bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of PX-866 in recurrent glioblastoma.
Authors: Pitz Marshall W. , MacNeil Mary Valeria , Macdonald David R. , Kakumanu Ankineedu Saranya , Thiessen Brian , Tsao Ming Sound , Kamel-Reid Suzanne , Squire Jeremy , Sederias Joana , Walsh Wendy , Eisenhauer Elizabeth A. , Mason Warren P.
Published: March 2020

2051

Background: Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system. The majority of GBM have genetic changes that increase the activity of the phosphatidylinositol-3-OH kinase (PI3K) signal transduction pathway, critical for cell motility, proliferation, and survival. We present the interim results of PX-866, an oral PI3K inhibitor, in patients (pts) with recurrent GBM. Methods: Pts with histologically confirmed GBM at first recurrence after treatment with chemoradiation and adjuvant temozolomide are given PX-866 8 mg daily on this single-arm phase II study. MRI and clinical exam are done every 8 weeks to determine treatment response. The trial has a 2-stage design with dual endpoints of objective response and early progression (within 8 weeks). In Stage I, 15 pts are evaluated and if 0 responses and 10 or more early progressions are seen, enrolment will stop. Otherwise, Stage II will enrol another 15 pts for efficacy analysis. Tumour tissue is collected for analysis of potential markers of PI3K inhibitory activity (PTEN, EGFRvIII, PIK3CA mutations). Results: Seventeen pts have been enroled to date: 14 evaluable for response and 15 for toxicity. Median age was 54 years (range 35-70), with 7 females and 10 males. No pts had received treatment for recurrent GBM, and median time between initial diagnosis and study enrolment was 300 days (range: 113-447 days). Pts have received a median of one 8-week cycle of PX-866 (range: 1-4). Twelve pts have discontinued therapy, 9 due to disease progression and 3 due to grade 3/4 liver enzyme abnormalities. Other adverse effects have included fatigue (10 pts/1 grade 3), diarrhea (6 pts/3 grade 3), nausea (7 pts/0 grade 3), vomiting (6 pts/0 grade 3), lymphopenia (14 pts/3 grade 3). Stage I response data are premature; it is not yet known if the trial will continue to Stage II. Archival tissue is available on all patients and is undergoing analysis. Conclusions: This is one of the first trials of a PI3K inhibitor in pts with recurrent GBM. PX-866 has been relatively well tolerated. Stage I response data are premature; while it is not yet known if the criteria will be met to continue to Stage II, prolonged SD has been observed in some pts. The correlative biomarker assays underway will be important to understand this observation.
Effect of the integrin inhibitor cilengitide on TGF-beta signaling.
Authors: Weller Michael , Silginer Manuela , Goodman Simon L. , Hasenbach Kathy , Thies Svenja , Schraml Peter , Tabatabai Ghazaleh , Moch Holger , Tritschler Isabel , Roth Patrick
Published: March 2020

2055

Background: Glioblastoma is the most malignant form of intrinsic brain tumors. One of its characteristic features, angiogenesis, is mediated by the expression of integrins αvβ3 and αvβ5 on tumor-associated vasculature. Cilengitide is a synthetic peptide which inhibits ligand binding to the αvβ3 and αvβ5 integrins. The addition of cilengitide to the standard treatment regimen of radiochemotherapy in patients with newly diagnosed glioblastoma demonstrated promising results without significant toxicity which led to the initiation of a randomized phase registration III trial. Besides other functions, av-integrins can be involved in the activation of the cytokine transforming growth factor (TGF)-β which contributes to the malignant phenotype of glioma cells. Methods: Integrin expression was examined by immunohistochemistry and flow cytometry. The effects of cilengitide on TGF-β signaling in glioma cells were investigated by PCR, immunoblot and ELISA. Further assessments included reporter assays and glioma xenografts in nude mice. Results: The target integrins of cilengitide are expressed in glioblastoma blood vessels and tumor cells. Exposure to cilengitide results in detachment and reduced phosphorylation of Smad2 in most glioma cell lines, including stem-like glioma cells. Furthermore, exposure of glioma cells to cilengitide is associated with reduced TGF-β-mediated reporter gene activity. Smad2 phosphorylation, but not attachment, can be rescued by co-exposure to recombinant TGF-β. Cilengitide results in decreased TGF-β1 and TGF-β2 mRNA and protein expression and loss of transcriptional activity of the TGF-β promoter. Blocking antibodies to integrins αv, αvβ3 or αvβ5, or silencing of integrins αv, β3, β5 or β8 by RNA interference mimics the effects of cilengitide on TGF-β expression. Intracranial LN-308 glioma xenografts in nude mice display reduced pSmad2 levels in response to cilengitide. Conclusions: This study demonstrate a novel mechanism which may in part mediate anti-glioblastoma activity of cilengitide. These anti-TGF-β properties of cilengitide might be exploited in future clinical trials.
Phase II study to evaluate the efficacy and safety of rilotumumab and bevacizumab (BEV) in subjects with recurrent malignant glioma (MG).
Authors: Affronti Mary Lou , Desjardins Annick , Friedman Henry S. , Peters Katherine B. , Herndon II James E , McSherry Frances , Lipp Eric S , Brickhouse Alise , Massey Woody C , Miller Elizabeth , Cheshire Sprague , Cone Christina , Kalinowski Katherine H , Kim Jung-Young , Lay Harry H , Poillucci Victoria , Southerland Cindy , Tetterton Jill , Vredenburgh James J
Published: March 2020

2074^

Background: Prognosis of recurrent MG remains poor with a median survival of 3-9 months. Few evidence based treatments are available and response rates have been < 20% with 6 month progression–free survival (PFS) of < 9-16%. Poor prognosis is linked to the MG’s ability to induce vascular proliferation and invasion. MG’s have an abundance of neo-vascularization and high levels of vascular endothelial growth factor (VEGF). BEV, an antibody to VEGF, is the most active agent tested for recurrent MG with an overall response rate of 21.2%. Rilotumumab is a human monoclonal antibody that blocks human hepatocyte growth factor (HGF) and its receptor c-Met. HGF/c-Met signaling plays a role in MG tumorigenicity inducing angiogenesis and expression of additional angiogenic autocrine factors such as VEGF. The novel combination of rilotumumab (C-Met inhibitor) with an anti-VEGF drug (BEV) to block vascular invasion and tumor proliferation may demonstrate synergistic tumor growth inhibition. Methods: A two-stage design is used to assess radiographic response rate with > 3 responses required for the first stage. Secondary endpoints were PFS, overall survival (OS) and toxicity. Subjects with recurrent BEV-naïve MGs received rilotumumab at 20 mg/kg in combination with BEV at 10 mg/kg every two weeks ≥ 28 days after the last surgical procedure. A brain MRI was obtained after each 6-week cycle. Results: 15 of the 19 patients required for the first stage have been accrued. 10(67%) were male and ≥ 50 years. 73% received ≥ 2 prior regimens and 46% had ≥ 2 prior progressions. Best tumor response included 1(7%) complete response, 2 (13%) partial responses, 8 (53%) stable disease, 1 (7%) progressive disease with 20% (3/15) non-evaluable due to early termination secondary to toxicity. Median PFS was 3.9 months (95% CI: 1, 7.1) with a 6-month PFS of 25.4% (95% CI: 6.4, 50.5) and 6-month OS of 68.3% (95% CI: 34, 87.1). Toxicities are listed below. Maximum average weight increase over all cycles was 6.3 % (SD ± 6.09). Conclusions: Rilotumumab in combination with BEV is an active regimen in MG. Toxicity will need to be closely monitored. [Table: see text]
Phase II trial of bevacizumab and fotemustine in recurrent grade III gliomas.
Authors: Soffietti Riccardo , Trevisan Elisa , Bosa Chiara , Bertero Luca , Ruda Roberta
Published: March 2020

2075

Background: Bevacizumab (BV) has shown activity in recurrent grade III gliomas, and few data are available on the combination of BV and nitrosoureas. Fotemustine (FTM) is a nitrosourea with elevated lipophilic properties. Methods: In this phase II study patients with grade III gliomas recurrent after surgery, radiation therapy and concomitant/adjuvant temozolomide were eligible. The treatment consisted of an induction phase with BV at 10mg/kg intravenously on day 1 and 15 and FTM at 75mg/m2 intravenously on day 1 and 8, followed after a 3 week interval by a maintenance phase with BV 10mg/kg and FTM 75mg/m2 every 3 weeks until tumor progression or unacceptable toxicity. Patients had undergone clinical and MRI assessment 1 month after the start of treatment and thereafter every 2 months. The primary endpoint was progression-free survival at 6 months (PFS-6), whereas secondary end-points were response rate (RR), based on RANO criteria, progression-free survival (PFS), overall survival (OS), and safety. Results: From May 2008 to September 2011, 32 patients (males 23, females 9, median age 46) were enrolled. PFS-6, PFS -12 and median PFS were 31%, 7% and 5 months (range: 1-43+), respectively. OS-6, OS-12 and median OS were 78%, 37.8% and 8.6 months (3.5-43+), respectively. Response rates were as follows: 4 CR (12.5%), 12 PR (37.5%), 14 SD (44%) and 2 PD (6%). A significant neurological improvement was observed in 48% of symptomatic patients, being steroids reduced or withdrawn in 83% of patients. 29/32 (91%) patients have progressed and patterns of tumor progression were local in 20 (69%), multicentric in previous multicentrinc tumors in 5 (17%), gliomatosis-like in 3 (10%) and local plus leptomeningeal seeding in 1 (4%). 23/29 patients had salvage treatment after failure. Toxicities after BV were as expected; 5 patients interrupted FTM for grade III-IV myelotoxicity. We did not observe any additional toxicity from the combination. Conclusions: The combination of bevacizumab and fotemustine in grade III gliomas recurrent after standard treatment seems to have some activity.
High-dose chemotherapy (HDC) followed by autologous stem cell transplant (ASCT) for recurrent/progressive CNS lymphoma.
Authors: Welch Mary Roberta , Sauter Craig Steven , Matasar Matthew J. , Moskowitz Craig , Omuro Antonio Marcilio Padula
Published: March 2020

2089

Background: In two reports by Soussain et al, promising efficacy was observed in recurrent primary CNS lymphoma with induction cytarabine/VP-16 (CYVE) followed by HDC-ASCT (busulfan, thiotepa and cyclophosphamide [BTC]), but significant toxicity, mainly from CYVE, has limited widespread use. We report our experience with HDC-ASCT with alternative induction regimens. Methods: Retrospective review of pts with recurrent/refractory non-Hodgkin lymphoma (NHL) with CNS involvement treated with HDC-ASCT (2000-present). Results: Seventeen pts met inclusion criteria: med age= 58 (41-65); 9 were women; med KPS prior to transplant= 90 (range 70-100). At initial presentation, 10 had primary CNS lymphoma (ocular: 1); 7 had systemic NHL without CNS involvement; 1 had both systemic and CNS disease. Pts had been heavily pre-treated. Among those with PCNSL, high dose MTX was used in all pts and WBRT in 4. Two pts had received a previous HDC-ASCT. Among systemic NHL pts, various regimens were used, mostly R-CHOP(4), but also R-EPOCH (1), CVP (1), ICE (1) and CODOX-M (1). At CNS recurrence, pts received various induction regimens prior to HD-ASCT: high-dose methotrexate (MTX)-based chemotherapy (N= 13), cytarabine-based regimens (N=2), and other (N= 2). All pts achieved a CR or near CR prior to HDC-ASCT. Harvesting was obtained with G-CSF alone in 9 pts; 8 required plerixafor. Two pts failed mobilization N=15 received HDC-ASCT. The HDC consisted of BTC (N=13); 1 received BEAM and 1 received reduced intensity fludarabine, melphalan and alemtuzumab. Eight pts experienced a grade III or IV toxicity – most commonly fatigue, febrile neutropenia, and infection. One previously transplanted pt died from sepsis. With a med follow-up of 11 months, post-transplant med-PFS has not been reached. The 12m PFS was 92% (95% CI 56-98). Because no patient has progressed, the OS was identical to PFS. Conclusions: HDC-ASCT was a highly effective salvage approach in this population of recurrent/refractory CNS lymphoma. To reduce the risk of harvesting failure at the time of recurrence, harvesting stem cells at the time of initial treatment could be considered in pts with high risk for relapse.
Poor prognostic factors of post-CNS recurrence survival in breast cancer patients.
Authors: Castaneda Altamirano Carlos , Gomez Henry Leonidas , Pinto Joseph A. , Schwarz Luis Jesus , Vigil C. E. , Vallejos Carlos
Published: March 2020

2097

Background: Survival after the onset of metastases in the central nervous system is very short. However, some variables could indicate subsets of worse prognosis. Our aim was to determine the value of clinicopathological characteristics and prognostic scores in the post-SNC recurrence survival. Methods: We evaluated a retrospective cohort of 2597 breast cancer patients treated at the Instituto Nacional de Enfermedades Neoplasicas (Lima-Peru) between 2000-2005. Clinicopathological data was retrieved, RPA and GPA brain metastases prognostic scores were constructed and phenotypes were categorized according to the IHC expression in [HR+,HER2-], [Any HR, HER2+] and Triple Negative. Survival was calculated according to the Kaplan Meier methodology and cases were stratified by variables evaluated. The log-rank or Breslow tests were used when appropriate and multivariate analysis was done by the cox regression. A P<0.05 was considered statistically significant. Results: One hundred and fifty seven cases developed CNS metastasis, from which 23 developed leptomeningeal metastases. The post recurrence CNS survival was 0.405 years. There were not differences according to phenotype (P=0.102), histological grade (P=0.647), number of brain metastases (P=0.695) and metastases volume (P=0.155). We found statistic differences in regard to leptomeningeal carcinomatosis (present, 0.249ys vs absent 0.436ys; P=0.033); CSF infiltration (present, 0.115ys vs absent, 1.044ys; P=0.022); status of primary tumor (controlled, 0.501ys vs uncontrolled, 0.263ys; P<0.001); ECOG performance status (<2, 0.504ys vs ≥2, 0.288ys; P=0.030); and time from BC diagnosis to SNC metastases (<8 moths, 0.115 vs ≥8 months, 0.425ys; P=0.023). Cox regression identifies to CSF infiltration as statistically significant (HR=9.77; P=0.025). In regard to Prognostic scores, we found differences when cases were stratified according to RPA score (Class I, 0.564ys vs Class II, 0.455ys vs Class III, 0.288ys; P=0.049) and GPA score (0-1, 0.26ys vs 1.5-3, 0.455ys vs 3.5-5, 0,564; 0.048). Conclusions: RPA and GPA scores are more accurate to identify poor survival subsets in this group of patients than other tumor features (phenotype or histology).
A phase I study of 1-methyl-D-tryptophan in patients with advanced malignancies.
Authors: Soliman Hatem Hussein , Neuger Anthony , Noyes David , Vahanian Nicholas N. , Link Charles J. , Munn David , Streicher Howard , Sullivan Daniel , Antonia Scott
Published: March 2020

2501

Background: The indoleamine 2, 3 dioxygenase pathway (IDO) can create immune suppression and unresponsiveness to tumor antigens in tumor-bearing hosts. 1-methyl-D-tryptophan (1-MT) is an oral inhibitor of the IDO pathway, currently in development as an immune adjuvant for anti-tumor vaccines and chemotherapy. The primary goal of this trial is to determine the MTD and toxicity for oral 1-MT. Secondary endpoints include response rates, PK, serum tryptophan catabolites, circulating T-reg cells, and C reactive protein (CRP) levels. Methods: This phase I study utilizes a 3+3 design comprised of ten dose levels (200, 300,400,600,800,mg QD, 600, 800,1200,1600,2000mg BID). Inclusion criteria: patients with measurable metastatic solid malignancy, age ≥18, life expectancy >4 months, and adequate organ/marrow function. Exclusion criteria: chemotherapy in the past 3 weeks, untreated brain metastases, active autoimmune disease, or malabsorptive GI disease. Continuous toxicity monitoring early stopping rules were used. Results: At submission, 48 out of the planned 50 patients were accrued. MTD was not reached at 2000mg BID. At 200mg QD dose, 3 patients previously treated with active immunotherapy (ipilimumab, n=2, CD40-mAb, n=1) developed an autoimmune hypophysitis. Since IDO is closely linked to both CTLA-4 and CD40/CD40L pathways this was considered on-target effect. Subsequently, patients with prior immunotherapy were excluded and no additional treatment related G3-5 adverse events were observed. Five patients showed SD>6 months (2 melanoma, 2 sarcoma 1 colon) as well as some mixed responses were seen in some patients including regression of a liver visceral metastases. 1-MT plasma PK AUC and Cmax were proportional with dose. Cmax (~40 μM at 2000mg BID) is at 2.9 hours and the t1/2 is at 10 hours. Elevations in CRP levels and declines in T-reg cell counts were seen across multiple dose levels. Additional correlative data analysis is ongoing. Conclusions: The treatment was well tolerated and orally bioavailable. Biologic activity in terms of prolonged disease stabilization, induction of hypophysitis, and changes in T-reg levels and CRP were observed. Trials combining 1-MT with docetaxel and a dendritic cell vaccine are ongoing.
Isolation of human anti-MICA antibody from cancer patients responding to immunotherapies.
Authors: May Kenneth F. , Franz Bettina , Harvey Christopher , Hodi F. Stephen , Dranoff Glenn , Wucherpfennig Kai
Published: March 2020

2502

Background: Immunotherapy is a promising modality for the treatment of cancer, and elucidating the mechanism of action is crucial to guiding patient selection and developing future immunotherapeutic strategies. Engagement of the immune molecule NKG2D by the cancer antigen MICA is important for immune surveillance of many cancers. Tumors can evade immune surveillance by shedding cell surface MICA, which leads to dampening of anti-tumor immunity. Investigations by our laboratory revealed that patients responding to immunotherapy can mount antibody responses targeting MICA, which permits re-engagement of immunity. Methods: Patients with advanced cancer treated at our institution with immunotherapies (tumor cell vaccination, ipilimumab) were identified, including several with long-term clinical remissions. Plasma was analyzed for MICA reactivity to three distinct MICA alleles, and rare memory B cells reactive to MICA were isolated using tetramerized MICA protein. Immunoglobulin heavy and light chain variable domains were sequenced with single cell RT-PCR to generate recombinant monoclonal antibody. Results: Plasma from patients treated with immunotherapy revealed considerable inter-patient variation in reactivity to MICA. Patients with marked plasma reactivity (including several with sustained clinical remissions) were selected for isolation of rare memory B cells reactive to MICA. From these cells, we have generated a recombinant fully-human MICA-reactive monoclonal antibody that exhibits binding to a variety of MICA alleles. Conclusions: We have developed novel methods to analyze anti-MICA antibody responses and isolate rare memory B cells from cancer patients who gained significant clinical benefit from immunotherapy. This has facilitated the generation of fully human recombinant anti-MICA monoclonal antibody. To our knowledge, this is the first example of a specific antibody reactive to a cancer antigen isolated from a cancer patient responding to immunotherapy. As these antibody responses likely played a role in tumor destruction, these results inform the development of new antibody-based immunotherapies targeting the NKG2D-MICA pathway.
Myeloid-derived suppressor cell quantity prior to treatment with ipilimumab at 10mg/kg to predict for overall survival in patients with metastatic melanoma.
Authors: Kitano Shigehisa , Postow Michael Andrew , Cortez Czrina , Rasalan Teresa , Gallardo Humilidad F. , Panageas Katherine , Yuan Jianda , Wolchok Jedd D. , Lesokhin Alexander M.
Published: March 2020

2518

Background: Ipilimumab, an antibody that blocks the function of the immune inhibitory molecule cytotoxic T lymphocyte antigen 4 (CTLA-4), significantly prolongs survival in patients with metastatic melanoma. Approximately 30% of patients derive clinical benefit from therapy. Defining biomarkers of response to ipilimumab therapy would enable selection of patients more likely to respond and is relevant for both practicing clinicians and for clinical trial design. We performed a pilot correlative study evaluating myeloid derived suppressor cells (MDSC), a population of immune suppressive monocytic cells, as a biomarker of clinical outcome. Methods: Peripheral blood from 26 patients with stage IV melanoma treated with ipilimumab 10mg/kg every 3 weeks for 4 doses at our center, as part of an expanded access program (BMS CA184-045) was assessed for MDSC quantity (%CD14+,HLA-DRlow/- cells) pre-treatment, at week 7, week 12, and week 24 by flow cytometry. MDSC ability to inhibit T cell proliferation was tested using an in vitro suppression assay. Results: We found that lower MDSC quantity pre-treatment predicted for improved overall survival (Hazard ratio 1.07 (1.03, 1.11) p=0.002) and trended toward associating with clinical benefit measured at week 24 imaging (p=0.09). This effect was independent of pre-treatment or week 7 absolute lymphocyte counts (ALC) and pre-treatment LDH when evaluated in a multivariate model with ALC and MDSC quantity HR 1.10; 95% CI 1.04, 1.17 p=0.0006 and LDH and MDSC quantity HR 1.06; 95% CI 1.01, 1.11 p = 0.013. Furthermore, a general trend of increasing MDSC number by week 24 from the pre-treatment baseline was associated with patients that did not achieve clinical benefit. MDSC suppressed peripheral blood T cell proliferation as measured by CFSE dilution in response to anti-CD3 antibody stimulation. Conclusions: Pre-treatment MDSC quantity may predict clinical response following ipilimumab therapy. Further studies evaluating MDSC as a biomarker of ipilimumab therapy are warranted both retrospectively and prospectively in a broader group of patients.
Cyclin-A1 expression in acute myeloid leukemia stem cells and its representation as an immunogenic antigen that can be targeted by cytotoxic T cells.
Authors: Ochsenreither Sebastian , Majeti Ravindra , Loeb Keith , Stirewalt Derek L. , Keilholz Ulrich , Weissman Irving L , Greenberg Philip D
Published: March 2020

2523

Background: Targeted T-cell therapy represents a more specific and less toxic alternative to allogeneic stem cell transplantation for providing a cytotoxic anti-leukemic response to eliminate the leukemic stem cell (LSC) compartment in acute myeloid leukemia (AML). The aim of this study was to identify a leukemia-associated antigen that is both immunogenic and exhibits selective high expression in AML LSCs. Methods: Expression microarrays of leukemic and normal cells were used to identify suitable candidate genes. Cyclin-A1 appeared to be differentially expressed, and was further analyzed by quantitative RT-PCR, intracellular FACS staining, and immunofluorescence microscopy. T-cell clones specific for cyclin-A1 were generated by stimulation in vitro with an overlapping peptide library, followed by cloning of responding cells. Specificity of the clones was documented by intracellular IFNg and tetramer staining. Cytotoxicity was determined by chromium release and caspase-3 cleavage assays. Results: To identify target candidates with a suitable expression pattern, microarray data from LSCs, hematopoietic cells and healthy tissues were compared. Cyclin-A1 was found to be selectively expressed in LSCs of >50% of AML patients, but minimally expressed in normal tissues with exception of testis. Using dendritic cells and monocytes pulsed with a cyclin-A1 peptide library, T-cells were generated against eight cyclin-A1 oligopeptides. Two HLA A2-restricted epitopes were further characterized, and specific T-cell clones recognized both peptide-pulsed target cells and the HLA A2-positive AML line THP-1. Furthermore, cyclin-A1-specific CD8 T-cells lysed primary AML cells. Conclusions: Cyclin-A1, known to be important in meiosis, is expressed in AML LSCs and testis and can be targeted by T-cells. Thus, cyclin-A1 is the first prototypic LSC-associated leukemia-testis-antigen. Cyclin-A1 already has been shown to be leukemogenic in mice and to promote proliferation and survival in AML blasts. This pro-oncogenic activity, together with high expression levels and a multitude of immunogenic epitopes, make it a promising target for T-cell based therapy approaches.
EGF-based cancer vaccine for advanced NSCLC: Results from a phase III trial.
Authors: Crombet Ramos Tania , Neninger Elia , Acosta Soraida , Amador Rosa Mari­a , Mendoza Silvia , Santiesteban Eduardo Rafael , Rodriguez Pedro Camilo , Garcia Beatriz , Popa Xitlally , Mazorra Zaima , Viada Carmen , Gonzalez Gisela , Lage Agustin
Published: March 2020

2527

Background: The prognosis of patients with advanced non small cell lung cancer (NSCLC) remains dismal. Epidermal Growth Factor Receptor (EGFR) is overexpressed in epithelial tumors and its role in the development of NSCLC is widely proven. The EGF vaccine is a therapeutic cancer vaccine composed by recombinant Epidermal Growth Factor (EGF) conjugated to a carrier protein, P64K from Neisseria Meningitides and Montanide, as adjuvant. The vaccine is intended to induce antibodies against self EGF that would block EGF-EGFR interaction. Methods: A multicentric, randomized Phase III trial was designed to assess the efficacy, immunogenicity and safety of the EGF cancer vaccine in advanced NSCLC patients. Patients older than 18 years with histology or cytology proven NSCLC at stage IIIB and IV were enrolled in the trial. All patients received no less than 4 platinum-based cycles and achieved at least stable disease, before entering the trial. A low-dose of cyclophosphamide was administered 3 days before the first immunization. Then, patients received 4 quarterly immunizations followed by monthly re-immunizations. Control patients received best supportive care. Results: In total, 405 patients bearing stage IIIB/IV NSCLC were recruited in 21 sites. The vaccine was very well tolerated. The most frequent adverse events consisted in grade 1/2 injection site pain, fever, headache, vomiting and chills. The vaccine was immunogenic. Antibody titers against EGF significantly increased with vaccination and on the contrary, EGF concentration in sera showed a fast reduction after immunization. There was an inverse correlation between the anti-EGF antibody titers and the EGF concentration in sera. Baseline EGF concentration was a worse prognostic factor for the control patients and a predictive factor for vaccinated subjects. The overall survival was significantly better for vaccinated patients as compared to controls. There was a direct correlation between the antibody titers and survival. Conclusions: The EGF cancer vaccine was very well tolerated and significantly increased overall survival of the vaccinated patients. Baseline EGF concentration predicted survival benefit. The EGF vaccine is a new therapeutic option for advanced NSCLC patients.
Phase I clinical trial of a genetically modified and oncolytic vaccinia virus GL-ONC1 with green fluorescent protein imaging.
Authors: Corral Jaime Jesus , Young Anne Mary , Mateo Joaquin , Yap Timothy Anthony , Denholm Katie Ann , Shah Krunal Jitendrakumar , Tunariu Nina , Sassi Salem , Karapanegiotou Lena , Mansfield David , Molife L Rhoda , Harrington Kevin J. , De Bono Johann Sebastian
Published: March 2020

2530

Background: GL-ONC1 is a genetically engineered vaccinia virus attenuated by insertion of the RUC-GFP (Renilla luciferase and Aequorea green fluorescent protein fusion gene), beta-galactosidase (lacZ) and beta-glucuronidase (gusA) reporter genes into the F14.5L, J2R (thymidine kinase) and A56R (hemaglutinin) loci. A phase I clinical trial of iv GL-ONC1 was pursued to evaluate safety, tolerability, tumour delivery, neutralizing antibody development and anti-tumour activity. Methods: GL-ONC1 was administered to patients with advanced solid tumours at escalating doses (1×105, 1×106, 1×107, 1×108, 1×109, 3×109 plaque-forming units (pfu) on day 1; 1.667×107 and 1.667×108 pfu on day 1-3 of a 28-day cycle) using a 3+3 dose escalation design. Green fluorescent protein (GFP) imaging was performed on skin rash and mucosal tumour lesions at baseline and after each cycle. Optional tumour biopsies were obtained for pharmacodynamic and viral delivery evaluation. Results: 27 patients (21 males, median age 60 years) were treated. One of six patients at the 1x109 pfu dose level developed a dose-limiting, grade 3 rise in aspartate transaminase levels after a single infusion. Other reported adverse events (grade 1/2) included pyrexia (21), musculoskeletal pain (9), fatigue (8), nausea (7), and vomiting (4). Two patients developed skin rash during the first week of treatment, which appeared green by GFP and were positive to viral plaque assay (VPA). VPA of blood, urine, stool and sputum were negative for viral shedding in all but one patient who had positive shedding for 11 days. Increased neutralizing antibody titres were detected in all tested patients apart from one. Best response by RECIST was stable disease at 48 weeks (1), 24 weeks (3) and 8-12 weeks (5). A patient with squamous cell carcinoma of the tongue had a biopsy after 4 cycles which showed positive IHC staining of vaccinia virus. This is the first time that a virus is shown to be delivered to solid tumour after iv delivery. Conclusions: GL-ONC1 administered iv is well tolerated, with documented colonisation in patient tumour, and preliminary evidence of anti-tumour activity.
A first-in-human, phase I safety and pharmacokinetic study of genz-644282, a non-camptothecin topoisomerase I inhibitor, in patients with advanced solid tumors.
Authors: Han Hyo S. , Tan Antoinette R. , Weiss Glen J. , Sullivan Daniel , Strosberg Jonathan R. , Collins Sara , Moss Rebecca Anne , Wu Jingyang , Ewesuedo Reginald , LoRusso Patricia
Published: March 2020

2534

Background: The approved topoisomerase I (TopI) inhibitors (irinotecan and topotecan) are camptothecin derivatives. The lactone ring structure of camptothecins negatively impacts their clinical potential.Genz-644282 is a novel non-camptothecin that induces TopI-DNA cleavage complexes at similar as well as unique genomic positions; that are more persistent. This study was designed using a pharmacokinetic-pharmacodynamic (PK-PD) model to predict the maximum tolerated dose (MTD). Methods: A PK-PD relationship of Genz-644282 to inhibit tumor growth was derived (Simeoni, Can Res 2004). Using an accelerated titration design, cohorts of 1, 3 or 6 patients received 3 weekly doses of Genz-644282 on a 28 day schedule starting with 0.5 mg/m2. After MTD on the 28 day schedule was exceeded, 21 day schedule was initiated. Results: 49 patients (N=44 data available: 26M :18F) were dosed. Tumor types were colorectal (15), breast (5), small cell lung (SCLC 3), non-small cell lung (4), others (17). As predicted from the PK-PD model 8 cohorts were evaluated on the 28 day schedule before defining the MTD. The MTD was 8 mg/m2 and 9 mg/m2 for the 28 day and 21 day schedules, respectively. Dose limiting toxicities that determined the MTD were: gr 4 thrombocytopenia (n=2); gr 2 thrombocytopenia (n=1) and gr 4 neutropenia (n=1) both of which resulted in ≥72h delays in initiating cycle 2. Treatment emergent adverse events (>10%) were nausea (45%), fatigue (39%), anorexia (32%), anemia (27%), vomiting (23%), thrombocytopenia (18%), diarrhea (16%), dehydration (16%), hyperglycemia (16%), cough (16%), dyspnea (14%), depression (11%) and hyponatremia (11%). Efficacy data suggest 2 responders with SCLC (1 minor response;1 complete response), and 2 patients (breast, gastric) with stable disease (≥ 6 months). PK data show a Genz-644282 half-life of approximately 50 h, a linear dose-exposure relationship, and no accumulation in between doses. Conclusions: Genz-644282 is a non-camptothecin TopI inhibitor in phase I development with ongoing expansion phase. The emerging pk, efficacy and safety data are suggestive of a distinct clinical profile of Genz-644282 from the camptothecins.
Phase Ib study of plitidepsin (APL) with gemcitabine (GEM) in refractory solid tumors and lymphoma patients.
Authors: Stein Mark N. , Ribrag Vincent , Gomez-Roca Carlos Alberto , Salles Gilles A. , Carella Angelo Michele , Gyan Emmanuel , Szyldergemajn Sergio A. , Kahatt Carmen Maria , Luque Manuel , Extremera Sonia , De Miguel Bernardo , Fernandez-Garcia Eva , Soria Jean-Charles
Published: March 2020

2539

Background: Combination chemotherapy (CT) regimens may improve the outcome of patients with advanced metastatic disease. APL (a marine-derived cyclodepsipeptide) is a cytotoxic agent that induces apoptosis by JNK-pathway activation and increased oxidative stress; it has also shown anti-angiogenic properties in vitro. GEM has a different mechanism of action and toxicity profile from APL, making this combination appropriate for clinical testing. Moreover, APL has been shown pre-clinically to potentiate the anti-tumor effect of GEM. Methods: Patients with ECOG-PS ≤ 1 received escalating doses of APL/GEM (1.8/750, 1.8/1000, 2.4/1000 and 3.0/1000 mg/m2) on days 1, 8 and 15 every four weeks. The primary objective was to determine of the maximum tolerated dose (MTD) and the recommended dose (RD) for APL/GEM. Secondary objectives included characterization of safety profile, pharmacokinetics (PK) and anti-tumor activity of APL/GEM. Results: 34 patients were included and 33 treated (23 solid tumors and 11 lymphomas) with a median age of 59 years (r: 28–86), median prior CT lines 3 (r:1-7) and a median of 2 cycles (r:1-12). Relative dose intensity was 66.7% (r: 37.7-85.7%) and 80.9% (r: 56.1-100.6%) for APL and GEM, respectively. The MTD was 3.0/1000 mg/m2, as 2/6 patients experienced dose limiting toxicities (DLTs) [grade (G) 4 thrombocytopenia and 2 missed doses due to G2 ALT/AST]. The RD was 2.4/1000 mg/m2, with no patients experiencing DLTs. Adverse events (AEs) were mainly G 1-2 anemia, thrombocytopenia and ALT/AST increase. Six patients with solid tumors had stable disease (SD) ≥ 3 months, one patient with NK T-cell lymphoma had a complete response, a patient with Hodgkin disease (HD) had a partial response and three other patients with HD had SD ≥ 3 months with tumor decrease at the RD. No relevant drug-drug interaction was observed for the dose levels tested. Conclusions: APL/GEM at the RD can be safely combined. Objective responses were observed in patients with HD and NK T-Cell lymphoma. Further studies of this combination in lymphoma are warranted.
A multicenter phase II neoadjuvant trial of bevacizumab combined with docetaxel plus carboplatin in the treatment of triple-negative breast cancer: Korean Cancer Study Group (KCSG-BR 0905, NCT 01208480).
Authors: Kim Hye Ryun , Jung Kyung Hae , Im Seock-Ah , Im Young-Hyuck , Kang Seok Yun , Park Kyong Hwa , Lee Keun Seok , Lee Soohyeon , Ahn Jin-Hee , Kim Sung-Bae , Lee Kyung-Hun , Park Yeon Hee , Ahn Jin Seok , Kim Ku Sang , Lee Hye Yoon , Ro Jungsil , Park Byeong-Woo , Kim Seung Il , Sohn Joo Hyuk
Published: March 2020

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Background: Triple negative breast cancer (TNBC) is dismal disease that is ineligible for endocrine or anti-HER2 therapy. We have conducted a phase II neoadjuvant trial to evaluate efficacy and tolerability of bevacizumab combined with docetaxel plus carboplatin in TNBC. Methods: Women with a histologically confirmed stage II or III TNBC were eligible. Hormone receptors and HER2 negativity were confirmed by immunohistochemistry and/or fluorescence in situ hybridization. Patients received 6 cycles of docetaxel 75 mg/m2, carboplatin AUC 5, and bevacizumab 15 mg/kg on day1 every 21 days. Bevacizumab was omitted in the last cycle to avoid wound complication. The primary endpoint was pathologic complete response (pCR) rate in both breast and axillary lymph node and secondary endpoints were clinical response rate, toxicity profiles, and breast conserving surgery (BCS) rate. Results: Forty-five TNBC patients were recruited from 7 institutes in the Korean Cancer Study Group (KCSG) between October 2010 and August 2011. The median age of the patients was 45 years (30-72 years). The T1, T2, and T3 were 4.4 %, 68.9 %, and 26.7 %, respectively and axillary lymph node was positive in 80% by breast MRI. Among 45 patients, 44 patients completed 6 cycles of therapy followed by surgery and one patient was withdrawn due to patient’s refusal of further therapy after 3rd cycle. The pCR rate was 42.2 % (19/45) and clinical response rate was 95.5 % (43/45) (CR, n= 6; PR, n=37; SD, n=1; not evaluable, n=1) based on RECIST criteria 1.1. BCS was undertaken in 77.7 % (35/45). The grade 3 or 4 adverse events were neutropenia (38), febrile neutropenia (4), vomiting (3), nausea (2), anemia (1), thrombocytopenia (1), stomatitis (1), gastrointestinal bleeding (1), and increased ALT (1). Only one patient experienced delayed wound healing after breast surgery. Conclusions: Bevacizumab in combination with docetaxel and carboplatin as neoadjuvant treatment provided an encouraging pCR rate (42.2 %) and a negligible wound healing problem after surgery. The adverse events were manageable.
Clinical importance of including new and nontarget lesion assessment of disease progression (PD) to predict overall survival (OS): Implications for randomized phase II study design.
Authors: Mietlowski William Leonard , Bao Weichao , Wood Patricia Ann , Williams Denise E , El-Hashimy Mona , Sarr Celine , Stein Andrew Marc , Shi Michael , Weber Dirk , Habr Dany , Porro Maria Grazia
Published: March 2020

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Background: Fridlyand (2011) retrospectively compared PFS vs. change in tumor burden as a primary endpoint in phase II non-small cell lung cancer (NSCLC) trials to inform phase III decision making and found the use of PFS was superior. Since the classic tumor burden model only uses measurements of target lesions, we investigated whether the model could be strengthened by incorporating new and non-target lesion progression. The ability to use a strong tumor burden model has the benefit of potentially earlier decision making and considerable timeline savings. Methods: We analyzed five phase III trials of combination chemotherapy ± targeted therapies with an OS primary endpoint: 1st, 2nd line NSCLC (ATTRACT-1, -2), 1st, 2nd line colorectal carcinoma (CONFIRM-1, -2), and 2nd line ovarian cancer (EPO906A2303). We applied Cox’s proportional hazards model to OS using the covariates of baseline tumor burden, 1st tumor assessment percentage change from baseline, new lesions, and non-target PD. Results: See table. Conclusions: We show that predictive models for OS should consider new and non-target lesions for PD, as well as target lesion tumor burden, findings independently corroborated by Suzuki (2011). We propose a longitudinal rank-based randomized phase II design, ranking a patient’s risk of death, differentially weighting PDs by type and time of PD, and percentage change in tumor burden. This may be more informative for phase II decision making for phase III trials based on OS, than PFS which only uses time of PD. Further studies with other tumor types and treatment modalities are warranted. [Table: see text]
Predictive model for survival and toxicity in early-phase trials in hematology.
Authors: Jamal Rahima , Chen Bingshu E , Hristova Gergana , Seymour Lesley , Assouline Sarit E.
Published: March 2020

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Background: Strict criteria are used to limit toxicity for patients (pts) enrolled in phase I/II clinical trials, but the ability to survive beyond 12 weeks, a common inclusion criterion, is subjective and error-prone. A prognostic score with 3 variables was designed and validated as an independent predictor of OS in pts with solid tumors included in phase I trials (Arkenau, JCO 2009). We examined the ability of objective measures to predict OS and risk of grade ≥3 toxicity in pts with hematologic malignancies enrolled in early-phase trials. Methods: A retrospective analysis was conducted on 290 pts in Phase I (79 pts) and II (211 pts) trials from the NCIC - Clinical Trials Group and our institution from 1995 to 2009. Only pts with survival data up to 90 days were included. Univariate model (UVA) was used to identify factors significantly associated with OS. A Cox proportional hazards model (MVA) included all factors identified from the UVA. Six prognostic factors were identified in the MVA, and each assigned a score of 0 or 1. Pts were categorized as high or low risk based on the total scores that they received, ≥3 were assigned to the high risk group, and a ≤2 to the low risk group. Kaplan-Meier method was used to generate the survival distribution for the high and low risk groups. Multivariate logistic regression was used to identify the risk factors for grade ≥3 toxicity. Results: The overall median survival was 238 days (95% CI 237 to 331), and 27% of pts had grade ≥ 3 toxicity. In the MVA, albumin (alb), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), lymphocytes, platelets (plts) and diagnosis were significantly associated with OS. Pts in the low risk group had a median survival of 10.6 months, relative to 2.4 months among pts in the high risk group. Survival at 90 days was 80% in lower risk vs. 36% in the high risk group. In addition, the MVA for toxicity showed that alb, ALP, LDH, plts and performance status were significantly associated with grade ≥3 toxicity. Conclusions: Our model predicts OS, 90 day survival and risk of grade ≥ 3 toxicity among pts with hematologic malignancies entered in Phase I/II trials. Future work will include a linear predictor score based on MVA to refine the prediction model. The model will also be validated using another dataset.
Difference between duration of treatment (DOT) and progression-free survival (PFS) as a marker of unbalanced censoring.
Authors: Amiri-Kordestani Laleh , Wilkerson Julia , Balasubramaniam Sanjeeve , Bates Susan Elaine , Fojo Antonio Tito
Published: March 2020

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Background: In the conduct of randomized trials Kaplan and Meier envisioned rates of censoring as similar between arms, providing accurate assessment of clinical trial results. Censoring is used when patients withdraw consent, leave study due to toxicity, or reach data cut-off without disease progression or death. Censoring can lead to erroneous conclusions as it can be either beneficial or detrimental to the arm under study. Such censoring can also explain how a statistically valid difference in PFS “disappears” when overall survival (OS) is examined. We hypothesized that censoring, especially that due to toxicity, would lead to a discrepancy between DOT and PFS since two different patient populations would be scored. Methods: We reviewed all phase III randomized studies of drugs approved by FDA since 2005 for pts with metastatic solid tumors, looking for DOT and PFS. We used standard statistical analyses using SAS. Results: We identified 55 Phase III studies conducted with abiraterone, axitinib, bevacizumab, cabazitaxel, cetuximab, eribulin, erlotinib, everolimus, ipilimumab, ixabepilone, lapatinib, panitumumab, pazopanib, sorafenib, sunitinib, temsirolimus and vandetinib. DOT was not provided in 27%. Forty-four comparisons (88 arms) were included in the analysis. The median PFS, DOT, delta PFS (difference in PFS between experimental and control arms) and delta DOT were: 161, 126, 51 and 36 days, respectively. The slopes of PFS vs DOT and delta PFS vs delta DOT were 1.16 and 1.03, respectively close to the ideal of 1.0. Five trials fell above the 90% CI boundary with delta PFS/delta DOT of 3 to 36, including two everolimus studies (PNET and breast cancer) two sunitinb studies (RCC and PNET) and one bevacizumab study (E2100, breast cancer). Conclusions: PFS and DOT as well as delta PFS and delta DOT should be concordant. The most likely explanation for a discordance between these values is toxicity-driven censoring and its occurrence raises concerns regarding the degree of efficacy. A greater utilization of “Time to Treatment Failure”, an endpoint that includes toxicity in its definition would be valuable in oncology trials, particularly those with high levels of toxicities.
Recommendation of dose banding of cytotoxics according to pharmacokinetic criteria.
Authors: Chatelut Etienne , White-Koning Melanie , Mathijssen Ron H.J. , Baker Sharyn D. , Sparreboom Alex
Published: March 2020

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Background: Dose-banding has been recently suggested in order to optimize chemotherapy preparation. Ranges (or bands) of body surface area (BSA) are predefined. The individual dose of a particular patient is calculated according to a single BSA value per band, usually the mid-point of the BSA band in which the actual BSA of the patient lies. Thanks to this simple procedure, chemotherapy provision can be rationalized and chemotherapies can be prepared in advance for drugs with sufficient long-term drug stability. The primary purpose of dose-banding is to reduce patient waiting time and improve capacity planning of the pharmacy production, but additional benefits can also be found, such as reduced potential for medication errors, reduced drug wastage, and prospective quality control of preparations. The objective of this analysis was to compare dose-banding to individual BSA-dosing (current practice) according to pharmacokinetic (PK) criteria. Methods: Dose-banding was defined according to three bands of BSA: BSA<1.7m², 1.7m²≤BSA<1.9m², and BSA≥1.9m² for which the values of 1.55m², 1.80m², and 2.05m² were allocated, respectively. By using individual actual values of clearance of six drugs (cisplatin, docetaxel, paclitaxel, doxorubicin, topotecan, and irinotecan) from a total of 1,206 adult cancer patients, the AUCs corresponding to the two dosing methods were compared to a target value of AUC for each drug. Results: Over all 6 drugs, by using dose-banding the percent change of individual dose in comparison with BSA dosing ranged between -14% and +22%. In terms of capacity to attain the target AUC, there was no significant difference in precision when using dose-banding as compared to BSA-dosing for all drugs except paclitaxel (precision of 23.2% versus 21.8%, respectively). For all drugs including paclitaxel, distributions of AUC values were very similar with both dosing methods. Conclusions: For these 6 drugs and maybe others, dose-banding may be implemented without any risk of increasing interindividual plasma exposure. Dose-banding would make it possible to anticipate chemotherapy preparation and analytical control without any delay for the patients.