Phase 1A clinical trial of the first-in-class fascin inhibitor NP-G2-044 evaluating safety and anti-tumor activity in patients with advanced and metastatic solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2548-2548
Author(s):  
Vincent Chung ◽  
Komal L. Jhaveri ◽  
Daniel D. Von Hoff ◽  
Xin-Yun Huang ◽  
Edward Graeme Garmey ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
Dendritic Cells ◽  
Cancer Patients ◽  
Checkpoint Inhibitors ◽  
Drug Synergism ◽  
Duration Of Treatment ◽  
Antigen Uptake ◽  
Increased Risk ◽  
Metastatic Activity

2548 Background: Fascin inhibitors block tumor metastasis and increase antigen uptake in intra-tumoral dendritic cells. Filopodia, finger-like protrusions on cell surfaces, are necessary for migration of metastatic tumor cells and intra-tumoral dendritic cells. Fascin is the primary actin cross-linker in filopodia and elevated levels correlate with increased risk of metastasis, disease progression and mortality. NP-G2-044 is a novel small molecule that inhibits function of fascin. Pre-clinical data demonstrate drug-associated reductions in tumor growth and metastasis, enhanced immune response and survival in treated animals, and drug-drug synergism when combined with anti-PD-1 antibodies. Methods: This multicenter phase 1A clinical trial was designed to evaluate safety and tolerability of NP-G2-044 and to identify the drug’s recommended phase 2 dose (RP2D) using a 3+3 dose escalation design. NP-G2-044 was administered to patients (pts.) with treatment-refractory solid tumor malignancies as a single oral daily dose for 6-week cycles that included 4 weeks on (daily dosing) and 2 weeks off (rest). Results: A total of 23 pts. were enrolled in 7 dose cohorts ranging from 200-2100 mg. QD. Overall, NP-G2-044 appeared well-absorbed and distributed with Tmax of ̃4 hrs and T1/2 of 20-24 hrs. Across all cohorts, no DLTs, drug-related SAEs or patient deaths were observed. Based on PK and safety findings, 1600 mg. daily was selected as the provisional RP2D. While no formal RECIST-based objective responses were observed, consistent with the drug’s non-cytotoxic mechanism of action, preliminary signals of anti-tumor and anti-metastatic activity were observed. These include dose proportional increases in duration of treatment, progression-free-survival, and metastasis-free interval, in particular for 4/4 late-stage ovarian cancer patients (table). Comparison of time on treatment (TOT) for ovarian cancer patients. Conclusions: In this first-in-human clinical trial, the novel fascin inhibitor, NP-G2-044, appeared safe and well tolerated. Signals of single-drug anti-tumor and anti-metastatic activity were observed. A phase 2A clinical trial with a particular focus on Ovarian Cancer will seek to elucidate signals of RP2D activity in both monotherapy and the combination of NP-G2-044 with anti-PD-(L)1 immune checkpoint inhibitors. Clinical trial information: NCT03199586. [Table: see text]

Fas gene promoter –670 polymorphism in gynecological cancer

2006 ◽  
Vol 16 (Suppl 1) ◽  
pp. 179-182 ◽  
Author(s):  
M. Ueda ◽  
Y. Terai ◽  
K. Kanda ◽  
M. Kanemura ◽  
M. Takehara ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cervical Cancer ◽  
Cancer Patients ◽  
Germ Line ◽  
Gynecological Cancer ◽  
Gene Promoter ◽  
Single Nucleotide ◽  
Increased Risk ◽  
Significant Difference ◽  
Germ Line Polymorphism

Single-nucleotide polymorphism at −670 of Fas gene promoter (A/G) was examined in a total of 354 blood samples from normal healthy women and gynecological cancer patients. They consisted of 95 normal, 83 cervical, 108 endometrial, and 68 ovarian cancer cases. Eighty-three patients with cervical cancer had statistically higher frequency of GG genotype and G allele than 95 controls (P= 0.0353 and 0.0278, respectively). There was no significant difference in the genotype or allele prevalence between control subjects and endometrial or ovarian cancer patients. The Fas −670 GG genotype was associated with an increased risk for the development of cervical cancer (OR = 2.56, 95% CI = 1.08–6.10) compared with the AA genotype. The G allele also increased the risk of cervical cancer (OR = 1.60, 95% CI = 1.05–2.43) compared with the A allele. Germ-line polymorphism of Fas gene promoter −670 may be associated with the risk of cervical cancer in a Japanese population.

The burden of polypharmacy and drug–drug interactions in older cancer patients treated with immunotherapy

2021 ◽  
pp. 107815522110120
Author(s):  
Deniz C Guven ◽  
Gozde Kavgaci ◽  
Oktay H Aktepe ◽  
Hasan C Yildirim ◽  
Taha K Sahin ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Cancer Patients ◽  
Injury Risk ◽  
Checkpoint Inhibitors ◽  
High Rate ◽  
Potentially Inappropriate Medications ◽  
Inappropriate Prescription ◽  
Prescription Practices ◽  
Increased Risk ◽  
Older Cancer Patients

Introduction Polypharmacy is a common problem in older cancer patients, although the data about polypharmacy and potentially inappropriate prescription practices is limited in patients treated with immune checkpoint inhibitors (ICIs). Therefore, we aimed to evaluate the polypharmacy frequency and drug-drug interactions in older cancer patients (≥65 years) treated with ICIs. Methods A total of 70 geriatric patients with advanced cancer were included. The polypharmacy was defined as regular use of 5 or more drugs. The START/STOPP Criteria Version 2 was used for the potentially inappropriate medications (PIM) and potential prescription omissions (PPO). The Medscape Drug Interaction Checker was used for potential drug-drug interactions. Results The patients had a median of 6 regular drugs, and polypharmacy was present in 77.1%. The polypharmacy risk was significantly increased in patients over 75 years of age (p = 0.028) and with opioid use (p = 0.048). The 50% of patients had category D or X interactions. Patients with higher Charlson Comorbidity Index had significantly increased risk for drug interactions (CCI ≤10 vs. >10, p = 0.017). The PIMs were present in 44.3% and the PPOs in 68.6% of the patients. While the overall survival and immune related adverse events were similar according to polypharmacy, in patients using seven or more drugs, the acute kidney injury risk was increased (HR: 4.667, p = 0.038). Conclusion In this study, we observed a high rate of polypharmacy and inappropriate prescription practices in ICI-treated patients. These issues pointed out the need for improved general medical care and attention for better comedication management in ICI-treated patients.

scholarly journals Colorectal Cancer Risk in Women with Gynecologic Cancers—A Population Retrospective Cohort Study

2021 ◽  
Vol 10 (14) ◽  
pp. 3127
Author(s):  
Szu-Chia Liao ◽  
Hong-Zen Yeh ◽  
Chi-Sen Chang ◽  
Wei-Chih Chen ◽  
Chih-Hsin Muo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Ovarian Cancer ◽  
Cervical Cancer ◽  
Cohort Study ◽  
Cancer Patients ◽  
Retrospective Cohort Study ◽  
Retrospective Cohort ◽  
Gynecologic Cancer ◽  
Ovarian Cancers ◽  
Increased Risk

We conducted a retrospective cohort study to evaluate the subsequent colorectal cancer (CRC) risk for women with gynecologic malignancy using insurance claims data of Taiwan. We identified patients who survived cervical cancer (N = 25,370), endometrial cancer (N = 8149) and ovarian cancer (N = 7933) newly diagnosed from 1998 to 2010, and randomly selected comparisons (N = 165,808) without cancer, matched by age and diagnosis date. By the end of 2011, the incidence and hazard ratio (HR) of CRC were estimated. We found that CRC incidence rates were 1.26-, 2.20-, and 1.61-fold higher in women with cervical, endometrial and ovarian cancers, respectively, than in comparisons (1.09/1000 person–years). The CRC incidence increased with age. Higher adjusted HRs of CRC appeared within 3 years for women with endometrial and ovarian cancers, but not until the 4th to 7th years of follow up for cervical cancer survivals. Cancer treatments could reduce CRC risks, but not significantly. However, ovarian cancer patients receiving surgery alone had an incidence of 3.33/1000 person–years for CRC with an adjusted HR of 3.79 (95% CI 1.11–12.9) compared to patients without any treatment. In conclusion, gynecologic cancer patients are at an increased risk of developing CRC, sooner for those with endometrial or ovarian cancer than those with cervical cancer.

scholarly journals BRCA1andBRCA2mutations in ovarian cancer patients from China: ethnic-related mutations inBRCA1associated with an increased risk of ovarian cancer

2017 ◽  
Vol 140 (9) ◽  
pp. 2051-2059 ◽  
Author(s):  
Tingyan Shi ◽  
Pan Wang ◽  
Caixia Xie ◽  
Sheng Yin ◽  
Di Shi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Increased Risk

Identifying Potential Markers for Monitoring Progression to Ovarian Cancer Using Plasma Label-free Proteomics

2019 ◽  
Author(s):  
Wenjie Wang ◽  
Hongyu Xie ◽  
Bairong Xia ◽  
LiuChao Zhang ◽  
Ce Wang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Plasma Protein ◽  
Late Stage ◽  
Early Stage ◽  
Label Free ◽  
Absolute Quantitation ◽  
Keywords Ovarian Cancer ◽  
Benign Ovarian Tumor ◽  
Increased Risk

Abstract PurposeCancer antigen 125 (CA125) is considered to have high sensitivity but poor specificity for ovarian cancer. New biomarkers utilized to early detect and monitor the progression of ovarian cancer patients are critically needed. Methods A total of 80 patients including 16 early stage, and matched with 17 late stage, 23 benign ovarian tumor (BOT) and 24 uterine fibroid (UF) patients were utilized to perform plasma proteomics analysis using isobaric tag for relative and absolute quantitation (iTRAQ) method to identify differential diagnostic proteins of ovarian cancer patients. A validation set of 9 early stage, 11 late stage, 17 BOT and 16 UF collected by an independent cohort of samples with the same matching principles was examined to confirm the expressed levels of differential expression proteins by ELISA analysis. Results CRP and ARHGEF 11 were identified as potential diagnostic biomarkers of ovarian cancer. Results of area under the curve (AUC) analysis suggested that combination of diagnostic proteins and CA125 achieved a much higher diagnostic accuracy compared with CA125 alone (AUC values: 0.98 versus 0.80), especially improved the specificity (0.97 versus 0.77). In addition, elevated plasma CRP levels were associated with increased risk of ovarian cancer. Conclusions Current study found that plasma protein CRP was an indicator for monitoring the progression of ovarian cancer. Combination of plasma protein biomarkers with CA125 could be utilized to early diagnose of ovarian cancer patients. Keywords ovarian cancer, proteomics, diagnosis, progression, CRP

Tumor-Associated Macrophages as a Source of Functional Dendritic Cells in Ovarian Cancer Patients

2002 ◽  
Vol 102 (3) ◽  
pp. 291-301 ◽  
Author(s):  
Christina S. Chu ◽  
Edward Y. Woo ◽  
Alanna J. Toll ◽  
Stephen C. Rubin ◽  
Carl H. June ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dendritic Cells ◽  
Cancer Patients ◽  
Tumor Associated Macrophages

Rates of immunosuppressive treatment and hospitalization after checkpoint inhibitor therapy in melanoma and lung cancer patients with autoimmune diseases.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14140-e14140
Author(s):  
David Andrew Bender ◽  
Catherine Spina ◽  
Samuel P. Heilbroner ◽  
Eric Xanthopoulos ◽  
Tony J. C. Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Autoimmune Diseases ◽  
Cancer Patients ◽  
Checkpoint Inhibitors ◽  
Oral Prednisone ◽  
Immunosuppressive Treatment ◽  
Lung Cancer Patients ◽  
Pharmacy Claims ◽  
Increased Risk

e14140 Background: Immune checkpoint inhibitors (ICIs) are known to cause immune-related adverse events. Patients with autoimmune diseases (AID) were excluded from most ICI clinical trials due to the potentially high risk of adverse effects. Data on the safety of ICIs in patients with a diagnosis of AID is therefore limited. Methods: A retrospective cohort study was conducted using a de-identified large oncology health care and pharmacy claims database with data from March 2010 until April 2017. Patients analyzed had a diagnosis of either melanoma or lung cancer and were treated with either of the anti-PD-1 inhibitors nivolumab or pembrolizumab. We assessed whether patients with AID compared with no AID were more likely to require medical interventions within 180 days of ICI therapy. We determined the percentage of patients receiving oral prednisone, IV methylprednisolone, or were hospitalized, which may represent responses to ICI toxicity. Results: 16.7% (16/96) of patients with either melanoma or lung cancer and AID received oral prednisone treatment within 180 days of ICI treatment, while 8.3% (131/1573) of patients without AID received oral prednisone during the same period. 8.4% (16/190) of patients with AID received IV methylprednisolone compared to 3.6% (79/2190) of patients without AID. Among melanoma patients, 24.1% (13/54) of patients with AID were hospitalized following ICI treatment, compared to 5.8% (28/480) of patients without ICI. Among lung cancer patients, 38.2% (52/136) of patients with AID were hospitalized compared to 31.6% (541/1711) of patients without AID. All comparisons are significant at p < 0.05 except hospitalizations in lung cancer patients. Conclusions: Patients with AID were more likely to receive interventions after ICI treatment that may represent responses to immune-related adverse events, suggesting that patients with AID are at increased risk for toxicity when being treated with ICIs.

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