Comparison of Tobramycin Pharmacokinetics After Administration by Cris and a Traditional Intravenous Piggyback Infusion

1995 ◽  
Vol 29 (5) ◽  
pp. 465-469
Author(s):  
Vincent F Mauro ◽  
Lori R Jacobs ◽  
Laurie S Mauro ◽  
Rodger D MacArthur ◽  
Donald B White
Keyword(s):  
Maximum Concentration ◽  
Elimination Rate ◽  
Random Order ◽  
Open Label ◽  
Medical College ◽  
Primary Endpoints ◽  
Significant Difference ◽  
Secondary Endpoints ◽  
Open Label Trial ◽  
Infusion System

Objective: To compare the administration pharmacokinetics of a 30-minute intravenous piggyback (ivpb) infusion of tobramycin with those of controlled-release infusion system (CRIS) using a 20-mL vial at rates of 60 and 120 mL/h. Design: Randomized, controlled, crossover, prospective, open-label trial. Setting: Medical college-affiliated hospital. Participants: Eight healthy volunteer men between the ages of 22 and 24 years weighing between 60 and 90 kg. Interventions: Volunteers received, in random order, tobramycin sulfate 2 mg/kg iv on 3 occasions separated by 1 week. The drug was administered using a 50-mL ivpb infusion at 100 mL/h for 30 minutes, and with the CRIS using a 20-mL vial with flow rates of 60 mL/h for 1 hour (slow) and 120 mL/h for 1 hour (fast). Main Outcome Measures: Primary endpoints were area under the time–concentration curve (AUC), time to reach maximum concentration (tmax), and maximum concentration (Cmax). Secondary endpoints were elimination rate constant (ke), clearance (Cl), and half-life (t1/2). Results: Six volunteers successfully completed the trial. The tmax values observed following fast CRIS and ivpb were 28 ± 8 and 32 ± 4 minutes, respectively, and not significantly different from each other. Both occurred significantly earlier than the tmax associated with slow CRIS (44 ± 7 min). The Cmax values observed following ivpb (11.2 ± 1.5 mg/L) and slow CRIS (10.9 ± 0.9 mg/L) administration were not significantly different from each other, but both were significantly lower than that of fast CRIS (13.4 ± 1.5 mg/L). The AUCs of slow and fast CRIS were 29.8 ± 4.8 and 31.2 ± 3.8 mg/L•h, respectively, and were not significantly different from each other. The AUC of fast CRIS was significantly greater than that observed with ivpb (27.4 ± 4.3 mg/L•h). No significant difference in ke (fast CRIS 0.32 ± 0.03 h-1; slow CRIS 0.33 ± 0.04 h-1; ivpb 0.34 ± 0.0 h-1) was observed among any of the methods. Conclusions: CRIS administration of tobramycin resulted in higher AUCs than did ivpb administration. Compared with ivpb, fast CRIS resulted in a higher Cmax, but the tmax values of fast CRIS and ivpb administration were not statistically different. Compared with ivpb, slow CRIS resulted in a more delayed tmax, but the Cmax values of slow CRIS and ivpb were not statistically different.

Methotrexate in Early Chikungunya Arthritis: A 6 Month Randomized Controlled Open-label Trial

2020 ◽  
Vol 16 (4) ◽  
pp. 319-323
Author(s):  
M.B. Adarsh ◽  
Shefali K. Sharma ◽  
Preksha Dwivedi ◽  
Mini P. Singh ◽  
Varun Dhir ◽  
...  
Keyword(s):  
Open Label ◽  
Steroid Use ◽  
Course Of Illness ◽  
Intention To Treat ◽  
Randomized Controlled ◽  
Significant Difference ◽  
Secondary Endpoints ◽  
Open Label Trial ◽  
Treat Analysis ◽  
Blinded Trial

Objective: Evidence for treating chikungunya arthritis early in the course of illness is scarce. This study assesses the efficacy of Methotrexate in early Chikungunya arthritis. Methods: It is a randomized controlled open-label assessor-blinded trial with a crossover design. Sixty patients with persistent post chikungunya arthritis with at least 3 or more tender or swollen joints (28 joint count) were recruited. MTX arm was given oral Methotrexate and NSAID arm was given NSAIDs (Naproxen 1 gm/day or Etoricoxib 120 mg/day). Patients were followed at 1, 2, 4 and 6 months. After 2 months patients in NSAID arm who have not achieved remission were given MTX. The primary endpoint was remission (no tender or swollen joints by 28 joint count) at 6 months. Secondary endpoints were change in CDAI, Indian HAQ, total steroid use, total NSAID use, and serious adverse effects. Intention to treat analysis was used. Results: TJC, SJC, CDAI and HAQ were matched between two at baseline. Remission was achieved by 28 patients (93%, CI- 78%-98%) in the NSAID arm and 26 patients (86%, CI-70%- 94%) in MTX arm (p=0.18). There was no significant difference in steroid need, change in HAQ, CDAI, TJC or SJC. Those who have not achieved remission had higher disease activity at baseline. Conclusion: A protocol-based approach with steroid and NSAIDs helped to achieve remission in most patients with early subacute phase of post-Chikungunya arthritis and the effect was comparable to that of early initiation of methotrexate.

Daily consumption of fermented soymilk helps to improve facial wrinkles in healthy postmenopausal women in a randomized, parallel-group, open-label trial

2018 ◽  
Vol 8 (2) ◽  
pp. 107 ◽  
Author(s):  
Mitsuyoshi Kano ◽  
Kazuyoshi Haga ◽  
Kouji Miyazaki ◽  
Fumiyasu Ishikawa
Keyword(s):  
Postmenopausal Women ◽  
Maximum Depth ◽  
Liquid Chromatography Mass Spectrometry ◽  
Daily Consumption ◽  
Open Label ◽  
Facial Wrinkle ◽  
Crow’S Feet ◽  
Parallel Group ◽  
Secondary Endpoints ◽  
Open Label Trial

Background: Soymilk fermented by lactobacilli and/or bifidobacteria is attracting attention due to the excellent bioavailability of its isoflavones. We investigated the effects of fermented soymilk containing high amounts of isoflavone aglycones on facial wrinkles and urinary isoflavones in postmenopausal women in a randomized, parallel-group, open-label trial. Healthy Japanese women were randomly divided into active (n = 44, mean age 56.3 ± 0.5) or control (n = 44, mean age 56.1 ± 0.5) groups, who consumed or did not consume a bottle of soymilk fermented by Bifidobacterium breve strain Yakult and Lactobacillus mali for 8 weeks. Maximum depth of wrinkles around the crow’s feet area and other wrinkle parameters were evaluated as primary and secondary endpoints respectively at weeks 0, 4, and 8 during the consumption period. Urinary isoflavone levels were determined by liquid chromatography-mass spectrometry. Results: The active group demonstrated significant improvements in the maximum depth (p=0.015) and average depth (p=0.04) of wrinkles, and significantly elevated urinary isoflavones (daidzein, genistein, and glycitein; each p < 0.001) compared with the control during the consumption period. No serious adverse effects were recorded.Conclusion: These findings suggest that fermented soymilk taken daily may improve facial wrinkles and elevate urinary isoflavones in healthy postmenopausal women.Key words: postmenopausal women; isoflavone; fermented soymilk; phytoestrogen; facial wrinkle 

Clinical evaluation of AI software for rib fracture detection and its impact on junior radiologist performance

2021 ◽  
pp. 028418512110438
Author(s):  
Xiang Liu ◽  
Dijia Wu ◽  
Huihui Xie ◽  
Yufeng Xu ◽  
Lin Liu ◽  
...  
Keyword(s):  
Detection System ◽  
Ct Images ◽  
Diagnostic Efficiency ◽  
Fracture Detection ◽  
Patient Level ◽  
Primary Endpoints ◽  
Significant Difference ◽  
Secondary Endpoints ◽  
Lesion Level ◽  
Missed Diagnosis

Background The detection of rib fractures (RFs) on computed tomography (CT) images is time-consuming and susceptible to missed diagnosis. An automated artificial intelligence (AI) detection system may be helpful to improve the diagnostic efficiency for junior radiologists. Purpose To compare the diagnostic performance of junior radiologists with and without AI software for RF detection on chest CT images. Materials and methods Six junior radiologists from three institutions interpreted 393 CT images of patients with acute chest trauma, with and without AI software. The CT images were randomly split into two sets at each institution, with each set assigned to a different radiologist First, the detection of all fractures (AFs), including displaced fractures (DFs), non-displaced fractures and buckle fractures, was analyzed. Next, the DFs were selected for analysis. The sensitivity and specificity of the radiologist-only and radiologist-AI groups at the patient level were set as primary endpoints, and secondary endpoints were at the rib and lesion level. Results Regarding AFs, the sensitivity difference between the radiologist-AI group and the radiologist-only group were significant at different levels (patient-level: 26.20%; rib-level: 22.18%; lesion-level: 23.74%; P < 0.001). Regarding DFs, the sensitivity difference was 16.67%, 14.19%, and 16.16% at the patient, rib, and lesion levels, respectively ( P < 0.001). No significant difference was found in the specificity between the two groups for AFs and DFs at the patient and rib levels ( P > 0.05). Conclusion AI software improved the sensitivity of RF detection on CT images for junior radiologists and reduced the reading time by approximately 1 min per patient without decreasing the specificity.

Sirolimus for patients with connective tissue disease-related refractory thrombocytopenia: a single-arm, open-label clinical trial

Rheumatology ◽  
2020 ◽  
Author(s):  
Chanyuan Wu ◽  
Qian Wang ◽  
Dong Xu ◽  
Mengtao Li ◽  
Xiaofeng Zeng
Keyword(s):  
Complete Remission ◽  
Connective Tissue ◽  
Connective Tissue Disease ◽  
Remission Rate ◽  
Complete Remission Rate ◽  
Severe Side Effect ◽  
Open Label ◽  
First Line Therapy ◽  
Primary Endpoints ◽  
Significant Difference

Abstract Objectives Connective tissue disease-related thrombocytopenia (CTD-TP) is a problematic disorder in clinical practice. Because the first-line therapy of glucocorticoid and/or immunosuppressants is not effective for refractory cases, alternative treatment approaches are urgently needed. The present study investigated the efficacy and safety of sirolimus in refractory CTD-TP patients. Methods This single-centre, single-arm, phase II study enrolled 20 refractory CTD-TP patients between September 2017 and September 2018 (registered on ClinicalTrials.gov: NCT03688191). Oral sirolimus administration was dose-adjusted to maintain a therapeutic range of 6–15 ng/ml for 6 months. The primary endpoints were partial and complete remission rates at 6 months. Results Twelve (60%) patients achieved the primary end point with a 50% complete remission rate after 6 months. Among the 14 SLE patients, the overall response rate was 71.4%, with a complete remission rate of 64.3%. None of the primary Sjögren's syndrome cases responded to sirolimus. There was no significant difference in baseline clinical characteristics or lymphocyte subpopulations between responders and non-responders. No severe side effect was detected during the study. Conclusion Sirolimus is an effective and safe treatment option for refractory CTD-TP patients. Trial registration https://clinicaltrials.gov, NCT03688191.

Exploratory randomized trial to evaluate the effect of indisetron tablets for preventing chemotherapy-induced nausea and vomiting (CINV)/acute-onset diarrhea induced by IRIS/FOLFIRI: HGCSG0704.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 624-624
Author(s):  
Sosuke Kato ◽  
Hiraku Fukushima ◽  
Kanji Kato ◽  
Satoshi Yuki ◽  
Kazuaki Harada ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Rescue Medication ◽  
Complete Response ◽  
Acute Onset ◽  
Complete Protection ◽  
Primary Endpoints ◽  
Significant Difference ◽  
Secondary Endpoints ◽  
Colorectal Cancer Patients ◽  
Ecog Ps

624 Background: Indisetron is a 5-HT3 receptor antagonist that also antagonizes 5-HT4receptors. Indisetron tablets showed the non-inferiority to ondansetron tablets in terms of efficacy for preventing CINV. Moreover, preclinical data administered with irinotecan showed indisetron significantly reduced stool frequency in mice and inhibited the colonic peristalsis in dogs. We designed a pilot study compared with granisetron in the efficacy and tolerability of indisetron for irinotecan-induced nausea, vomiting and especially in diarrhea. Methods: Advanced colorectal cancer patients treated with FOLFIRI or IRIS (Irinotecan + S-1) with or without bevacizumab were enrolled in this study. Treatment: Arm A: indisetron tablets 8mg po day1. Arm B: granisetron 3mg iv day 1. The primary endpoints were the incidence of acute-onset diarrhea and complete protection from vomiting. Secondary endpoints were tolerability, complete protection from nausea and rate of no rescue medication. Results: Between May 2008 and July 2012, 33 patients (pts) were randomized. The study was closed prematurely due to poor accrual. Arm A: 16 pts, arm B 17 pts. Median age A: 68 y.o., B: 66 y.o.: ECOG PS 0/1: A: 12/4, B: 14/3pts. There was no significant difference of the incidence of acute-onset diarrhea between both groups (18.8% in A vs. 35.3% in B, p = 0.438). The proportion of complete protection from vomiting was 87.5% in A and 88.2% in B (p = 1.000). Similarly, complete protection from nausea, rate of no rescue medication, proportion of patients with a complete response (defined as no emetic episodes and no rescue medication) did not have a significant difference. Severity of nausea/vomiting and AE induced by 5-HT3 receptor antagonist were also similar between two groups. Conclusions: Compared with granisetron, indisetron showed effective and feasible results for preventing CINV induced by FOLFIRI or IRIS. Indisetron had also not improved the incidence of acute-onset diarrhea induced by irinotecan. Clinical trial information: UMIN000010162.

scholarly journals Post-streptokinase PCI in STEMI patients exceeding the 24-h guidelines

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
El-Zahraa M. Esmat Sultan ◽  
Khaled R. Abdel Meguid ◽  
Hesham B. Mahmoud
Keyword(s):  
End Point ◽  
Timi Flow ◽  
Primary Endpoints ◽  
Significant Difference ◽  
Close Observation ◽  
Secondary Endpoints ◽  
Group 2 ◽  
Group 1 ◽  
The Ideal

Abstract Background Due to delay in obtaining approval from insurance institution, performing PCI after successful reperfusion using streptokinase was postponed for ˃24 h-1 week. The study was conducted to investigate safety and efficacy of such delay in comparison to the ideal guidelines of PCI (≤ 24 h) in 129 STEMI patients received streptokinase followed by PCI. Patients were divided into two groups: (group 1 = 57; early PCI ≤ 24 h.) and (group 2 = 72; late PCI > 24 h.). Results Primary end point was death, congestive heart failure and reinfarction up to 30 days. Secondary end point was TIMI flow < G3, ischemic stroke, intracranial hemorrhage and non-intracranial bleeding. No statistical significant difference was found between both groups regarding LVEF, dimensions and myocardium wall preservation and incidence of complications and TIMI flow. No primary endpoints were detected. Five patients had secondary endpoints in early PCI and four in the late PCI. Suction device and IV Eptifibatide were used more in early PCI (p = 0.003). Conclusions The study suggests that relatively late PCI (> 24 h–1wk) after successful reperfusion using streptokinase in STEMI patients seems to be safe and effective in 30-day follow-up, provided that patients received DAPT and were subjected to close observation. The results seem safely applicable when we are forced to this choice; however lack of more investigations to this hypothesis is considered a limitation.

scholarly journals Immediate versus deferred antiretroviral therapy in HIV-infected patients presenting with acute AIDS-defining events (toxoplasmosis, Pneumocystis jirovecii-pneumonia): a prospective, randomized, open-label multicenter study (IDEAL-study)

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Guido Schäfer ◽  
◽  
Christian Hoffmann ◽  
Keikawus Arasteh ◽  
Dirk Schürmann ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Antiretroviral Therapy ◽  
Proteinase Inhibitor ◽  
Opportunistic Infections ◽  
Pneumocystis Pneumonia ◽  
Pneumocystis Jirovecii Pneumonia ◽  
Open Label ◽  
Significant Difference ◽  
Secondary Endpoints

Abstract Background To evaluate clinical outcomes after either immediate or deferred initiation of antiretroviral therapy in HIV-1-infected patients, presenting late with pneumocystis pneumonia (PCP) or toxoplasma encephalitis (TE). Methods Phase IV, multicenter, prospective, randomized open-label clinical trial. Patients were randomized into an immediate therapy arm (starting antiretroviral therapy (ART) within 7 days after initiation of OI treatment) versus a deferred arm (starting ART after completing the OI-therapy). All patients were followed for 24 weeks. The rates of clinical progression (death, new or relapsing opportunistic infections (OI) and other grade 4 clinical endpoints) were compared, using a combined primary endpoint. Secondary endpoints were hospitalization rates after completion of OI treatment, incidence of immune reconstitution inflammatory syndrome (IRIS), virologic and immunological outcome, adherence to proteinase-inhibitor based antiretroviral therapy (ART) protocol and quality of life. Results 61 patients (11 patients suffering TE, 50 with PCP) were enrolled. No differences between the two therapy groups in all examined primary and secondary endpoints could be identified: immunological and virologic outcome was similar in both groups, there was no significant difference in the incidence of IRIS (11 and 10 cases), furthermore 9 events (combined endpoint of death, new/relapsing OI and grade 4 events) occurred in each group. Conclusions In summary, this study supports the notion that immediate initiation of ART with a ritonavir-boosted proteinase-inhibitor and two nucleoside reverse transcriptase inhibitors is safe and has no negative effects on incidence of disease progression or IRIS, nor on immunological and virologic outcomes or on quality of life.

Final results of study 20050181: A randomized phase III study of FOLFIRI with our without panitumumab (pmab) for the second‑line treatment (tx) of metastatic colorectal cancer (mCRC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3535-3535 ◽  
Author(s):  
Alberto F. Sobrero ◽  
Marc Peeters ◽  
Timothy Jay Price ◽  
Yevhen Hotko ◽  
Andres Cervantes-Ruiperez ◽  
...  
Keyword(s):  
Descriptive Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Second Line ◽  
Primary Analysis ◽  
Primary Endpoints ◽  
Significant Difference ◽  
Secondary Endpoints ◽  
Event Rates

3535 Background: The primary analysis of study 20050181 showed that in patients (pts) with wild-type (WT) KRAS mCRC, pmab plus FOLFIRI given as second-line therapy significantly improved progression-free survival (PFS) vs FOLFIRI alone. Here, we report on a prespecified descriptive analysis planned for 30 months (mos) after the last pt was enrolled. Methods: Pts with mCRC, ECOG 0-2, who had one prior fluoropyrimidine-based chemotherapy regimen were randomized 1:1 to pmab 6.0 mg/kg Q2W+FOLFIRI (Arm 1) vs FOLFIRI (Arm 2). Co-primary endpoints were OS and PFS (central assessment). Secondary endpoints included objective response rate (ORR) and safety. Tumor KRAS status was determined by a blinded central lab. Results: 1186 pts were randomised and received tx: 591 in Arm 1, 595 In Arm 2. 1083 pts (91%) had KRAS results. Adverse event rates were consistent with the primary analysis. Results are shown below. Conclusions: In pts with WT KRAS mCRC receiving pmab+FOLFIRI vs FOLFIRI, PFS and ORR were significantly improved, and there was a trend toward improved OS. Post-progression anti-EGFR tx may have attenuated any significant difference in OS between tx arms. In pts with MT KRAS mCRC, no difference in efficacy was observed between tx arms. KRAS testing is critical to select appropriate pts for tx with pmab. [Table: see text]

A phase I, open-label, nonrandomized, pharmacokinetic study of trifluridine/tipiracil (TAS-102) in Chinese patients with solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14079-e14079
Author(s):  
Xicheng Wang ◽  
Jianfeng Zhou ◽  
Yan Li ◽  
Yuping Ge ◽  
Yanping Zhou ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Chinese Patients ◽  
Open Label ◽  
Significant Difference ◽  
Inactive Metabolite ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Experienced Grade ◽  
Clinical Trial Information

e14079 Background: Trifluridine/tipiracil (TAS-102) is an oral combination of an antineoplastic thymidine-based nucleoside analog, trifluridine (FTD), and the thymidine phosphorylase inhibitor, tipiracil (TPI). Trifluridine/tipiracil is demonstrated as a valid treatment choice for Asian and Western patients (pts) with metastatic colorectal cancer refractory or intolerant to standard chemotherapies in earlier studies. Its pharmacokinetic (PK) profile was also investigated in American and Japanese phase 1 studies, but never in Chinese pts. This study was conducted to investigate the PK profile of Trifluridine/tipiracil in a Chinese population with solid tumors. Methods: Pts who has responded poorly to existing standard treatment received Trifluridine/tipiracil (35 mg/m2/dose), orally BID, on days 1-5 and days 8-12 every 4 weeks until one of discontinuation criteria was met. Blood samples for PK analysis of FTD (the active compound), fluorothymine (FTY, inactive metabolite) and TPI were collected after single and multiple doses of Trifluridine/tipiracil on days 1 and 12 of cycle 1. The safety, tolerability, and antitumor activity of Trifluridine/tipiracil were also assessed as secondary endpoints. Results: A total of 15 pts were administered Trifluridine/tipiracil and analyzed for PKs. The PKs of FTD, FTY, and TPI in Chinese pts were comparable to those in Japanese pts. Compared with American pts, although the AUC0-t of TPI on day 12 was significantly lower in Chinese pts, the Cmax and AUC0-t of FTD were not significantly different. Thirteen (86.7%) pts reported treatment-emergent adverse events (TEAEs), and eight (53.3%) pts experienced grade 3 TEAEs, of which anemia and fatigue were most frequently (≥10% of patients) reported. Grade 4 or 5 TEAEs were not observed. Conclusions: The PKs of Trifluridine/tipiracil in Chinese pts were comparable to those in Japanese pts. The exposure of FTD was showed without significant difference between Chinese, Japanese and American pts. Trifluridine/tipiracil was well-tolerated in Chinese pts and had the similar safety profile in comparison with previous studies. Clinical trial information: NCT02261532.

HALO 110-101: A phase Ib, randomized, open-label study of PEGPH20 (pegvorhyaluronidase alfa) in combination with cisplatin (CIS) + gemcitabine (GEM) (PEGCISGEM) or atezolizumab and CIS + GEM (PEGCISGEMATEZO) in hyaluronan-high subjects with locally advanced or metastatic cholangiocarcinoma and gallbladder cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS543-TPS543 ◽  
Author(s):  
Mitesh J. Borad ◽  
Rachna T. Shroff ◽  
Ghassan K. Abou-Alfa ◽  
J. Randolph Hecht ◽  
Andrea J. Bullock ◽  
...  
Keyword(s):  
Gallbladder Cancer ◽  
Immune Cell ◽  
Locally Advanced ◽  
Safety Data ◽  
Data Monitoring Committee ◽  
Open Label ◽  
Dosing Schedule ◽  
Primary Endpoints ◽  
Safety Parameters ◽  
Secondary Endpoints

TPS543 Background: Cholangiocarcinoma (CCA) is treated with CIS and GEM (CISGEM), but prognosis is poor. Hyaluronan (HA) accumulation in solid tumors may impede drug and immune cell access. PEGPH20 targets tumors that accumulate HA (HA-high). This study (NCT03267940) plans to enroll 70 subjects to evaluate the safety and activity of PEGPH20 + programmed cell death-ligand 1 (PD-L1) agent atezolizumab, (PEGCISGEMATEZO), & PEGPH20 + CISGEM (PEGCISGEM) in HA-high subjects with CCA and gallbladder cancer. Study will comprise initial run-in and expansion portions. Primary endpoints include incidence of AEs and other laboratory/safety parameters and ORR (RECIST v1.1). Secondary endpoints include PK parameters; DOR, DCR, PFS, and ORR (RECIST v1.1 and immune-modified RECIST); and OS and OS by PD-L1 expression. Methods: ~6 HA-high subjects will be enrolled in PEGCISGEM arm run-in portion and undergo at ≥1 cycle; subsequently, 6 HA-high subjects will enter the PEGCISGEMATEZO arm. Treatment period will be 21-day cycles. In the expansion portion, ~50 HA-high subjects will be enrolled and randomized in a 2:2:1 ratio into PEGCISGEMATEZO, PEGCISGEM, and CISGEM arms. PEGPH20 is planned to be administered at 3.0 μg/kg on Days 1, 8 and 15 of all cycles in both portions. ATEZO will be administered at 1200 mg 1–3 hours after PEGPH20 on Day 1 of each 21-day cycle in the PEGCISGEMATEZO arm in both portions. In the PEGCISGEM & PEGCISGEMATEZO arms, dosing schedule for CISGEM is the same during both portions, with administration of 25 mg/m2 CIS and 1000 mg/m2 GEM on Days 2 and 9 of each cycle. In CISGEM control arm (expansion only), dosing schedule will be on Days 1 and 8 of each cycle. Treatment will continue until death, withdrawal of consent, disease progression, or unacceptable toxicity. Tumor response will be evaluated using RECIST v1.1. AEs will be graded per NCI CTCAE v4.03. Tumor samples will be tested retrospectively for PD-L1 expression. Safety data will be periodically monitored by an independent data monitoring committee. Clinical trial information: NCT03267940.

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