bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating myeloid-derived suppressor cells (MDSC) and correlation to poor prognosis, Th2-polarization, inflammation, and nutritional damages in patients with gastric cancer.
Authors: Gonda Kenji , Shibata Masahiko , Kanke Yasuyuki , Yazawa Takashi , Monma Tomoyuki , Suzuki Satoshi , Nakamura Izumi , Ohki Shinji , Shimura Tatsuo , Ohto Hitoshi , Takenoshita Seiichi
Published: March 2020

3063

Background: Recent studies have shown that myeloid-derived suppressor cells (MDSC), which have been identified in most patients, are potent suppressors of T cell activation. MDSC have been reported to be correlated with tumorigenesis and the progression of tumors. We have previously reported significant correlations of MDSC with nutritional damage and inflammation in many types of cancer. In this study the quantitative detection of MDSC in peripheral blood was analyzed in the prognosis in patients with gastric cancer. Methods: We tested PBMCs from 29 preoperative patients with gastric cancer and 18 healthy volunteers using flow cytometric analysis (CD14-CD11b+CD33+). Markers for nutritional status (serum levels of total protein), inflammation (NLR: neurphil/lymphocyte ratio, serum levels of vascular endothelial growth factor: VEGF) and Th2-polarization (PBMC’s production of IL-6 and IL-10) were measured in this study. The prognosis of the patients was assessed by Kaplan-Meier tests for correlation with levels of MDSC. Results: MDSC levels in 29 preoperative patients with gastric cancer were significantly higher than in normal volunteers. These levels were not associated with pathological characteristics. However they were significantly correlated with the production of IL-6 and IL-10, VEGF levels and NLR. A significant inverse correlation with levels of total protein was obtained. MDSCs were increased in stage IV patients compared with healthy volunteer and 2-year survival rate of the patients with higher levels of MDSC (> 1.104%PBMC) was significantly poorer (median OS, 498 vs 473 days; p = 0.048), while there was no significant difference in patients with stages I, II, and III. Conclusions: These data suggest that increased MDSC is an effective biomarker for immunosuppression due to Th2-polarization, nutritional impairment, systemic inflammation and poor prognosis in advanced patients with gastric cancer.
Biologic meshes in cancer patients: A double-edged sword—Differences in production of IL6 and IL12 caused by acellular dermal matrices in human immune cells.
Authors: Guenthner-Biller Maria Margarete , Enders Sabine , Knabl Julia , Engelstaedter Verena , Duewell Peter , Rack Brigitte Kathrin , Mayr Doris , Jeschke Udo , Dian Darius
Published: March 2020

3064

Background: Acellular dermal matrices (ADM) have been used in different fields of surgery for almost 20 years. In 2005 Breuing et al first described its use in breast cancer patients. It is assumed that it is safe to use in an oncologic setting, but data from controlled studies are still missing. Because of its lack of cells ADM are considered not to cause an immune reaction. With increasing knowledge about the importance of immunology in breast cancer more information about ADM on different immune cell populations is needed. IL6 and IL12 are two central cytokines and key regulators of immune supression and activation. Methods: Strattice (ST; LifeCell) CollaMend (CM; Bard Davol), Biodesign (BD; Cook Biotec) as well as TiLoop a synthetic mesh (TL; pfm medical) were used in this study. We isolated myeloid dendritic cells (MDC), untouched plasmacytoid dendritic cells (PDC), naïve B-cells and CD8+ T-cells using the MACS System and co-cultered them with the biologic meshes or TL. For positive controls, we used CpG ODN 2216 3 µg/ml and LPS in a concentration of 100 ng/ml. Cytokine concentration of IL12p70 and IL6 were determined after seven days by using sandwich Elisa sets. Statistical significance was determined by the nonparametric Friedman-Test. The single hypothesis was calculated with a paired Wilcoxon Test. Results: There was a highly significant difference between the different ADM and TL in the immunologic response. The statistical difference for IL 6 was p= 0.0006131 for B cells and p= 0.00418 for T cells between TL and ADM. ST also caused significantly more IL6 than CM and BD. We found similar differences in IL 12 with p= 0.00194 for B cells and p= 0.003636 in T cells in regard to the difference between TL and ADM. For IL 12 there was no statistical difference between the ADM. We didn´t see any significant differences in the cytokine profile between the various ADM/TL in the MDC and PDC subpopulations. Conclusions: Despite the assumed lack of immune answer to ADM, immune cells reacted in our study with significantly different cytokine profiles. These findings can have implications regarding the activation or suppression of effector cells in a cancer patient.
Multicenter trial for assessing tolerability of combination therapy with cisplatin, irinotecan, and PSK in extensive-stage small-cell lung cancer: RNCLC-01 study.
Authors: Kashii Tatsuhiko , Miwa Toshiro , Kajiura Shinya , Kinoshita Ichiro , Oizumi Satoshi , Nakagawa Ken , Nagase Seisuke , Akashi Yusaku , Takada Minoru , Iwamoto Yasuo , Tsuboi Masahiro ,   Research Network for Chemotherapy of Lung Cancer
Published: March 2020

3072

Background: Polysaccharide-K (PSK, Krestin) is a protein-bound polysaccharide, extracted from cultured mycelium of Coriplus versicolor, and is associated with immunostimulatory activity. Although combination use of PSK with chemotherapy has been shown to prolong the response period in patients with small-cell lung cancer (SCLC), the efficacy of PSK in combination chemotherapy including cisplatin has been less examined. We examined safety and efficacy of combination therapy with cisplatin, irinotecan, and PSK in extensive-stage (ED) SCLC. Methods: Eligible pts included: histologically confirmed ED-SCLC without prior chemotherapy, age under 75 years, ECOG performance status ≤ 1, with evaluable disease and adequate organ function. Treatment: irinotecan 60 mg/m2 on days 1, 8, and 15 and cisplatin 60 mg/m2 on day 1 every 4 weeks for 4 to 6 courses, and oral PSK 3,000 mg/body daily. The treatment with PSK was continued after the end of cisplatin and irinotecan administrations, and was combined as a part of second-line therapy after exacerbations. Results: Between January 2008 and July 2010, 17 patients were enrolled, and the efficacy and prognosis were evaluated in 15 of 17 patients. Response rate was 66.6%, one-year survival rate was 66.6%, and two-year survival rate was 33.2%. The major toxicities were diarrhea and myelosuppression, and the common toxicity of PSK-containing combination chemotherapy was not observed. Conclusions: The combination chemotherapy with cisplatin, irinotecan, and PSK was effective and well tolerated in ED-SCLC. Clinical trial information: NCT00546130.
VTX-2337, a TLR8 agonist, plus chemotherapy in recurrent ovarian cancer: Preclinical and phase I data by the Gynecologic Oncology Group.
Authors: Monk Bradley J. , Brady William E. , Lankes Heather A. , Facciabene Andrea , Manjarrez Kristi , Hershberg Robert Mark , Fracasso Paula M. , Bell-McGuinn Katherine M. , Walker Joan L. , McCourt Carolyn K. , Aghajanian Carol , Coukos George
Published: March 2020

3077

Background: Given the absence of clear molecular drivers in high-grade serous ovarian cancer, targeting the tumor micro-environment with immunotherapy is an emerging approach. VTX-2337 is a potent, small molecule agonist of TLR8 which stimulates the innate immune response, and was previously evaluated as a single agent in cancer patients. We report data combining VTX-2337 with chemotherapy in recurrent ovarian cancer. Methods: VTX-2337 was tested in an ovarian cancer mouse model with an intact human immune system. Additionally, an open-label phase I study of VTX-2337 + pegylated liposomal doxorubicin (PLD) in recurrent ovarian cancer (NCT01294293, N=13) was performed. PLD (40 mg/m2) was given on day 1 of a 28-day cycle. Three dose levels of VTX-2337 (2.5, 3.0, 3.5 mg/m2, N=13) were serially tested and given by SC injection on days 3, 10, and 17. VTX-2337 (3.0 mg/m2) was also tested with paclitaxel (80 mg/m2; N=7) given on days 1, 8, and 15 of a 28 day cycle. Responses were evaluated using RECIST1.1. PK and serum immune cytokines were measured. Patients remained on therapy until toxicity or progression. Results: In the mouse model, clinical responses to PLD were increased. Innate immunity along with CD8+ T cell responses were also induced. In humans, treatment with PLD + VTX-2337 increased various cytokines and chemokines (G-CSF, MCP-1, MIP-1β, TNF-α). The PK of PLD was not affected by VTXE2337. The combination was well tolerated with no DLTs. AEs consisted of those seen with single-agent PLD (Gr 3/4 toxicities, N=6) or VTXE2337 (Gr 1/2 injection site reaction, transient fever, flu-like symptoms). There was 1 partial response (13%) and 63% had stable disease. Paclitaxel + VTX-2337 was also well tolerated. Conclusions: VTX-2337 enhances the effect of PLD in a preclinical model of ovarian cancer, and the combination is well-tolerated in patients. Clinical data and biomarkers consistent with immunostimulation, provide rationale for the on-going randomized, placebo-controlled, phase II trial comparing PLD vs PLD + VTX-2337 (GOG-3003, NCT01666444). Clinical trial information: NCT01666444.
Targeting myeloid-derived suppressor cells and the PD-1/PD-L1 axis to enhance immunotherapy with anti-CEA designer T cells for the treatment of colorectal liver metastases.
Authors: Burga Rachel A. , Thorn Mitchell , Nguyen Cang T. , Licata Lauren , Espat N. Joseph , Junghans Richard Paul , Katz Steven C.
Published: March 2020

3079

Background: Immunotherapy for colorectal cancer liver metastases (CRCLM) is limited by the intrahepatic immunosuppressive environment mediated in part by myeloid derived suppressor cells (MDSC), which expand in response to tumor. T cell suppression can be mediated by programmed death ligand-1 (PD-L1, CD274) on MDSC binding to programmed death-1 (PD-1, CD279) on T cells. We hypothesize blocking PD-L1 will improve adoptive cellular therapy efficacy for CRCLM through inhibition of MDSC-mediated T cell suppression. Methods: “Designer” T cells (dTc) were produced from activated murine splenocytes transduced with chimeric antigen receptor (CAR) specific for CEA. C57BL/6 mice were injected with CEA+ MC38 tumor cells via spleen, and liver MDSC (CD11b+Gr1+) were purified with immunomagnetic beads after two weeks. MDSC were co-cultured with stimulated dTc with or without in vitro PD-L1 blockade. Results: MDSC expanded 2.4-fold in response to CRCLM, and expressed high levels of PD-L1 (63.8% PD-L1+). PD-L1 was equally expressed on both monocytic (CD11b+Ly6G-Ly6C+) and granulocytic (CD11b+Ly6G+) MDSC subsets (43.6% PD-L1+ and 27.9% PD-L1+, respectively). Expression of related ligand, PD-L2 was found to be negligible in both subsets. The cognate inhibitory receptor, PD-1, was expressed on dTc (23.8% PD-1+) and native T cells (37.3% PD-1+). Increasing endogenous T cell expression of PD-1 significantly correlated with MDSC expansion (r=0.9774, p<0.0001) in response to CRCLM. Co-culture of dTc with MDSC demonstrated the suppressive effect of MDSC on dTc proliferation which was abrogated with in vitro targeting of PD-L1. The percentage of dTc proliferating in the presence of CEA+ tumor decreased from 72.2% to 29.3% (p<0.001) with the addition of MDSC, and immunosuppression was reversed with blockade of PD-L1, which resulted in a 1.6-fold increase in dTc proliferation (p=0.01 ). Conclusions: Liver MDSC expand in the presence of CRCLM and mediate suppression of anti-CEA dTc via PD-L1. Our results indicate that blockade of PD-L1:PD-1 engagement is a viable strategy for enhancing the efficacy of adoptive cell therapy for liver metastases.
Phase I clinical study of NK105, paclitaxel-encapsulating micelles, on a weekly schedule, in patients with malignant tumors (dose-escalation phase).
Authors: Kato Ken , Mukai Hirofumi , Esaki Taito , Ohsumi Shozo , Hozumi Yasuo
Published: March 2020

3082

Background: NK105 is the formulation of a novel drug delivery system that encapsulates paclitaxel (PTX) in polymeric micelles and possibly resolves the safety issues associated with the additives contained in the conventional PTX formulation. In the phase II study of NK105 administered to gastric cancer patients on a 150Emg/m2 triweekly schedule, peripheral sensory neuropathy was mitigated compared to prior data for conventional PTX, without any reduction in efficacy. Based on the dose-density theory, we conducted a phase I study of NK105 on a weekly schedule to determine the dose-limiting toxicity (DLT) and recommended dosage (RD), and to evaluate the pharmacokinetic profile. Methods: Patients with advanced solid tumors refractory to standard therapy received NK105 at dosage levels of 50-100 mg/m2 as a 30-min infusion without premedication, once a week for three weeks, followed by one week of rest. Pharmacokinetic analysis was conducted in cycles 1 and 2. Results: Sixteen patients were enrolled in the study. In the 100Emg/m2 cohort (n=7), one patient experienced DLT (grade 4 neutropenia lasting 5 days), and dose reduction or delay was necessary in 4 of the 7 patients during the first course due to neutropenia. It was decided that 100 mg/m2 was the maximum tolerated dosage, and the RD was set at 80 mg/m2. Grade 3 or more severe adverse drug reactions reported for the 80Emg/m2 cohort were neutropenia, anemia, fatigue, hearing impaired and ataxia. Comparison of the pharmacokinetic parameters of NK105 with those of PTX at the same dosage (100 mg/m2) showed that the AUC0-inf. and Vdss of NK105 were approximately 50-fold and 1/15 of the reported PTX values, respectively. A refractory gastric cancer patient and an esophageal cancer patient each showed a partial response, at dosages of 80 mg/m2 and 100 mg/m2, respectively. Conclusions: 80Emg/m2 weekly administration of NK105 was well tolerated and showed anti-tumor activity, including partial responses and several occurrences of stable disease. The expansion phase of the study is ongoing at the RD of 80 mg/m2. Clinical trial information: JapicCTI-101233.
Active immunotherapy in patients with progressive disease (PD) after first-line therapy: Racotumomab experience.
Authors: Gomez Roberto E , Alfonso Saily , Santiesteban Eduardo Rafael , Neninger Elia , Ardigo Maria Laura , Vazquez Ana Maria , Crombet Tania , Perez Rolando , Lage Agustin , Macias Amparo
Published: March 2020

3086

Background: Racotumomab is a therapeutic vaccine that induces a cellular and humoral immune response against NeuGc-containing gangliosides expressed in several tumors but not in normal human tissues. A previous randomized, double blinded, placebo-controlled trial has demonstrated low toxicity of racotumomab and a statistically significant benefit in overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC) who had achieved partial or complete response or disease stabilization after first line therapy. Methods: An open, non-randomized study was performed to evaluate if racotumomab could also be beneficial in patients with progressive disease. Patients with recurrent and advanced stages (IIIB/IV) of NSCLC, in progression after completion of first-line onco-specific treatment as per the NCCN Oncology Therapeutic Guidelines (surgery, chemotherapy and/or radiotherapy) were included in the study. Most of them had received 4 to 6 cycles of cisplatin/vinblastin. Vaccination consisted of 5 intradermic doses of racotumomab (1 every 14 days), followed by 1 dose every 28 days until patient refusal or worsening of ECOG status. The patients did not receive second-line therapy. Results: 180 patients were included in an intent to treat (ITT) survival analysis (Kaplan Meier estimate), after at least 10 months of follow-up. Median survival was 8.06 months. OS rate (%) at 24 months was 21%. A control group of 85 consecutive patients treated at the same institution by the same investigators, who did not receive second-line therapy or racotumomab showed a median survival of 6.26 months (log rank test p= 0.011). OS rate (%) at 24 months was only 7%. A per protocol survival analysis including only the 124 patients (68.8%) who received ≥ 5 doses of racotumomab showed a median survival of 12 months. OS rate (%) at 24 months was 30%. Conclusions: Patients with PD after first-line treatment show favorable results in survival when vaccinated with racotumomab. This result is similar to previous clinical trials where racotumomab was administered to patients with objective response (partial or complete) or stable disease after first line therapy.
A phase II study of intratumoral administration of the autologous immature dendritic cell (DC) vaccine used after lesion photodynamic therapy (PhDT) and immunomodulation with cyclophosphamide (Cy) in pretreated patients with disseminated malignant melanoma.
Authors: Novik Alexey Viktorovich , Baldueva Irina Alexandrovma , Gelfond Mark Lvovich , Protsenko Svetlana , Nehaeva Tatyana Leonidovna , Waal Andrei Ivanovich , Vorobeychikov Eugene Vladimirovich , Danilova Anna Borisovna , Danilov Alexey Olegovich , Semenova Anna Igorevna , Teletaeva Gulfiya Midhatovna , Moiseyenko Vladimir
Published: March 2020

3088

Background: Immature DC can be loaded in vivo with tumor-specific antigens after tissue destruction and induce specific immune response even in pretreated patients with unfavorable prognosis. We assess clinical efficacy of this approach in melanoma patients after at least 1 line of drug therapy in metastatic setting. Methods: Totally, 14 pts were enrolled: 11 men, 3 women. Stage M1a in 4 (28%) pts, M1b in 1 (7%) and M1c was in 9 (64%) pts. Patient received Cy 300 mg IM at D0, photoditasine (PH) at D3, PhDT therapy on injectable lesion 2 hrs after PH (662 nm, 300 J). The immature DC derived from peripheral blood stem-cells were injected in irradiated lesion 6 hrs after photodynamic therapy at D3 and daily until D7 of the 21-day cycle. Vaccine dose was 60-100*10^6 cells. Toxicity was measured by CTC AE v4, efficacy by RECIST 1.0. Primary endpoint was clinical benefit rate (CBR), secondary – overall survival (OS), response rate (RR), time to progression (TTP) and toxicity. Results: 14 pts were evaluable for toxicity, 13 for response. 37 cycles of therapy were performed. 2 patients achieved PR lasting 393 and 218+ days. 5 patients were stable for 33+, 108, 113, 168 and 239 days. RR was 15 (95% CI 2-39)%, CBR – 54 (95% CI 27-81)%. Median OS was 334 days, TTP – 113 days. RR was well correlated with OS (p=0,014). No SAE or AE of 4th degree occurred. The only grade 3 toxicity was fever. All grade 1-2 AEs were immune-related: fever (the most frequent AE), pain in the lesions, flu-like reactions, myalgia as well as high serum ALT, AST and bilirubin in patients with liver metastases. Conclusions: Thus, using the described approach for immunotherapy of melanoma has clinical efficacy and worth further developing.
A phase I study of an MVA vaccine targeting p53 in cancer.
Authors: Chung Vincent M. , Hardwick Nicola , Ellenhorn Joshua D.I. , Espenschied Jonathan R. , Lim Dean , Chu Peiguo , Qian Dajun , Kim Joseph , Chao Joseph , Fakih Marwan , Yen Yun , Diamond Don J.
Published: March 2020

3089

Background: Despite chemotherapy, survival for most patients with metastatic gastrointestinal cancer is <2 years. These dismal statistics reflect lack of effective therapy. We are conducting a first-in-human trial of modified vaccinia Ankara (MVA), an attenuated viral vaccine that targets wild-type (wt) p53. This approach applies to the majority of p53-involved tumors, since the bulk of the p53 sequence is identical, except for individual point mutations. Our phase I study evaluates the safety and tolerability of the vaccine. Methods: Patients with metastatic colon, gastric and pancreas cancer that failed standard treatment were eligible for vaccination if >10% of the cells stained strongly positive for p53. A standard 3+3 design was employed and patients were accrued to either the 108 pfu or 5.6 x 108pfu dose levels. A total of 3 injections were given, each spaced apart by 3 weeks and patients were evaluated for dose limiting toxicities. Results: Three patients were accrued to the 108 pfu dose level; 2 patients with colon cancer and 1 patient with pancreatic cancer. There were no dose limiting toxicities and the injection was well tolerated and only local irritation at the injection site was seen. The dose was escalated to 5.6 x 108 pfu; 3 patients were accrued, 1 with colon cancer and 2 with pancreatic cancer. There were no dose limiting toxicities observed in the 3 patients. Grade 2 toxicities that were at least possibly related to the vaccine include injection site reaction and fatigue seen in one patient each. One patient with pancreatic cancer had stable disease on CT after completion of the 3 injections. This dose level is being expanded to accrue an additional 6 patients to evaluate safety and immunogenicity using cytokine flow cytometry to characterize p53-specific CD4+ and CD8+ T cell response. Of the cell-surface markers employed, PD1 showed extraordinary strong expression prior to vaccine injection. All patients had a humoral response to the MVA backbone. Conclusions: Our MVA p53 vaccine is well tolerated with minimal grade 1-2 toxicities. The highest dose tested is 5.6 x 108 pfu and additional patients are being accrued to evaluate immunogenicity. Since many cancers have mutant p53, this is an attractive target and may potentially be used with many other cancers. Clinical trial information: NCT01191684.
Safety and efficacy of the HER2-derived GP2 peptide vaccine in combination with trastuzumab for breast cancer patients in the adjuvant setting.
Authors: Patil Ritesh , Clifton Guy T. , Litton Jennifer Keating , Shumway Nathan M. , Vreeland Timothy J , Berry John S. , Trappey Alfred F , Ponniah Sathibalan , Peoples George Earl , Mittendorf Elizabeth Ann
Published: March 2020

3096

Background: GP2 is a 9 amino acid HLA-A2/A3 restricted HER2-derived peptide. GP2 + GM-CSF has been shown to be safe and effective in eliciting anti-HER2 immune response in breast cancer patients. Preclinical data has demonstrated that pretreatment of cells with trastuzumab (Tz) enhances susceptibility to lysis by GP2-specific cytotoxic T lymphocytes (CTLs). We conducted a phase Ib study to evaluate the combination of the GP2 vaccine and Tz. Methods: HLA-A2/A3 + patients with HER2 overexpressing breast cancer receiving Tz as standard therapy were enrolled. The study was designed as a 3+3 dose escalation trial with an expansion cohort evaluating 4 dose levels of the vaccine administered as 6 inoculations given every 3 weeks in combination with Tz (6mg/kg). Toxicity was graded 48-72 hr post vaccination using NCI Toxicity Criteria. Ejection fraction (EF) was monitored every 3 mo. Immunologic response was assessed in vivo by injection site local reaction (LR) and in vitro by quantifying the number of GP2-specific CTLs by HLA-A2: IgG dimer assays and their functional activity by ELISPOT. Results: 19 patients enrolled (median age 47 yr, mean tumor size 3.4 cm, 74% were grade 3, 53% ER/PR+, 63% node positive, 74% received anthracycline based therapy). Maximum local toxicities were grade 1 (77% of patients) and grade 2 (6%), and maximum systemic toxicities were grade 1 (24%) and grade 2 (5%). There were no grade 3 or 4 local or systemic toxicities. There was no significant change in EF at 3 mo (57± 1%, p=0.23) or 6 mo (59±1%, p=0.8) compared to baseline (58±0.9%). Mean post-vaccine series LR was significantly larger than initial vaccination LR (68.2 ± 8.6 mm vs 28.0 ± 10.3 mm, p=0.0004). In vitro assays demonstrated an increase in the maximal number of post- versus pre-vaccination GP2-specific CTLs by dimer assay (1.45 ± 0.19 vs 0.96 ± 0.19%, p=0.06) and increased ELISPOT activity [median 86 range (3-194) vs 34 (range 0-295) spots/106 cells]. Conclusions: GP2 vaccine in combination with Tz is both safe and immunogenic in HER2-overexpressing breast cancer patients in the adjuvant setting. Toxicity was limited to mild local and systemic reactions. There were no dose limiting toxicities or cardiac events.
A phase I trial of intratumoral administration of HF10 in patients with refractory superficial cancer: Immune correlates of virus injection.
Authors: Gildener-Leapman Neil , Ferris Robert L. , Ohr James , Argiris Athanassios , Nemunaitis John J. , Senzer Neil N. , Bedell Cindi , Gross Neil D. , Vetto John T. , Tanaka Maki , Nishiyama Yukihiro , Ungerleider Richard S.
Published: March 2020

3099

Background: HF10 is a spontaneously occurring, oncolytic, mutant Herpes Simplex Virus type 1 (HSV-1). Several deletions/insertions in its genome render it nonpathogenic. HF10 has been tested in solid tumors accessible for injection. Methods: We report correlative studies from an open label, non-randomized, multicenter, single dose escalation phase I study in patients with refractory superficial cancer. The study was a “3 + 3” design with 4-dose cohorts at escalating doses of HF10 (1 x 105 TCID50/dose with incremental dose escalations up to 1 x 107 TCID50/dose), which has been completed. Body fluids (qPCR), peripheral blood (flow cytometry) and serum (30-plex cytokine assay) were examined for viral levels, quantitative immune cell variation, and cytokines, respectively. Results: Seventeen patients were enrolled and 15 treated (9 H/N; 4 melanoma; 1 colon; 1 sarcoma). Best response was stable disease in six patients and progressive disease in nine patients. Three of the 15 patients had an adverse event possibly related to the study therapy. These AEs were grade 1 hypotension (1) and flu-like symptoms (2): typical of treatment with oncolytic viruses. qPCR analysis transiently revealed virus in the saliva of two patients (day 2 and day 22); viral clearance was achieved after 1 and 7 days respectively. Comparing the two highest and two lowest dose HF10 cohorts, CD8+PD1+ cells were decreased with increasing HF10 dose (p=0.023). Increased monocyte population (CD14+CD11c+) appeared to correlate with increased HF10 dose (p=0.063). IL-8 increased in all samples (p=0.0078 Wilcoxon Signed rank test) post injection. Conclusions: Single dose intratumoral injection was well tolerated with mild-drug related AEs and rapid viral clearance. Six patients achieved stable disease during the study period. There appears to be a generalized IL-8 related inflammatory response coincident with increased peripheral blood monocytes after HF10 administration. Decreased CD8+PD1+ cells may indicate a shift towards a non-exhausted, functional CTL phenotype. These results justify the currently accruing study of multiple administrations of HF10 at the highest administered dose. Clinical trial information: NCT01017185.
Validation of DPYD variants DPYD*2A, I560S, and D949V as predictors of 5-fluorouracil (5-FU)-related toxicity in stage III colon cancer (CC) patients from adjuvant trial NCCTG N0147.
Authors: Lee Adam , Shi Qian , Pavey Emily S , Sargent Daniel J. , Alberts Steven R. , Sinicrope Frank A. , Berenberg Jeffrey , Goldberg Richard M. , Diasio Robert B.
Published: March 2020

3510

Background: Prediction of 5-FU-related adverse events (5FU-AEs) continues to be problematic. Pharmacogenetic studies on the rate-limiting enzyme in 5-FU metabolism, dihydropyrimidine dehydrogenase (DPD), suggest a link between three variants and both decreased enzyme activity and increased toxicity: c.1905+1 G>A (DPYD*2A; rs3918290), c.1679 T>G (I560S; DPYD*13; rs55886062), and c.2846A>T (D949V; rs67376798). Since the adverse impact of DPYD variants on 5-FU toxicity remains controversial, we determined associations between the three known DPYD variants and 5FU-AEs in stage III CC patients receiving FOLFOX or FOLFIRI (+ cetuximab) after curative resection. Methods: 2886 patients were genotyped by multiplexed single-base extension assays using the IPLEX Gold Kit and analyzed on the Sequenom MassARRAY system. Grade 3+ AEs were recorded per CTCAE v3. Fisher’s exact test, unequal variance two-sample t-test, and Wilcoxon rank sum test were used to compare categorical variables, continuous variables, and counts between patients with wild-type and mutant status. Logistic regressions were used to assess univariate and multivariate associations. Results: Patients displayed the following characteristics: male gender 53.2%, median age 58 [19-86], proficient DNA mismatch repair status 88.6%, PS-0 76.6%, + irinotecan 8.1%, and + cetuximab 45.9%. A total of 27 (0.9%), 4 (0.1%), and 32 (1.1%) patients carried the DPYD*2A, I560S, and D949V variants, respectively. Analysis identified significant associations between DPYD*2A and D949V variants and toxicity, with grade 3+ 5FU-AEs identified in 22 DPYD*2A carriers (OR=11.9, 95% CI 4.0-32.7, p<0.0001) and 22 D949V carriers (OR=5.5, 95% CI 2.5-12.1, p< 0.0001). No interaction effect was found between DPYD*2Aand D949V on grade 3+ 5FU-AEs (p = 0.98), nor on overall grade 3+ AEs (p = 0.97). No significant association was identified between I560S and grade 3+ 5FU-AEs. Conclusions: In the largest study to date, statistically significant associations were found between DPYD*2A and D949V variants and increased incidence of grade 3+ 5FU-AEs, suggesting utility in 5-FU toxicity prediction.
Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC).
Authors: Oliner Kelly S. , Douillard Jean-Yves , Siena Salvatore , Tabernero Josep , Burkes Ronald L. , Barugel Mario Edmundo , Humblet Yves , Bodoky Gyorgy , Cunningham David , Jassem Jacek , Rivera Fernando , Kocáková Ilona , Ruff Paul , Blasinska-Morawiec Maria , Smakal Martin , Williams Richard Thomas , Rong Alan , Wiezorek Jeffrey S. , Sidhu Roger , Patterson Scott D.
Published: March 2020

3511

Background: Analysis of a phase III pmab monotherapy study indicated that KRAS and NRAS mutations beyond KRAS exon 2 may be predictive of pmab efficacy (Peeters et al, 2013). Methods: The primary objective of this prospectively defined retrospective analysis of PRIME was to assess the effect of pmab + FOLFOX vs FOLFOX on overall survival (OS) in pts with mCRC based on RAS (KRAS or NRAS) or BRAF mutation status. "Gold standard" bidirectional Sanger sequencing and WAVE-based SURVEYOR Scan Kits from Transgenomic (conducted independently) were used to detect mutations in KRAS exon 3, exon 4; NRAS exon 2, exon 3, exon 4; and BRAF exon 15. Results: RAS ascertainment rate was 90%. Tx HRs for pts with WT RAS were 0.78 (95% CI, 0.62 - 0.99; p = 0.04) for OS (median gain of 5.8 months in the pmab arm) and 0.72 (95% CI, 0.58 - 0.90; p = < 0.01) for PFS. Tx HRs for WT KRAS exon 2/mutant (MT) other RAS were 1.29 (95% CI, 0.79 - 2.10; p = 0.31) for OS and 1.28 (95% CI, 0.79 - 2.07; p = 0.32) for PFS. Tx HRs for pts with WT or MT BRAF were inconsistent with a predictive biomarker (Table). Prognostic effects of the tested biomarkers will be presented. Conclusions: A statistically significant OS benefit was observed in pts with WT RAS mCRC treated with pmab + FOLFOX vs FOLFOX. Pmab is unlikely to benefit pts with any RAS mutations. In this analysis, BRAF mutation had no predictive value. Clinical trial information: NCT00364013. [Table: see text]
EGFR and KRAS mutations during anti-EGFR monoclonal antibody treatment in metastatic colorectal cancer: Clinically relevant?
Authors: Karayan-Tapon Lucie , Ferru Aurelie , Cortes Ulrich , Villalva Claire , Tourani Jean Marc , Silvain Christine , Levillain Pierre , Tougeron David
Published: March 2020

3513

Background: It is well-established that only patients with wild-type KRAS metastatic colorectal cancer (mCRC) benefit from treatment with an epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb). Recently, in patients with tumor progression after anti-EGFR mAb, occurrence of EGFR mutation (n=2/10) [Montagut C et al., Nat Med 2012] or KRAS mutation (n=6/10) [Misale S et al., Nature 2012] in metastases has been identified. These mutations could explain treatment resistance but still need to be confirmed with simultaneous analysis of KRAS and EGFR mutations. Methods: We analyzed 37 tumor samples after anti-EGFR mAb treatment for mCRC (34 from metastasis lesions and 3 from primary tumors). We analyzed KRAS (codons 12 and 13), BRAFV600E and EGFRS492R mutations using a highly sensitive technique, pyrosequencing (TheraScreen KRAS Pyro Kit, Qiagen). All tumors were KRAS, BRAFV600E and EGFRS492Rwild-type before anti-EGFR mAb treatment. Results: The majority of patients were treated using anti-EGFR mAb in first-line chemotherapy (70%) and combined with cytotoxic chemotherapy (96%). Cetuximab was used in 86% and panitumumab in 14% of the cases. Among the 37 tumor specimens, 8 were collected after disease progression, and the others after disease control. No EGFRS492R mutation was detected. No tumors developed BRAF mutation but one tumor acquired a KRAS mutation. Nevertheless, the KRAS mutation in this patient (G12V) was detected, after 5-fluorouracil plus cetuximab therapy, only in the primary tumor in the colon but not in the liver metastasis. Moreover, there was a disease control (partial response). Conclusions: Our results suggest that EGFRS492R and acquired KRAS mutations during anti-EGFR mAb therapy are not the only factors accounting for anti-EGFR resistance. Moreover, occurrence of KRAS mutation during anti-EGFR therapy could differ between primary tumor and metastases.
FOLFIRI plus bevacizumab (bev) as second-line therapy in patients (pts) with metastatic colorectal cancer (mCRC) who have failed first-line bev plus oxaliplatin-based therapy: The randomized phase III EAGLE study.
Authors: Tamagawa Hiroshi , Iwamoto Shigeyoshi , Takahashi Takao , Nakamura Masato , Munemoto Yoshinori , Kato Takeshi , Hata Taishi , Denda Tadamichi , Morita Yoshitaka , Inukai Michio , Kunieda Katsuyuki , Nagata Naoki , Kurachi Kiyotaka , Ina Kenji , Oshiro Takashi , Shimoyama Tatsu , Baba Hideo , Oba Koji , Sakamoto Junichi , Mishima Hideyuki
Published: March 2020

3516

Background: The phase III ML18147 study (NCT00700102) showed a survival benefit for the continuation of bev after 1st-line bev-containing therapy in pts with mCRC. Continuation of bev beyond disease progression in this setting was approved by the FDA in Jan 2013. In the randomized, phase II SPIRITT study (NCT00418938) assessing 2nd-line treatment for mCRC, progression-free survival (PFS) was longer in the bev arm compared with the panitumumab arm, but the difference was not statistically significant. We describe the results of EAGLE, a multicenter, randomized phase III study evaluating the optimal dose of 2nd-line bev in Japan (UMIN000002557). Methods: Pts were randomized 1:1 to receive bev 5 mg/kg (Arm A) or 10 mg/kg (Arm B) plus FOLFIRI Q2W. Key eligibility criteria: age ≥20 years, mCRC, ECOG PS ≤1, and treatment failure to prior 1st-line bev plus oxaliplatin-based therapy (≥4 cycles). The primary endpoint was PFS. Secondary endpoints included time to treatment failure (TTF), PFS from 1st-line therapy, response rate (RR) and safety. The planned sample size was 370 pts to detect 30% risk reduction with 90% power assuming a two-sided significance level of 0.05. Results: 387 pts were randomized between Sep 2009 and Jan 2012; 367 pts formed the full analysis set (Arm A 179 pts; Arm B 188 pts). Baseline characteristics were well balanced between the treatment arms. Respectively for Arm A and B, PFS was 6.2 and 6.3 months (HR 1.03, 95% CI: 0.82-1.30; p=0.815), TTF 5.3 and 5.3 months (HR 1.08, 95% CI: 0.87-1.33; p=0.485), PFS from 1st-line therapy 17.6 and 17.8 months (HR 0.99, 95% CI: 0.78-1.25; p=0.919) and RR 11.7% and 10.1%. Frequently reported AEs in Arm A and B, respectively, were: hypertension (13.0%, 18.1%), proteinurea (36.8%, 35.2%), GI perforation (4.7%, 3.1%), grade 3/4 neutropenia (46.1%, 39.9%), grade 3/4 fatigue (7.8%, 10.9%), and grade 3/4 anorexia (5.7%, 5.2%). Treatment-related deaths occurred in 2 pts in each arm. Conclusions: The study did not meet its primary endpoint. PFS in Arm A was comparable to that reported in the ML18147 study. Safety in both arms was consistent with previously reported studies. Clinical trial information: UMIN000002557.
Effectiveness of bevacizumab added to gold standard chemotherapy in metastatic colorectal cancer (mCRC): Final results from the Itaca randomized clinical trial.
Authors: Passardi Alessandro , Scarpi Emanuela , Cavanna Luigi , Fontana Annalisa , Vertogen Bernadette , Ruscelli Silvia , Tamburini Emiliano , Ragazzini Angela , Frassineti Giovanni Luca , Nanni Oriana , Amadori Dino
Published: March 2020

3517

Background: Evidence from available RCTs indicates that the addition of bevacizumab (B) to chemotherapy (CT) results into an improved survival in metastatic colorectal cancer (mCRC). However, the magnitude of this effect is different across trials, with marginal benefit observed when gold standard CT regimens are used. With these premises we performed a phase III randomized clinical study to evaluate the effectiveness of gold standard mCRC first line CT + B. This study was funded by the Italian Ministry of Health. Methods: mCRC patients candidate were randomized to receive first line CT +B or first line CT alone. CT regimens included FOLFOX4 (oxaliplatin 85 mg/m2 d1, folinic acid FA 100 mg/m2 dd1,2, 5FU 400 mg/m2 iv bolus dd 1,2 plus 5FU 600 mg/m2 22-h ic dd1,2 – Q14 days) or FOLFIRI (irinotecan 180 mg/m2d1, FA and 5FU as in FOLFOX4, Q 14 days); B 5 mg/kg was administered Q 14 days. The primary end point was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Response Rate (ORR) and safety. Three hundreds ten events were required to statistically differentiate PFS between groups with 80% power. Results: Between 11/2007 and 03/2012, 376 patients were randomized. Patient characteristics were well balanced between the two arms. FOLFOX4 was used in 60% of the patients and FOLFIRI in 40%. After a median follow up of 18.4 months, 313 progressions and 179 deaths were observed. No statistically significant differences in PFS, OS and ORR were observed (see table). B containg regimens were associated with more frequent hypertension, bleeding, proteinuria and asthenia. Conclusions: The addition of B to a gold standard CT for mCRCdoes not result into an improved prognosis in terms ofPFS, ORR, OS. ITACA’s results (control arm) suggest that the chemotherapeutic schedules used in some of the previously published bevacizumab trials might be suboptimal. Clinical trial information: 2007-004539-44. [Table: see text]
Noninferiority of S-1 to UFT/LV as adjuvant chemotherapy for stage III colon cancer: A randomized phase III trial (ACTS-CC).
Authors: Nakamoto Yoshihiko , Ishiguro Megumi , Yoshida Motoki , Ikejiri Koji , Mochizuki Izumi , Mochizuki Hidetaka , Kotake Kenjiro , Kameoka Shingo , Takahashi Keiichi , Watanabe Toshiaki , Watanabe Masahiko , Boku Narikazu , Tomita Naohiro , Matsubara Yoshihiro , Sugihara Kenichi ,   ACTS-CC Study Group
Published: March 2020

3518

Background: The ACTS-CC trial is a phase III trial designed to validate non-inferiority of S-1 to UFT/LV, a standard treatment in Japan as adjuvant chemotherapy for stage III colon cancer. This is the first report which evaluated the efficacy of S-1 as adjuvant therapy for colon cancer. Methods: 20-80 aged patients with stage III colon cancer who underwent curative surgery were randomly assigned to receive S-1 (80, 100, or 120 mg/day according to BSA on days 1 to 28, followed by 14 days rest, 4 courses) or UFT/LV (UFT: 300 to 600 mg/day according to BSA and, LV: 75 mg/day on days 1 to 28, followed by 7 days rest, 5 courses). Primary endpoint was DFS. Sample size was 1,480 determined with one-sided alpha of 0.05, power of 0.80, and non-inferiority margin of hazard ratio (HR) of 1.29. Results: Among 1535 enrolled patients between Apr. 2009 and Jun. 2010, 1518 patients (758 in S-1 group, 760 in UFT/LV group) were included in the efficacy analysis. Median follow-up was 41.3 months, the mean age at enrollment was 64.5 years, wide lymph node dissection (D3) was done in 79.8%, the median number of dissected lymph nodes was 17, and stage IIIA/IIIB/IIIC were 15%/71%/14%. The 3-year DFS rate was 75.5% in S-1 group and 72.5% in UFT/LV group. The HR of DFS was 0.85 (95%CI: 0.70-1.03) and non-inferiority of S-1 was demonstrated (p<0.0001). The completion rate of the protocol treatment was 76.5% in S-1 group and 72.5% in UFT/LV group. The overall incidence of grade ≥3 adverse events (AEs) in S-1 group and UFT/LV group were 16.0% and 14.4%: 4.4% and 5.5% for diarrhea, 4.9% and 3.5% for anorexia, 0.7% and 0.4% for leucopenia, 0.9% and 0.1% for anemia, 0.1% and 0.4% for thrombocytopenia, 1.2% and 1.5% for hyperbilirubinemia, 0.8% and 2.1% for AST elevation, and 1.1% and 3.3% for ALT elevation, respectively. Conclusions: Adjuvant therapy of S-1 for stage III colon cancer was demonstrated to be non-inferior in DFS to that of UFT/LV. Although AE profiles differed between S-1 group and UFT/LV group in this trial, incidence and degree of AEs were acceptable, and the completion rate of the protocol treatment was high. Adjuvant chemotherapy using S-1 will be a treatment option for stage III colon cancer. Clinical trial information: NCT00660894.
Prognostic value of early objective tumor response (EOTR) to first-line systemic therapy in metastatic colorectal cancer (mCRC): Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD database.
Authors: Sommeijer Dirkje Willemien , Shi Qian , Meyers Jeffrey P , Sjoquist Katrin Marie , Hoff Paulo Marcelo , Seymour Matthew T. , Cassidy James , Goldberg Richard M. , Douillard Jean-Yves , Hecht J. Randolph , Hurwitz Herbert , Tournigand Christophe , Tebbutt Niall C. , Aranda Enrique , Souglakos John , Kabbinavar Fairooz F. , Chibaudel Benoist , De Gramont Aimery , Sargent Daniel J. , Zalcberg John Raymond ,   for the ARCAD Group
Published: March 2020

3520

Background: EOTR has been suggested as a potential surrogate for overall survival (OS) in patients (pts) with mCRC and allows early assessment of treatment efficacy, facilitating adaptive trial design. We assessed at the individual patient level, the correlation between EOTR (complete or partial response) at 6, 8 and 12 weeks (wk), OS and progression free survival (PFS) in pts with mCRC treated with 1stline chemotherapy with or without a targeted agent as a first step in a surrogacy demonstration. Methods: IPD from 13,949 pts enrolled on 15 randomized Phase III trials in 1st line mCRC were used; 8 trials included targeted (anti-angiogenic and anti-EGFR) agents. EOTR prognostic value was assessed by landmark analyses using Cox models stratified by treatment assignment. P-values <0.01 were considered statistically significant to account for multiple comparisons. Results: Of 13,949 pts, 11,987 had sufficient response data to be included in the analysis. Median OS was 21.7 months (mo) in pts with an EOTR vs. 16.5 mo without EOTR at 6 wk (p<.0001, Hazard Ratio [HR] 0.64, 95% confidence interval [CI] 0.58-0.70, c statistic [c] 0.55). HRs were similar whether pts were treated with targeted therapies (p<.0001, HR 0.68, 95% CI 0.58-0.80, x 0.54) or non-targeted therapies (p<.0001, HR 0.61, 95% CI 0.55-0.69, x 0.55). Median PFS was 8.4 mo in pts with EOTR at 6 wk vs. 7.0 mo in pts without EOTR (p<.0001, HR 0.79, 95% CI 0.73-0.85). EOTR at 8 and 12 wks were also significantly associated with longer OS and PFS. The prognostic value of EOTR at 6, 8 and 12 wks remained significant (p<0.0001) after adjusting for age, gender, performance statusand location of metastatic disease (lung or liver). Overall tumor response (to 26 wk) however provided superior OS prediction (p<.0001, HR 0.51, 95% CI, 0.47-0.56, CS 0.61) vs. EOTR. Conclusions: Early response measured at 6, 8 or 12 wk after starting 1st line treatment was a strong and independent predictor of both OS and PFS in patient with mCRC and warrants further consideration as a potential endpoint for future trials, particularly randomized phase II trials.
Prognostic impact of KRAS and BRAFV600E mutations stratified by tumor site in resected stage III colon cancer patients treated with adjuvant mFOLFOX6 with or without cetuximab: NCCTG N0147 (Alliance).
Authors: Sinicrope Frank A. , Mahoney Michelle R. , Smyrk Thomas C. , Thibodeau Stephen N. , Goldberg Richard M. , Nelson Garth D. , Sargent Daniel J. , Alberts Steven R. ,   North Central Cancer Treatment Group (Alliance)
Published: March 2020

3523

Background: The association of KRAS or BRAFV600E mutations with prognosis in colon cancers has been inconsistent. Since primary tumor site may influence outcome, we analyzed KRAS and BRAFV600E stratified by tumor site in resected stage III colon cancers from a randomized adjuvant trial of mFOLFOX6 + cetuximab chemotherapy (N= 2,686) where no survival difference by treatment was found. Methods: 2,580 tumors were analyzed for mutations in BRAFV600E (exon 15) or KRAS (codons 12, 13), and for deficient DNA mismatch repair (dMMR). Cox models were used, adjusting for mutation status, age, sex, treatment, T-stage, histologic grade, nodal status, tumor site, and MMR. After study initiation, eligibility was restricted to patients (pts) with KRAS wild-type (WT) tumors. At a median follow-up 4.1 yrs, 83% of pts are alive. Results: KRAS and BRAFV600E mutations were detected in 716 (28%) and 346 (14%) tumors, respectively; dMMR was found in 314 (12%). Proximal (to splenic flexure) tumors (50%) were associated with older age and were more likely to be high grade (33 vs 18%), T-stage3,4 (88 vs 82%), mutated for KRAS (33 vs 23%) or BRAFV600E (23 vs 4%), and dMMR (21 vs 3%)[all p <0.02]. Pts with distal vs proximal tumors showed improved disease-free survival (DFS)[ HR 0.7, 95% CI (0.6-0.9); p<0.01 unadjusted for KRAS or BRAF;]. Mutant KRAS [HR=1.5 (1.2-1.7); p<.0001] or mutant BRAF [HR=1.4 (1.1-1.7); p=0.02] were each independently associated with worse DFS. The KRAS and tumor site interaction was significant (unadjusted pinteraction=0.02; adjusted pinteraction=0.07), with poorer DFS among distal tumors having mutant KRAS [HR 1.7 (1.3-2.2); p<.0001]. No interaction was observed for BRAFV600E and tumor site, despite worse DFS for mutant BRAFV600E among proximal tumors [HR 1.3 (1-1.8); p=0.04]. Conclusions: The adverse prognostic impact of KRAS, but not BRAFV600E, mutations was confined to the distal colon. This finding underscores the importance of tumor site in the interpretation of the prognostic impact of KRAS status, and motivates similar analyses in pts with advanced disease.