scholarly journals Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide

2021 ◽  
Vol 13 (593) ◽  
pp. eabb3768
Author(s):  
Brock J. Sishc ◽  
Lianghao Ding ◽  
Taek-Keun Nam ◽  
Collin D. Heer ◽  
Samuel N. Rodman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Hydrogen Peroxide ◽  
Head And Neck ◽  
Mammary Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
High Dose ◽  
Link Type ◽  
Stereotactic Ablative Body Radiotherapy ◽  
Dose Per Fraction

Avasopasem manganese (AVA or GC4419), a selective superoxide dismutase mimetic, is in a phase 3 clinical trial (NCT03689712) as a mitigator of radiation-induced mucositis in head and neck cancer based on its superoxide scavenging activity. We tested whether AVA synergized with radiation via the generation of hydrogen peroxide, the product of superoxide dismutation, to target tumor cells in preclinical xenograft models of non–small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, and pancreatic ductal adenocarcinoma. Treatment synergy with AVA and high dose per fraction radiation occurred when mice were given AVA once before tumor irradiation and further increased when AVA was given before and for 4 days after radiation, supporting a role for oxidative metabolism. This synergy was abrogated by conditional overexpression of catalase in the tumors. In addition, in vitro NSCLC and mammary adenocarcinoma models showed that AVA increased intracellular hydrogen peroxide concentrations and buthionine sulfoximine– and auranofin-induced inhibition of glutathione- and thioredoxin-dependent hydrogen peroxide metabolism selectively enhanced AVA-induced killing of cancer cells compared to normal cells. Gene expression in irradiated tumors treated with AVA suggested that increased inflammatory, TNFα, and apoptosis signaling also contributed to treatment synergy. These results support the hypothesis that AVA, although reducing radiotherapy damage to normal tissues, acts synergistically only with high dose per fraction radiation regimens analogous to stereotactic ablative body radiotherapy against tumors by a hydrogen peroxide–dependent mechanism. This tumoricidal synergy is now being tested in a phase I-II clinical trial in humans (NCT03340974).

Phase Ib study of PGG beta glucan in combination with anti-MUC1 antibody (BTH1704) and gemcitabine for the treatment of advanced pancreatic cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. TPS493-TPS493 ◽  
Author(s):  
Neeta K. Venepalli ◽  
Chintan Chandrakant Gandhi ◽  
Howard Ozer ◽  
Dominic Ho ◽  
Yang Lu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Tumor Cells ◽  
Advanced Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Mucin 1 ◽  
Beta Glucan ◽  
Dose Escalation Study ◽  
Functional Changes ◽  
Clinical Trial Information

TPS493 Background: Mucin 1 (MUC1) is a tumor associated membrane-bound glycoprotein that promotes oncogenesis through promotion of epithelial cell polarity loss, anti-apoptosis, and hypoxia driven angiogenesis. MUC1 overexpression is associated with aggressive behavior and poor outcomes in pancreatic ductal adenocarcinoma (PDAC), and increased resistance to gemcitabine (G) in vitro. BTH1704 (BTH) is a humanized monoclonal antibody (MAb) targeting aberrantly glycosylated MUC1. Imprime PGG (PGG) is a soluble yeast-derived b 1,3/1,6 glucan that binds complement receptor 3 (CR3) on innate immune cells priming them to exert anti-tumor activity against complement (iC3b) opsonized tumor cells. Following incubation of PGG with whole blood from healthy subjects, variability in PGG binding to neutrophils and monocytes has been observed, with higher binding and functional changes correlating with higher levels of endogenous anti-b glucan antibodies. BTH binds to antigens (MUC1), leading to iC3b opsonization of tumor cells thus, allowing PGG-primed leukocytes to kill the iC3b-opsonized tumor cells. This forms the rationale for testing BTH1704 combined with G + PGG. Methods: This is a single institution Phase 1b dose escalation study with a standard 3x3 design to determine the maximal administered dose (MAD) of BTH combined with G + PGG in patients with previously treated advanced PDAC.Each dose cohort includes at least one subject with high and one low PGG binding capability. Primary objectives: establish MAD of BTH combined with G + PGG. Secondary objectives: characterize adverse effects, clinical response, time to progression, progression free and overall survival. Correlative objectives: quantify PGG binding, MDSC phenotyping of PBMC, anti b glucan antibody levels, MUC1 IHC. Inclusion criteria: confirmed advanced PDAC, ECOG PS 0-2, rest period 2-6 weeks from prior first- or second-line treatment. Exclusion criteria: uncontrolled chronic illness. Administration and design: BTH and PGG are administered on days 1, 8, 15, and 22 of a 28-day cycle; G is administered on days 1, 8, and 15. The study is currently enrolling patients. Clinical trial information: NCT02132403. Clinical trial information: NCT02132403.

Response to guadecitabine (SGI-110) combined with cisplatin and gemcitabine (GCG) in platinum refractory germ cell tumors (GCTs).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17057-e17057 ◽  
Author(s):  
Simon J. Crabb ◽  
Robert A Huddart ◽  
Emma Brown ◽  
Denise Dunkley ◽  
Nichola Downs ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Lung Metastases ◽  
Germ Cell Tumors ◽  
Retroperitoneal Lymph Node Dissection ◽  
Platinum Resistance ◽  
High Dose ◽  
Hypomethylating Agent ◽  
Platinum Refractory ◽  
Β Hcg

e17057 Background: Treatment options for platinum refractory GCTs are limited. Platinum resistance derives, in part, from tumour suppressor gene promotor methylation. In vitro, this reverses on co-administration of a DNA hypomethylating agent. Guadecitabine is a next generation hypomethylating agent. SPIRE is a phase Ib/IIa clinical trial to establish a GCG dose/schedule. Methods: We report 2 platinum refractory GCT patients (pts) treated (txd) in SPIRE with GCG (guadecitabine 20 mg/m2, SC, day (D) 1-5; cisplatin 70 mg/m2, IV, D8; gemcitabine 1000 mg/m2, IV, D8 + 15; filgrastim 300 μg, SC, D15-21; q21). Results: Pt 1: 21 yo man, testicular mixed GCT (seminoma/malignant teratoma intermediate). Prior tx: 2001, orchidectomy; 2005, 3 x BEP (bleomycin, etoposide, cisplatin) + retroperitoneal lymph node dissection. 2015, 2 x TI (paclitaxel, ifosfamide), 3 x TIP (cisplatin, ifosfamide, paclitaxel); 2016, 3 x HDCE (high dose carboplatin/ etoposide + autologous stem cell transplantation); 2017, 6 x GOP (gemcitabine, oxaliplatin, paclitaxel). In 2017, received 6 x GCG in SPIRE for CT confirmed lung metastases (mets) and rising β-hCG (human chorionic gonadotropin). Response: RECIST stable disease with metabolic CR on PET in lungs and > 90% β-hCG reduction. In Cycle 6, pt developed symptomatic brain mets, treated with WBRT (40Gy, 20#) + cyberknife to the six mets completed 2018. Since 2018, ongoing complete marker and radiologic (brain and systemic) remission (20 months). Pt 2: 44 yo man, primary mediastinal non-seminomatous GCT. Prior tx: 2008, 4 x BEP + mediastinal mass resection; 2015, 4 x TIP; 2016, 1 x HDCE. In 2017, received 5 x GCG in SPIRE for a PET avid mediastinal/pulmonary relapse and AFP (alpha-fetoprotein) rise. Response: RECIST stable and > 50% AFP reduction for 6 months (subsequent progression with intracerebral metastasis). Treatment was well tolerated. Grade 4 neutropenia/ thrombocytopenia occurred in both and febrile neutropenia in pt 1. Both required a 25% dose reduction in Cis/Gem. Conclusions: GCG produced exceptional clinical responses in both platinum refractory GCT pts. Prospective evaluation is warranted. Clinical trial information: 16332228.

MR imaging of head and neck lesions using high-dose gadodiamide injection: a phase III clinical trial

1995 ◽  
Vol 5 (6) ◽  
Author(s):  
T.J. Vogl ◽  
A. Western ◽  
M.G. Mack ◽  
P. Kj�rsgaard ◽  
M. Juergens ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Mr Imaging ◽  
Head And Neck ◽  
Phase Iii ◽  
High Dose ◽  
Phase Iii Clinical Trial

Phase I Trial of Retinoic Acid and cis-Platinum for Advanced Squamous Cell Cancer of the Head and Neck Based on Experimental Evidence of Drug Synergism

1998 ◽  
Vol 118 (5) ◽  
pp. 597-602
Author(s):  
Robert A. Weisman ◽  
Randolph Christen ◽  
Gerrit Los ◽  
Vicky Jones ◽  
Charles Kerber ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Phase I ◽  
Head And Neck ◽  
Squamous Cell ◽  
Squamous Cell Cancer ◽  
Cell Cancer ◽  
Complete Response ◽  
High Dose ◽  
Neck Squamous Cell Cancer

OBJECTIVE: Cis-platinum and 13- cis-retinoic acid have received much attention in the treatment of head and neck squamous cell cancer. Even though they have different mechanisms of action, little information is available on their interaction. This paper reviews experimental evidence for retinoic acid- cis-platinum synergy and presents toxicity data from patients with stage IV head and neck squamous cell cancer participating in a phase I trial combining 13- cis-retinoic acid and cis-platinum. METHODS: Patients were given 13- cis-retinoic acid orally daily for 7 days before and daily during high-dose (150 mg/m 2 per week for 4 weeks) intraarterial cis-platinum treatment with concurrent radiation. Toxicity was scored with use of the cancer and leukemia group B scale. RESULTS: In the phase I clinical trial, 15 patients were treated to determine a maximum tolerated dosage for 13- cis-retinoic acid of 20 mg/day. Grade 4 hematologic toxicity was dose limiting in 3 of 8 patients treated with 40 mg/day and in 1 patient treated with 60 mg/day. There were no deaths caused by toxicity; 12 of the 15 patients received all four weekly doses and the remaining 3 received three doses. Of 10 patients with fully evaluable data, all achieved a complete response at the primary site and 9 had a complete response in the neck. One patient had persistent neck disease after chemoradiation, and this tumor was removed with neck dissection. CONCLUSIONS: 13- cis-retinoic acid and cis-platinum are strongly synergistic against head and neck squamous cell cancer in vitro. Pretreatment with retinoic acid results in stronger synergy than concurrent drug exposure alone. Preliminary clinical experience with combined retinoic acid and cis-platinum in a design that parallels the in vitro study indicates that toxicity is acceptable with 13- cis-retinoic acid dosages of 20 mg/day in a high-dose-intensity intraarterial chemoradiation regimen. (Otolaryngol Head Neck Surg 1998;118:597–602.)

scholarly journals Pentraxin 3 is a stromally-derived biomarker for detection of pancreatic ductal adenocarcinoma

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Michelle R. Goulart ◽  
Jennifer Watt ◽  
Imran Siddiqui ◽  
Rita T. Lawlor ◽  
Ahmet Imrali ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ex Vivo ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Diagnostic Biomarkers ◽  
All Trans Retinoic Acid ◽  
Desmoplastic Stroma ◽  
Predictive Role

AbstractPancreatic ductal adenocarcinoma (PDAC), characterized by dense desmoplastic stroma laid down by pancreatic stellate cells (PSC), has no reliable diagnostic biomarkers for timely detection. A multi-center cohort of PDAC patients and controls (chronic pancreatitis, intra-ductal papillary neoplasms, gallstones and otherwise healthy) donated serum in an ethically approved manner. Serum PTX3 above 4.34 ng/mL has a higher sensitivity (86%, 95% confidence interval (CI): 65–97%) and specificity (86%, 95% CI: 79–91%), positive predictive value (97%) and likelihood ratio (6.05), and is superior when compared to serum CA19-9 and CEA for detection of PDAC. In vitro and ex vivo analyses of PTX3, in human PDAC samples, PSCs, cell lines and transgenic mouse model for PDAC, suggest that PTX3 originates from stromal cells, mainly PSC. In activated PSC, PTX3 secretion could be downregulated by rendering PSC quiescent using all-trans-retinoic acid (ATRA). PTX3 organizes hyaluronan in conjunction with tumor necrosis factor-stimulated gene 6 (TSG-6) and facilitates stellate and cancer cell invasion. In SCALOP clinical trial (ISRCTN96169987) testing chemo-radiotherapy without stromal targeting, PTX3 had no prognostic or predictive role. However, in STARPAC clinical trial (NCT03307148), stromal modulation by ATRA even at first dose is accompanied with serum PTX3 response in patients who later go on to demonstrate disease control but not those in whom the disease progresses. PTX3 is a putative stromally-derived biomarker for PDAC which warrants further testing in prospective, larger, multi-center cohorts and within clinical trials targeting stroma.

Adjuvant anti-PD-1 ab (Toripalimab) versus high-dose IFN-a2b in resected mucosal melanoma: A phase randomized trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9573-9573
Author(s):  
Chuanliang Cui ◽  
Bin Lian ◽  
Lu Si ◽  
Zhihong Chi ◽  
Xinan Sheng ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Randomized Trial ◽  
Head And Neck ◽  
Adjuvant Radiotherapy ◽  
Population Data ◽  
Disease Recurrence ◽  
Mucosal Melanoma ◽  
High Dose ◽  
Open Label ◽  
Clinical Trial Information

9573 Background: Immunotherapies including anti PD-1 ab and high-dose IFN-a2b (HDI) have been approved for adjuvant therapies in resected cutaneous melanoma, but their roles in mucosal melanoma are still unknown. To determine the efficacies of toripalimab versus HDI as adjuvant therapy in patients (pts) with resected mucosal melanoma, this open-label, phase randomized trial was conducted. Methods: Mucosal melanoma pts who have undergone complete resections of localized with or without regional lymphatic disease were randomly (1:1) assigned to receive HDI (15x106 IU/m2/d1-5/w/ 4weeks IH, followed by 9x106 IU tiw IH) or toripalimab (3mg/kg intravenously q2w) for 52 weeks unless disease recurrence, unacceptable toxicity or consent withdrawal. Head and neck primary would receive adjuvant radiotherapy within 6-8weeks after enrollment. The primary end point was RFS in the intention-to-treat population. Data cutoff was December 10, 2020. Clinical trial information: NCT03178123. Results: From Jul 2017 to May 2019, 187 pts were screened, and 145 were randomized into HDI group (n = 72) and toripalimab group (n = 73). The median age was 58years; M:F 37.2%: 62.8%; localized disease 80.7%, regional lymphatic disease 19.3%; local excision ± CLND 37.2%, wide excision ± CLND 62.8%; head and neck primary 39.3%( 87.5% received adjuvant radiotherapy); PDL-1positive 51.0%(CPS≥1%, 22C3), PDL-1 negative 49.0%. There was no difference in baseline characteristics between two groups. At a median follow-up of 31.5 months, there were 93 RFS events (43 in HDI group vs. 50 in toripalimab group), 76 DMFS events (35 vs. 41respectively) and 65 OS events (30 vs. 35 respectively). The median RFS, DMFS and OS were shown in the table. In the HDI group, 32.6% of pts received anti PD-1 ab in the following treatment. Grade 3/4 AEs were reported in 83.3% of pts in HDI group (most decrease of leukocytes or neutrophils) and 15.1% of pts in toripalimab group (mainly increase of amylase or liver enzymes). Discontinuations of treatment due to any AE occurred in 20.8% of HDI group and 15.1% of toripalimab group. Conclusions: Both adjuvant toripalimab and HDI therapy improve RFS of mucosal melanoma. Toripalimab shows longer RFS in PDL1 (+) subgroup and better tolerance than HDI. Clinical trial information: NCT03178123. [Table: see text]

PO-0941 INADEQUACY OF USING THE LINEAR-QUADRATIC MODEL IN HIGH-DOSE-PER-FRACTION RADIOTHERAPY: IN VITRO AND IN VIVO STUDY

2012 ◽  
Vol 103 ◽  
pp. S371
Author(s):  
Y. Shibamoto ◽  
S. Otsuka ◽  
H. Iwata ◽  
A. Miyakawa ◽  
C. Sugie ◽  
...  
Keyword(s):  
In Vivo Study ◽  
Quadratic Model ◽  
High Dose ◽  
Linear Quadratic ◽  
Linear Quadratic Model ◽  
Dose Per Fraction

Use of in vitro dose response effects to select antineoplastics for high-dose or regional administration regimens.

1986 ◽  
Vol 4 (12) ◽  
pp. 1827-1834 ◽  
Author(s):  
D D Von Hoff ◽  
G M Clark ◽  
G R Weiss ◽  
M H Marshall ◽  
J B Buchok ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Head And Neck ◽  
Dose Response ◽  
Chemotherapeutic Agents ◽  
Small Cell ◽  
High Dose ◽  
Small Cell Lung ◽  
Regional Administration

Several preclinical and clinical studies have documented that dose or dose intensity of chemotherapeutic agents are important factors for response of patients' tumors. This finding has prompted empiric trials of certain chemotherapeutic agents in high-dose or regional administration treatment regimens. The present study was performed to identify agents that would be particularly good candidates for high-dose or regional administration regimens against particular types of tumors. Using a human tumor cloning technique, we constructed dose in vitro response lines for ten different chemotherapeutic agents against seven different histologic types of malignancies. Slopes of the lines indicated the agents with the greatest increases of in vitro response per increment in dose of the agent. Tumors against which the agents gave the steepest dose response lines included lymphoma, head and neck cancer, ovarian cancer, and small-cell lung cancer, while the dose response lines for non-small-cell lung cancer, breast cancer, and colon cancer were quite flat. Suggestions for clinical trials based on these findings include the use of high-dose melphalan for patients with lymphoma, head and neck, and ovarian cancer; the use of mitoxantrone in high-dose regimens for patients with breast cancer; high-dose cisplatin regimens for patients with small-cell lung cancer; high-dose bleomycin regimens for patients with non-small-cell lung and head and neck cancer; and regional perfusion of liver metastases from colorectal cancer with cisplatin. Prospective testing of high-dose or regional administration regimens suggested by this new model should indicate its use for prediction of the best agent to use in high-dose regimens against a particular tumor type.

scholarly journals Effects of nanomicelle curcumin capsules on prevention and treatment of oral mucosits in patients under chemotherapy with or without head and neck radiotherapy: a randomized clinical trial

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Seyed Javad Kia ◽  
Maryam Basirat ◽  
Hamid Saeidi Saedi ◽  
Seyed Ali Arab
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Head And Neck ◽  
Oral Mucositis ◽  
Control Group ◽  
Study Group ◽  
Link Type ◽  
Prevention And Treatment ◽  
And Control ◽  
Head And Neck Radiotherapy

Abstract Background One of the most prevalent complications of chemotherapy and radiotherapy is oral mucositis (OM) and manifests as erythema and ulceration. Curcumin is one of the components of turmeric and possesses anti-inflammatory and anti-oxidative features. Some of studies have proved the effectiveness of Curcumin in OM. This study aimed to investigate the effects of nanomicelle Curcumin on OM related chemotherapy and head and neck radiotherapy. Methods In this clinical trial study, 50 patients underwent chemotherapy with or without head and neck radiotherapy were divided into study and control group. The study group was received Curcumin nanomicelle capsules 80 mg twice a day and the control group took placebo two times a day for 7 weeks and the severity and pain of OM was measured. Results Oral mucositis severity in control group in the first (P = 0.010), fourth (P = 0.022) and seventh (P < 0.001) weeks were significantly more than the study group. Pain grade in study group was lower than control group only in the seventh week. (P = 0.001) Additionally, NRS incremental gradient in control group was more than study group. OM severity in patients who underwent only chemotherapy in the control group were significantly more than the study group in all weeks. In patients who were under chemotherapy and head and neck radiotherapy, OM in control group was significantly more intense than the study group only in the fourth and seventh weeks. Conclusions Nabomicelle Curcumin capsules is effective on prevention and treatment of head and neck radiotherapy and especially chemotherapy induced OM. Trial registration Registered 12 February 2019 at Iranian Registry of Clinical Trials (IRCT). IRCT code: IRCT20100101002950N6. https://en.irct.ir/trial/36665. GUMS ethical code: IR.Gums.Rec.1397.296.

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