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1.
J Clin Oncol ; : JCO2302076, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38776484

ABSTRACT

PURPOSE: The interleukin-6/Janus kinase (JAK)/signal transducers and activators of transcription 3 axis is a reported driver of chemotherapy resistance. We hypothesized that adding the JAK1/2 inhibitor ruxolitinib to standard chemotherapy would be tolerable and improve progression-free survival (PFS) in patients with ovarian cancer in the upfront setting. MATERIALS AND METHODS: Patients with ovarian/fallopian tube/primary peritoneal carcinoma recommended for neoadjuvant chemotherapy were eligible. In phase I, treatment was initiated with dose-dense paclitaxel (P) 70 mg/m2 once daily on days 1, 8, and 15; carboplatin AUC 5 intravenously day 1; and ruxolitinib 15 mg orally (PO) twice a day, every 21 days (dose level 1). Interval debulking surgery (IDS) was required after cycle 3. Patients then received three additional cycles of chemotherapy/ruxolitinib, followed by maintenance ruxolitinib. In the randomized phase II, patients were randomly assigned to paclitaxel/carboplatin with or without ruxolitinib at 15 mg PO twice a day for three cycles, IDS, followed by another three cycles of chemotherapy/ruxolitinib, without further maintenance ruxolitinib. The primary phase II end point was PFS. RESULTS: Seventeen patients were enrolled in phase I. The maximum tolerated dose and recommended phase II dose were established to be dose level 1. One hundred thirty patients were enrolled in phase II with a median follow-up of 24 months. The regimen was well tolerated, with a trend toward higher grade 3 to 4 anemia (64% v 27%), grade 3 to 4 neutropenia (53% v 37%), and thromboembolic events (12.6% v 2.4%) in the experimental arm. In the randomized phase II, the median PFS in the reference arm was 11.6 versus 14.6 in the experimental, hazard ratio (HR) for PFS was 0.702 (log-rank P = .059). The overall survival HR was 0.785 (P = .24). CONCLUSION: Ruxolitinib 15 mg PO twice a day was well tolerated with acceptable toxicity in combination with paclitaxel/carboplatin chemotherapy. The primary end point of prolongation of PFS was achieved in the experimental arm, warranting further investigation.

2.
Gynecol Oncol ; 185: 186-193, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38447347

ABSTRACT

OBJECTIVE: Evaluate the antitumor activity and safety profile of the triplet combination of mirvetuximab soravtansine (MIRV), carboplatin, and bevacizumab in recurrent, platinum-sensitive ovarian cancer. METHODS: Participants with recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer (1-2 prior lines of therapy) received MIRV (6 mg/kg adjusted ideal body weight), carboplatin (AUC5), and bevacizumab (15 mg/kg) once every 3 weeks. Carboplatin could be discontinued after 6 cycles per investigator discretion; continuation of MIRV+bevacizumab as maintenance therapy was permitted. Eligibility included folate receptor alpha (FRα) expression by immunohistochemistry (≥50% of cells with ≥2+ intensity; PS2+ scoring); prior bevacizumab was allowed. Tumor response, duration of response (DOR), progression-free survival (PFS), and adverse events (AEs) were assessed. RESULTS: Forty-one participants received triplet therapy, with a median of 6, 12, and 13 cycles of carboplatin, MIRV, and bevacizumab, respectively. The confirmed objective response rate was 83% (9 complete and 25 partial responses). The median DOR was 10.9 months; median PFS was 13.5 months. AEs (any grade) occurred as expected, based on each agent's safety profile; most common were diarrhea (83%), nausea (76%), fatigue (73%), thrombocytopenia (71%), and blurred vision (68%). Most cases were mild to moderate (grade ≤2), except for thrombocytopenia, for which most drug-related discontinuations occurred, and neutropenia. CONCLUSIONS: This triplet regimen (MIRV+carboplatin+bevacizumab) was highly active, with a tolerable AE profile in participants with recurrent, platinum-sensitive, FRα-expressing ovarian cancer. Thrombocytopenia was the primary cause of dose modifications. These outcomes compare favorably to historical data reported for platinum-based chemotherapy plus bevacizumab regimens in similar patient populations.


Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Bevacizumab , Carboplatin , Carcinoma, Ovarian Epithelial , Folate Receptor 1 , Immunoconjugates , Maytansine , Ovarian Neoplasms , Humans , Female , Bevacizumab/administration & dosage , Bevacizumab/adverse effects , Carboplatin/administration & dosage , Carboplatin/adverse effects , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Aged , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Adult , Maytansine/analogs & derivatives , Maytansine/adverse effects , Maytansine/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Immunoconjugates/administration & dosage , Immunoconjugates/adverse effects , Carcinoma, Ovarian Epithelial/drug therapy , Progression-Free Survival , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Fallopian Tube Neoplasms/drug therapy , Aged, 80 and over , Peritoneal Neoplasms/drug therapy , Thrombocytopenia/chemically induced
3.
Gynecol Oncol ; 180: 1-5, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38029652

ABSTRACT

OBJECTIVE: Investigate the prevalence of ERBB2/HER2 gene amplification among patients with gynecologic malignancies. METHODS: The American Association of Cancer Research (AACR) Genomics Evidence of Neoplasia Information Exchange (GENIE) (version 13.1) database was accessed and patients with endometrial, ovarian, and cervical cancer were identified. Patients with available data on the presence of copy-number gene alterations were selected for further analysis. Incidence of ERBB2 amplification following stratification by tumor site and histology was evaluated. Data from the OncoKB database, as provided by cBioPortal, was utilized to determine presence of pathogenic genomic alterations. RESULTS: A total of 6961 patients who met the inclusion criteria were identified: 49.1% with ovarian cancer, 45.2% with endometrial cancer and 5.7% with cervical cancer respectively. Overall incidence of ERBB2 amplification was 3.8%. Highest incidence of ERBB2 amplification was observed among patients with mucinous ovarian (14.4%), uterine serous (13.2%), uterine clear cell (9.4%), and uterine carcinosarcoma (7.9%). ERBB2 amplification was rare among patients with TP53 wild-type endometrioid endometrial cancer (0.4%). High incidence of mutations in genes of the PI3K pathway was observed among patients with ERBB2 amplified tumors. CONCLUSION: ERBB2 amplification is frequently encountered among patients with uterine serous carcinoma, and mucinous ovarian carcinoma. In addition, a high incidence was also observed among those with uterine clear cell carcinoma, and uterine carcinosarcoma. For patients with endometrioid endometrial carcinoma, incidence of ERBB2 amplification is low, especially in the absence of TP53 mutations.


Subject(s)
Carcinoma, Endometrioid , Carcinosarcoma , Endometrial Neoplasms , Genital Neoplasms, Female , Ovarian Neoplasms , Uterine Cervical Neoplasms , Uterine Neoplasms , Humans , Female , Genital Neoplasms, Female/genetics , Gene Amplification , Uterine Cervical Neoplasms/genetics , Phosphatidylinositol 3-Kinases/metabolism , Mutation , Ovarian Neoplasms/pathology , Uterine Neoplasms/genetics , Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Carcinoma, Endometrioid/pathology , Carcinosarcoma/pathology , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism
4.
N Engl J Med ; 389(23): 2162-2174, 2023 Dec 07.
Article in English | MEDLINE | ID: mdl-38055253

ABSTRACT

BACKGROUND: Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. METHODS: We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. RESULTS: A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). CONCLUSIONS: Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).


Subject(s)
Carcinoma, Ovarian Epithelial , Maytansine , Ovarian Neoplasms , Female , Humans , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Carcinoma, Ovarian Epithelial/genetics , Immunoconjugates/administration & dosage , Immunoconjugates/adverse effects , Immunoconjugates/therapeutic use , Maytansine/administration & dosage , Maytansine/adverse effects , Maytansine/analogs & derivatives , Maytansine/therapeutic use , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Folate Receptor 1/antagonists & inhibitors , Folate Receptor 1/genetics , Drug Resistance, Neoplasm/genetics , Platinum Compounds/pharmacology
5.
Gynecol Oncol ; 177: 14-19, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37611378

ABSTRACT

OBJECTIVE: Investigate the incidence of homologous recombination DNA damage response (HR-DDR) genomic alterations among patients with uterine sarcoma. METHODS: The American Association for Cancer Research GENIE v13.0 database was accessed and patients with uterine leiomyosarcoma, adenosarcoma, undifferentiated uterine sarcoma, high-grade endometrial stromal sarcoma, low-grade endometrial stromal sarcoma, and endometrial stromal sarcoma not otherwise specified were identified. We determined the incidence of pathogenic alterations in the following genes involved in HR-DDR: ATM, ARID1A, ATRX, BAP1, BARD1, BLM, BRCA2, BRCA1, BRIP1, CHEK2, CHEK1, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, MRE11, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, WRN. Data from the OncoKB database, as provided by cBioPortal, was utilized to determine the presence of pathogenic genomic alterations. RESULTS: A total of 509 patients contributing with 525 samples were identified. Median patient age at sample collection was 56 years while the majority were White (80.7%). The most common histologic subtype was leiomyosarcoma (63.8%) followed by adenosarcoma (12.3%). The overall incidence of HR-DDR genomic alterations was 28.2%. The most commonly altered genes were ATRX (18.2%), BRCA2 (4%), and RAD51B (2.6%). The highest incidence of HR-DDR genomic alterations was observed among patients with leiomyosarcoma (35.4%), adenosarcoma (27%) and undifferentiated uterine sarcoma (30%), while those with low-grade endometrial stromal sarcoma had the lowest (2.9%) incidence. CONCLUSIONS: Approximately 1 in 3 patients with uterine sarcoma harbor a pathogenic alteration in HR-DDR genes. Incidence is high among patients with uterine leiomyosarcoma and adenosarcoma.

6.
Nat Commun ; 14(1): 4513, 2023 07 27.
Article in English | MEDLINE | ID: mdl-37500647

ABSTRACT

This phase I, dose-escalation trial evaluates the safety of combining interferon-gamma (IFN-γ) and nivolumab in patients with metastatic solid tumors. Twenty-six patients are treated in four cohorts assessing increasing doses of IFN-γ with nivolumab to evaluate the primary endpoint of safety and determine the recommended phase two dose (RP2D). Most common adverse events are low grade and associated with IFN-γ. Three dose limiting toxicities are reported at the highest dose cohorts. We report only one patient with any immune related adverse event (irAE). No irAEs ≥ grade 3 are observed and no patients require corticosteroids. The maximum tolerated dose of IFN-γ is 75 mcg/m2, however based on a composite of safety, clinical, and correlative factors the RP2D is 50 mcg/m2. Exploratory analyses of efficacy in the phase I cohorts demonstrate one patient with a complete response, and five have achieved stable disease. Pre-planned correlative assessments of circulating immune cells demonstrate intermediate monocytes with increased PD-L1 expression correlating with IFN-γ dose and treatment duration. Interestingly, post-hoc analysis shows that IFN-γ induction increases circulating chemokines and is associated with an observed paucity of irAEs, warranting further evaluation. ClinicalTrials.gov Trial Registration: NCT02614456.


Subject(s)
Neoplasms , Nivolumab , Humans , Nivolumab/therapeutic use , Interferon-gamma , Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/adverse effects
7.
Clin Cancer Res ; 29(15): 2800-2807, 2023 08 01.
Article in English | MEDLINE | ID: mdl-37097611

ABSTRACT

PURPOSE: Addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to PARP inhibitors (PARPi) overcomes PARPi resistance in high-grade serous ovarian cancer (HGSOC) cell and mouse models. We present the results of an investigator-initiated study of combination PARPi (olaparib) and ATRi (ceralasertib) in patients with acquired PARPi-resistant HGSOC. PATIENTS AND METHODS: Eligible patients had recurrent, platinum-sensitive BRCA1/2 mutated or homologous recombination (HR)-deficient (HRD) HGSOC and clinically benefited from PARPi (response by imaging/CA-125 or duration of maintenance therapy; > 12 months first-line or > 6 months ≥ second-line) before progression. No intervening chemotherapy was permitted. Patients received olaparib 300 mg twice daily and ceralasertib 160 mg daily on days 1 to 7 of a 28-day cycle. Primary objectives were safety and objective response rate (ORR). RESULTS: Thirteen patients enrolled were evaluable for safety and 12 for efficacy; 62% (n = 8) had germline BRCA1/2 mutations, 23% (n = 3) somatic BRCA1/2 mutations, and 15% (n = 2) tumors with positive HRD assay. Prior PARPi indication was treatment for recurrence (54%, n = 7), second-line maintenance (38%, n = 5) and first-line treatment with carboplatin/paclitaxel (8%, n = 1). There were 6 partial responses yielding an ORR of 50% (95% confidence interval, 0.15-0.72). Median treatment duration was 8 cycles (range 4-23+). Grade (G) 3/4 toxicities were 38% (n = 5); 15% (n = 2) G3 anemia, 23% (n = 3) G3 thrombocytopenia, 8% (n = 1) G4 neutropenia. Four patients required dose reductions. No patient discontinued treatment due to toxicity. CONCLUSIONS: Combination olaparib and ceralasertib is tolerable and shows activity in HR-deficient platinum-sensitive recurrent HGSOC that benefited and then progressed with PARPi as the penultimate regimen. These data suggest that ceralasertib resensitizes PARPi-resistant HGSOCs to olaparib, warranting further investigation.


Subject(s)
Antineoplastic Agents , Ovarian Neoplasms , Animals , Female , Humans , Mice , Antineoplastic Agents/therapeutic use , Ataxia Telangiectasia Mutated Proteins/genetics , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Carcinoma, Ovarian Epithelial/drug therapy , Homologous Recombination , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Phthalazines , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
8.
Clin Cancer Res ; 29(8): 1515-1527, 2023 04 14.
Article in English | MEDLINE | ID: mdl-36441795

ABSTRACT

PURPOSE: PARP inhibitors have become the standard-of-care treatment for homologous recombination deficient (HRD) high-grade serous ovarian cancer (HGSOC). However, not all HRD tumors respond to PARPi. Biomarkers to predict response are needed. [18F]FluorThanatrace ([18F]FTT) is a PARPi-analog PET radiotracer that noninvasively measures PARP-1 expression. Herein, we evaluate [18F]FTT as a biomarker to predict response to PARPi in patient-derived xenograft (PDX) models and subjects with HRD HGSOC. EXPERIMENTAL DESIGN: In PDX models, [18F]FTT-PET was performed before and after PARPi (olaparib), ataxia-telangiectasia inhibitor (ATRi), or both (PARPi-ATRi). Changes in [18F]FTT were correlated with tumor volume changes. Subjects were imaged with [18F]FTT-PET at baseline and after ∼1 week of PARPi. Changes in [18F]FTT-PET uptake were compared with changes in tumor size (RECISTv1.1), CA-125, and progression-free survival (PFS). RESULTS: A decrease in [18F]FTT tumor uptake after PARPi correlated with response to PARPi, or PARPi-ATRi treatment in PARPi-resistant PDX models (r = 0.77-0.81). In subjects (n = 11), percent difference in [18F]FTT-PET after ∼7 days of PARPi compared with baseline correlated with best RECIST response (P = 0.01), best CA-125 response (P = 0.033), and PFS (P = 0.027). All subjects with >50% reduction in [18F]FTT uptake had >6-month PFS and >50% reduction in CA-125. Utilizing only baseline [18F]FTT uptake did not predict such responses. CONCLUSIONS: The decline in [18F]FTT uptake shortly after PARPi initiation provides a measure of drug-target engagement and shows promise as a biomarker to guide PARPi therapies in this pilot study. These results support additional preclinical mechanistic and clinical studies in subjects receiving PARPi ± combination therapy. See related commentary by Liu and Zamarin, p. 1384.


Subject(s)
Antineoplastic Agents , Ovarian Neoplasms , Humans , Female , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Pilot Projects , Antineoplastic Agents/therapeutic use , Ovarian Neoplasms/diagnostic imaging , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Carcinoma, Ovarian Epithelial/drug therapy , Biomarkers , Positron-Emission Tomography/methods
9.
J Clin Oncol ; 40(34): 3965-3974, 2022 12 01.
Article in English | MEDLINE | ID: mdl-36252167

ABSTRACT

PURPOSE: In patients with high-grade ovarian cancer, predictors of bevacizumab efficacy in first-line setting are needed. In the ICON-7 trial, a poor tumor intrinsic chemosensitivity (defined by unfavorable modeled cancer antigen-125 [CA-125] ELIMination rate constant K [KELIM] score) was a predictive biomarker. Only the patients with high-risk disease (suboptimally resected stage III, or stage IV) exhibiting unfavorable KELIM score < 1.0 had overall survival (OS) benefit from bevacizumab (median: 29.7 v 20.6 months; hazard ratio [HR], 0.78). An external validation study in the GOG-0218 trial was performed. METHODS: In GOG-0218, 1,873 patients were treated with carboplatin-paclitaxel ± concurrent-maintenance bevacizumab/placebo. Patient KELIM values were calculated with CA-125 kinetics during the first 100 chemotherapy days by the Lyon University team. The association between KELIM score (favorable ≥ 1.0, or unfavorable < 1.0) and bevacizumab benefit for progression-free survival (PFS)/OS was independently assessed by NGR-GOG using univariate/multivariate analyses. RESULTS: KELIM was assessable in 1,662 patients with ≥ 3 CA-125 available values. An unfavorable KELIM score was associated with bevacizumab benefit compared with placebo (PFS: HR, 0.70; 95% CI, 0.59 to 0.82; OS: HR, 0.87; 95% CI, 0.73 to 1.03), whereas a favorable KELIM was not (PFS: HR, 0.96; 95% CI, 0.79 to 1.17; OS: HR, 1.11; 95% CI, 0.89 to 1.39). The highest benefit was observed in patients with a high-risk disease exhibiting unfavorable KELIM, for PFS (median: 9.1 v 5.6 months; HR, 0.64; 95% CI, 0.53 to 0.78), and for OS (median: 35.1 v 29.1 months; HR, 0.79; 95% CI, 0.65 to 0.97). CONCLUSION: This GOG-0218 trial investigation validates ICON-7 findings about the association between poor tumor chemosensitivity and benefit from concurrent-maintenance bevacizumab, suggesting that bevacizumab may mainly be effective in patients with poorly chemosensitive disease. Bevacizumab may be prioritized in patients with a high-risk and poorly chemosensitive disease to improve their PFS/OS (patient KELIM score calculator available on the Biomarker Kinetics website).


Subject(s)
Ovarian Neoplasms , Paclitaxel , Female , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , CA-125 Antigen , Carboplatin , Carcinoma, Ovarian Epithelial/drug therapy , Disease-Free Survival , Ovarian Neoplasms/pathology
10.
J Natl Compr Canc Netw ; 20(9): 972-980, 2022 09.
Article in English | MEDLINE | ID: mdl-36075393

ABSTRACT

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.


Subject(s)
Cystadenocarcinoma, Serous , Ovarian Neoplasms , Peritoneal Neoplasms , Carcinoma, Ovarian Epithelial/diagnosis , Carcinoma, Ovarian Epithelial/therapy , Cystadenocarcinoma, Serous/pathology , Female , Humans , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/pathology , Ovarian Neoplasms/therapy , United States
11.
J Oncol Pharm Pract ; 28(5): 1102-1110, 2022 Jul.
Article in English | MEDLINE | ID: mdl-34134553

ABSTRACT

INTRODUCTION: Poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) have become a cornerstone of therapy in the management ovarian cancer and other cancers. PARPi are associated with significant toxicities and management strategies are primarily founded on clinical trial experience. This study aimed to provide an evaluation of patients receiving PARPi therapy within an academic health-system. METHODS: A retrospective, observational study of adult patients with gynecologic malignancy was conducted at the University of Pennsylvania Health System. Data was collected on patients prescribed a PARPi between December 2014 and October 2019. The primary endpoint was the status of PARPi therapy at the end of the study period. Key secondary endpoints included toxicity management strategies, time to discontinuation due to toxicity, progression free survival (PFS), and overall survival (OS). RESULTS: Of the 85 patients included, 45 (53%) received olaparib, 24 (28%) niraparib, and 16 (19%) rucaparib. Twenty-nine patients (34%) continued on therapy, 15 (18%) discontinued due to toxicity, and 41 (48%) discontinued due to progression. Fifty-one percent of patients required a dose reduction due to toxicities. The median time to discontinuation due to toxicity was 69 days (9-353). Median PFS was 181 days (9-365) and median OS was 338 days (9-365). CONCLUSION: PARPi therapy is associated with numerous toxicities that are best managed through a multi-modal approach. Importantly, about half the patients in the current study required a dose reduction. Overall, this observational study outlines the incidence of PARPi toxicities and reviews potential management strategies, further guiding practitioners in an area with limited real-world experience.


Subject(s)
Antineoplastic Agents , Endometrial Neoplasms , Ovarian Neoplasms , Adult , Humans , Female , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Retrospective Studies , Antineoplastic Agents/adverse effects , Ovarian Neoplasms/drug therapy , Endometrial Neoplasms/drug therapy
12.
Gynecol Oncol ; 163(2): 246-253, 2021 11.
Article in English | MEDLINE | ID: mdl-34620496

ABSTRACT

OBJECTIVE: Platinum-resistant, high-grade serous ovarian cancer (HGSOC) has limited treatment options. Preclinical data suggest that poly(ADP-ribose) polymerase inhibitors (PARPi) and ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) are synergistic. CAPRI (NCT03462342) is an investigator-initiated study of olaparib plus ceralasertib in recurrent HGSOC. Herein, we present results from the platinum-resistant cohort. METHODS: A Simon 2-stage design was utilized. Platinum-resistant HGSOC patients received ceralasertib 160 mg orally daily, days 1-7 and olaparib 300 mg orally twice daily, days 1-28 of a 28-day cycle until toxicity or progression. Primary endpoints were toxicity and efficacy including objective response rate (ORR) by RECIST. Secondary endpoint was progression-free survival (PFS). The null hypothesis (≤5% ORR) would be rejected if there were ≥ 1 responses in 12 patients. RESULTS: Fourteen PARPi-naïve patients were evaluable for toxicity; 12 were evaluable for response. Three had BRCA1 mutations (1 germline, 2 somatic). Adverse events possibly related to treatment were primarily grade (G) 1/2. G3 toxicities included nausea (14.3%), fatigue (7.1%), anorexia (7.1%), and anemia (7.1%). No objective responses occurred. Best response was stable disease in 9 patients and progressive disease in three. Five patients had a ≥ 20% to <30% reduction in disease burden, including 3 with BRCA1 mutations. Three of 11 patients (27%; 2 with BRCA1 mutations) evaluable by Gynecologic Cancer Intergroup criteria had >50% CA-125 decline, including 2 with CA-125 normalization. Median PFS was 4.2 months overall (90% CI:3.5-8.2) and 8.2 months (3.6 months-not determined) for patients with BRCA1 mutations. CONCLUSIONS: Olaparib plus ceralasertib is well-tolerated. No objective responses occurred, though a signal of activity was seen particularly in disease associated with BRCA1. Further evaluation of this combination should include alternate dosing strategies in genomically-selected populations.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Indoles/adverse effects , Morpholines/adverse effects , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/drug therapy , Phthalazines/administration & dosage , Piperazines/administration & dosage , Pyrimidines/adverse effects , Sulfonamides/adverse effects , Administration, Oral , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , BRCA1 Protein/genetics , Drug Administration Schedule , Drug Resistance, Neoplasm , Female , Humans , Indoles/administration & dosage , Magnetic Resonance Imaging , Middle Aged , Morpholines/administration & dosage , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/genetics , Ovarian Neoplasms/mortality , Ovary/diagnostic imaging , Ovary/pathology , Phthalazines/adverse effects , Piperazines/adverse effects , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Progression-Free Survival , Protein Kinase Inhibitors , Pyrimidines/administration & dosage , Response Evaluation Criteria in Solid Tumors , Sulfonamides/administration & dosage , Tomography, X-Ray Computed
13.
J Natl Compr Canc Netw ; 19(2): 191-226, 2021 02 02.
Article in English | MEDLINE | ID: mdl-33545690

ABSTRACT

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country's fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.


Subject(s)
Carcinoma, Ovarian Epithelial , Ovarian Neoplasms , Adenocarcinoma, Clear Cell , Carcinoma, Ovarian Epithelial/diagnosis , Carcinoma, Ovarian Epithelial/epidemiology , Carcinoma, Ovarian Epithelial/therapy , Female , Humans , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/therapy
14.
J Pain Symptom Manage ; 61(3): 566-570.e1, 2021 03.
Article in English | MEDLINE | ID: mdl-32976942

ABSTRACT

CONTEXT: A minority of patients with advanced or metastatic gynecologic cancer utilize palliative care and lack of knowledge may be a barrier to receiving palliative care services. OBJECTIVES: To identify sources used by patients with advanced or metastatic gynecologic cancer to learn about palliative care and evaluate for differences in knowledge about palliative care and palliative care utilization by knowledge source. METHODS: Patients with gynecologic cancer receiving treatment for advanced or metastatic gynecologic cancer at a single academic medical center were surveyed about their awareness of and knowledge about palliative care. Medical chart review was conducted. RESULTS: Of the 111 women surveyed, 70 had heard of palliative care (63%). Sixty-eight specified from where they learned of palliative care: cancer care (n = 28; 41.2%), word of mouth (n = 26; 38.2%), work (n = 6; 8.8%), self-education (n = 4; 5.9%), personal experience (n = 2; 2.9%), or do not know (n = 2; 2.9%). Knowledge about palliative care (P = 0.35) and palliative care utilization (P = 0.81) did not differ by awareness of palliative care. CONCLUSION: Most women receiving treatment for advanced gynecologic cancer have heard of palliative care from sources other than their cancer care providers. Knowledge about palliative care and source of knowledge about palliative care were not associated with palliative care utilization. Awareness of palliative care and palliative care utilization may be improved by increasing the low rate of health provider-based education and engaging cancer patients' social networks.


Subject(s)
Genital Neoplasms, Female , Hospice and Palliative Care Nursing , Academic Medical Centers , Female , Genital Neoplasms, Female/therapy , Humans , Palliative Care , Surveys and Questionnaires
15.
Gynecol Oncol ; 159(2): 394-401, 2020 11.
Article in English | MEDLINE | ID: mdl-32800655

ABSTRACT

OBJECTIVE: To determine the impact on overall survival (OS) of different modalities of adjuvant therapy for the treatment of stage III endometrial cancer (EC), by histology. METHODS: Stage 3 endometrioid (EAC), serous (SER), clear cell (CC), and carcinosarcoma (CS) patients who underwent primary surgical staging from 2000 to 2013 were identified in SEER-Medicare. Adjuvant therapy was defined by a 4-arm comparator grouping (none; RT only; CT only; combination RT), as well as by an 8-arm comparator grouping (none; RT only; CT only; concurrent CT-RT; concurrent CT-RT then CT; Serial CT-RT; serial RT-CT; sandwich). Modality of RT and CT were analyzed using Kaplan-Meier estimates, log rank tests, and multivariable cox modeling. RESULTS: Of 2870 cases identified (1798 EAC, 606 SER, 118 CC, 348 CS), 31.5% received no adjuvant therapy. The remainder received RT or CT alone, concurrent RT-CT, serial or sandwich modalities. OS differed by adjuvant therapy in adjusted and unadjusted models, when combining all histologies, and when stratifying by histology using both the 4-arm, and 8-arm comparator analyses (log rank p < .05, all). By histology, in adjusted analyses, sandwich modality had the greatest improvement in OS for endometrioid, but pairwise comparisons did not identify a superior chemotherapy-based regimen. For serous and clear cell, the greatest improvement in OS was seen with concurrent RT-CT, and for carcinosarcoma, CT alone. CONCLUSIONS: OS for advanced EC significantly differs by histology and mode of adjuvant therapy. Future studies should evaluate the efficacy of combination-based adjuvant therapy versus chemotherapy alone, by histologic subtype and molecular signature.


Subject(s)
Chemoradiotherapy, Adjuvant/statistics & numerical data , Chemotherapy, Adjuvant/statistics & numerical data , Endometrial Neoplasms/mortality , Radiotherapy, Adjuvant/statistics & numerical data , Aged , Aged, 80 and over , Combined Modality Therapy , Disease-Free Survival , Endometrial Neoplasms/therapy , Female , Humans , Retrospective Studies , SEER Program
16.
Gynecol Oncol ; 157(2): 379-385, 2020 05.
Article in English | MEDLINE | ID: mdl-32081463

ABSTRACT

PURPOSE: To evaluate the safety and clinical activity of mirvetuximab soravtansine, an antibody-drug conjugate comprising a humanized anti-folate receptor alpha (FRα) monoclonal antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent, in combination with bevacizumab in patients with FRα-positive, platinum-resistant ovarian cancer. METHODS: Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer were administered mirvetuximab soravtansine (6 mg/kg, adjusted ideal body weight) and bevacizumab (15 mg/kg) once every 3 weeks. Eligibility included FRα positivity by immunochemistry and prior bevacizumab exposure was permitted. Adverse events, tumor response, and progression-free survival (PFS) were determined. RESULTS: Sixty-six patients, with a median of 3 prior lines of therapy (range, 1-8), received the combination of mirvetuximab soravtansine and bevacizumab at full dosing during the escalation and expansion stages of the study. Adverse events were generally mild-to-moderate (≤grade 2) with diarrhea, blurred vision, nausea, and fatigue being the most common treatment-related toxicities. Six cases of pneumonitis (9%; all grade 1 or 2), an adverse event of special interest, were observed. The confirmed objective response rate (ORR) was 39%, including 5 complete responses and 21 partial responses, and the median PFS was 6.9 months. The combination was particularly active in the subset of patients (n = 16) who were bevacizumab-naïve, less heavily pretreated (1-2 prior lines), and whose tumors exhibited medium/high FRα expression (ORR, 56% with a median duration of response of 12 months; PFS, 9.9 months). CONCLUSION: The combination of mirvetuximab soravtansine with bevacizumab is well tolerated in patients with platinum-resistant, recurrent ovarian cancer. The encouraging efficacy measures compare favorably to reported outcomes for bevacizumab combined with standard chemotherapy in similar patient populations.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab/administration & dosage , Bevacizumab/adverse effects , Carcinoma, Ovarian Epithelial/immunology , Drug Resistance, Neoplasm , Female , Folate Receptor 1/immunology , Humans , Immunoconjugates/administration & dosage , Immunoconjugates/adverse effects , Maytansine/administration & dosage , Maytansine/adverse effects , Maytansine/analogs & derivatives , Middle Aged , Organoplatinum Compounds/pharmacology , Ovarian Neoplasms/immunology , Progression-Free Survival
17.
Gynecol Oncol ; 155(3): 420-428, 2019 12.
Article in English | MEDLINE | ID: mdl-31623857

ABSTRACT

OBJECTIVE: We sought to determine safety and efficacy of the AKT inhibitor, GSK2141795, combined with the MEK inhibitor, trametinib, in endometrial cancer. METHODS: Patients with measurable recurrent endometrial cancer were eligible. One to two prior cytotoxic regimens were allowed; prior use of a MEK or PI3K pathway inhibitor was excluded. Initial trial design consisted of a KRAS mutation stratified randomized phase II with a safety lead-in evaluating the combination. For the safety lead in, the previously recommended phase 2 dose (RP2D; trametinib 1.5 mg, GSK2141795 50 mg) was chosen for Dose Level 1 (DL1). RESULTS: Of 26 enrolled patients, 14 were treated on DL1 and 12 were treated on DL-1 (trametinib 1.5 mg, GSK2141795 25 mg). Most common histologies were endometrioid (58%) and serous (27%). Four of 25 (16%) patients were KRAS mutant. Dose limiting toxicities (DLTs) were assessed during cycle 1. DL1 had 8 DLTs (hypertension (n = 2), mucositis (2), rash (2), dehydration, stroke/acute kidney injury). DL1 was deemed non-tolerable so DL-1 was explored. DL-1 had no DLTs. Sixty-five percent of patients had ≥ grade 3 toxicity. There were no responses in DL1 (0%, 90%CI 0-15%) and 1 response in DL-1 (8.3%, 90%CI 0.4-33.9%). Proportion PFS at 6 months for DL1 is 14%, and 25% for DL-1. CONCLUSION: The combination of trametinib and GSK2141795 had high levels of toxicity in endometrial cancer at the previously RP2D but was tolerable at a reduced dose. Due to insufficient preliminary efficacy at a tolerable dose, the Phase II study was not initiated.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Endometrial Neoplasms/drug therapy , MAP Kinase Kinase Kinases/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Diamines/administration & dosage , Diamines/adverse effects , Endometrial Neoplasms/enzymology , Female , Humans , Middle Aged , Progression-Free Survival , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyridones/administration & dosage , Pyridones/adverse effects , Pyrimidinones/administration & dosage , Pyrimidinones/adverse effects
18.
Sarcoma ; 2019: 3561501, 2019.
Article in English | MEDLINE | ID: mdl-30881199

ABSTRACT

OBJECTIVES: The benefit of adjuvant chemotherapy in patients with localized uterine leiomyosarcoma (LMS) remains unclear due to a lack of randomized studies and data only from small retrospective series to rely on. We sought to identify factors associated with the administration of chemotherapy and to determine the trends in the usage of adjuvant chemotherapy in patients with nonmetastatic uterine LMS. METHODS: Patients diagnosed with nonmetastatic uterine LMS between 2004 and 2014 were identified from the National Cancer Database (NCDB). Multiple regression was used to determine factors with a significant impact on patient receipt of chemotherapy. Kaplan-Meier curves and the Cox model were used to determine the effect of adjuvant chemotherapy on overall survival (OS). RESULTS: 2,732 uterine LMS patients were identified. Patients older than 65 were less likely to receive chemotherapy than their younger counterparts. Patients with stage I or stage II cancer were less likely to receive chemotherapy, whereas individuals with positive regional lymph nodes and those who had received radiation were more likely. In this cohort, adjuvant chemotherapy had no significant impact on OS (HR, 1.04; 95% CI, 0.90-1.22; P=0.5768). However, administration of chemotherapy significantly increased from 2004 to 2014 (P < 0.0001). CONCLUSIONS: Expected tumor characteristics such as higher stage of tumor were associated with receipt of chemotherapy. Although adjuvant chemotherapy demonstrated no benefit over observation on OS in patients with nonmetastatic LMS, the number of patients being treated with chemotherapy continued to increase from 2004 to 2014.

19.
Oncologist ; 24(4): 425-429, 2019 04.
Article in English | MEDLINE | ID: mdl-30635448

ABSTRACT

Prognosis for women with epithelial ovarian cancer remains poor. One new molecular target in epithelial ovarian cancer is folate receptor alpha (FRα). This commentary discusses the characteristics that contribute to its attractiveness as a candidate for therapeutic intervention.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Folate Receptor 1/antagonists & inhibitors , Carcinoma, Ovarian Epithelial/metabolism , Carcinoma, Ovarian Epithelial/pathology , Clinical Trials as Topic , Female , Humans , Molecular Targeted Therapy , Prognosis
20.
Clin Cancer Res ; 25(6): 1727-1736, 2019 03 15.
Article in English | MEDLINE | ID: mdl-30413525

ABSTRACT

PURPOSE: Reversible, low-grade ocular adverse events (AE) are associated with administration of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeted antibody-drug conjugate undergoing phase III clinical evaluation in platinum-resistant ovarian cancer. This study investigated the underlying mechanisms of ocular toxicity and evaluated primary prophylactic use of corticosteroid eye drops in patients receiving mirvetuximab soravtansine. PATIENTS AND METHODS: Target expression in the human eye was determined by IHC. The ocular toxicity profile of mirvetuximab soravtansine was assessed preclinically using Dutch-Belted rabbits. In a phase I clinical study, patients with ovarian cancer were treated with 6 mg/kg mirvetuximab soravtansine intravenously once every 3 weeks, including one expansion cohort with corticosteroid eye drops administered daily for the first 10 days of each treatment cycle. RESULTS: FRα expression was absent from human corneal tissues. Ocular abnormalities in the rabbit eye appeared phenotypically consistent with off-target effects on the cornea. Forty patients were enrolled in the expansion cohort. Reversible grade 1 or 2 blurred vision and keratopathy occurred in 16 (40%) and 12 (30%) patients, respectively; no grade 3/4 ocular events were observed. Compared with those patients who did not receive primary prophylaxis, corticosteroid eye drop use resulted in fewer dose reductions (5% vs. 15%) and none discontinued due to ocular AEs. CONCLUSIONS: Preclinical modeling was predictive of the corneal-related symptoms seen in some patients dosed with mirvetuximab soravtansine. Primary prophylactic use of topical corticosteroid eye drops resulted in a trend toward symptomatic improvement and a reduction in ocular AE-related dose modifications in patients treated with mirvetuximab soravtansine.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Corneal Diseases/prevention & control , Glucocorticoids/administration & dosage , Immunoconjugates/adverse effects , Maytansine/analogs & derivatives , Ovarian Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Animals , Antibodies, Monoclonal, Humanized/administration & dosage , Cornea/drug effects , Cornea/pathology , Corneal Diseases/chemically induced , Corneal Diseases/pathology , Drug Administration Schedule , Drug Evaluation, Preclinical , Drug Resistance, Neoplasm , Female , Folate Receptor 1/antagonists & inhibitors , Folate Receptor 1/metabolism , Humans , Immunoconjugates/administration & dosage , Infusions, Intravenous , Male , Maytansine/administration & dosage , Maytansine/adverse effects , Middle Aged , Ophthalmic Solutions/administration & dosage , Ovarian Neoplasms/pathology , Rabbits , Toxicity Tests, Subacute , Treatment Outcome
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