherapy trial using glioblastoma apoptotic body-pulsed dendritic cells.
Authors: Moertel Christopher L. , Olin Michael , Dahlheimer Tambra , Gustafson Michael , Sumstand Darin , McKenna David , Low Walter , Nascene David , Dietz Allen , Ohlfest John
Published: March 2020

2546

Background: We recently reported that tumor cell vaccines cultured in 5% oxygen (O2) had enhanced the immunogenicity relative to those grown in standard atmospheric O2. In order to develop an “off-the-shelf” source of whole cell antigen we screened a panel of primary glioblastoma (GBM) cell lines, leading to identification of (GBM6) as an ideal candidate. GBM6 was extensively characterized and shown to express glioma-associated antigens (IL13Ra2, Sox2, Epha2, etc.). A Phase I clinical trial was initiated to evaluate the safety and feasibility of a vaccine consisting of dendritic cells (DC) pulsed with apoptotic bodies from GBM6 grown in 5% O2. Methods: Patients ranging from 3 to 71 years with recurrent GBM (n=6) or ependymoma (n=1) were enrolled. Monocytes were collected via apheresis, matured into DC and pulsed with apoptotic bodies derived from GBM6. The first three patients received escalating doses of DC (5x106, 10x106, and 15x106), the remainder received 15 x 106 DC. Pulsed dendritic cellswere injectedsubcutaneously into the supra-scapular region. Imiquimod cream was applied at the injection site just prior to vaccination and 24 hours later. The vaccine schedule dictated administration every 2 weeks for 8 weeks (total of 5 doses) then monthly to progression or a total of 52 weeks. Prior to each vaccination, patients met eligibility parameters and had no progression on MRI. Patients were imaged monthly and blood was drawn to evaluate toxicity and immune response. Results: No vaccine-related toxicity has been reported. Time to progression ranges from 6.5 weeks for the patient treated at the first dose level to 35 weeks for one patient receiving 15 x 106 DC. The latter patient experienced a partial response at 20 weeks. Two patients have stable disease at 18.5 and 28 weeks, respectively. One patient was not evaluable. Flow cytometric analysis demonstrated expansion of central memory T cells amidst declining effector memory cells following vaccination in three patients at a dose of 15x106 DC. Conclusions: Apoptotic body-pulsed DC vaccination was well tolerated and preliminarily demonstrated clinical activity but a minimum of 15x106 DC was required for a modulation of central memory T cells.
Effect of dexrazoxane on doxorubicin-induced testicular toxicity.
Authors: Ben-Aharon Irit , Tzabari Moran , Savion Naftaly , Shalgi Ruth , Stemmer Salomon M.
Published: March 2020

2556

Background: Seminal advances in anti-cancer therapy result in growing numbers of young male cancer survivors for whom treatment-induced infertility represents a major late-term concern. Doxorubicin (DXR) has been previously shown to exert toxic effect on the testicular germinal epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), we aimed to study its potential effect to reduce DXR-induced testicular toxicity. Methods: Male mice were injected intraperitoneally with 5mg/kg DXR or 100mg/kg DEX or the combination of both and scarified at one month post treatment. Saline-injected mice served as controls. Testes were excised, weighed and further processed. For oxidative stress determination glutathione assay was performed on testes' lysates and P38 protein levels were determined by western blot analysis. Bax levels were used to assess apoptosis. Immunohistochemistry and confocal microscopy were used to study the effect of DXR, DEX and their combination, on the testis histology as well as on the spermatogonial reserve. Results: One month after DEX and DXR treatment, a striking decline in testicular weight was observed (decrease by 60% compared with control values; decrease of 54% in DXR-only treated mice; p<0.05). DEX prevented DXR-induced oxidative stress. However, DEX enhanced DXR-induced apoptosis within the testes and furthermore, the combination depleted the spermatogonial reserve one month after treatment. Conclusions: DEX activity in the testis may differ from its activity in cardiomyocytes. Adding DEX to DXR may exacerbate DXR-induced testicular toxicity.
Lymphoid and myeloid biomarkers for clinical outcome of combined immunotherapy with granulocyte-macrophage colony-stimulating factor-tranduced allogeneic prostate cancer cells (GVAX) and ipilimumab in castration-resistant prostate cancer patients.
Authors: van den Eertwegh Alfons JM , de Gruijl Tanja , Santegoets Saskia , Stam Anita , von Blomberg Mary E , Hege Kristen , Sacks Natalie , Jooss Karin , Lowy Israel , Gerritsen Winald R.
Published: March 2020

2562

Background: In a phase-I dose escalation trial in patients with castration-resistant prostate cancer we showed that GVAX and ipilimumab had an acceptable safety profile. Moreover, we observed tumor responses and prolonged survival as compared to the Halabi predicted overall survival (OS). However, ipilimumab can also lead to severe immune-related adverse events. To avoid unnecessary exposure to this risk, it is essential to identify biomarkers that correlate with clinical activity. Methods: Patients had castration-resistant prostate cancer and were chemotherapy-naïve. They received bi-weekly GVAX for a 24 week period combined with monthly intravenous administrations of ipilimumab. Each cohort of 3 patients received an escalating dose of ipilimumab at 0·3, 1·0, 3·0 or 5·0 mg/kg. In an expansion cohort 16 patients were treated with GVAX and 3·0 mg/kg ipilimumab. Flowcytometric monitoring of lymphoid and myeloid subsets in blood were performed. Results: We observed a significantly prolonged OS for patients with high pre-treatment frequencies of CD4+CTLA-4+, CD4+PD-1+, or differentiated CD8+ T cells, or low pre-treatment frequencies of differentiated CD4+ T cells or CD4+CD25hiFoxP3+ regulatory T cells. In contrast, increased frequencies of granulocytic Myeloid-Derived Suppressor Cells (MDSC) and high pre-treatment frequencies of monocytic CD14+HLA-DRlo/- MDSC were associated with reduced OS. Treatment-induced CD4+ T cell differentiation and CD4+ and CD8+ T cell activation was associated with clinical benefit. Moreover, treatment-induced activation of CD1c+ conventional Dendritic Cells (cDC) and 6-sulfo LacNAc+ inflammatory DC were associated with significantly prolonged OS. Conclusions: Together these data provide an immune profile to predict clinical outcome. Importantly, cluster analysis revealed pre-treatment, CRPC-associated expression of CTLA-4+ by CD4+ T cells to be a dominant predictor for OS after GVAX/ipilimumab. This potentially biomarker for patient selection should be validated in patients treated with ipilimumab.
A phase I study of MEHD7945A (MEHD), a first-in-class HER3/EGFR dual-action antibody, in patients (pts) with refractory/recurrent epithelial tumors: Expansion cohorts.
Authors: Cervantes-Ruiperez Andres , Juric Dejan , Hidalgo Manuel , Messersmith Wells A. , Blumenschein George R. , Baselga José , Roda Perez Desamparados , Dienstmann Rodrigo , Calles Antonio , Jimeno Antonio , Sanabria Sandra , Littman Catherine , Amler Lukas C. , Pirzkall Andrea , Tabernero Josep
Published: March 2020

2568

Background: Dysregulated human epidermal growth factor receptor tyrosine kinase (HER RTK) signaling is an important driver of tumor growth, metastasis, and survival. Extensive co-expression and heterodimerization suggest that simultaneous blockade of multiple HER RTKs may be more effective than blockade of a single RTK. MEHD is a novel dual-action human IgG1 antibody. Each antigen-binding fragment blocks ligand binding to HER3 or EGFR, and intended to inhibit signaling from all major ligand-dependent HER dimers. MEHD has single-agent activity in multiple tumor models including models resistant to anti-HER3 or anti-EGFR. Methods: This Phase I study evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) activity of intravenous MEHD every 2 weeks (q2w). Tumor PD assessments were pre- and post-dose FDG-PET and IHC for pS6, pPRAS40 or pERK in tumor biopsies. Tumor CT assessments were performed q8w. No dose-limiting toxicity (DLT) was observed in six 3+3 cohorts from 1-30 mg/kg (n=30). We report results from 4 tumor-specific cohorts receiving 14 mg/kg MEHD (recommended Phase II dose). Results: As of 21 Nov 2011, 36 pts (CRC=12, NSCLC=9, SCCHN=10, pancreatic=5), median age 62.5 (35–87), all PS 0-1, median # prior regimens 3.5 (1-8), received a median of 4 doses (1-9) of MEHD; 18 pts remain on study. PK data are consistent with human anti-EGFR antibodies. No related Grade (G) ≥3 adverse events (AEs) have been observed. Common related G1/2 AEs included rash/dermatitis (53%), diarrhea (36%), fatigue (22%), paronychia (19%), dry skin, nausea, and decreased appetite (all 17%), asthenia and stomatitis/oral pain (all 14%). Related AEs ≤ 24 h after first infusion included G1/2 headache (42%), fever (33%), and chills (17%), and decreased in intensity and frequency with later infusions. Early PD data indicate target inhibition in 8/36 pts (SCCHN=2, NSCLC=2, CRC=4), and best response by RECIST includes 2 PR (both SCCHN), 6 pts with SD ≥ 8 weeks (NSCLC=2, CRC=4), 7/8 previously treated with EGFR inhibitors. Conclusions: MEHD at 14 mg/kg q2w has an encouraging safety profile and evidence of anti-tumor activity. Phase II studies are planned.
Messenger RNA vaccination and B-cell responses in NSCLC patients.
Authors: Sebastian Martin , von Boehmer Lotta , Zippelius Alfred , Mayer Frank , Reck Martin , Atanackovic Djordje , Thomas Michael , Schneller Folker , Stoehlmacher-Williams Jan , Goekkurt Eray , Bernhard Helga , Groeschel Andreas , Scheel Birgit , Koch Sven D. , Lander Thomas , Rippin Gerd , Wiegand Volker , Gnad-Vogt Ulrike Senta , Kallen Karl-Josef , Knuth Alexander
Published: March 2020

2573^

Background: Vaccination with mRNA is a novel technology in cancer immunotherapy. CV9201 consists of self-adjuvanted mRNA molecules (RNActive) coding for five non small cell lung cancer (NSCLC)-associated tumor antigens (MAGE-C1, MAGE-C2, NY-ESO-1, BIRC5, 5T4). We report final results of a phase I/IIa trial of CV9201 in patients (pts.) with NSCLC. Methods: Pts. with stage IIIB/IV NSCLC with a response or stable disease after first-line chemotherapy or chemoradiation were eligible. Cohorts of 3 pts. were treated at three dose levels (400µg, 800µg and 1600µg CV9201) and observed for DLTs to select the highest tolerated dose for phase IIa. Primary endpoint was safety and tolerability; secondary endpoints were immune response, clinical efficacy and survival. Pts. received up to five vaccinations of CV9201 within 15 weeks. Antigen-specific immune responses against each of the 5 antigens were measured at baseline, and two weeks after the 3rd and 5th vaccination. Frequency of lymphocyte subsets and expression of activation and maturation markers were measured and retrospectively correlated with immunological and clinical parameters. Results: 46 pts. were included (9 phase I; 37 phase IIa); No DLTs occurred, and the 1600 µg dose was investigated in phase IIa. The most frequent related adverse events were mild to moderate injection site reactions and flu-like symptoms. 3 patients (7%) had potentially related grade 3 AEs (fatigue, injection site granuloma, asthma attack) and no related SAEs were reported. There were no objective responses. Data on PFS and survival will be presented. Antigen specific immune responses against at least one antigen were induced in 65% of pts. (39% cellular and 49% humoral). Consistently, a significant ≥2 fold increase of pre germinal center B cells (pGCB) was observed in 61% of pts. This increase of pGCB correlated significantly (p=0.0028) with increase of total CD4 effector T cells. Frequency of CD 4 T Reg cells did not increase during treatment. Conclusions: Vaccination with CV9201 has a favorable safety profile and induces T and B cell responses against all included antigens. Vaccine-induced increase of pGCB is a new finding and might be used as a biomarker in cancer immunotherapy.
Randomized phase II trial of multipeptide vaccination with or without a single pre-vaccine dose of denileukin diftitox in advanced melanoma.
Authors: Gajewski Thomas , Matijevich Karen , Zha Yuanyuan
Published: March 2020

2582

Background: The efficacy of immunotherapy approaches such as vaccines in melanoma appears limited, in part, due to immune suppressive mechanisms in the tumor microenvironment. One of these mechanisms is the presence of CD4+CD25+FoxP3+ regulatory T cells (Tregs). It has been hypothesized that strategies to reduce Treg numbers should improve the efficacy of melanoma vaccines. Methods: The study design was to randomize 24 HLA-A2+ patients to receive vaccine alone or denileukin diftitox (18 mcg/kg i.v.) as a single dose 4 days prior to the first vaccination. The vaccine formulation consisted of 4 melanoma antigen peptides (derived from MelanA, gp100, MAGE3, and NA17A) emulsified in Montanide and GM-CSF, administered i.d./s.c. every 2 weeks. The primary endpoints were assessment of depletion of Tregs from the peripheral blood, and measurement of antigen-specific CD8+ T cell responses by ELISPOT. Secondary endpoints included clinical response and analyses of the tumor microenvironment for changes in Treg infiltration. Results: The treatment was well tolerated. Enrollment was halted at 16 patients when it was clear that immune response endpoints would not be reached. There was no significant decrease in Treg numbers, nor was there an increase in vaccine-induced T cell responses, when patients received denileukin diftitox prior to vaccination. In patients with biopsiable tumors, there was no decrease in Tregs in metastatic lesions post-versus-pre-treatment. Of the 9 patients who showed clinical benefit (1 PR, 8 SD), 4 of them received denileukin diftitox and 5 did not. Estimated time to progression was 146 days in the group that received denileukin diftitox and 131 days in the group that did not. Conclusions: Denileukin diftitox given as a single dose prior to vaccination was not sufficient to deplete Tregs or improve the potency of this melanoma vaccine. Alternative strategies to reduce Tregs, such as multiple doses of denileukin diftitox or anti-CD25 mAbs, should be considered.
Multivariate screening of prognostic factors to identify a novel, simple, and objective marker to optimize patient selection and predict survival benefit in early-phase trials.
Authors: Stavraka Chara , Pinato David James , O'Cathail Sean Micheal , Williams Farah J , Seckl Michael , Blagden Sarah Patricia
Published: March 2020

2608

Background: Several prognostic indices have been devised to optimize patient selection for phase I trials. However, there is no consensus as to the optimal score and none qualifies as a marker of response. We developed a simple score through a multivariate screening of individual variables and compared its performance with existing prognostic scores including the Royal Marsden, Nijmegen and Prince Margaret Hospital scores. Methods: We retrospectively analyzed characteristics and outcomes of 120 referrals to our phase I center (2007 - 2011). Independent predictors for overall survival (OS) were identified from univariate (Kaplan Meier) and multivariate (Cox regression) analyses and used to create the Hammersmith Hospital score (HS). This was compared with the other indices for predicting progression free survival (PFS), OS and 90 day mortality (90 DM). Multivariate logistic regression and ROC curves were used to estimate 90 DM and c-index was used to estimate the prognostic ability of the different indices. Changes in HS following treatment (ΔHS) were calculated at 6 weeks RECIST in a subset of patients receiving targeted therapies (n= 50). Results: Median age was 62 years (range: 28 – 80); median OS 4.3 months (range: 0.2 – 39); 34% male; 25% PS>1. Multivariate screening identified albumin <35 g/L, lactate dehydrogenase (LDH) >450 U/L and sodium <135mmol/L as the strongest independent predictors of OS (p<0.05). These were entered into a 3-point score (HS) that classifies patients as being at high risk (score 2-3) vs. low risk (score 0-1) of worse OS (HR= 5.8, p<0.001), PFS (HR= 2.7, p= 0.04) and 90 DM (OR= 5.9, p= 0.001). All scores predicted for OS on univariate analysis (p<0.05). On multivariate analysis HS performed best to predict OS (HR= 3.9, p<0.001 C-index score= 0.71), PFS (HR= 2.6 p= 0.04) and 90 DM with area under the ROC curve 0.71. ΔHS independently predicted for OS (p<0.001), with worsening of the score reflecting poorer OS. Prospective validation is ongoing. Conclusions: HS is a simple score that outperforms other prognostic indices. This can be used to select individuals for future studies as well as an additional marker of response.
Should patients with extrapulmonary small cell carcinoma receive prophylactic cranial irradiation? An Irish experience.
Authors: Naidoo Jarushka , Deady Sandra , Comber Harry , Calvert Paula
Published: March 2020

2609

Background: Extrapulmonary small cell carcinoma (EPSCC) is a rare disease. Management is based on small cell lung carcinoma, and experience of disease biology on single institution studies. Prophylactic cranial irradiation (PCI) is not routinely administered in EPSCC. This study investigates the role of PCI in EPSCC, by analyzing the incidence, treatment and survival of patients with brain metastases in a national cohort. Secondary aims were to investigate disease biology and epidemiology. Methods: An audit was undertaken of patients diagnosed with primary EPSCC from the National Cancer Registry of Ireland, between 1995-2007. The number of patients who developed brain metastases, received cranial radiotherapy, and their survival data, were documented. Patient and disease characteristics, treatment, and survival data stratified by stage and primary site, were tabulated. Results: 280 patients were found. 141 (50.4%) patients were male, and 139 (49.6%) were female. 186 (66.4%) patients had extensive stage disease, 65 (23.2%) had limited stage disease, and in 29 (10.3%) patients the stage was not known. 17 patients (5.4%) developed brain metastases, 11 of which (64.7%) received cranial irradiation. These patients had a median progression-free survival (PFS) of 5.2 months, and a median overall survival (OS) of 10.2 months. The commonest primary sites were the oesophagus (n=43, 15.4%), cervix uteri (n=17, 6.0%), bladder (n=13, 4.6%) and prostate (n=10, 3.6%). There were 315 events of distant metastasis, and 21 local recurrence events. The commonest metastatic sites were the liver, 110 (34.9%), lymph nodes 58 (20.7%), lung 38 (12.1%), and bone 36 (12.8%). The median PFS and OS for limited stage EPSCC was 8.8 months and 14.9 months, and 1.5 months and 2.3 months for extensive stage EPSCC. Conclusions: Brain metastases were uncommon in this cohort (5.4%), and patients lived longer, suggesting a low rate of mortality from brain metastases. PCI is thus probably not warranted in EPSCC. Prospective data are necessary to support PCI in EPSCC. This is one of the largest datasets on EPSCC, providing insights into disease biology.
Phase I study of BPM 31510 in advanced solid tumors: Updated analysis of a novel treatment with promising activity.
Authors: Hendifar Andrew Eugene , Chawla Sant P. , Quon Doris , Chua Victoria S , Fernandez Lita , Nagre Sandeep , Okunnu Marita , Chmielowski Bartosz , Singh Arun S. , Akmaev Slava , Chatman David , McCook John , Luan Shen , Sarangarajan Rangaprasad , Song Paul Y. , Narain Niven R
Published: March 2020

3015

Background: BPM 31510 is a novel small molecule that targets the metabolic machinery of the cancer microenvironment to reverse the aerobic glycolytic phenotype of cancer cells. Effector downstream signaling results in re-capitulation of BCL-2 mediated apoptosis and disruption in tumor vasculature by modulation of VEGF. (NR Narain et al., Proceedings of AACR Meeting Abstracts 2011). Methods: A standard 3+3 phase I, dose-escalation study design was used in patients with advanced solid tumors refractory to standard treatment. Primary objectives were establishment of the maximum tolerated dose (MTD) and safety/pharmacokinetic (PK) correlates. Secondary objectives included exploratory pharmacodynamics (PD) and preliminary efficacy (RECIST-1.1) of BPM 31510 in sequential cohorts of 3 to 6 pts. Results: At time of submission, 34 patients with advanced cancer who had failed multiple chemotherapeutic regimens had been enrolled in 7 dose cohorts (ranging from 5.6 mg/kg to 78.2 mg/kg). Patients received a median of 2 cycles (1-7). 2 patients have had grade 3 elevation in PT/INR, otherwise there have been no grade 3/4 treatment related toxicities to date. The pharmacokinetics of BPM 31510 are linear and there were no sex differences in the parameters normalized by dose and body surface area. Tmax and Cmax are associated with the end of the infusion. The values for t1/2 ranged from 2.18 to 13.3 hr, with little or no dependence of t1/2 on dose. Objective tumor responses have been noted at the dose of 58.6mg/kg with 1 partial response (myxoid liposarcoma) and 1 minor response (pleomorphic sarcoma). Six patients (19%) have had disease stabilization (> 4 months). Conclusions: Interim data from this phase I study indicate that BPM 31510 is well tolerated with no dose limiting toxicities to date. A partial response and minor response were observed and correlates with dose escalation. Taken together, there is strong rationale for further clinical development of this compound as an anti-cancer agent.
Phase I trial of the polo-like kinase (Plk) inhibitor volasertib (BI 6727) combined with cisplatin or carboplatin in patients with advanced solid tumors.
Authors: Dumez Herlinde , Gombos Andrea , Schöffski Patrick , Gil Thierry , Vulsteke Christof , Meeus Marie-Anne , Cescutti Jessica , Munzert Gerd Michael , Pilz Korinna , Awada Ahmad
Published: March 2020

3018^

Background: Volasertib (V) is a first in class, selective and potent cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Plk. This phase I study evaluates dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety and pharmacokinetics (PK) of V combined with cisplatin (Cis) or carboplatin (Ca). Methods: Sequential cohorts of patients (pts) received a single 2h infusion of V with Cis (arm A) or Ca (arm B) every 3 wks. Cis and Ca were given for up to 6 cycles (Cy); V was continued until progression or intolerance. MTD was the highest dose at which ≤1/6 pts experienced a DLT in Cy 1. MTD cohorts were expanded to 12 DLT-evaluable pts to further characterize safety. Results: As of January 11 2012, 61 pts (arm A: 30; arm B: 31) were treated. Pt characteristics were (arm A/B): median age 55/58 yrs, male 16/18 pts, ECOG PS 0: 13/14 pts, PS 1: 17/17 pts. Tumors included (pts): non-small cell lung cancer (15); sarcoma (8); colorectal cancer (6); melanoma (4); urothelial cancer (4); other (24). Pts received V + Cis for a median [range] of 3.5 Cy [1-6], V + Ca for 2 Cy [1-6] and V for 3.5 Cy [1-20] in arm A and 2 Cy [1-14] in B. PK analyses are ongoing. MTD was reached at V 300 mg + Cis 100 mg/m2 and V 300 mg + Ca AUC 6. Five partial responses (PR) were seen. 15/30 pts in arm A and 12/31 in B achieved stable disease (SD) or PR. PR or SD for >6 Cy was observed in 6/30 pts and 5/31 pts in arms A and B, respectively. Conclusions: In this phase I study, V in combination with Cis or Ca at full single-agent doses was well tolerated. Furthermore, several objective responses and cases of sustained SD were observed in heavily pretreated pts with advanced solid tumors.[Table: see text]
A phase Ib study of the Akt inhibitor GDC-0068 with docetaxel (D) or mFOLFOX-6 (F) in patients (pts) with advanced solid tumors.
Authors: Saura Cristina , Jones Suzanne , Mateo Joaquin , Hollebecque Antoine , Cleary James M. , Roda Perez Desamparados , Zhu Jin , Musib Luna C. , Patel Premal H. , Cervantes-Ruiperez Andres , Isakoff Steven J. , Soria Jean-Charles , Molife L Rhoda , Tabernero Josep , Bendell Johanna C.
Published: March 2020

3021

Background: Activation of the Akt pathway is observed in multiple tumors and may contribute to chemoresistance. GDC-0068 is an ATP-competitive small molecule inhibitor of all three isoforms of Akt; in a phase Ia study, it was well tolerated with maximum tolerated dose (MTD) of 600 mg daily (21 days on/7days off) and pharmacodynamic down-regulation of Akt signaling in tumors at doses ≥100 mg. In vitro, GDC-0068 shows synergism with cytotoxic agents. This phase Ib study defines the dose limiting toxicities (DLT), MTD, safety and pharmacokinetics (PK) of GDC0068 in combination with D and F. Methods: Using a 3+3 designeligible patients (pt) with advanced/metastatic solid tumors were treated with either D, 75 mg/m2 day 1 and GDC-0068 daily on days 2-15 of a 21 day cycle (Arm A); or F, bolus 5FU 400mg/m2, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2 all day 1, and infusional 5FU 2400mg/m2 for 46 hours and GDC-0068 daily on days 1-7 of a 14 day cycle (Arm B). PK sampling was performed in Cycles 1 and 2. Results: 23 pts have enrolled; Arm A (GDC-0068, mg): 100 (n=3), 200 (n=4), and 400 (n=5); Arm B:100 (n=6) and 200 (n=5). Median prior therapies = 3. GDC-0068-related adverse events in ≥ 10% of pts were diarrhea, nausea, vomiting, fatigue, and decreased appetite. All GDC-0068-related AEs were grade 1 or 2, except one grade 4 neutropenia in Arm A. No DLTs have been reported to date. Preliminary data show no alteration in the PK of GDC-0068, D or F compared to phase Ia or historical data. Two heavily pretreated pts with cervical and PTEN-loss colon cancers treated in Arm B demonstrated both RECIST partial response and tumor marker decrease by first CT evaluation. Conclusions: The combination of GDC-0068 with D or F is well-tolerated and shows early signs of anti-tumor activity. Dose-escalations continue.
A pharmacokinetic (PK) pharmacodynamic (PD) driven first-in-human study of the oral class I PI3K inhibitor CH5132799, in patients with advanced solid tumors.
Authors: Omlin Aurelius Gabriel , Spicer James F. , Sarker Debashis , Pinato David James , Agarwal Roshan , Cassier Philippe Alexandre , Stavraka Chara , Blanco Monsterrat , Suder Aneta , Allan Suzanne , Heaton Simon , Decordova Shaun , Pope Lorna , Prince Jenny , Noguchi Kohei , Jones Keith , Inatani Michiyasu , Shiokawa Rie , Banerji Udai , Blagden Sarah Patricia
Published: March 2020

3022

Background: The phosphatidylinositol 3-kinase (PI3K) pathway is a promising target in cancer. CH5132799 is a novel PI3K inhibitor, selectively inhibiting class I PI3Ks (α, β, δ and γ) with no inhibition of class II and III or mTOR, and with potent antitumor activity in preclinical studies (Tanaka et al, Clin Cancer Res; 17; 3272-81, 2011). First-in-human study objectives were determination of maximum tolerated dose (MTD), safety/tolerability, PK/PD and clinical activity (RECIST). Methods: A 3+3 dose escalation design was used. The initial dosing schedule of CH5132799(schedule A) was once a day (QD). Due to a relatively short half-life, a twice a day (BID) schedule (schedule B) was introduced. PK profiles were studied over 72 hours. PD analyses included quantification of various phosphoproteins in platelet rich plasma (PRP). Tumor assessments were performed at baseline and cycle 3 day 1 (C3D1) and FDG-PET scans at baseline, C1D8 and C3D1. Results: 29 patients (pts) with a variety of solid tumors have been treated (A 23 pts, B 6 pts, the most common tumors were breast, oesophageal, colorectal and ovarian). The starting doses were 2 mg (A) and 48 mg (B). The current doses being explored are 96 mg (A) and 72 mg (B). The most frequently reported drug-related AEs were Grade 1/2 diarrhea, nausea, fatigue, anorexia and anemia. 1 DLT (Grade 3 elevated LFT) was observed in a hepatocellular carcinoma pt at 48 mg BID. MTD has not yet been determined. The preliminary mean ±SD Cmax and AUC at 96 mg QD were 202±129 ng/ml and 1407±935 ng·hr/ml respectively, which is consistent with an efficacious exposure based on preclinical models. Some patients achieved the expected exposure at over 32 mg. From single dose of 48mg there was a reduction of phosphorylation of AKT in PRP after treatment, consistent with pathway modulation. A patient with clear cell ovarian cancer and a PIK3CA mutation treated at 48 mg BID showed >50% decrease in SUV on a PET scan at C1D8 and a 75% decrease in CA-125 at C2D1. 5 pts exhibited SD (>8 weeks). Conclusions: CH5132799 is well tolerated either QD ≤96 mg or BID ≤48 mg. Dose-escalation continues and updated safety/efficacy/PK/PD data will be presented.
A phase I study of Debio 0932, an oral HSP90 inhibitor, in patients with solid tumors.
Authors: Isambert Nicolas , Hollebecque Antoine , Berge Yann , van Ingen Hein , Brienza Silvano , Destaillats Alice , Soria Jean-Charles , Fumoleau Pierre , Delord Jean-Pierre
Published: March 2020

3026

Background: Debio 0932 is an oral second-generation heat shock protein 90 (HSP90) inhibitor that has shown extended tumor retention, blood-brain-barrier penetration, and promising anti-tumor activity both as monotherapy and combination against a broad range of tumors in pre-clinical models. Here we report the results of the dose escalation part of a phase I study in patients with advanced solid tumors or lymphoma (NCT01168752). Methods: This was an open-label, non-randomized, 3 + 3 dose-escalation study to determine the maximum tolerated dose (MTD) of Debio 0932 when given QD or Q2D during the first 30 days of treatment in patients with advanced solid tumours or lymphoma resistant to standard therapy. The starting dose in both treatment groups was 50mg. Doses were increased according to an algorithm based on observed toxicity and dose limiting toxicities (DLT). Tumor assessments were performed every 8 weeks. Results: Patient characteristics and results are summarized below. DLTs occurred at 1600mg in both dose groups. Adverse events (AE) were mostly CTCAE grade 1 or 2, with no apparent dose relationship. No ocular or cardiac toxicity was observed. The main reason for treatment withdrawal was progressive disease. Investigator-reported cases of SD and PR were observed. Conclusions: Debio 0932 mono-therapy was generally well tolerated and showed promising signs of efficacy in patients with advanced solid tumors. The recommended phase II dose, established at 1000mg QD, will be tested in an additional 30 patients in an ongoing expansion study. A phase I-II study of Debio 0932 in combination with standard of care in the first- and second-line treatment of NSCLC is planned. [Table: see text]