A phase IA dose-escalation study of PHI-101, a new checkpoint kinase 2 inhibitor, for platinum-resistant recurrent ovarian cancer

Background PHI-101 is an orally available, selective checkpoint kinase 2 (Chk2) inhibitor. PHI-101 has shown anti-tumour activity in ovarian cancer cell lines and impaired DNA repair pathways in preclinical experiments. Furthermore, the in vivo study suggests the synergistic effect of PHI-101 through combination with PARP inhibitors for ovarian cancer treatment. The primary objective of this study is to evaluate the safety and tolerability of PHI-101 in platinum-resistant recurrent ovarian cancer. Methods Chk2 inhibitor for Recurrent EpitheliAl periToneal, fallopIan, or oVarian cancEr (CREATIVE) trial is a prospective, multi-centre, phase IA dose-escalation study. Six cohorts of dose levels are planned, and six to 36 patients are expected to be enrolled in this trial. Major inclusion criteria include ≥ 19 years with histologically confirmed epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal cancer. Also, patients who showed disease progression during platinum-based chemotherapy or disease progression within 24 weeks from completion of platinum-based chemotherapy will be included, and prior chemotherapy lines of more than five will be excluded. The primary endpoint of this study is to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of PHI-101. Discussion PHI-101 is the first orally available Chk2 inhibitor, expected to show effectiveness in treating recurrent ovarian cancer. Through this CREATIVE trial, DLT and MTD of this new targeted therapy can be confirmed to find the recommended dose for the phase II clinical trial. This study may contribute to developing a new combination regimen for the treatment of ovarian cancer. Trial registration ClinicalTrials.gov Identifier: NCT04678102.

Antitumor activity and safety of camrelizumab plus famitinib in patients with platinum-resistant recurrent ovarian cancer: results from an open-label, multicenter phase 2 basket study

BackgroundCombination treatments with immune-checkpoint inhibitor and antiangiogenic therapy have the potential for synergistic activity through modulation of the microenvironment and represent a notable therapeutic strategy in recurrent ovarian cancer (ROC). We report the results of camrelizumab (an anti-programmed cell death protein-1 antibody) in combination with famitinib (a receptor tyrosine kinase inhibitor) for the treatment of platinum-resistant ROC from an open-label, multicenter, phase 2 basket trial.MethodsEligible patients with platinum-resistant ROC were enrolled to receive camrelizumab (200 mg every 3 weeks by intravenous infusion) and oral famitinib (20 mg once daily). All patients had disease progression during or <6 months after their most recent platinum-based chemotherapy. Primary endpoint was confirmed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 based on investigator’s assessment. Secondary endpoints included disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), overall survival (OS), 12-month OS rate and safety profile.ResultsOf the 37 women enrolled, 11 (29.7%) patients had primary platinum resistant, 15 (40.5%) patients had secondary platinum resistant and 11 (29.7%) patients had primary platinum refractory disease. As the cut-off date of April 9, 2021, nine (24.3%) patients had achieved a confirmed objective response, the ORR was 24.3% (95% CI, 11.8 to 41.2) and the DCR was 54.1% (95% CI, 36.9 to 70.5). Patients with this combination regimen showed a median TTR of 2.1 months (range, 1.8–4.1) and a median DoR of 4.1 months (95% CI, 1.9 to 6.3). Median PFS was 4.1 months (95% CI, 2.1 to 5.7), and median OS was 18.9 months (95% CI, 10.8 to not reached), with the median follow-up duration of 22.0 months (range, 12.0–23.7). The estimated 12-month OS rate was 67.2% (95% CI, 49.4 to 79.9). The most common ≥grade 3 treatment-related adverse events were hypertension (32.4%), decreased neutrophil count (29.7%) and decreased platelet count (13.5%). One (2.7%) patient died of grade 5 hemorrhage that was judged possibly related to study treatment by investigator.ConclusionThe camrelizumab with famitinib combination appeared to show antitumor activity in heavily pretreated patients with platinum-resistant ROC with an acceptable safety profile. This combination might provide a novel alternative treatment strategy in platinum-resistant ROC setting and warranted further exploration.Trial registration numberNCT03827837.

Đánh giá kết quả điều trị bệnh nhân ung thư biểu mô buồng trứng tái phát bằng phác đồ paclitaxel tại Bệnh viện K

TÓM TẮT Đặt vấn đề: Ung thư biểu mô buồng trứng (UTBMBT) là bệnh ác tính của tế bào biểu mô buồng trứng. Bệnh có tiên lượng xấu. Mặc dù điều trị ban đầu tối ưu, UTBMBT sẽ tái phát và cần được điều trị. Điều trị UTBMBT tái phát còn gặp nhiều khó khăn. Nghiên cứu này nhằm đánh giá một số đặc điểm lâm sàng, cận lâm sàng UTBMBT tái phát kháng platinum và kết quả điều trị phác đồ paclitaxel nhóm bệnh nhân này. Phương pháp nghiên cứu: Chúng tôi đưa vào nghiên cứu 65 bệnh nhân được điều trị phác đồ paclitaxel cho ung thư biểu mô buồng trứng tái phát khángplatinum, thỏa mãn các tiêu chuẩn lựa chọn và tiêu chuẩn loại trừ. Với phương pháp nghiên cứu mô tả cắt ngang. Kết quả: Các vị trí tái phát thường gặp nhất là hạch (54,3%), phúc mạc (50%), gan (23,9%). Tăng CA125 ở thời điểm tái phát (77,8%) tỷ lệ đáp ứng chung là 22,5%. Tỷ lệ kiểm soát bệnh (bao gồm đáp ứng hoàn toàn, đáp ứng một phần và bệnh giữ nguyên) đạt 62,5%. Trung vị thời gian sống thêm không tiến triển 26,1 tuần (CI 95%: 20,9 - 28,4). Độc tính trên hệ tạo huyết là giảm bạch cầu đa nhân trung tính độ 1,2. Độc tính trên gan 9,3% chủ yếu tăng men gan độ 1,2. Không có độc tính trên thận. Các tác dụng không mong muốn khác như rụng tóc độ 2: 2,7%, viêm miệng gặp ở 2,1% bệnh nhân, thần kinh cảm giác 15%, chỉ gặp ở độ 1. Có mối liên quan giữa đáp ứng điều trị và nồng độ CA 125. Kết luận: Phác đồ paclitaxel sử dụng điều trị UTBMBT tái phát kháng platinum là phác đồ phù hợp về tính hiệu quả và an toàn cho các bệnh nhân UTBMBT đã trải qua phác đồ hóa trị trước đó. ABSTRACT OUTCOMES OFRECURRENT EPITHELIAL OVARIAN CANCER PATIENTS TREATED WITH PACLITAXEL REGIMEN AT K HOSPITAL Introduction: Epithelial ovarian cancer is a malignant abnormality of the epithelial cell of the ovary. The disease has a poor prognosis. Despite optimal initial therapy, the majority of patients will relapse and require further treatment. Treatment of recurrent ovarian cancer is still challenging. This study aims to describe clinical and subclinical characteristics of patients with platinum - resistant relapsed ovarian carcinoma and evaluate the treatment results of the paclitaxel regimen on these patients. Methods: We enrolled 65 patients with platinum - resistant recurrent epithelial ovarian cancer treated with paclitaxel regimen, met the inclusion and exclusion criteria. Results: The most common recurrent sites were lymph nodes (54.3%), peritoneum (50%), and liver (23.9%). CA125 increased at the time of recurrence (77.8%), the overall response rate was 22.5%. Disease control rates (including complete response, partial response, and stable disease) were achieved at 62.5%. Median progression - free survival was 26.1 weeks (95% CI: 20.9 - 28.4). Hematopoietic system toxicities include neutropenia of grade 1, 2. Hepatotoxicity occupied 9.3%, mainly liver enzymes elevation of grade 1, 2. No renal toxicity was observed. Other undesirable effects include hair loss of grade 2 (2.7%), stomatitis(2.1%), sensory nerve 15% but only grade 1. There was a relationship between treatment response and CA 125 levels. Conclusion: The paclitaxel regimen used to treat platinum - resistant recurrent epithelial ovarian cancer is the appropriate regimen in terms of efficacy and safety. After several lines of chemotherapy regimens. Keywords: Recurrent epithelial ovarian cancer, platinum - resistant, paclitaxel.

Comparison of the Efficacy and Safety of PARP Inhibitors as a Monotherapy for Platinum-Sensitive Recurrent Ovarian Cancer: A Network Meta-Analysis

BackgroundThe present COVID-19 pandemic has tended toward normality. To provide convenient, safe, and effective home treatment programs for patients with recurrent ovarian cancer (ROC), the clinical efficacy and safety of poly (ADP-ribose) polymerase inhibitor (PARPi) (including olaparib, niraparib, and rucaparib) monotherapy as a maintenance treatment for platinum-sensitive ROC were systematically evaluated.MethodsNumerous electronic databases were systematically searched for randomized controlled trials (RCTs) of PARPi maintenance treatment for ROC that were published before June 2021. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoint was grade 3-4 adverse effects (AEs). After data extraction and the quality evaluation of the included studies, Bayesian network meta-analysis (NMA) was performed using R software. The ability of each treatment was ranked using the surface under the cumulative ranking (SUCRA) curve.ResultsThe analysis included five studies and 1390 patients. The NMA results demonstrated that compared with the placebo, olaparib and niraparib exhibited significant benefits in the gBRCA-mutated population, and respectively reduced the risk of death by 31% (HR = 0.69, 95% CI: 0.53-0.90) and 34% (HR = 0.66, 95% CI: 0.44-0.99). Olaparib, niraparib, and rucaparib were all found to be very effective in prolonging PFS in patients with ROC. All three PARPi treatments increased the number of grade 3-4 AEs in patients with ROC as compared with the placebo.ConclusionsOverall, olaparib and niraparib maintenance treatment can significantly prolong the OS of patients with gBRCA mutations. Furthermore, the three investigated PARPi monotherapy maintenance treatments can prolong PFS regardless of BRCA mutation status. Although the incidence of AEs in the treatment groups was found to be significantly higher than that in the placebo group, the patients in the treatment group tolerated the treatment. Home oral PARPi treatment can balance tumor treatment and pandemic prevention and control, and is the most convenient, safe, and effective home treatment method available against the background of the current COVID-19 pandemic. Systematic Review Registrationhttps://inplasy.com/inplasy-2021-6-0033/.

Effect of combination of Yiqi Jianpi Yangxue Decoction and chemotherapy on quality of life and adverse reactions of patients with recurrent ovarian cancer

Purpose: To investigate the effect of combined treatment with Yiqi Jianpi Yangxue Decoction and chemotherapy (carboplatin + paclitaxel) on quality of life (QOL) and adverse reactions of patients with recurrent ovarian cancer (ROC).Methods: One hundred and fourteen (114) ROC patients in The Second Children & Women’s Healthcare of Jinan City were split into chemotherapy group (n = 60) and combination group (n = 54), based on whether or not they were treated with Yiqi Jianpi Yangxue Decoction. Differences in clinical efficacy, adverse reactions, levels of tumor marker, levels of immune indexes, and scores on Karnofsky Performance Status (KPS) between the two groups were evaluated.Results: Treatment effectiveness was higher in the combination group than in the chemotherapy group (p < 0.05). Compared with the chemotherapy group, post-treatment levels of HE4 and CA125 in the combination group were lower, while the levels of CD3+, CD4+ and CD8+, and population of NK cells were higher (p < 0.05). After treatment, the KPS score in the combination group was higher than the corresponding score in the chemotherapy group (p < 0.05).Conclusion: Combination of Yiqi Jianpi Yangxue Decoction and chemotherapy (carboplatin + paclitaxel) produces significant enhancement of clinical efficacy in the treatment of ROC. The combination treatment is highly safe, and improves the health status and QOL of patients. Therefore, the combination treatment appears to be suitable for the management of ovarian cancer.

High Density of CD16+ Tumor-Infiltrating Immune Cells in Recurrent Ovarian Cancer Is Associated with Enhanced Responsiveness to Chemotherapy and Prolonged Overall Survival

Background: Ovarian cancer (OC) is the most aggressive and fatal malignancy of the female reproductive system. Debulking surgery with adjuvant chemotherapy represents the standard treatment, but recurrence rates are particularly high. Over the past decades, the association between the immune system and cancer progression has been extensively investigated. However, the interaction between chemotherapy and cancer immune infiltration is still unclear. In this study, we examined the prognostic role of CD16 expression in OC, as related to the effectiveness of standard adjuvant chemotherapy treatment. Methods: We analyzed the infiltration by immune cells expressing CD16, a well-characterized natural killer (NK) and myeloid cell marker, in a tissue microarray (TMA) of 47 patient specimens of primary OCs and their matching recurrences by immunohistochemistry (IHC). We analyzed our data first in the whole cohort, then in the primary tumors, and finally in recurrences. We focused on recurrence-free survival (RFS), overall survival (OS), and chemosensitivity. Chemosensitivity was defined as RFS of more than 6 months. Results: There was no significant correlation between CD16 expression and prognosis in primary carcinomas. However, interestingly, a high density of CD16-expressing tumor-infiltrating immune cells (TICs) in recurrent carcinoma was associated with better RFS (p = 0.008) and OS (p = 0.029). Moreover, high CD16 cell density in recurrent ovarian carcinoma showed a significant association with chemosensitivity (p = 0.034). Univariate Cox regression analysis revealed that the high expression of CD16+ TIC in recurrent cancer biopsies is significantly associated with an increased RFS (HR = 0.49; 95% CI 0.24–0.99; p = 0.047) and OS (HR = 0.28; 95% CI 0.10–0.77; p = 0.013). However, this was not independent of known prognostic factors such as age, FIGO stage, resection status, and the number of chemotherapy cycles. Conclusions: The high density of CD16-expressing TICs in recurrent ovarian cancer is associated with a better RFS and OS, thereby suggesting a previously unsuspected interaction between standard OC chemotherapy and immune cell infiltration.

Epigenetic Therapy Augments Classic Chemotherapy in Suppressing the Growth of 3D High-Grade Serous Ovarian Cancer Spheroids over an Extended Period of Time

Recurrent high-grade serous ovarian cancer (HGSC) is clinically very challenging and prematurely shortens patients’ lives. Recurrent ovarian cancer is characterized by high tumor heterogeneity; therefore, it is susceptible to epigenetic therapy in classic 2D tissue culture and rodent models. Unfortunately, this success has not translated well into clinical trials. Utilizing a 3D spheroid model over a period of weeks, we were able to compare the efficacy of classic chemotherapy and epigenetic therapy on recurrent ovarian cancer cells. Unexpectedly, in our model, a single dose of paclitaxel alone caused the exponential growth of recurrent high-grade serous epithelial ovarian cancer over a period of weeks. In contrast, this effect is not only opposite under treatment with panobinostat, but panobinostat reverses the repopulation of cancer cells following paclitaxel treatment. In our model, we also demonstrate differences in the drug-treatment sensitivity of classic chemotherapy and epigenetic therapy. Moreover, 3D-derived ovarian cancer cells demonstrate induced proliferation, migration, invasion, cancer colony formation and chemoresistance properties after just a single exposure to classic chemotherapy. To the best of our knowledge, this is the first evidence demonstrating a critical contrast between short and prolonged post-treatment outcomes following classic chemotherapy and epigenetic therapy in recurrent high-grade serous ovarian cancer in 3D culture.