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.

Role of Circulating Biomarkers in Platinum-Resistant Ovarian Cancer

Ovarian cancer (OC) is the second most common cause of death in women with gynecological cancer. Considering the poor prognosis, particularly in the case of platinum-resistant (PtR) disease, a huge effort was made to define new biomarkers able to help physicians in approaching and treating these challenging patients. Currently, most data can be obtained from tumor biopsy samples, but this is not always available and implies a surgical procedure. On the other hand, circulating biomarkers are detected with non-invasive methods, although this might require expensive techniques. Given the fervent hope in their value, here we focused on the most studied circulating biomarkers that could play a role in PtR OC.

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.

Safety and efficacy of the tumor-selective adenovirus enadenotucirev with or without paclitaxel in platinum-resistant ovarian cancer: a phase 1 clinical trial

BackgroundTreatment outcomes remain poor in recurrent platinum-resistant ovarian cancer. Enadenotucirev, a tumor-selective and blood stable adenoviral vector, has demonstrated a manageable safety profile in phase 1 studies in epithelial solid tumors.MethodsWe conducted a multicenter, open-label, phase 1 dose-escalation and dose-expansion study (OCTAVE) to assess enadenotucirev plus paclitaxel in patients with platinum-resistant epithelial ovarian cancer. During phase 1a, the maximum tolerated dose of intraperitoneally administered enadenotucirev monotherapy (three doses; days 1, 8 and 15) was assessed using a 3+3 dose-escalation model. Phase 1b included a dose-escalation and an intravenous dosing dose-expansion phase assessing enadenotucirev plus paclitaxel. For phase 1a/b, the primary objective was to determine the maximum tolerated dose of enadenotucirev (with paclitaxel in phase 1b). In the dose-expansion phase, the primary endpoint was progression-free survival (PFS). Additional endpoints included response rate and T-cell infiltration.ResultsOverall, 38 heavily pretreated patients were enrolled and treated. No dose-limiting toxicities were observed at any doses. However, frequent catheter complications led to the discontinuation of intraperitoneal dosing during phase 1b. Intravenous enadenotucirev (1×1012 viral particles; days 1, 3 and 5 every 28-days for two cycles) plus paclitaxel (80 mg/m2; days 9, 16 and 23 of each cycle) was thus selected for dose-expansion. Overall, 24/38 (63%) patients experienced at least 1 Grade ≥3 treatment-emergent adverse event (TEAE); most frequently neutropenia (21%). Six patients discontinued treatment due to TEAEs, including one patient due to a grade 2 treatment-emergent serious AE of catheter site infection (intraperitoneal enadenotucirev monotherapy). Among the 20 patients who received intravenous enadenotucirev plus paclitaxel, 4-month PFS rate was 64% (median 6.2 months), objective response rate was 10%, 35% of patients achieved stable disease and 65% of patients had a reduction in target lesion burden at ≥1 time point. Five out of six patients with matched pre-treatment and post-treatment biopsies treated with intravenous enadenotucirev plus paclitaxel had increased (mean 3.1-fold) infiltration of CD8 +T cells in post-treatment biopsies.ConclusionsIntravenously dosed enadenotucirev plus paclitaxel demonstrated manageable tolerability, an encouraging median PFS and increased tumor immune-cell infiltration in platinum-resistant ovarian cancer.Trial registration numberNCT02028117.