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A phase 1b dose escalation study of ipafricept (OMP54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer.
Moore, KN, Gunderson, CC, Sabbatini, P, McMeekin, DS, Mantia-Smaldone, G, Burger, RA, Morgan, MA, Kapoun, AM, Brachmann, RK, Stagg, R, et al
Gynecologic oncology. 2019;(2):294-301
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Abstract
OBJECTIVES The WNT pathway is an important oncologic driver of epithelial ovarian cancer (EOC). The first-in-class recombinant fusion protein ipafricept (IPA) blocks Wnt signaling through binding of Wnt ligands. This phase Ib trial was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RPh2) for IPA in combination with taxane and platinum therapy (C/P). METHODS Dose escalation started with a standard 3 + 3 design for IPA/C/P with q3w intravenous IPA on Day 1, in cycles 1 to 6 with C (AUC = 5 mg/ml·min) and P (175 mg/m2). For enhanced bone safety the trial was revised to 6-patient cohorts with a q3w regimen of IPA on Day 1 and C/P on Day 3 (IPA → C/P). RESULTS 37 patients have been treated; 30 of whom were treated following protocol revision to q3w IPA(D1) → C/P(D3) (2 & 4 mg/kg). IPA-related TEAEs that occurred in ≥15% included: fatigue (40%); nausea (35%); diarrhea and decreased appetite (22%) each; dysgeusia (19%); and vomiting (16.2%). 22% reported ≥1 IPA related TEAE Grade ≥3 the most common of which was neutropenia at 16%. There were no DLTs; the MTD was not reached. The maximum administered dose based on bone safety was 6 mg/kg. The overall response rate (ORR) was 75.7%. Median PFS was 10.3 months (95% CI 8.5-14.2) and OS 33 months (95% CI 23.4-NR). CONCLUSIONS IPA is well tolerated in combination with sequential C/P. ORR, PFS and OS are comparable to historical data but bone toxicity at efficacy doses of this particular Wnt inhibitor limit further development in EOC.
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FORWARD I: a Phase III study of mirvetuximab soravtansine versus chemotherapy in platinum-resistant ovarian cancer.
Moore, KN, Vergote, I, Oaknin, A, Colombo, N, Banerjee, S, Oza, A, Pautier, P, Malek, K, Birrer, MJ
Future oncology (London, England). 2018;(17):1669-1678
Abstract
Mirvetuximab soravtansine, an antibody-drug conjugate that binds with high affinity to folate receptor-α to provide tumor-directed delivery of the potent microtubule-disrupting agent DM4, has emerged as a promising investigational agent for the treatment of ovarian cancer, particularly in the setting of platinum-resistant disease. Here we describe the rationale and design of FORWARD I (NCT02631876), the first randomized, multicenter Phase III study to compare the safety and efficacy of mirvetuximab soravtansine versus investigator's choice of chemotherapy in women with folate receptor-α-positive, platinum-resistant epithelial ovarian, primary peritoneal or fallopian tube cancer. Patients will be randomized in a 2:1 ratio. The primary end point is progression-free survival, and key secondary objectives include comparison of overall response rates, overall survival and duration of response.
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An open-label, multicenter, phase I trial of a cremophor-free, polymeric micelle formulation of paclitaxel combined with carboplatin as a first-line treatment for advanced ovarian cancer: a Korean Gynecologic Oncology Group study (KGOG-3016).
Lee, SW, Kim, YM, Kim, YT, Kang, SB
Journal of gynecologic oncology. 2017;(3):e26
Abstract
OBJECTIVE This phase I study aimed to determine the maximum tolerated dose (MTD) of Genexol-PM, when combined with carboplatin, as a first-line treatment in patients with advanced ovarian cancer. METHODS This open-label, multicenter, phase I, dose-escalation study included 18 patients (median age: 59.0 years, range: 40-75 years) diagnosed with advanced epithelial ovarian cancer. All patients had measurable residual disease after debulking surgery. Patients were assigned to groups (n=6 each group) that received different doses of Genexol-PM (220, 260, and 300 mg/m², once every 3 weeks) and 5 area under the curve (AUC) carboplatin. Safety and efficacy were analyzed for each dose group. RESULTS In this intention-to-treat population, 3 out of 18 patients dropped out of the study: 1 due to dose-limiting toxicity (DLT), 1 due to hypersensitivity, and 1 was lost during follow-up. DLTs were not reported at 220 mg/m² or 260 mg/m², but at 300 mg/m², 1 patient experienced DLT (grade 3 general pain). The MTD of Genexol-PM was not determined, but a dose of 300 mg/m² or less could be recommended for the phase II study. Most patients (73.9%) with adverse events recovered without sequelae, and no death occurred that was related to the disease or treatment. The best overall response rate was 94.1%. CONCLUSION Genexol-PM combined with carboplatin was well tolerated as a first-line treatment, and good responses were observed in patients with advanced ovarian cancer. Based on these results, we recommended a dose of 300 mg/m² or less for a phase II study.
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Interim analysis of a phase I/IIa trial assessing E39+GM-CSF, a folate binding protein vaccine, to prevent recurrence in ovarian and endometrial cancer patients.
Jackson, DO, Byrd, K, Vreeland, TJ, Hale, DF, Herbert, GS, Greene, JM, Schneble, EJ, Berry, JS, Trappey, AF, Clifton, GT, et al
Oncotarget. 2017;(9):15912-15923
Abstract
BACKGROUND Folate binding protein(FBP) is an immunogenic protein over-expressed in endometrial(EC) and ovarian cancer(OC). We are conducting a phase I/IIa trial of E39 (GALE 301)+GM-CSF, an HLA-A2-restricted, FBP-derived peptide vaccine to prevent recurrences in disease-free EC and OC patients. This interim analysis summarizes toxicity, immunologic responses, and clinical outcomes to date. METHODS HLA-A2+ patients were vaccinated(VG), and HLA-A2- or -A2+ patients were followed as controls(CG). Six monthly intradermal inoculations of E39+250mcg GM-CSF were administered to VG. Demographic, safety, immunologic, and recurrence rate(RR) data were collected and evaluated. RESULTS This trial enrolled 51 patients; 29 in the VG and 22 in the CG. Fifteen patients received 1000mcg E39, and 14 received <1000mcg. There were no clinicopathologic differences between groups(all p ≥ 0.1). E39 was well-tolerated regardless of dose. DTH increased pre- to post-vaccination (5.7±1.5 mm vs 10.3±3.0 mm, p = 0.06) in the VG, and increased more in the 1000mcg group (3.8±2.0 mm vs 9.5±3.5 mm, p = 0.03). With 12 months median follow-up, the RR was 41% (VG) vs 55% (CG), p = 0.41. Among the 1000mcg patients, the RR was 13.3% vs 55% CG, p = 0.01. Estimated 2-year DFS was 85.7% in the 1000mcg group vs 33.6% in the CG (p = 0.021). CONCLUSIONS This phase I/IIa trial reveals that E39+GM-CSF is well-tolerated and elicits a strong, dose-dependent in vivo immune response. Early efficacy results are promising in the 1000 mcg dose cohort. This study proves the safety and establishes the dose of E39 for a larger prospective, randomized, controlled trial in HLA-A2+ EC and OC patients to prevent recurrence.
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Combination of Aprepitant, Azasetron, and Dexamethasone as Antiemetic Prophylaxis in Women with Gynecologic Cancers Receiving Paclitaxel/Carboplatin Therapy.
Koshiyama, M, Matsumura, N, Imai, S, Yamanoi, K, Abiko, K, Yoshioka, Y, Yamaguchi, K, Hamanishi, J, Baba, T, Konishi, I
Medical science monitor : international medical journal of experimental and clinical research. 2017;:826-833
Abstract
BACKGROUND The aim of this study was to evaluate the antiemetic effect of aprepitant and to determine how to provide triple combination therapy (aprepitant/azasetron/dexamethasone) to women receiving paclitaxel/carboplatin moderately emetogenic chemotherapy (MEC). MATERIAL AND METHODS The current study was a prospective study of 163 women with gynecologic cancers. We compared the digestive symptoms scores (nausea, vomiting, appetite loss, and dietary intake) of 37 women with ovarian cancers before and after aprepitant administration. We also compared these symptoms in women who underwent 193 cycles of triple combination therapy with symptoms of women who underwent 226 cycles of double combination therapy. For triple combination therapy, azasetron, dexamethasone (reduced dose: 40% of 20 mg), and aprepitant (125 mg) were administered on Day 1, followed by only aprepitant (80 mg) administration on Days 2 and Day 3. RESULTS In 37 women with ovarian cancer, three symptoms, nausea, appetite loss, and dietary intake, were significantly improved by primarily adding aprepitant to double combination therapy in the delayed phase of MEC. Upon comparing their digestive symptoms in all cycles, however, these three symptoms were not significantly different in the delayed phase. Furthermore, all four symptoms in all cycles were worse following triple combination therapy than following double combination therapy in the acute phase (p<0.02). The control of digestive symptoms was generally insufficient without the administration of dexamethasone. CONCLUSIONS Primary aprepitant as an addition to MEC demonstrated efficacy in improving digestive symptoms in the delayed phase. However, its effect may decrease with repeated use. To improve the antiemetic effect, the dose reduction of dexamethasone should be restricted on Day 1 and dexamethasone should be used throughout the delayed phase as well.
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Phase 1b safety study of farletuzumab, carboplatin and pegylated liposomal doxorubicin in patients with platinum-sensitive epithelial ovarian cancer.
Kim, KH, Jelovac, D, Armstrong, DK, Schwartz, B, Weil, SC, Schweizer, C, Alvarez, RD
Gynecologic oncology. 2016;(2):210-4
Abstract
OBJECTIVE Farletuzumab is a humanized monoclonal antibody that binds to folate receptor alpha, over-expressed in epithelial ovarian cancer (EOC) but largely absent in normal tissue. Previously, carboplatin plus pegylated liposomal doxorubicin showed superior progression-free survival and an improved therapeutic index compared with carboplatin/paclitaxel in relapsed platinum-sensitive EOC. This study assessed safety of farletuzumab/carboplatin/pegylated liposomal doxorubicin in women with platinum-sensitive recurrent EOC. METHODS This multicenter, single-arm study enrolled patients with platinum-sensitive EOC in first or second relapse for treatment with weekly farletuzumab 2.5mg/kg plus carboplatin AUC5-6 and pegylated liposomal doxorubicin 30mg/m(2) every 4weeks for 6cycles. Subsequently, maintenance with single-agent farletuzumab 2.5mg/kg once weekly or farletuzumab 7.5mg/kg once every three weeks continued until progression. The primary objective was to assess the safety of farletuzumab/carboplatin/pegylated liposomal doxorubicin. RESULTS Fifteen patients received a median of 12.0cycles (range, 3-26) of farletuzumab as combination therapy or maintenance, for a median of 45.0weeks (range 9-95). Farletuzumab/carboplatin/pegylated liposomal doxorubicin was generally well tolerated, with no farletuzumab-related grades 3-4 adverse events. The most commonly reported adverse events were associated with combination chemotherapy: fatigue (73.3%), nausea (46.7%), and neutropenia (40%). Ten patients had grade ≥3 adverse events, most frequently neutropenia and fatigue. No cardiac toxicity was seen. Best overall responses (RECIST) were a complete response for one patient, partial responses for 10 patients, and stable disease for four patients. CONCLUSIONS Farletuzumab plus carboplatin/pegylated liposomal doxorubicin in women with platinum-sensitive EOC demonstrated a safety profile consistent with that of carboplatin plus pegylated liposomal doxorubicin.
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A phase I study of farletuzumab, a humanized anti-folate receptor α monoclonal antibody, in patients with solid tumors.
Sasaki, Y, Miwa, K, Yamashita, K, Sunakawa, Y, Shimada, K, Ishida, H, Hasegawa, K, Fujiwara, K, Kodaira, M, Fujiwara, Y, et al
Investigational new drugs. 2015;(2):332-40
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Abstract
Farletuzumab is a humanized monoclonal antibody against folate receptor α (FRA). The purpose of the study is to assess safety and tolerability, the pharmacokinetic (PK) profile, and preliminary antitumor effect. Patients with ovarian cancer (OC) or FRA-expressing solid tumors who are resistant to standard treatments were eligible for the study. After single-dose administration for PK assessment, farletuzumab was administered by intravenous injection, repeating every week until disease progression. Dose-limiting toxicities (DLTs) were defined as grade 4 hematological and grade 3/4 nonhematological toxicities. Dose escalation was planned in 4 cohorts (50, 100, 200, and 400 mg/m(2)). Fourteen patients with OC and two patients with gastric cancer (GC) received farletuzumab infusion. Neither DLTs nor grade 3/4 toxicities were reported in all cohorts. Major adverse events, including grade 1/2 infusion related reaction (15 patients, 93.8%), headache (seven patients, 43.8%), and nausea and decreased appetite (five patients each, 31.3%), were observed and medically managed. AUC and Cmax increased dose-dependently and linear PK profiles were observed. No tumor shrinkage was recorded, but long-term disease stabilization for 25 and 20 months was observed in one patient with clear cell OC (100 mg/m(2)) and one patient with GC (400 mg/m(2)), respectively. No cumulative toxicity occurred in any patient. Farletuzumab was well tolerated in Japanese patients with a similar PK profile as compared with the US population. Long-term disease stabilization was observed in a subpopulation of clear cell OC and GC; both of them were resistant and progressive after standard chemotherapies (ClinicalTrials.gov Identifier: NCT01049061).
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A phase II study of paclitaxel and carboplatin with a biweekly schedule in patients with epithelial ovarian cancer: Gynecologic Cancer Network trial.
Yoneyama, K, Konishi, H, Yahata, T, Fujita, K, Aoki, Y, Doi, D, Matsushima, T, Kodama, S, Honma, S, Kato, H, et al
Journal of Nippon Medical School = Nippon Ika Daigaku zasshi. 2014;(1):28-34
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AIM: The objective of this multicenter phase II study was to evaluate the effects of biweekly paclitaxel and carboplatin combination chemotherapy on response rate and toxicities in patients with epithelial ovarian cancer. PATIENTS AND METHODS Patients with International Federation of Gynecology and Obstetrics stage II to IV ovarian cancer received paclitaxel at a dose of 120 mg/m(2) and carboplatin at an area under the curve of 3 mg/mL per minute every 2 weeks for 8 or more cycles. Inclusion criteria included an Eastern Cooperative Oncology Group performance status of 0 to 2 and no previous chemotherapy. Informed consent was obtained from each patient before the start of treatment. RESULTS From March 2003 through July 2009, 42 patients from 5 institutions were eligible to be evaluated for response and toxicity. The median age was 60.5 years (age range, 34-81 years). The International Federation of Gynecology and Obstetrics stage was stage II in 3 patients, stage III in 31 patients, and stage IV in 8 patients. The response rate was 66.7% (95% confidence interval: 50.5%-80.4%). Sixty-nine percent (29 of 42) of patients received 8 or more cycles of chemotherapy. The median progression-free survival was 18.5 months, and overall survival was 59.1 months. The most common grade 3 or 4 hematological toxicity was neutropenia (61.0%). No patients had grade 3 or 4 thrombocytopenia. The most common grade 3 nonhematological toxicities were neuropathy (4.9%) and nausea (2.4%). CONCLUSION Paclitaxel combined with carboplatin using a biweekly schedule is a safe and effective chemotherapy regimen for patients with epithelial ovarian cancer. Our results suggest that a biweekly schedule is well tolerated and is less toxic than a triweekly schedule.
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A phase II evaluation of motesanib (AMG 706) in the treatment of persistent or recurrent ovarian, fallopian tube and primary peritoneal carcinomas: a Gynecologic Oncology Group study.
Schilder, RJ, Sill, MW, Lankes, HA, Gold, MA, Mannel, RS, Modesitt, SC, Hanjani, P, Bonebrake, AJ, Sood, AK, Godwin, AK, et al
Gynecologic oncology. 2013;(1):86-91
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OBJECTIVES Vascular endothelial growth factors (VEGF) and their receptors have a critical role in stimulating the growth of ovarian cancer cells. Motesanib is a small molecule inhibitor of multiple receptor tyrosine kinases including VEGF receptors 1-3, as well as c-KIT and platelet-derived growth factor which are related to the VEGF family. PATIENTS AND METHODS Twenty-two eligible patients with recurrent ovarian, fallopian tube or primary peritoneal carcinoma were treated with an oral daily dose of 125 mg of motesanib. Peripheral blood was analyzed for circulating tumor cells (CTC) and circulating endothelial cells/circulating endothelial progenitors (CEC/CEP), VEGF levels and cell-free circulating DNA (cfDNA). RESULTS The study was abruptly halted after four patients developed posterior reversible encephalopathy syndrome. One patient had a partial response and seven patients had stable disease at the time they were removed from study treatment. Twelve of the 22 patients (50%) had indeterminate responses at trial closure. Early closure without clinical efficacy data precludes meaningful correlative studies. CONCLUSIONS The serious central nervous system toxicity observed in patients with recurrent ovarian cancer precluded full examination of this agent in this population. There were no clear cut explanations for the high incidence of this known class effect in the study population compared with patients with other cancers.
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Eribulin mesylate (halichondrin B analog E7389) in platinum-resistant and platinum-sensitive ovarian cancer: a 2-cohort, phase 2 study.
Hensley, ML, Kravetz, S, Jia, X, Iasonos, A, Tew, W, Pereira, L, Sabbatini, P, Whalen, C, Aghajanian, CA, Zarwan, C, et al
Cancer. 2012;(9):2403-10
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BACKGROUND Eribulin mesylate is a tubulin inhibitor with activity superior to paclitaxel in NIH:OVCAR-3 human epithelial ovarian cancer xenograft models. In this study, the authors assessed the efficacy of eribulin in platinum-resistant and platinum-sensitive recurrent ovarian cancer. METHODS Patients with recurrent, measurable epithelial ovarian cancer who had received ≤2 prior cytotoxic regimens and who had adequate organ function were enrolled into 2 separate cohorts: 1) platinum-resistant patients (who had a progression-free interval <6 months after their last platinum-based therapy) and 2) platinum-sensitive patients (who had a progression-free interval ≥6 months after their last platinum-based therapy). Eribulin 1.4 mg/m(2) was administered over 15 minutes intravenously on days 1 and 8 every 21 days. Efficacy was determined by objective response on computed tomography studies. RESULTS In the platinum-resistant cohort, 37 patients enrolled, and 36 patients were evaluable for response and toxicity. Two patients achieved a partial response (5.5%), and 16 patients (44%) had stable disease as their best response. The median progression-free survival was 1.8 months (95% confidence interval, 1.4-2.8 months). In the platinum-sensitive cohort, 37 patients enrolled, and all were evaluable for response. Seven patients achieved a partial response (19%). The median progression-free survival was 4.1 months (95% confidence interval, 2.8-5.8 months). The major toxicity was grade 3 or 4 neutropenia (42% of platinum-resistant patients; 54% of platinum-sensitive patients). CONCLUSIONS Eribulin produced an objective response in 5.5% of women with platinum-resistant, recurrent ovarian cancer and in 19% of women with platinum-sensitive disease. The median progression-free survival was 1.8 months in the platinum-resistant group and 4.1 months in the platinum-sensitive group.