A randomized placebo-controlled trial of saracatinib (AZD0530) plus weekly paclitaxel in platinum-resistant ovarian, fallopian-tube, or primary peritoneal cancer (SaPPrOC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5514-5514 ◽  
Author(s):  
Iain A. McNeish ◽  
Jonathan A. Ledermann ◽  
Lee C. Webber ◽  
Lindsay E. James ◽  
Stanley B. Kaye ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Controlled Trial ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Weekly Paclitaxel ◽  
Serious Adverse Events ◽  
Peritoneal Cancer ◽  
Platinum Resistant ◽  
Duration Of Response ◽  
Grade 3

5514 Background: Weekly paclitaxel (wPxl) has activity in platinum-resistant ovarian cancer (PROC). Upregulated Src kinase activity is seen in Pxl-resistant ovarian cancer models. This trial investigated the combination of wPxl and the oral Src inhibitor saracatinib (AZD0530) in PROC. Methods: Patients with PROC (defined as relapse within 6 months of prior platinum chemotherapy, confirmed either by CT scan or symptomatic CA125 rise) were randomised 2:1 to receive four 8 week cycles of wPxl (80mg/m2/week x6 with 2 week break) plus saracatinib (S; 175mg od) or placebo (P) continuously, starting 1 week prior to wPxl, until disease progression. Patients were stratified as <6 months or ≥6 months taxane interval/no prior taxane. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints included overall survival (OS), response rate (RR), duration of response (DoR), time to progression (TTP) and toxicity. Results: 107 patients were randomised during 2011-12, 71 (66.4%) to wPxL+S and 36 (33.6%) to wPxL+P. Taxane interval was <6 months in 23 (22.1%), ≥6 months in 76 (72.4%). 43 (41.0%) had received >2 lines of prior chemotherapy; 78% (wPxL+S) vs 72% (wPxL+P) of patients received ≥1 cycle of wPxl; relative dose intensity was 96% vs 98% for wPxL+S and wPxL+P respectively. The 6-month PFS rate was 29% (wPxL+S) vs 35% (wPxL+P). Median PFS was 3.9 vs 5.3 months (HR 1.04; 95% CI 0.68, 1.59; p=0.86); median OS was 12.7 vs 12.8 months (HR 1.50, 95% CI 0.63, 3.56; p=0.36); RR were 0.0% vs 2.9% (CR) and 29% vs 38.9% (PR) for wPxL+S vs wPxL+P respectively. Median DoR was 5.6 vs 3.6 months; TTP was 3.9 vs 5.5 months (HR 1.10; 95% CI 0.71, 1.72;p=0.67). Grade 3+ Serious Adverse Events were 36.2% vs 30.6%; the most frequent toxicities (any grade) were abdominal pain (4.3%) and febrile neutropenia (4.3%) for wPxL+S, and vomiting (5.6%) for wPxL+P. Conclusions: In this randomised phase II trial, the addition of saracatinib to wPxl did not improve 6-month PFS in patients with PROC. Clinical trial information: NCT01196741.

Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5507-5507 ◽  
Author(s):  
Adriaan Vanderstichele ◽  
Els Van Nieuwenhuysen ◽  
Sileny Han ◽  
Nicole Concin ◽  
Toon Van Gorp ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Single Agent ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Free Survival ◽  
Clinical Endpoints ◽  
Platinum Resistant ◽  
Randomized Phase Ii ◽  
Duration Of Response ◽  
Grade 3

5507 Background: The CLIO trial (NCT02822157) evaluated olaparib single-agent therapy versus standard of care chemotherapy in platinum-resistant (recurrence within 6 months after last platin) ovarian cancer (PROC). Methods: Eligible patients with measurable disease and ≥1 prior line of chemotherapy were randomized 2:1 to Olaparib (OLA) monotherapy (300 mg tablets, BID) or physician’s choice chemotherapy (CT; PLD 40 mg/m2 q 4 wks; Topotecan 1.25 mg/m2 day 1—5 q 3 wks; Paclitaxel 80 mg/m2 day 1, 8,15 q 3 wks; Gemcitabine 1000 mg/m2 day 1, 8 and 15 q 4 wks). Primary endpoint was objective overall response (ORR) per RECIST v1.1. Germline BRCA status was available for all patients. Disease control rate (DCR) was defined as response for at least 12 wks. Results: 100 patients with PROC were randomized 2:1 to OLA (N = 67) or CT (N = 33). Median prior lines of treatment was 3 (range: 1—8). ORR (unconfirmed) was 18% (12/67) for OLA and 6% (2/33) for CT. ORR for OLA was 38% (5/13) in gBRCAm and 13% (7/54) in gBRCAwt patients. Of note, 2 patients with gBRIP1 mutation had no response under OLA. DCR was 35.8% (24/67) for OLA and 42% (14/33) for CT. DCR under OLA in gBRCAm was 62% (8/13) compared to 30% (16/54) in gBRCAwt disease. The median duration of response (DOR) and the median progression-free survival (PFS) was similar: 5.4 months vs 4.5 months (DOR) and 2.9 vs 3.4 months (PFS) for OLA and CT, respectively. Grade ≥3 treatment-related AEs occurred in 60% vs 52% for OLA and CT, respectively. Somatic HRR mutation analysis is ongoing and will be presented. Conclusions: Olaparib monotherapy showed a favorable response rate in PROC compared with chemotherapy also in gBRCAwt patients. Analysis of clinical endpoints in relation to HRR is ongoing and will be presented. Clinical trial information: NCT02822157.

LOTUS (NCT02162719): A double-blind placebo (PBO)-controlled randomized phase II trial of first-line ipatasertib (IPAT) + paclitaxel (P) for metastatic triple-negative breast cancer (TNBC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1009-1009 ◽  
Author(s):  
Rebecca Alexandra Dent ◽  
Sung-Bae Kim ◽  
Seock-Ah Im ◽  
Marc Espie ◽  
Sibel Blau ◽  
...  
Keyword(s):  
Objective Response ◽  
Locally Advanced ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Akt Inhibitor ◽  
Double Blind ◽  
Common Grade ◽  
Duration Of Response ◽  
Grade 3 ◽  
Median Cumulative Dose

1009 Background: The oral Akt inhibitor IPAT is being evaluated in cancers with a high prevalence of PI3K/Akt pathway activation, including TNBC. Methods: Eligible patients (pts) had measurable inoperable locally advanced/metastatic TNBC previously untreated with systemic therapy. Pts were stratified by prior (neo)adjuvant therapy, chemotherapy-free interval and tumor PTEN status, and randomized 1:1 to P 80 mg/m2 (d1, 8 & 15) with either IPAT 400 mg or PBO (d1–21) q28d until progression or unacceptable toxicity. Co-primary endpoints were progression-free survival (PFS) in the ITT population and pts with PTEN-low tumors by IHC. Secondary endpoints included objective response rate (ORR), duration of response (DoR) and overall survival in the ITT and IHC PTEN-low populations, efficacy in pts with PIK3CA/AKT1/PTEN-altered tumors by next-generation sequencing (NGS), and safety. Results: Baseline characteristics were generally balanced between arms. Efficacy is shown below. The most common grade ≥3 AEs (grouped terms) were diarrhea (23% IPAT+P vs 0% PBO+P; no grade 4 or colitis in either arm), neutropenia (18% vs 8%), asthenia (5% vs 6%), peripheral neuropathy (5% vs 5%) and pneumonia (5% vs 0%). More pts receiving IPAT+P than PBO+P had an AE leading to dose reduction of IPAT/PBO (21% vs 6%) or P (38% vs 11%) but median cumulative dose intensity was similar (IPAT/PBO: 99% vs 100%; P: 100% vs 100%). AEs led to IPAT/PBO discontinuation in 13% vs 11% of pts, respectively; 2 pts (3%) discontinued IPAT for grade 3 diarrhea. Conclusions: Adding IPAT to P for TNBC modestly improved PFS in the ITT pts. The effect was more pronounced in the prespecified subgroup with PIK3CA/AKT1/PTEN alterations, warranting further evaluation of IPAT in these pts. AEs were manageable. Clinical trial information: NCT02162719. [Table: see text]

INNOVATE: A phase II study of TTFields (200 kHz) concomitant with weekly paclitaxel for recurrent ovarian cancer—Updated safety and efficacy results.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5580-5580 ◽  
Author(s):  
Ignace Vergote ◽  
Roger von Moos ◽  
Luis Manso ◽  
Cristiana Sessa
Keyword(s):  
Ovarian Cancer ◽  
Adverse Events ◽  
Cancer Patients ◽  
Electric Fields ◽  
Skin Irritation ◽  
Intermediate Frequency ◽  
Weekly Paclitaxel ◽  
Ca 125 ◽  
Serious Adverse Events ◽  
Platinum Resistant

5580 Background: TTFields are a non-invasive, regional antimitotic treatment modality, which have been approved for the treatment of recurrent and newly diagnosed glioblastoma by the FDA. TTFields act by delivering intermediate frequency alternating electric fields to the tumor, predominantly by disrupting the formation of the mitotic spindle during metaphase. INNOVATE was the first trial testing TTFields (200kHz) in ovarian cancer patients. Methods: Thirty-one recurrent, platinum-resistant, unresectable ovarian cancer patients were enrolled in the INNOVATE trial and treated with TTFields in combination with weekly paclitaxel. The primary endpoint was treatment emergent adverse events. Secondary endpoints included progression free-survival, overall survival and radiological response rate. Results: The median age was 60 (range – 45-77), most patients (77%) had serous histology. 52% had an ECOG score of 0. The median number of prior chemotherapy regimens was 4.1 (range 1-11). All patients were platinum-resistant, and 97% of patients received prior taxane-containing regimens. Ten (32%) patients suffered from serious adverse events (SAEs) during the study, none were related to TTFields. Of all reported SAEs, 31% were related to gastrointestinal disorders (ileus, jaundice and ascites) and 31% were respiratory events (dyspnea, pleural effusion and pulmonary embolism). Only one SAE which, related to the tumor, led to permanent discontinuation of the device. Most patients were reported to have mild-moderate, TTFields-related skin irritation, out of whom only two patients (6.4%) had severe-grade events. The median PFS was 8.9 months (95% CI 4.7, NA). Of the evaluable tumors, 25% had partial response and another 46.4% stable disease – a clinical benefit of 71.4%. Six patients (19.4%) had a CA 125 response, translating into a decrease of 50% or more in serum levels. The median OS was not reached. Conclusions: TTFields concomitant to weekly paclitaxel are tolerable and safe in heavily pre-treated platinum-resistant ovarian cancer ovarian cancer patients. These data support further clinical testing of TTFields with chemotherapy in ovarian cancer. Clinical trial information: NCT02244502.

The efficacy and safety of nedaplatin single therapy in 30 patients with platinum-resistant ovarian cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17075-e17075
Author(s):  
Yuka Kasamatsu ◽  
Munetaka Takekuma ◽  
Nobuhiro Kado ◽  
Emi Yoshioka ◽  
Shiho Kuji ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Chemotherapy Regimen ◽  
Progression Free Survival ◽  
Median Number ◽  
Efficacy And Safety ◽  
Standard Chemotherapy ◽  
Peritoneal Cancer ◽  
Free Interval ◽  
Platinum Resistant ◽  
Platinum Analogues

e17075 Background: This study aimed to investigate the efficacy and safety of Nedaplatin single therapy for patients with platinum-resistant ovarian, tubal and primary peritoneal cancer after completing standard chemotherapy. Methods: From September 2002 to August 2016, 30 patients who were diagnosed with platinum-resistant ovarian cancer, were treated with Nedaplatin single therapy after completing all standard chemotherapy at our institution. Nedaplatin (80-100mg/m2) was adiministered intravenously on day 1 of a 28 day cycle. We retrospectively investigated the response rate, toxicities, and survival based on the use of Nedaplatin single therapy. Results: The median age was 58.5 years (23-76). The median number of prior chemotherapy regimen was 3 (1-7). The median platinum-free interval between the final use of platinum analogues and starting Nedaplatin single therapy was 9.4 months (0.9-54.9). Among 22 patients who had measurable disease, 8 (36.4%) responded partially to Nedaplatin single therapy. Seven patients (23.3%) experienced hematological toxicities of Grade 3/4. Six patients (20.0%) experienced non-hematological toxicities Grade 2. No treatment-related death occurred. The median progression-free survival was 3.2 months (0-23.3), and over all survival was 9.2 months (1.1-56.4) after treatment with Nedaplatin single therapy. Age (<70 years, p=0.017) and platinum-free interval (<6 months, p=0.013) were the prognosis factors for survival in univariate analyses. Conclusions: Nedaplatin single therapy seemed to be an effective and safe chemotherapy regimen for platinum-resistant ovarian cancer after completing standard chemotherapy.

scholarly journals Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252665
Author(s):  
Christine S. Walsh ◽  
Mitchell Kamrava ◽  
Andre Rogatko ◽  
Sungjin Kim ◽  
Andrew Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Interim Analysis ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Time To Progression ◽  
Free Survival ◽  
Platinum Resistant ◽  
Duration Of Response

Objective To evaluate the combination of pembrolizumab, cisplatin and gemcitabine in recurrent platinum-resistant ovarian cancer. Methods Patients received six cycles of chemotherapy with gemcitabine and cisplatin on day 1 and day 8 of a 21-day treatment cycle. Pembrolizumab was administered on day 1 of cycles 3–6 and as maintenance monotherapy in cycles 7–34. Palliative radiation to a non-target symptomatic lesion was allowed. The primary objective was overall response rate by RECIST 1.1 criteria. Secondary objectives included safety, progression-free survival, time to progression, duration of response and overall survival. Results An interim analysis for futility was performed at 18 evaluable patients. Overall response rate was 60%, duration of response was 4.9 months and time to progression was 5.2 months. Progression-free survival at 6 and 12 months was 43% and 5%. Median progression-free survival was 6.2 months and median overall survival was 11.3 months. In all patients, CA125 levels reflected response and progression. There were no pseudoprogression events. After receiving palliative radiation during pembrolizumab maintenance, a patient with recurrent ovarian clear cell carcinoma had an exceptional and durable response that is ongoing for greater than 2 years. After consultation with the sponsor, based on the modest duration of response observed at the interim analysis for futility, the decision was made to close the trial to further accrual. Conclusions The addition of pembrolizumab to cisplatin and gemcitabine did not appear to provide benefit beyond chemotherapy alone in patients with recurrent platinum-resistant ovarian cancer.

scholarly journals Pimasertib Versus Dacarbazine in Patients With Unresectable NRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1727 ◽  
Author(s):  
Celeste Lebbé ◽  
Caroline Dutriaux ◽  
Thierry Lesimple ◽  
Willem Kruit ◽  
Joseph Kerger ◽  
...  
Keyword(s):  
Phase Ii ◽  
Cutaneous Melanoma ◽  
Controlled Trial ◽  
Objective Response ◽  
Progression Free Survival ◽  
Open Label ◽  
Serious Adverse Events ◽  
Unresectable Stage ◽  
Secondary Endpoints ◽  
Grade 3

This study investigated the efficacy and safety of pimasertib (MEK1/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc/IVM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to pimasertib (60 mg; oral twice-daily) or DTIC (1000 mg/m2; intravenously) on Day 1 of each 21-day cycle. Patients progressing on DTIC could crossover to pimasertib. Primary endpoint: investigator-assessed progression-free survival (PFS); secondary endpoints: overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety. Overall, 194 patients were randomized (pimasertib n = 130, DTIC n = 64), and 191 received treatment (pimasertib n = 130, DTIC n = 61). PFS was significantly improved with pimasertib versus DTIC (median 13 versus 7 weeks, respectively; hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42–0.83; p = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95% CI 1.00–4.98; p = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively; HR 0.89, 95% CI 0.61–1.30); 64% of patients receiving DTIC crossed over to pimasertib. Serious adverse events (AEs) were more frequent for pimasertib (57%) than DTIC (20%). The most common treatment-emergent AEs were diarrhea (82%) and blood creatine phosphokinase (CPK) increase (68%) for pimasertib, and nausea (41%) and fatigue (38%) for DTIC. Most frequent grade ≥3 AEs were CPK increase (34%) for pimasertib and neutropenia (15%) for DTIC. Mean QoL scores (baseline and last assessment) were similar between treatments. Pimasertib has activity in NRAS-mutated cutaneous melanoma and a safety profile consistent with known toxicities of MEK inhibitors. Trial registration: ClinicalTrials.gov, NCT01693068.

scholarly journals Safety and Activity of Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha–Targeting Antibody–Drug Conjugate, in Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: A Phase I Expansion Study

2017 ◽  
Vol 35 (10) ◽  
pp. 1112-1118 ◽  
Author(s):  
Kathleen N. Moore ◽  
Lainie P. Martin ◽  
David M. O’Malley ◽  
Ursula A. Matulonis ◽  
Jason A. Konner ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Response Rate ◽  
Folate Receptor ◽  
Objective Response ◽  
Antibody Drug Conjugate ◽  
Primary Peritoneal Cancer ◽  
Peritoneal Cancer ◽  
Platinum Resistant ◽  
Duration Of Response ◽  
Antibody Drug

Purpose This phase I expansion cohort study evaluated the safety and clinical activity of mirvetuximab soravtansine (IMGN853), an antibody–drug conjugate consisting of a humanized anti–folate receptor alpha (FRα) monoclonal antibody linked to the tubulin-disrupting maytansinoid DM4, in a population of patients with FRα-positive and platinum-resistant ovarian cancer. Patients and Methods Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer received IMGN853 at 6.0 mg/kg (adjusted ideal body weight) once every 3 weeks. Eligibility included a minimum requirement of FRα positivity by immunohistochemistry (≥ 25% of tumor cells with at least 2+ staining intensity). Adverse events, tumor response (via Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), and progression-free survival (PFS) were determined. Results Forty-six patients were enrolled. Adverse events were generally mild (≤ grade 2), with diarrhea (44%), blurred vision (41%), nausea (37%), and fatigue (30%) being the most commonly observed treatment-related toxicities. Grade 3 fatigue and hypotension were reported in two patients each (4%). For all evaluable patients, the confirmed objective response rate was 26%, including one complete and 11 partial responses, and the median PFS was 4.8 months. The median duration of response was 19.1 weeks. Notably, in the subset of patients who had received three or fewer prior lines of therapy (n = 23), an objective response rate of 39%, PFS of 6.7 months, and duration of response of 19.6 weeks were observed. Conclusion IMGN853 exhibited a manageable safety profile and was active in platinum-resistant ovarian cancer, with the strongest signals of efficacy observed in less heavily pretreated individuals. On the basis of these findings, the dose, schedule, and target population were identified for a phase III trial of IMGN853 monotherapy in patients with platinum-resistant disease.

A randomized phase II trial with gemcitabine with or without pertuzumab (rhuMAb 2C4) in platinum-resistant ovarian cancer (OC): Preliminary safety data

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13001-13001 ◽  
Author(s):  
D. Glenn ◽  
F. Ueland ◽  
A. Bicher ◽  
D. Dizon ◽  
M. Gold ◽  
...  
Keyword(s):  
Adverse Events ◽  
Controlled Trial ◽  
Single Agent ◽  
Safety Data ◽  
Study Drug ◽  
Hematological Toxicity ◽  
Serious Adverse Events ◽  
Platinum Resistant ◽  
Platinum Based Chemotherapy ◽  
Grade 3

13001 Background: Pertuzumab (P), a humanized HER2 antibody, represents a new class of targeted agents called HER dimerization inhibitors (HDIs). P inhibits dimerization of HER2 with EGFR, HER3 and HER4, and subsequently inhibits signaling through MAP and PI3 kinases. Single agent P has demonstrated clinical benefit in advanced OC (ASCO 2005 abstract #5051). Methods: 40 pts with platinum-resistant OC (progressed within 6 months of receiving a platinum-based chemotherapy) were enrolled in this 1:1 randomized, double blind, placebo controlled trial of gemcitabine with or without P. Gemcitabine was administered IV on day 1 and 8 at 800 mg/m2 of a 21 day cycle. Blinded placebo or 420 mg P was administered IV on day 1. Gemcitabine was dose reduced for neutropenia or thrombocytopenia. P was not dose reduced. Results: 40 pts have been enrolled and treated with at least 1 cycle of gemcitabine in combination with blinded study drug. The median age was 58.5 (range 18–82); 26 had PS ECOG 0, 13 ECOG 1, 1 ECOG 2. The most common grade 3/4 events were neutropenia in 7 pts (17.5%), thrombocytopenia in 6 pts (15%), small bowel obstruction in 4 pts (10%), constipation in 3 pts (7.5%) and elevated ALT in 3 pts (7.4%). There was one grade 3 diarrhea, but no grade 3 or 4 rash. There were 4 serious adverse events (SAEs) attributed to study drug. These were a pleural effusion, thrombocytopenia, febrile neutropenia, and a deep vein thrombosis. Nine pts required one or two dose reductions of gemcitabine for hematological toxicity. Of 29 pts with post-baseline echo or MUGA values obtained, no pt had LVEF drop to <50%. The adverse events evaluated after 40 pts did not meet the prespecified criteria to call for an independent safety monitoring board evaluation of unblinded data. Conclusions: Preliminary safety data indicate that pertuzumab or placebo combined with gemcitabine is well tolerated with no unexpected additive toxicity. The nature and frequency of the adverse events are similar to what has been observed with either single agent gemcitabine or P. Updated data will be presented at ASCO. [Table: see text]

A randomized, double-blind, placebo-controlled trial of trametinib, a MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 291-291 ◽  
Author(s):  
Jeffrey R. Infante ◽  
Bradley G. Somer ◽  
Joon Oh Park ◽  
Chung-Pin Li ◽  
Max E. Scheulen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Response Rate ◽  
Controlled Trial ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Mek Inhibitor ◽  
Kras Mutations ◽  
Double Blind ◽  
Duration Of Response ◽  
Grade 3

291 Background: Trametinib, an oral MEK1/2 inhibitor, holds promise for tumors that frequently harbor RAS activating mutations, such as pancreatic cancer. Trametinib monotherapy or in combination with gemcitabine showed preliminary activity in patients (pts) with advanced pancreatic cancer. Methods: Eligible pts with untreated metastatic pancreatic cancer were randomized (double-blind, 1:1) to receive gemcitabine 1000 mg/m2 intravenously weekly x 7 for 8 weeks, then weekly x 3 every 4 weeks, plus either trametinib 2 mg or placebo daily. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and duration of response (DoR). OS and ORR were also analyzed based on baseline KRAS status as determined in plasma cell free DNA (cfDNA). Results: Baseline characteristics for the 160 randomized and treated pts were similar across arms. Skin related events (73% vs. 34%), diarrhea (54% vs. 28%), thrombocytopenia (40% vs. 28%), and stomatitis (36% vs. 8%) were more frequent with trametinib, as was grade 3/4 anemia (22% vs. 11%). However, rates of grade ≥ 3 thrombocytopenia, neutropenia and febrile neutropenia were similar between the arms. More pts on trametinib arm required dose reduction or interruption due to AEs (68% vs. 49% and 74% vs. 43%, respectively). Median OS was 8.4 months with trametinib compared to 6.7 months with placebo [HR 0.98 (95% CI: 0.67, 1.44, p=0.453)]. Median PFS was 16 weeks on trametinib and 15 weeks on placebo arm. ORRs and median DoRs were 22% and 23.9 weeks and 18% and 16.1 weeks on trametinib and placebo arm, respectively. The median OS and ORR in the subgroup of pts with KRAS mutations (n=143) was similar to OS and ORR for all randomized pts. Conclusions: This is first randomized, placebo-controlled trial evaluating the combination of gemcitabine with a MEK inhibitor. There was an increased incidence of skin, GI, and hematologic toxicities with trametinib compared to placebo. The addition of trametinib did not improve OS, PFS, or response rate. These outcomes remained independent of KRAS mutations based on cfDNA. Clinical trial information: NCT01231581.

scholarly journals Phase II Evaluation of Pemetrexed in the Treatment of Recurrent or Persistent Platinum-Resistant Ovarian or Primary Peritoneal Carcinoma: A Study of the Gynecologic Oncology Group

2009 ◽  
Vol 27 (16) ◽  
pp. 2686-2691 ◽  
Author(s):  
David S. Miller ◽  
John A. Blessing ◽  
Carolyn N. Krasner ◽  
Robert S. Mannel ◽  
Parviz Hanjani ◽  
...  
Keyword(s):  
Phase Ii ◽  
Gynecologic Oncology ◽  
Progression Free Survival ◽  
Gynecologic Oncology Group ◽  
Oncology Group ◽  
Free Survival ◽  
Peritoneal Cancer ◽  
Platinum Resistant ◽  
Grade 3 ◽  
Dose Delay

Purpose To estimate the antitumor activity of pemetrexed in patients with persistent or recurrent platinum-resistant epithelial ovarian or primary peritoneal cancer and to determine the nature and degree of toxicities. Patients and Methods A phase II trial was conducted by the Gynecologic Oncology Group. Patients must have had cancer that had progressed on platinum-based primary chemotherapy or recurred within 6 months. Pemetrexed at a dose of 900 mg/m2 was to be administered as an intravenous infusion over 10 minutes every 21 days. Dose delay and adjustment was permitted for toxicity. Treatment was continued until disease progression or unacceptable adverse effects. Results From July 6, 2004, to August 23, 2006, 51 patients were entered. A total of 259 cycles (median, four; range one to 19 cycles) of pemetrexed were administered, with 40% of patients receiving six or more cycles. Overall, the treatment was well tolerated. More serious toxicities (grade 3 and 4) included neutropenia in 42%, leukopenia in 25%, anemia in 15%, and constitutional in 15% of patients. No treatment-related deaths were reported. One patient (2%) had a complete and nine patients (19%) had partial responses, with a median duration response of 8.4 months. Seventeen patients (35%) had stable disease for a median of 4.1 months. Eighteen patients (38%) had increasing disease. Three patients (6%) were not assessable. Median progression-free survival was 2.9 months, and overall survival was 11.4 months. Conclusion Pemetrexed has sufficient activity in the treatment of recurrent platinum-resistant ovarian cancer at the dose and schedule tested to warrant further investigation.

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