Combined regimen of inhalable STING agonist plus chemoimmunotherapy in platinum-resistant or platinum-refratory ovarian cancer: A randomized, open-label, phase II trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6071-6071
Author(s):  
Yan Zhang ◽  
Qian Mei ◽  
Yuanguang Meng ◽  
Meixia Chen ◽  
Yang Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Disease Control ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Critical Role ◽  
Objective Response ◽  
Advanced Ovarian Cancer ◽  
Effective Control ◽  
Hematological Toxicity ◽  
Platinum Resistant

6071 Background: Approximately 70% patients with advanced ovarian cancer have a relapse and ultimately succumb to their disease. Treatment options are limited in this context with an unacceptable low response (less than 20%). Immunotherapy with checkpoint inhibitors presented to date are not very convincing with 10-15% response because of inadequate immunity. We previously discovered the critical role of manganese in innate immune sensing of tumors by activating STING signaling. This ongoing, randomized, phase II study is to assess STING agonist plus nPP chemotherapy and anti-PD-1 antibody sintilimab in platinum-resistant/refractory ovarian cancer. Methods: Enrolled patients were 2:1 randomizedly assigned to receive nab-paclitaxel (180-220mg/m2), cisplatin (60-80mg/m2) and sintilimab 200mg per 3 weeks with (cohort 1) or without (cohort 2) inhalable MnCl2 (0.4mg/kg) daily. Safety was assessed by CTCAE v5.0, and clinical response by MRI or CT every 2 cycles referred to RECIST version 1.1. The primary endpoints were objective response rate (ORR) and safety. Key secondary end points were disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results: 27 patients were enrolled, and 21 were included in efficacy population by the end of Jan. 2020. All enrolled patients were with heavily treated history, median 4 lines of prior therapy, median 19 cycles of multiagent regimens. The addition of MnCl2 to the combined chemo-immunotherapy did not appear to exacerbate treatment-related adverse events (AEs). The most common AEs are hematological toxicity (87%), nausea (56%) and vomiting (47%) in both two cohorts. All 14 evaluable patients (14/19) from cohort 1 had an effective control (11 PR [78.6%], 3 SD [21.4%]) . Ten patients (71.4%) achieved PR at the first tumor scan assessment. For 8 cases from cohort 2, 7 were assessable and all showed SD, 4 of whom exhibited SD with enlarged lesions and disease progression after 4-cycle treatment. Conclusions: MnCl2 administration induced encouraging objective clinical responses (78.6%) and disease control (100%) in relapsed/refractory ovarian cancer. The combined regimen showed accepted and manageable safety profile. Clinical trial information: NCT03989336.

Multicenter Phase 2 Study of Combined Gemcitabine and Epirubicin as Second-Line Treatment for Patients With Advanced Ovarian Cancer

2010 ◽  
Vol 20 (6) ◽  
pp. 953-957 ◽  
Author(s):  
Viviana Murgia ◽  
Roberto Sorio ◽  
Claudia Griso ◽  
Orazio Caffo ◽  
Carmela Arcuri ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Advanced Ovarian Cancer ◽  
Hematological Toxicity ◽  
Line Treatment ◽  
Second Line ◽  
Phase 2 ◽  
Platinum Resistant ◽  
Gynecology And Obstetrics

Objective:The aim of this phase 2 trial was to evaluate the tolerability and efficacy of combined gemcitabine (G) and epirubicin (E) as second-line treatment for patients with advanced ovarian cancer.Methods:Treatment with G 1000 mg/m2 (days 1 and 8) and E 60 mg/m2 (day 1) every 3 weeks for 3 or, in the absence of progression, 6 courses.Results:Fifty patients with advanced ovarian cancer (31 serous, 2 endometrioid, 10 unclassified adenocarcinoma, and 7 other) and a median age of 60 years (range, 38-74 years) were enrolled after giving their informed consent. Performance status according to the Eastern Cooperative Oncology Group was 0 in 29 patients (58%), 1 in 17 patients (34%), and 2 in 4 patients (8%), and the initial stages according to the International Federation of Gynecology and Obstetrics were I to II in 4 patients (8%), III in 31 patients (62%), and IV in 15 patients (30%). They had previously received a median of 1.5 lines of treatment (range, 1-4). The median platinum-free interval was 5 months (range, 0-12 months): 32 patients had relapse within 6 months and 18 patients had relapse after 6 months.The response rate was 42% (2% complete response and 40% partial response), with a median duration of 7.2 months: the corresponding figures were 37.5% and 5.2 months in the platinum-resistant patients and 50% and 8.8 months in the platinum-sensitive patients. The main grade 3 to 4 hematological toxicity was neutropenia (56% of cases). After a median follow-up of 13.5 months, median progression-free survival was 5 months, and median overall survival was 23.5 months.Conclusions:This E + G combination seems to be active and safe in platinum-resistant/refractory patients.

Phase II trial of guadecitabine priming and pembrolizumab in platinum resistant recurrent ovarian cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6025-6025
Author(s):  
Daniela Matei ◽  
Alok Pant ◽  
John William Moroney ◽  
Gini F. Fleming ◽  
Edward Tanner ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Cytotoxic T Cell ◽  
Clinical Benefit Rate ◽  
Platinum Resistant ◽  
Grade 3 ◽  
Anti Tumor Activity

6025 Background: Platinum resistant ovarian cancer (PROC) remains a disease of high need. Immune checkpoint inhibitors (ICI) have modest activity. We hypothesized that priming with a hypomethylating agent (HMA) guadecitabine (G) will improve the anti-tumor activity of ICI in PROC by enhancing tumor cell recognition by CD8+ T cells. Methods: This open-label phase II study used a Simon’s two-stage design. Eligible patients (pts) had recurrent PROC; ECOG PS of 0-1; normal end organ function; and measurable disease. Up to 5 prior cytotoxic regimens were allowed. Treatment consisted of G 30mg/m2 sq D1-4 and pembrolizumab (P) 200mg iv D5. Each cycle was 21 days. The primary endpoint was response rate (RR). Secondary endpoints were progression-free survival (PFS), clinical benefit rate (CBR), and toxicity assessment. Translational endpoints were LINE1 methylation in PBMCs, global tumor methylation, and immune endpoints. Tumor biopsies were obtained at baseline and after 2 cycles. If 2 patients experienced clinical benefit in stage I [n = 16], enrollment proceeded to stage II. The null hypothesis was rejected for ≥ 6 responses in 35 evaluable patients. Results: 48 pts were enrolled, 43 were treated, and 33 were evaluable for response. Histology was serous (35), endometrioid (2), clear cell (3) and other (3). Median age was 63 (range 40-88) and median number of prior regimens was 4 [range 1-8]. Two PRs were recorded in the first stage, allowing second stage of enrollment. Overall, there were 2 PRs (RR = 6.6%) and 16 pts had stable disease (SD) [48%]. The clinical benefit rate (PR + SD > 3 months) was 27%. One patient continued treatment for > 2 yrs. Grade 3-4 related toxicities were neutropenia [20], lymphopenia, (9), anemia (2), neutropenic fever (1), rash (1), and others (8). There were 13 grade 3-4 SAEs and 4 grade 5 SAEs, assessed as being unrelated to treatment. LINE1 was hypomethylated in PBMCs D5 vs. D1 (n = 21, p = 0.001). Epic arrays measured global tumor methylation, with 39579 CpG sites (0.05%) being differentially methylated (C2D5 vs. C1D1, n = 11, paired t-test; p < 0.01). Main pathways affected included endosomal transport, K+ transport, cathecolamine secretion, etc. PDL1 staining in archival tissue showed tumor staining > 0 in 16 of 35 and tumor/stroma interface staining > 0 in 20 of 35 specimens. Antigen-specific cytotoxic T cell activity was increased in CD8+ cells from ascites (C2D5 vs. C1D1). Conclusions: G+P has modest anti-tumor activity in patients with PROC, but some patients experienced prolonged disease stabilization. Biomarkers of response are being investigated. Clinical trial information: NCT02901899.

Clinical activity of imatinib mesylate in combination with docetaxel in patients with advanced, platinum-resistant ovarian cancer—Hoosier Oncology Group GYN03–62

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5091-5091 ◽  
Author(s):  
D. Matei ◽  
R. E. Emerson ◽  
N. Menning ◽  
J. Schilder ◽  
J. McClean ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Response Rate ◽  
Advanced Ovarian Cancer ◽  
Ovarian Tumors ◽  
Phase Ii Clinical Trial ◽  
Ovarian Cancer Cells ◽  
Clinical Activity ◽  
Platinum Resistant

5091 Background: Ovarian tumors harborc-Kit and PDGF receptors. We showed in an in-vitro model that Imatinib (G) inhibits the growth of ovarian cancer cells. We hypothesized that G in combination with chemotherapy inhibits the growth of ovarian tumors. Data from a phase II clinical trial utilizing G in combination with Docetaxel (D) in patients with advanced ovarian cancer (OC) are presented. Methods: This was an open label, one stage, multi-center phase II clinical trial. Planned sample size was 23. Patients with relapsed, platinum-resistant or refractory OC expressing PDGFR or c-kit were eligible. PDGFR and c-kit expression was assessed prior to enrollment by IHC using archival tumor tissue. G was administered at 600mg/d continuously and D was given weekly (30mg/m2) for 4 weeks, with 2 weeks break. Each cycle was 6 weeks, with a maximum of 6 cycles allowed. Tumor assessments were obtained after 2, 4 and 6 cycles. Response rate by RECIST was the primary endpoint. Results: 34 patients were screened. 17 tumors were c-kit + and 25 were PDGFRα +. 23 patients were enrolled. Of those, 4 patients had c-kit+/PDGFR- tumors, 12 were PDGFR+/c-kit- and 7 were c-kit+/PDGFR+. Median age was 55 (range 33–76) and median PS was 0 (range 0–2). Median number of prior treatments was 3 (range 1–9). Efficacy and toxicity data are available for 20 and 14 patients, respectively. Based on RECIST, there were 3 patients with PR and 3 patients with SD lasting at least 12 weeks. Of these 6 patients, 2 pts were c-kit+, 2 were PDGFR+ and 2 were PDGFR and c-kit+. All 6 patients had carboplatin and taxane resistant disease. Grade 3–4 toxicities were: neutropenia (2), thrombocytopenia (1), fatigue (1), dehydration (1), constipation (1), cardiac ischemia (1), nausea/vomiting (2), urinary frequency (1). Other G1–2 toxicities were: N/V (9), diarrhea (7), fatigue (8), mucositis (4), anemia (4), hypocalcemia (5), rash (6), anorexia (7), edema (5), hemolysis (1), non-neutropenic infections (7). Additional data will be available in May 2006. Conclusions: The combination G+D is tolerated well. Clinical activity consisted of 3 PRs (15% response rate) and 3 SD > 3 months in pts with heavily pre-treated, platinum resistant OC expressing c-kit or PDGFRα. [Table: see text]

Second-Line Treatment with Intravenous Gemcitabine and Oral Etoposide in Platinum-Resistant Advanced Ovarian Cancer Patients: Results of a Phase II Study

Oncology ◽  
2011 ◽  
Vol 80 (3-4) ◽  
pp. 238-246 ◽  
Author(s):  
M. Bruzzone ◽  
M.G. Centurioni ◽  
P. Giglione ◽  
M. Gualco ◽  
D.F. Merlo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Advanced Ovarian Cancer ◽  
Oral Etoposide ◽  
Line Treatment ◽  
Second Line ◽  
Platinum Resistant

Volasertib Versus Chemotherapy in Platinum-Resistant or -Refractory Ovarian Cancer: A Randomized Phase II Groupe des Investigateurs Nationaux pour l'Etude des Cancers de l'Ovaire Study

2016 ◽  
Vol 34 (7) ◽  
pp. 706-713 ◽  
Author(s):  
Eric Pujade-Lauraine ◽  
Frédéric Selle ◽  
Béatrice Weber ◽  
Isabelle-Laure Ray-Coquard ◽  
Ignace Vergote ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Ovarian Cancer ◽  
Disease Control ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Progression Free Survival ◽  
Platinum Resistant ◽  
Grade 3

Purpose Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. This phase II trial evaluated volasertib or single-agent chemotherapy in patients with platinum-resistant or -refractory ovarian cancer who experienced failure after treatment with two or three therapy lines. Patients and Methods Patients were randomly assigned to receive either volasertib 300 mg by intravenous infusion every 3 weeks or an investigator’s choice of single-agent, nonplatinum, cytotoxic chemotherapy. The primary end point was 24-week disease control rate. Secondary end points included best overall response, progression-free survival (PFS), safety, quality of life, and exploratory biomarker analyses. Results Of the 109 patients receiving treatment, 54 received volasertib and 55 received chemotherapy; demographics were well balanced. The 24-week disease control rates for volasertib and chemotherapy were 30.6% (95% CI, 18.0% to 43.2%) and 43.1% (95% CI, 29.6% to 56.7%), respectively, with partial responses in seven (13.0%) and eight (14.5%) patients, respectively. Median PFS was 13.1 weeks and 20.6 weeks for volasertib and chemotherapy (hazard ratio, 1.01; 95% CI, 0.66 to 1.53). Six patients (11%) receiving volasertib achieved PFS fore more than 1 year, whereas no patient receiving chemotherapy achieved PFS greater than 1 year. No relationship between the expression of the biomarkers tested and their response was determined. Patients treated with volasertib experienced more grade 3 and 4 drug-related hematologic adverse events (AEs) and fewer nonhematologic AEs than did patients receiving chemotherapy. Discontinuation resulting from AEs occurred in seven (13.0%) and 15 (27.3%) patients in the volasertib and chemotherapy arms, respectively. Both arms showed similar effects on quality of life. Conclusion Single-agent volasertib showed antitumor activity in patients with ovarian cancer. AEs in patients receiving volasertib were mainly hematologic and manageable.

Uplift (ENGOT-ov67): A pivotal cohort to evaluate XMT-1536 (upifitamab rilsodotin), a NaPi2b-directed antibody drug conjugate for platinum-resistant ovarian cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5607-TPS5607
Author(s):  
Debra L. Richardson ◽  
Erika P. Hamilton ◽  
Ana Oaknin ◽  
Leslie M. Randall ◽  
Susana N. Banerjee ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Advanced Ovarian Cancer ◽  
Primary Objective ◽  
Antibody Drug Conjugate ◽  
Regulatory Review ◽  
Platinum Resistant

TPS5607 Background: XMT-1536 (upifitamab rilsodotin), is a first-in-class Dolaflexin ADC targeting NaPi2b, a sodium-dependent phosphate transport protein, broadly expressed in solid tumors such as serous epithelial ovarian cancer (OC) and non-small cell lung adenocarcinoma. XMT-1536 uses the Dolaflexin platform to deliver approximately 10 DolaLock auristatin payload molecules per antibody and is being evaluated in a Phase I study (NCT03319628). Observation of preliminary antitumor activity was reported in the ovarian cancer expansion cohort, including in patients previously treated with bevacizumab and PARPi (Tolcher et al, ASCO 2019; Richardson et al, ASCO 2019; Hamilton et al, ESMO 2020). Updated data on the OC cohort included 31 patients with higher NaPi2b expression as of December 2020 (Mersana Therapeutics, 2021). In these patients, the ORR was 32% and the DCR was 74%. Complete responses were observed in 2 patients with platinum-resistant ovarian cancer, both of whom had received prior treatment with bevacizumab and PARP inhibitors. Platinum resistant ovarian cancer remains a serious unmet medical need as treatment options are limited and response rates to these treatments are low. Based on the favorable safety and efficacy profile of XMT-1536, UPLIFT was designed as a Phase 2 single-arm registrational cohort of patients with platinum resistant ovarian cancer as part of the ongoing Phase I FIH dose escalation and expansion study to accelerate development and provide a streamlined pathway to regulatory review. Methods: The UPLIFT cohort is enrolling patients with platinum resistant high grade serous ovarian, fallopian tube and primary peritoneal cancer with up to 4 prior lines of therapy. The RP2D of XMT-1536 was determined to be 43 mg/m2 administered intravenously every 4 weeks (q4w) and will be the dose evaluated in the UPLIFT cohort. UPLIFT will enroll approximately 180 patients with platinum-resistant advanced ovarian cancer to obtain approximately 100 patients with higher NaPi2b expression. Prior bevacizumab is required for those patients with 1 or 2 prior lines of therapy. Tumor samples (fresh or archived) will be collected prior to enrollment for retrospective tumor tissue evaluation of NaPi2b expression. The primary objective is assessment of confirmed objective response rate to XMT-1536 as assessed by Investigator in patients with higher NaPi2b expression. Secondary endpoints include confirmed objective response rate regardless of NaPi2b expression, duration of response, and adverse events. Correlative aims include assessing blood and tissue biomarkers for association with clinical benefit. This study is being conducted in collaboration with ENGOT and GOG. Patients will be enrolled globally. Clinical trial information: NCT03319628.

A phase 1b/2 study of napabucasin with weekly paclitaxel in advanced, previously treated platinum resistant ovarian cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5548-5548 ◽  
Author(s):  
Carlos Becerra ◽  
Agustin A. Garcia ◽  
John L. Hays ◽  
Michael W. Method ◽  
Stephen Lane Richey ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Objective Response ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Complete Response ◽  
Dose Escalation Study ◽  
Clinical Safety ◽  
Platinum Resistant ◽  
Grade 3 ◽  
Expansion Cohort

5548 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Napabucasin has shown potent synergistic preclinical anti-tumor activity with paclitaxel (PTX). In a phase Ib dose escalation study in patients (pts) with advanced solid tumors, napabucasin plus weekly PTX was well tolerated. A phase II expansion cohort was opened for patients with platinum resistant ovarian cancer. Methods: Pts with advanced ovarian cancer who had disease progression either during or in the 6 months following platinum-based systemic therapy were enrolled. napabucasin was administered orally at a starting dose of 240, 480, or 500 mg twice daily with PTX 80 mg/m2 IV weekly on 3 of every 4 weeks. AEs were evaluated using CTCAE v4.03 and objective assessments were performed per RECIST 1.1 every 8 weeks. Results: A total of 98 pts were enrolled. The average number of prior lines of systemic treatment was 3.5, including prior taxane-based therapy in 100% of patients. Treatment was well tolerated. Related grade 3 adverse events occurring ≥ 5% of pts included diarrhea (12.2%) and vomiting (5.1%). Among pts who received RECIST evaluation (n = 76), the disease control rate (DCR, proportion with SD at 8 weeks + PR + CR) was 65%, and the objective response rate (ORR, PR+CR) was 20%, with complete response in 3 pts (4%). In all patients (ITT, n = 98), the median progression-free survival (mPFS) was 3.0 months and median overall survival (mOS) was 9.3 months. Conclusions: Clinical safety and encouraging signs of anti-cancer activity, including three complete responses, were observed in pts with pre-treated platinum resistant ovarian cancer who received treatment with napabucasin plus weekly PTX. Further clinical evaluation in controlled trials is warranted. Clinical trial information: NCT01325441.

Bevacizumab in patients with advanced platinum-resistant ovarian cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5006-5006 ◽  
Author(s):  
S. A. Cannistra ◽  
U. Matulonis ◽  
R. Penson ◽  
R. Wenham ◽  
D. Armstrong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Adverse Events ◽  
Phase Ii ◽  
Single Agent ◽  
Objective Response ◽  
Prior Chemotherapy ◽  
Multiple Tumor ◽  
Platinum Resistant ◽  
Phase Ii Studies ◽  
Duration Of Response

5006 Background: Bevacizumab (BV), a recombinant, humanized monoclonal antibody directed against vascular endothelial growth factor, has demonstrated clinical benefit in multiple tumor types. Activity in ovarian cancer (OC) has been reported in phase II studies in patients (pts) with recurrent disease. We now describe the activity/safety of BV in pts with platinum-resistant OC (PROC) that progressed after topotecan or liposomal doxorubicin (LD). Methods: Eligibility criteria for this multicenter, Phase II study included primary or secondary PROC that progressed within 3 months of topotecan or LD, 3 or fewer prior chemotherapy regimens, and a performance status (PS) 0 or 1. BV was dosed at 15 mg/kg q 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as defined by RECIST. A two-stage design was utilized with H1 set at 15%. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), and safety. Results: The study enrolled 44 of the intended 53 pts, closing early due to a higher than expected rate of gastrointestinal perforations (GIP). Baseline characteristics included median age 60 yrs (range 31–87); PS 0 in 26 pts, 1 in 18 pts; 2 prior chemotherapy regimens in 20 pts, 3 in 24 pts. Preliminary efficacy: ORR (CR+PR), 7/44 (16%). Median duration of response was 12 weeks, with 2 pts continuing on study >5 months. Serious adverse events (SAEs) were reported in 18/44 pts (41%). Selected SAEs included GIP 5 (11%; one occurred more than 30 days after coming off study while on paclitaxel and commercial Avastin®), bowel obstruction 5 (11%), arterial thromboembolic events 4 (9%), delayed wound healing 2 (5%), and one case each of pulmonary hypertension, hypertensive encephalopathy, and hypoxia. Conclusions: BV has single agent activity in women with PROC, but is associated with substantial toxicity in this population. Trials are ongoing in less heavily treated, newly diagnosed pts with OC to evaluate the efficacy and safety of BV in these disease settings. Identification of risk factors for BV-associated adverse events requires further study. [Table: see text]

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