ABSTRACT
AIM: We investigated the efficacy and safety of durvalumab (D) with or without tremelimumab (T) in addition to single-agent chemotherapy (CT) in patients with platinum-resistant recurrent ovarian cancer (PROC) lacking homologous recombination repair (HRR) gene mutations. PATIENTS AND METHODS: KGOG 3045 was an open-label, investigator-initiated phase II umbrella trial. Patients with PROC without HRR gene mutations who had received ≥2 prior lines of therapy were enrolled. Patients with high PD-L1 expression (TPS ≥25%) were assigned to arm A (D + CT), whereas those with low PD-L1 expression were assigned to arm B (D + T75 + CT). After completing arm B recruitment, patients were sequentially assigned to arms C (D + T300 + CT) and D (D + CT). RESULTS: Overall, 58 patients were enrolled (5, 18, 17, and 18 patients in arms A, B, C, and D, respectively). The objective response rates were 20.0, 33.3, 29.4, and 22.2%, respectively. Grade 3-4 treatment-related adverse events were observed in 20.0, 66.7, 47.1, and 66.7 of patients, respectively, but were effectively managed. Multivariable analysis demonstrated that adding T to D + CT improved progression-free survival (adjusted HR, 0.435; 95% CI, 0.229-0.824; P = 0.011). Favorable response to chemoimmunotherapy was associated with MUC16 mutation (P = 0.0214), high EPCAM expression (P = 0.020), high matrix remodeling gene signature score (P = 0.017), and low FOXP3 expression (P = 0.047). Patients showing favorable responses to D + T + CT exhibited significantly higher EPCAM expression levels (P = 0.008) and matrix remodeling gene signature scores (P = 0.031) than those receiving D + CT. CONCLUSIONS: Dual immunotherapy with chemotherapy showed acceptable response rates and tolerable safety in HRR non-mutated PROC, warranting continued clinical investigation.
Subject(s)
Antibodies, Monoclonal, Humanized , Antibodies, Monoclonal , B7-H1 Antigen , Ovarian Neoplasms , Humans , Female , Epithelial Cell Adhesion Molecule , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
AIM: Angiogenesis inhibitor apatinib targets vascular endothelial growth factor receptors and improves the outcomes of patients with gynecologic malignancy. This study aimed to evaluate the efficacy and safety of angiogenesis inhibitor apatinib plus chemotherapy in recurrent platinum-resistant ovarian cancer (RPR-OC) patients. METHODS: This study retrieved 67 RPR-OC patients who received apatinib plus chemotherapy or chemotherapy alone and divided them into apatinib + chemo (N = 30) and chemo alone (N = 37) groups according to the actual medication. RESULTS: Objective response rate (36.7% vs. 16.2%, p = 0.056) and disease control rate (80.0% vs. 59.5%, p = 0.072) showed an increased trend in apatinib + chemo group versus chemo alone group. The progression-free survival (PFS) (p = 0.010) and overall survival (OS) (p = 0.042) were prolonged in apatinib + chemo group versus chemo alone group. The median (95%confidence interval [CI]) PFS was 5.9 (5.5-6.3) months in apatinib + chemo group and 3.8 (2.0-5.6) months in chemo alone group. The median (95%CI) OS was 20.5 (16.5-24.5) months in apatinib + chemo group and 13.6 (8.6-18.6) months in chemo alone group. Apatinib plus chemotherapy was independently related with better PFS (hazard ratio [HR]: 0.354, p < 0.001) and OS (HR: 0.116, p < 0.001). Subgroup analyses indicated that patients with a more serious disease condition might benefit more from apatinib plus chemotherapy. No difference was found in adverse events of all grade or grade ≥3 between the two groups (all p > 0.05). CONCLUSION: Angiogenesis inhibitor apatinib plus chemotherapy shows better treatment efficacy than chemotherapy alone with controllable safety profile in RPR-OC patients.
Subject(s)
Angiogenesis Inhibitors , Antineoplastic Combined Chemotherapy Protocols , Neoplasm Recurrence, Local , Ovarian Neoplasms , Pyridines , Humans , Pyridines/administration & dosage , Pyridines/therapeutic use , Pyridines/pharmacology , Female , Middle Aged , Ovarian Neoplasms/drug therapy , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/pharmacology , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Neoplasm Recurrence, Local/drug therapy , Aged , Drug Resistance, Neoplasm , Cohort Studies , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Progression-Free Survival , Treatment OutcomeABSTRACT
PURPOSE: Evaluate the antitumor activity and safety profile of the combination of mirvetuximab soravtansine and bevacizumab in patients with platinum-resistant ovarian cancer. METHODS: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, whose most recent platinum-free interval was ≤6 months, were administered mirvetuximab soravtansine (6 mg/kg adjusted ideal body weight) and bevacizumab (15 mg/kg), intravenously, once every 3 weeks. Eligibility included FRα expression by immunohistochemistry (IHC; ≥25% of cells with ≥2+ intensity). Prior bevacizumab and/or PARP inhibitor (PARPi) treatment were permitted. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and safety. RESULTS: Ninety-four patients received combination treatment with mirvetuximab soravtansine and bevacizumab. Median age was 62 years (range, 39-81). Fifty-two percent had ≥3 prior therapies; 59% had prior bevacizumab; and 27% had prior PARPi. ORR was 44% (95% CI 33, 54) with 5 complete responses, median DOR 9.7 months (95% CI 6.9, 14.1), and median PFS 8.2 months (95% CI 6.8, 10.0). Treatment-related adverse events were consistent with the profiles of each agent, with the most common being blurred vision (all grades 57%; grade 3, 1%), diarrhea (54%; grade 3, 1%), and nausea (51%; grade 3, 1%). CONCLUSION: The mirvetuximab soravtansine plus bevacizumab doublet is an active and well-tolerated regimen in patients with FRα-expressing platinum-resistant ovarian cancer. Promising activity was observed for patients regardless of level of FRα expression or prior bevacizumab. These data underscore the potential for mirvetuximab soravtansine as the combination partner of choice for bevacizumab in this setting.
Subject(s)
Antineoplastic Agents , Immunoconjugates , Ovarian Neoplasms , Humans , Female , Middle Aged , Bevacizumab/therapeutic use , Ovarian Neoplasms/pathology , Folate Receptor 1 , Drug Resistance, Neoplasm , Carcinoma, Ovarian Epithelial/drug therapy , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapyABSTRACT
OBJECTIVE: This study assessed the efficacy, safety, and health-related quality of life (HRQoL) of the treatment regimen of dostarlimab, a programmed death-1 inhibitor, combined with niraparib, a poly (ADP-ribose) polymerase inhibitor, in patients with BRCA wild type (BRCAwt) recurrent platinum-resistant ovarian cancer (PROC) who had previously received bevacizumab treatment. METHODS: This Phase II, open-label, single-arm, multicenter study, conducted in the USA, enrolled patients with recurrent PROC to receive niraparib and dostarlimab until disease progression or unacceptable toxicity (up to 3 years). A preplanned interim futility analysis was performed after the first 41 patients had undergone ≥1 radiographic evaluation (approximately 9 weeks from the first treatment). RESULTS: The prespecified interim futility criterion was met and the study was therefore terminated. For the 41 patients assessed, the objective response rate (ORR) was 7.3% (95% confidence interval: 1.5-19.9); no patients achieved a complete response, 3 patients (7.3%) achieved a partial response (duration of response; 3.0, 3.8, and 9.2 months, respectively), and 9 patients (22.0%) had stable disease. In total, 39 patients (95.1%) experienced a treatment-related adverse event, but no new safety issues were observed. HRQoL, assessed using FOSI, or Functional Assessment of Cancer Therapy - Ovarian Symptom Index scores, worsened over time compared with baseline scores. CONCLUSIONS: The study was terminated due to the observed ORR at the interim futility analysis. This highlights a need for effective therapies in treating patients with recurrent BRCAwt PROC.
Subject(s)
Antineoplastic Agents , Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/chemically induced , Quality of Life , Carcinoma, Ovarian Epithelial/drug therapy , Antineoplastic Agents/therapeutic use , Indazoles/adverse effects , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Neoplasm Recurrence, Local/drug therapyABSTRACT
OBJECTIVE: Assess if MEK inhibitor blockade of RAS-ERK pathway adaptive response in high grade serous ovarian cancers (HGSOC) improves platinum sensitivity. METHODS: Three HGSOC cell lines and three patient derived organoid (PDOs) samples from ascites of platinum resistant HGSOC patients were collected. Cell lines and PDOs were exposed to carboplatin and MEK inhibitors cobimetinib or trametinib. Cytotoxic effects of MEK inhibitors alone or combined with carboplatin were established. Western blots demonstrated RAS-ERK pathway blockage after MEK inhibitor treatment. RNA sequencing assessed gene expression after MEK inhibitor treatment. Cell line NF1 gene knockdown was performed with corresponding chemosensitivity levels. RESULTS: High carboplatin IC50 levels indicated platinum resistance in cell lines and PDOs. Cobimetinib induced cytotoxicity in cell lines and PDOs, while trametinib was less effective. Western blot confirmed MEK-ERK pathway blockage at minimal concentrations of MEK inhibitors in cell lines and PDOs. Phosphorylated-ERK levels of untreated cells indicated higher levels of RAS-ERK pathway activation in OVSAHO and OVCAR7 compared to OVCAR3. OVSAHO harbors a NF1 mutation and had highest levels of RAS-ERK activation. Cotreatment with carboplatin and MEK inhibitors showed varying synergistic cytotoxic effects at different combinations. Synergistic effect was most prominent in the OVSAHO carboplatin and cobimetinib combination. RNA sequencing identified downregulation of c-MYC and FOXM1 gene expression after MEK inhibitor treatment. NF1 gene knockdown showed an acquired increased IC50 compared to parental cells. CONCLUSION: MEK inhibitors block RAS-ERK pathways in platinum resistant HGSOC cells and PDOs. MEK inhibitors with carboplatin have select synergistic effects which may indicate a strategy to improve platinum sensitivity.
Subject(s)
Antineoplastic Agents , Ovarian Neoplasms , Humans , Female , MAP Kinase Signaling System/physiology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Carboplatin/pharmacology , Carboplatin/therapeutic use , Apoptosis , Cell Line, Tumor , Antineoplastic Agents/therapeutic use , Protein Kinase Inhibitors/pharmacology , Carcinoma, Ovarian Epithelial/drug therapy , Mitogen-Activated Protein Kinase KinasesABSTRACT
BACKGROUND: Single-agent chemotherapy with or without bevacizumab (Bev) is a standard therapy for platinum-resistant ovarian cancer (PR-OC). However, there is a lack of literature on chemotherapy agent selection in heterogenous PR-OC. Therefore, we aimed to clarify the heterogeneous treatment effects of each chemotherapy agent. METHODS: Patients who underwent single-drug chemotherapy agents or Bev combination therapy for PR-OC between January 2009 and June 2022 were included in this study. We assessed the impact of each chemotherapy agent on the time to treatment failure (TTF) according to histological type, platinum-free interval (PFI), and Bev usage. RESULTS: A total of 158 patients received 343 different chemotherapy regimens. In patients with clear cell carcinoma/mucinous carcinoma (CC/MC), gemcitabine (GEM) had the strongest effect with a median TTF of 5.3 months, whilst nedaplatin (NDP) had the lowest effect with a median TTF of 1.4 months. In contrast, in the non-CC/MC group, irinotecan (CPT-11) and NDP had a better TTF than GEM and pegylated liposomal doxorubicin (PLD). There were notable differences in the treatment efficacy of NDP according to PFI. Specifically, NDP prolonged the TTF in patients with a PFI ≥ 3 months. Compared with GEM alone, GEM + Bev tended to prolong the TTF more effectively; however, an additive effect was not observed with PLD + Bev. CONCLUSIONS: This study demonstrated that the effect of chemotherapy agents differed according to the tumor and background characteristics of the patient. Our findings will improve selection of effective therapies for patients with PR-OC by considering their background characteristics.
Subject(s)
Antineoplastic Agents , Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/pathology , Antineoplastic Agents/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Bevacizumab/therapeutic use , Doxorubicin/therapeutic use , Gemcitabine , Irinotecan/therapeutic use , Polyethylene Glycols , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
INTRODUCTION: To evaluate the efficacy of cytoreductive surgery versus chemotherapy for the treatment of limited regional, platinum-resistant ovarian cancer (PROC). MATERIALS AND METHODS: The clinical records of all patients with PROC treated in our center between March 2015 and March 2022 were retrospectively reviewed. We compared the oncology outcomes of patients who received cytoreduction or chemotherapy alone at relapse and presented information about postoperative adjuvant chemotherapy. RESULTS: Among 52 patients with limited regional recurrence, 40.4% (21/52) underwent cytoreduction because of platinum resistance, and 59.6% (31/52) received chemotherapy alone. No residual disease (R0) was achieved in 20 patients (95.2%). The severe morbidity rate within 30 days after the surgery was 15%. The median follow-up was 70.6 months. Compared with the chemotherapy alone group, the surgery group with R0 had better progression-free survival (PFS) (10.6 vs. 5.1 months; hazard ratio (HR) = 0.421; P = 0.0035) and post-relapse survival (PRS) (32.6 vs. 16.3 months; HR = 0.478; P = 0.047), but there was no difference in overall survival (OS) between the two groups. Laparoscopy is associated with lesser intraoperative blood loss with no differences in survival and postoperative complications compared to the open approach (P = 0.0042). Subgroup survival analysis showed that compared with chemotherapy alone, surgery prolonged PFS in patients regardless of tumor size (greater than or equal to 4 cm or less). Surgery group patients who achieved R0 had an objective response rate (ORR) of 36.8% (7/19), among whom 40% (4/10) received platinum rechallenge chemotherapy and 33.3% (3/9) were administered non-platinum chemotherapy. CONCLUSION: When well-selected PROC patients with limited regional recurrence achieved R0, their outcomes were superior to those of patients who received only chemotherapy with an acceptable morbidity rate. Laparoscope technology could be a reliable alternative surgical approach. The reintroduction of platinum agents may be considered following surgery. Further analyses in a larger population are warranted to elucidate the risks and benefits of this surgery and adjuvant chemotherapy strategy.
Subject(s)
Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/surgery , Ovarian Neoplasms/pathology , Cytoreduction Surgical Procedures , Retrospective Studies , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/surgery , Carcinoma, Ovarian Epithelial , RecurrenceABSTRACT
AIM: Apatinib is an effective treatment for patients with gynecological cancers. This study aimed to further explore the efficacy and safety of apatinib plus chemotherapy in patients with recurrent platinum-resistant ovarian cancer (PROC). METHODS: Totally, 105 patients with recurrent PROC receiving apatinib plus chemotherapy (N = 51) and chemotherapy alone (N = 54) were retrospectively enrolled in this cohort study. RESULTS: Objective response rate (37.3% vs. 14.8%) (p = 0.009) and disease control rate (80.4% vs. 61.1%) (p = 0.030) were increased in the apatinib plus chemotherapy group versus the chemotherapy group. The median (95% confidence interval [CI]) progression-free survival (PFS) and overall survival (OS) were 5.5 (3.4-7.6) and 21.4 (16.2-26.6) months in the apatinib plus chemotherapy group, and they were 3.8 (3.0-4.6) and 14.8 (11.9-17.7) months in the chemotherapy group. Meanwhile, the Kaplan-Meier curves revealed that PFS (p = 0.008) and OS (p = 0.012) were prolonged in the apatinib plus chemotherapy group versus the chemotherapy group. This finding was confirmed by multivariate Cox's proportional regression analyses: enter method (hazard ratio [HR] = 0.515, p = 0.007 for PFS; HR = 0.222, p < 0.001 for OS) and step-forward method (HR = 0.608, p = 0.019 for PFS; HR = 0.346, p = 0.001 for OS). Additionally, the incidence of hypertension was increased in the apatinib plus chemotherapy group versus the chemotherapy group (p = 0.038), while others were not different between the two groups (all p > 0.05). Grades 3 and 4 adverse events were neutropenia, hypertension, leukopenia, hand-foot syndrome, nausea and vomiting, fatigue, thrombocytopenia, and anemia in the apatinib plus chemotherapy group. CONCLUSION: Apatinib combined with chemotherapy is a superior choice over chemotherapy alone for recurrent PROC management.
Subject(s)
Ovarian Neoplasms , Paclitaxel , Humans , Female , Paclitaxel/adverse effects , Cohort Studies , Retrospective Studies , Neoplasm Recurrence, Local/therapy , Carcinoma, Ovarian Epithelial/drug therapy , Doxorubicin/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Ovarian cancer is the most lethal gynecologic cancer. High-grade serous carcinoma (HGSC) is the most frequent histologic subtype and while it is a highly platinum-sensitive cancer at initial treatment, nearly 90 % of stage IIIC patients recur in 5 years and eventually become resistant to platinum treatment. Historically, the definition of platinum-resistant disease is based on the time interval between last platinum therapy and recurrence shorter than 6 months. Nowadays the use of sophisticated imaging techniques and serum markers to detect recurrence makes the accuracy of this clinical definition less clear and even more debatable as we begin to better understand the molecular landscape of HGSC and markers of platinum resistance and sensitivity. HGSC is characterized by a low frequency of recurrent mutations, great genomic instability with widespread copy number variations, universal TP53 mutations, and homologous recombination deficiency in more than 50 % of cases. Platinum agents form DNA adducts and intra- and inter-strand cross-links in the DNA. Most of DNA repair pathways are involved at some point in the repair of platinum induced DNA damaging, most notably homologous recombination, Fanconi Anemia, and nucleotide excision repair pathways. Mechanisms of platinum resistance are related mostly to the limitation of platinum-DNA adduct formation by changing cellular pharmacology, and to the prevention of cell death after DNA damage due to alterations in DNA repair pathways and cell cycle regulation. Understanding these mechanisms of sensitivity and resistance may help to define the utility of platinum re-challenge in each situation and guide new therapeutic opportunities. Moreover, the discovery of mechanisms of synthetic lethality related to alterations in DNA repair and cell cycle regulation pathways has opened up a new avenue for drug therapy in the last decade. In the present article, we review pathways involved in platinum-induced DNA damage repair and their relationship with genomic alterations present in HGSC. Moreover, we report new treatment strategies that are underway to target these alterations.
Subject(s)
Carcinoma, Ovarian Epithelial/genetics , Drug Resistance, Neoplasm/genetics , Gene Expression Profiling , Animals , Antineoplastic Agents/therapeutic use , DNA Repair/drug effects , Female , Humans , Platinum Compounds/therapeutic useABSTRACT
PURPOSE: Platinum-resistant ovarian cancer (PROC) is usually treated with single-agent chemotherapy. A synergistic effect of gemcitabine and platinum has been reported in PROC. We evaluated the efficacy and safety of gemcitabine and carboplatin with or without bevacizumab (GC ± B) in patients with PROC. METHODS: From April 2014 to April 2018, patients with PROC received gemcitabine on days 1 and 8, and carboplatin on day 1, with or without bevacizumab (Bev) on day 1 every 3 weeks. The primary endpoint was objective response rate (ORR). The secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and rate of adverse events. RESULTS: In total, 215 cycles were administered to 31 patients, of whom 21 received Bev and the median number of cycle for each patient was 6 (range, 2-19). The median platinum-free interval (PFI) was 4 months. The ORR and DCR were 51.9% and 92.6%, respectively. Median PFS and OS were 7.9 months and 16.1 months, respectively. PFS and OS of patients with 3-6 months PFI were significantly longer than those with PFI < 3 months (median PFS, 9.7 vs. 5.8 months; p < 0.01; median OS, 20.0 vs. 12.1 months; p = 0.03). Grade 3 or 4 hematological toxicities observed included neutropenia (71.0%), leukopenia (54.8%), anemia (51.6%), and thrombocytopenia (25.8%). No other grade 2-4 nonhematological toxicity was observed except for hypertension in one and CBDCA hypersensitivity reaction in two. CONCLUSION: GC ± B may be effective and safe treatment alternative for PROC, especially with PFI of 3-6 months, despite hematological toxicity.
Subject(s)
Ovarian Neoplasms , Platinum , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , Carboplatin , Deoxycytidine/analogs & derivatives , Humans , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/etiology , GemcitabineABSTRACT
The aim of treatment in recurrent or refractory epithelial ovarian cancer is palliation. In a patient with platinum-resistant status, several chemotherapy regimens have been reported with similar response rates. Among these agents, the oral etoposide holds an advantage of the route of administration and management in the out-patient setting. This retrospective study was conducted to evaluate the effectiveness of oral etoposide. Data of patients with recurrent or refractory epithelial ovarian, primary peritoneal and fallopian tube cancer who received oral etoposide treatment in Ramathibodi Hospital, Mahidol University from January 1997 to December 2017 were collected. Progression-free survival (PFS) and overall survival (OS) were primary and secondary outcomes, respectively. The oral etoposide at a dose of 50 mg/m2 was prescribed. Sixty-six records were analysed. Median OS and median PFS were 8.3 months (95% confidence interval (CI): 6.8, 10.4) and 3.1 months (95%CI: 2.3, 3.9), respectively. Other factors including age, body mass index (BMI), histopathology subtype, primary treatment, result of the primary surgery, platinum status, site and size of recurrent cancer, treatment after discontinuation of oral etoposide and the line of chemotherapy regimen were not associated with the prognosis. The initial cancer stage was the only independent poor prognostic factor. The main toxicity was neutropenia. Impact StatementWhat is already known on this subject? After the recurrence of epithelial ovarian cancer, peritoneal cancer or fallopian tube cancer, the aim of treatment in this setting is palliation with accentuating on symptomatic control and enhancing the quality of life. According to previous clinical trials, the chemotherapy regimens which were considered as a second-line or beyond the second-line therapy have been reported with similar response rates. Among these agents, the oral etoposide could be administrated by oral route. There were several articles reported the effectiveness of oral etoposide in different dosage.What do the results of this study add? This study adds that administration of oral etoposide at a dose of 50 mg/m2 showed fairish oncologic outcomes with manageable toxicity.What are the implications of these findings for clinical practice and/or further research? The results will provide evidence that the oral etoposide can be considerate as a choice of palliative chemotherapy because of an advantage of the route of administration and management in the out-patient setting.
Subject(s)
Fallopian Tube Neoplasms , Ovarian Neoplasms , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Etoposide , Female , Humans , Neoplasm Recurrence, Local/pathology , Ovarian Neoplasms/pathology , Quality of Life , Retrospective StudiesABSTRACT
OBJECTIVE: GAS6 and AXL are expressed in high-grade serous ovarian cancer but not in normal ovarian tissue. AVB-500, a novel high affinity Fc-sAXL fusion protein, binds GAS6 preventing AXL signaling. This Phase 1b study (NCT03639246) evaluated safety, efficacy, and exploratory predictive markers of AVB-500 combined with paclitaxel (PAC) or pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer (PROC), and used a model informed drug development (MIDD) approach for identification of the recommended phase 2 dose (RP2D). METHODS: Eligible patients received AVB-500 at 10, 15, or 20 mg/kg IV q2wk combined with PAC (n = 23) or PLD (n = 30). Patients were treated until progression or unacceptable toxicity. All were followed for survival. RESULTS: No dose limiting toxicities were observed and serum GAS6 was completely suppressed across the three dose levels evaluated. AVB-500 + PAC yielded better clinical activity than AVB-500 + PLD with an ORR of 34.8% (8/23, 2 complete responses) and median DoR, PFS, and OS of 7.0, 3.1, and 10.3 months, respectively. Subgroup analyses showed AVB-500 + PAC patients who had no prior bevacizumab or whose AVB-500 trough levels were >13.8 mg/L exhibited the best clinical response. The ORR and median PFS and OS in patients with these characteristics were ≥50%, ≥7.5 months, and ≥19 months, respectively. Given AVB-500 nor the combination with chemotherapy was expected to cause DLTs, the RP2D of AVB-500 was 15 mg/kg identified using an MIDD approach. CONCLUSION: AVB-500 was well-tolerated in combination with PAC or PLD and contributed to the clinical activity of PAC in PROC patients. Subgroup analyses identified a population of PROC patients who may benefit the most from AVB-500 treatment, which will be further assessed in an ongoing Phase 3 PROC trial.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Ovarian Epithelial/drug therapy , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/drug therapy , Recombinant Fusion Proteins/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Ovarian Epithelial/pathology , Doxorubicin/administration & dosage , Doxorubicin/analogs & derivatives , Drug Resistance, Neoplasm/drug effects , Female , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Middle Aged , Neoplasm Recurrence, Local/pathology , Ovarian Neoplasms/pathology , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Polyethylene Glycols/administration & dosage , Proto-Oncogene Proteins/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Recombinant Fusion Proteins/adverse effects , Axl Receptor Tyrosine KinaseABSTRACT
OBJECTIVES: In a prospective study of platinum-resistant ovarian cancer patients, we examined whether the Disease-related Symptoms-Physical (DRS--P) scale of the NCCN/FACT-Ovarian Cancer Symptom Index-18 (NFOSI-18) is responsive to clinical change in patients estimated by their provider to survive at least six months. METHODS: The NFOSI-18, and other FACT measures, was collected at study entry and 3 and 6 months post-enrollment. Measures were compared for those who died or dropped off study prior to 3 months or prior to 6 months (assumed as health deterioration over time), or those who stayed on study through 6 months (presumed as stable disease over time). Statistical analyses included a fitted linear mixed model for estimating the group differences over time, Cox regression to assess the probability of survival with patient-reported outcomes, and effect size. RESULTS: DRS-P scores of patients who completed only one assessment were significantly lower compared to patients who were able to complete two assessments [5.9 points lower (2.0-9.8); p < 0.01], or three assessments [8.1 points lower (4.8-11.5); p < 0.01]. Measures of abdominal discomfort, functional well-being, emotional well-being, and quality of life were also significant, but treatment side effects were not. Further, in every scale except for neurotoxicity, higher (better) baseline scores were associated with a decreased likelihood of death, after adjusting for age, performance and disease status. CONCLUSION: The NFOSI-18 DRS-P scale is responsive to clinical change. It has potential as an indicator of changing health status with ovarian cancer disease progression, distinct from treatment side effects.
Subject(s)
Antineoplastic Agents/pharmacology , Ovarian Neoplasms/therapy , Patient Reported Outcome Measures , Quality of Life , Terminal Care/methods , Aged , Antineoplastic Agents/therapeutic use , Cancer Survivors/psychology , Cancer Survivors/statistics & numerical data , Disease Progression , Drug Resistance, Neoplasm , Female , Follow-Up Studies , Health Status , Humans , Middle Aged , Neoplasm Recurrence, Local , Ovarian Neoplasms/complications , Ovarian Neoplasms/mortality , Ovarian Neoplasms/psychology , Prospective Studies , Terminal Care/statistics & numerical dataABSTRACT
OBJECTIVES: To estimate the maximally tolerated dose (MTD) and describe toxicities associated with lenvatinib and weekly paclitaxel in patients with recurrent endometrial and platinum resistant epithelial ovarian cancer. METHODS: Using a 3 + 3 design patients were given weekly paclitaxel 80 mg/m2 IV day 1, 8, 15 and oral levantinib daily on a 28-day cycle. Lenvatinib dose levels were 8 mg, 12 mg, 16 mg, 20 mg. Toxicities were recorded using CTCAE v4.03 and response was determined with imaging after cycle 2, then every 3rd cycle, using RECIST 1.1 criteria. RESULTS: 26 patients were enrolled; 19 with ovarian cancer (14 high grade serous, 1 low grade serous, 2 clear cell, 1 endometrioid, and 1 carcinosarcoma), and 7 with endometrial cancer (3 serous, and 4 endometrioid). The MTD was established at lenvatinib 16 mg and weekly paclitaxel 80 mg/m2. Toxicities (all grades) occurring in ≥25% of patients included anemia, neutropenia, lymphopenia, mucositis, nausea, diarrhea, anorexia, hypertension, fatigue, proteinuria, epistaxis, hoarseness. Twenty-three patients were evaluable for response and PFS; 15 (65%) had a partial response, 7 (30%) stable, 1 (4%) progressive disease with an objective response rate of 65%; 71% in ovarian and 50% in endometrial cancer. Median progression free survival (PFS) is 12.4 months; 14.0 months in endometrial cancer, 7.2 months in ovarian cancer; 54% had a PFS > 6 months. The median duration of response for PR patients (n = 15) was 10.9 months. CONCLUSIONS: The regimen was tolerable with manageable side effects. Encouraging activity was observed in endometrial and ovarian cancer, and warrants further development.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Genital Neoplasms, Female/drug therapy , Peritoneal Neoplasms/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Carcinoma, Ovarian Epithelial/drug therapy , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Resistance, Neoplasm , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/metabolism , Fallopian Tube Neoplasms/drug therapy , Fallopian Tube Neoplasms/metabolism , Female , Genital Neoplasms, Female/metabolism , Humans , Middle Aged , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Paclitaxel/pharmacokinetics , Peritoneal Neoplasms/metabolism , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/adverse effects , Phenylurea Compounds/pharmacokinetics , Quinolines/administration & dosage , Quinolines/adverse effects , Quinolines/pharmacokineticsABSTRACT
Combination of chemotherapy and gene therapy provides an effective strategy for cancer treatment. However, the lack of suitable codelivery systems with efficient endo/lysosomal escape and controllable drug release/gene unpacking is the major bottleneck for maximizing the combinational therapeutic efficacy. In this work, we developed a photoactivatable Pt(IV) prodrug-backboned polymeric nanoparticle system (CNPPtCP/si(c-fos)) for light-controlled si(c-fos) delivery and synergistic photoactivated chemotherapy (PACT) and RNA interference (RNAi) on platinum-resistant ovarian cancer (PROC). Upon blue-light irradiation (430 nm), CNPPtCP/si(c-fos) generates oxygen-independent N3⢠with mild oxidation energy for efficient endo/lysosomal escape through N3â¢-assisted photochemical internalization with less gene deactivation. Thereafter, along with Pt(IV) prodrug activation, CNPPtCP/si(c-fos) dissociates to release active Pt(II) and unpack si(c-fos) simultaneously. Both in vitro and in vivo results demonstrated that CNPPtCP/si(c-fos) displayed excellent synergistic therapeutic efficacy on PROC with low toxicity. This PACT prodrug-backboned polymeric nanoplatform may provide a promising gene/drug codelivery tactic for treatment of various hard-to-tackle cancers.
Subject(s)
Antineoplastic Agents , Nanoparticles , Ovarian Neoplasms , Prodrugs , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Drug Delivery Systems , Drug Resistance, Neoplasm , Female , Genetic Therapy , Humans , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Photochemotherapy , Platinum , Polymers/therapeutic use , Prodrugs/therapeutic useABSTRACT
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.
Subject(s)
Biomarkers, Tumor/blood , Drug Resistance, Neoplasm , Ovarian Neoplasms/metabolism , Female , Humans , Ovarian Neoplasms/blood , Platinum/therapeutic use , PrognosisABSTRACT
OBJECTIVE: Report final results of a phase I/II study of VB-111, a targeted anti-cancer gene therapy with a dual mechanism: anti angiogenic/vascular disruption and induction of an anti-tumor directed immune response, in combination with paclitaxel in patients with platinum-resistant ovarian cancer. METHODS: Study NCT01711970 was a prospective, open label, dose escalation study assessing combination treatment of VB-111 and weekly paclitaxel. In the Phase I part of the study, patients were treated with escalating doses of intravenous VB-111 and paclitaxel. In Phase 2, patients were treated with therapeutic doses of VB-111 and paclitaxel 80 mg/m2. Assessments included safety, overall survival (OS), progression free survival (PFS), and tumor response (CA-125 and RECIST). RESULTS: 21 patients with recurrent platinum-resistant ovarian cancer were enrolled. 17/21 received the therapeutic dose. Patients had a median of 3 prior lines of therapy. Half of the subjects were platinum refractory, and half were previously treated with antiangiogenics. No DLTs were observed. VB-111 was well tolerated and associated with mild flu-like symptoms. In the therapeutic dose cohort, a 58% CA-125 GCIG response rate was seen in evaluable patients. The median OS was 16.6 months in patients treated with therapeutic dose compared to 5.8 months in sub-therapeutic dose (p = 0.028). Tumor specimens taken after treatment demonstrated tumor infiltrated with cytotoxic CD8 T-cells in regions of apoptotic cancer cells. CONCLUSIONS: Treatment with VB-111 in combination with paclitaxel was safe and well tolerated. Favorable tumor responses and overall survival outcomes were associated with induction of an immunotherapeutic effect.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Immunotherapy/methods , Ovarian Neoplasms/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Bleomycin/pharmacology , Bleomycin/therapeutic use , Cisplatin/pharmacology , Cisplatin/therapeutic use , Female , Humans , Middle Aged , Vinblastine/pharmacology , Vinblastine/therapeutic useABSTRACT
OBJECTIVES: To evaluate the safety and preliminary efficacy of demcizumab (DLL4 targeted IgG2 humanized monoclonal antibody; potent inhibitor of the Notch pathway) in combination with weekly paclitaxel in platinum-resistant epithelial ovarian cancer (EOC); and to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD). METHODS: We conducted a 3 + 3 dose-escalation trial in patients with recurrent, platinum-resistant EOC with RECIST v. 1.1 measurable disease and ≤4 prior chemotherapy regimens. Two dosing cohorts (2.5 mg/kg and 5 mg/kg) were targeted; however, an intermediate dose level (3.5 mg/kg) was to be evaluated if the 5 mg/kg dose was not tolerable. Demcizumab was administered on days 1 and 15 and paclitaxel, weekly on days 1, 8, and 15 for each of three 28-day cycles: the 3-cycle doublet could be repeated once if safe. Thereafter, paclitaxel was administered until unacceptable toxicity or disease progression. RESULTS: Nineteen patients were enrolled. No dose-limiting toxicities (DLT) were observed; however, the intermediate dose level (3.5 mg/kg) was enrolled and expanded based on emerging safety data from other trials in the demcizumab program. The MTD was not reached. The most common treatment emergent adverse events (TEAE) were diarrhea (68%), fatigue (58%), peripheral edema (53%), and nausea (53%). Pulmonary hypertension, grade 2 (n = 2) and grade 1 (n = 1), was observed. Overall response rate (ORR) was 21% (95% CI: 6-45%); clinical benefit rate (CBR) was 42% (95% CI: 20-66%). CONCLUSIONS: Demcizumab in combination with paclitaxel has a manageable toxicity profile and showed activity in patients with heavily pretreated platinum-resistant ovarian cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Ovarian Epithelial/drug therapy , Fallopian Tube Neoplasms/drug therapy , Ovarian Neoplasms/drug therapy , Peritoneal Neoplasms/drug therapy , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Dose-Response Relationship, Drug , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Progression-Free Survival , Survival AnalysisABSTRACT
OBJECTIVE: Pegylated liposomal doxorubicin (PLD) in vitro may have immunomodulatory abilities and preclinical evidence suggests it synergizes with immune checkpoint blockade. We hypothesized that combining PLD and pembrolizumab would be active in patients with platinum-resistant ovarian cancer (PROC). METHODS: This was a single-arm, multi-center phase II trial. Eligible patients had PROC with ≤2 prior lines of cytotoxic therapy for recurrent or persistent disease. Twenty-six patients were enrolled and given pembrolizumab 200 mg intravenously (IV) every 3 weeks and PLD 40 mg/m2 IV every 4 weeks. Patients were assessed radiographically every 8 weeks. The primary endpoint was clinical benefit rate (CBR), defined as complete response (CR) + partial response (PR) + stable disease (SD) ≥24 weeks. The study was powered to detect an improvement in CBR from 25% to 50%, with rejection of the null hypothesis if at least 10 patients achieved clinical benefit. T-cell inflamed gene expression profiles (GEP) and PD-L1 were assessed and correlated with clinical outcome. RESULTS: Twenty-three patients were evaluable for best overall response. The study satisfied its primary endpoint, with 12 patients achieving clinical benefit for a CBR of 52.2% (95% CI 30.6-73.2%). There were 5 PRs (21.7%) and 1 CR (4.3%), for an overall response rate (ORR) of 26.1%. Six patients had SD lasting at least 24 weeks. Combination therapy was well tolerated without unexpected toxicities. CONCLUSIONS: The combination of pembrolizumab and PLD was manageable, without unexpected toxicities, and showed preliminary evidence of clinical benefit in the treatment of platinum resistant ovarian cancer. ORR and median PFS of combination therapy in this study was higher than historical comparisons of PLD alone or anti-PD-1/PD-L1 agents alone. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02865811.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Ovarian Epithelial/drug therapy , Doxorubicin/analogs & derivatives , Ovarian Neoplasms/drug therapy , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Ovarian Epithelial/diagnosis , Carcinoma, Ovarian Epithelial/immunology , Carcinoma, Ovarian Epithelial/pathology , Disease Progression , Disease-Free Survival , Dose-Response Relationship, Drug , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Drug Administration Schedule , Drug Resistance, Neoplasm , Female , Humans , Infusions, Intravenous , Middle Aged , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/immunology , Ovarian Neoplasms/pathology , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/adverse effects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Progression-Free SurvivalABSTRACT
BACKGROUND: We present the study rationale and design of the JGOG3023 study, an open-label, parallel-arm, randomized, phase II trial that aimed to assess the efficacy and safety of chemotherapy with or without bevacizumab in patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who were previously treated with bevacizumab for front-line or platinum-sensitive ovarian cancer. We hypothesize that patients treated with a combination of single-agent chemotherapy and bevacizumab will show improved progression-free survival (PFS) compared with those treated with single-agent chemotherapy alone, in the setting beyond disease progression following prior bevacizumab treatment. METHODS/DESIGN: A total of 106 patients who have recurrence or progression of ovarian cancer, while receiving chemotherapy or within 6 months after the final dose of platinum, after completing at least three cycles of bevacizumab plus platinum chemotherapy will be randomized in a 1:1 ratio to treatment with single-agent chemotherapy or single-agent chemotherapy combined with bevacizumab. For chemotherapy, one of the following four drugs will be chosen by an investigator: pegylated liposomal doxorubicin, topotecan, paclitaxel, or gemcitabine. The primary endpoint is investigator-assessed PFS. The secondary endpoints are overall survival, objective response rate, number of paracentesis, and response rate by CA125. Safety will be evaluated by the incidence of adverse events. DISCUSSION: This study will assess the efficacy and safety of bevacizumab in combination with single-agent chemotherapy, which could be used continuously after disease progression following standard platinum-based chemotherapy with bevacizumab. TRIAL REGISTRATION: UMIN000017247 (registered April 22, 2015).