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.

Halo 110-101: Early safety results of pegvorhyaluronidase alfa (PEGPH20; PVHA) + cisplatin (C) + gemcitabine (G) ± atezolizumab (ATZ) in patients (pts) with locally advanced or metastatic cholangiocarcinoma (CCA) and gallbladder cancer (GBC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 408-408
Author(s):  
Do-Youn Oh ◽  
Mann Muhsin ◽  
Andrea J. Bullock ◽  
Ghassan K. Abou-Alfa ◽  
Rachna T. Shroff ◽  
...  
Keyword(s):  
Immune Cell ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Primary Endpoints ◽  
Secondary Endpoints ◽  
Phase Clinical Trial ◽  
The Mean ◽  
The Individual ◽  
Dose Limiting Toxicity ◽  
Clinical Trial Information

408 Background: Standard of care for CCA/GBC is C-G therapy. MAbs (ATZ, pembrolizumab) targeting PD-L1 show promise in treating CCA/GBC. Hyaluronan (HA), which may impede drug and immune cell access, is high (67%) in CCA/GBC tumors. PEGPH20 enzymatically degrades HA. HALO 110-101 (NCT03267940) evaluates safety and activity of PEG-C-G-ATZ or PEG-C-G versus C-G in CCA/GBC pts. Methods: This study comprises two parts. In Run-In (RI) six pts were enrolled in PEG-C-G arm, then six pts in PEG-C-G-ATZ arm. Eight additional pts may be enrolled for tolerability. In Expansion (EX), up to 50 pts will be enrolled for efficacy. Treatment (Tx) cycle is 21 days (d). PEGPH20 dose is 3 μg/kg on d1, eight and 15 and ATZ dose is 1200 mg (one–three hours after PEGPH20) on d1 (PEG-C-G-ATZ only). C-G is dosed at 25 mg/m2 C and 1000 mg/m2 G on d2 and nine. In C-G arm (EX only), C-G is dosed on d1 and 8. Primary endpoints are ORR (RECIST v1.1), AEs (NCI CTCAE v4.03), laboratory/safety (RI only); secondary endpoints are PK; DOR, DCR, PFS; OS, OS by PD-L1 expression; ORR and DOR (imRECIST). Results: Eighteen pts have been enrolled (nine in each arm). The mean (SD) age is 57 (12.2) yrs in PEG-C-G and 69 (8.8) yrs in PEG-C-G-ATZ. 56% were men. All pts experienced ≥ 1 AE. The most common AEs are nausea, fatigue (50% each); decreased appetite (44%); anemia, constipation (39% each); thrombocytopenia, oedema peripheral, AST increased, myalgia (33% each). To date, there has been one dose-limiting toxicity (febrile neutropenia) in the PEG-C-G arm. There have been no deaths due to AEs. Conclusions: The overall safety profile of PEGPH20 + C + G ± ATZ is acceptable and consistent with safety observed for the individual components. There were no DLTs resulting in a dose reduction of PEGPH20, which is being dosed at 3 μg/kg in the EX phase. Clinical trial information: NCT03267940. [Table: see text]

ICORG 06-41: A phase II trial of single-agent sorafenib in the treatment of platinum-pretreated relapsed gastroesophageal adenocarcinoma (GECa).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 88-88 ◽  
Author(s):  
Louise Catherine Connell ◽  
Seamus O'Reilly ◽  
Glenn Webb ◽  
Brian Moulton ◽  
Imelda Parker ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Locally Advanced ◽  
Safety Data ◽  
Primary Objective ◽  
Open Label ◽  
Oncology Research ◽  
Translational Studies ◽  
Gastroesophageal Adenocarcinoma

88 Background: Over 1 million individuals worldwide annually are diagnosed with GECa. The majority of patients(pts) present with inoperable locally advanced or metastatic disease(dx). Even with resectable dx 5 year survival is low at ~40% with current best treatment (tx). Following initial platinum based therapy there is no established standard 2nd line tx. Besides HER2-directed therapy there has been little progress with targeted biologic agents. ICORG, the all-Ireland Cooperative Oncology Research Group investigated the utility of the tyrosine kinase inhibitor sorafenib in a multicentre trial. Methods: A prospective Phase II, nonrandomised, open label, one arm study of single agent sorafenib in the tx of platinum pre-treated relapsed GECa was conducted. Primary objective was dx control rate (DCR) post 4 months of tx. Secondary endpoints were OS, PFS, TTP, ORR, tolerability/toxicity and biomarkers of tx response/resistance. The protocol allowed for an interim analysis to be performed if clinically indicated. A sample size of 54 pts was identified using the single stage Fleming design approach to test whether the proportion responding, P, is ≤ 0.35 or ≥ 0.50. Pts received Sorafenib 400mg bid p.o. continuously q28days until dx progression or intolerable toxicity. Response by RECIST was evaluated by CT q8weeks. For pts with sufficient tumour samples translational studies were done. Results: An interim review performed in Nov 2012 (35 months post study opening) indicated that 33/41 evaluable pts recruited to date had progressed before completing 4 months of tx. Therefore, the number of evaluable pts with dx control could not reach the pre-specified figure of 22, & the hypothesis P >= 0.50 was rejected. Fifteen pts had just 1 cycle of tx, 5 of whom completed ≤ 2 weeks. A further 14 pts had 2 cycles. Median survival time to progression was 56 days (95% CI 53 – 59 days).Median OS was 120 days (95% CI 91 – 149 days). Safety data analyses and translational studies are ongoing and will be available for presentation at the meeting. Conclusions: Sorafenib as monotherapy is inactive in platinum pretreated pts with relapsed GECa. A significant unmet clinical need for novel effective therapies remains. Clinical trial information: 2008-005062-31.

Initial safety run-in findings with bavituximab plus pembrolizumab in patients with advanced gastric or gastroesophageal cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16537-e16537
Author(s):  
Ian Chau ◽  
Haeseong Park ◽  
Jeeyun Lee ◽  
Jessicca Martin Rege ◽  
Kerry Culm-Merdek ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Cell ◽  
Gastroesophageal Junction ◽  
Safety Data ◽  
Chylous Ascites ◽  
Phase Iii ◽  
Open Label ◽  
Agent Based ◽  
Starting Dose ◽  
Post Hoc

e16537 Background: Bavituximab, an investigational, chimeric monoclonal antibody designed to inhibit the immunosuppressive effects of phosphatidylserine (PS), is being evaluated in combination with pembrolizumab in patients with advanced gastric and gastroesophageal junction (GEJ) cancer. Bavituximab binds in a high-affinity complex with β2-glycoprotein and PS to reverse immunological non-responsiveness and activate multiple immune cell receptors. Post-hoc data from the Phase III Sunrise second-line lung cancer study indicated that patients who progressed on study treatment with bavituximab plus docetaxel and continued with a checkpoint inhibitor showed significantly improved overall survival. Cumulative data suggest that bavituximab may potentiate pembrolizumab-mediated checkpoint inhibition, potentially increasing overall clinical benefit. ONCG100 is a phase 2, multicenter, open-label, single-arm global study designed to assess the safety, tolerability and efficacy of bavituximab and pembrolizumab when administered in combination to advanced gastric or GEJ adenocarcinoma patients, regardless of PD-L1 status, who have progressed on or after at least one prior standard therapy (NCT04099641). Methods: The safety run-in phase of the trial evaluated the safety and tolerability of de-escalating doses of bavituximab when administered in combination with the approved dose and schedule of pembrolizumab (200mg, Q3W). Adverse events were evaluated by CTCAE v5.0. Results: Three patients enrolled and completed the safety-run in phase of the study where bavituximab was administered at the starting dose of 3 mg/kg QW in combination with pembrolizumab. There were no dose-limiting toxicities observed during the 21-day monitoring period. A total of 4 treatment emergent adverse events were observed; 2 of which were reported as related to treatment with bavituximab (arthralgia and fatigue, both grade 1). There was one treatment-unrelated SAE reported (chylous ascites, grade 2), which resolved allowing the patient to continue treatment. Conclusions: The 3 mg/kg dose of bavituximab was readily combined during the safety run-in phase of the study with the approved dose of pembrolizumab. The AE profiles for this combination were manageable and expected given the known profiles of each agent. Based upon these findings, the recommended dose for expansion for the combination was declared and the expansion phase of the study opened. Updated safety data from the study will be presented. Clinical trial information: NCT04099641 .

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.

scholarly journals Neoadjuvant chemo-free combination of camrelizumab and apatinib for locally advanced resectable oral squamous cell carcinoma – A pilot study

2021 ◽  
Author(s):  
Wu-tong Ju ◽  
Rong-hui Xia ◽  
Dong-wang Zhu ◽  
Sheng-jin Dou ◽  
Guo-pei Zhu ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Neoadjuvant Therapy ◽  
Squamous Cell ◽  
Locally Advanced ◽  
Open Label ◽  
T Cell Infiltration ◽  
Primary Endpoints ◽  
Vegfr Inhibitor

Abstract Novel neoadjuvant therapy regimens are needed to improve the outcomes of patients with locally advanced resectable oral squamous cell carcinoma (OSCC). We conducted a prospective, open-label, single-arm trial (n = 21, NCT04393506) to determine the safety and feasibility of neoadjuvant camrelizumab (an anti-PD-1 antibody) plus apatinib (a VEGFR inhibitor) for locally advanced resectable OSCC. The primary endpoints were safety and major pathological response (MPR). Neoadjuvant camrelizumab plus apatinib was well-tolerated and the MPR rate was 40% (8/20), meeting the primary endpoint. All five patients with CPS ˃ 10 had MPR. Additionally, patients achieving MPR showed more CD4+ T cell infiltration and a higher CD8+/FoxP3+ ratio than those without MPR (p < 0.05), and decreased CD31 and ɑ-SMA expression were observed after neoadjuvant therapy. Our findings demonstrate that neoadjuvant therapy with a chemo-free combination of camrelizumab and apatinib is safe and yields a promising MPR rate, supporting further trials.

scholarly journals Rationale and design of a phase II trial of durvalumab treatment in patients with NSCLC ineligible for stage III chemoradiotherapy following radiation monotherapy (SPIRAL-RT study)

2020 ◽  
Vol 12 ◽  
pp. 175883592092784 ◽  
Author(s):  
Tadaaki Yamada ◽  
Junji Uchino ◽  
Yusuke Chihara ◽  
Takayuki Shimamoto ◽  
Masahiro Iwasaku ◽  
...  
Keyword(s):  
Phase Ii ◽  
Antitumor Agents ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Stage Iii ◽  
Open Label ◽  
Free Survival ◽  
The Pacific ◽  
Secondary Endpoints

Background: In the PACIFIC study, progression-free survival (PFS) and overall survival (OS) of patients with unresectable, locally advanced, stage III non-small cell lung cancer (NSCLC) were prolonged by durvalumab as maintenance therapy after radical concurrent chemoradiotherapy using platinum-based antitumor agents. However, no data were obtained to reveal the efficacy of durvalumab after radiation monotherapy in patients unsuitable for chemoradiotherapy. Here, we describe an ongoing single-arm, prospective, open-label, multicenter phase II trial of durvalumab in patients with NSCLC ineligible for stage III chemoradiotherapy following radiation monotherapy (SPIRAL-RT study). Methods: Durvalumab at 10 mg/kg body weight is administered every 2 weeks after radiation therapy until individual patients meet the discontinuation criteria. The treatment duration is up to 12 months. The primary endpoint is the 1-year PFS rate. Secondary endpoints are response rate, PFS, OS, and safety. Durvalumab treatment after radiation monotherapy is expected to prolong 1-year PFS rate and have acceptable adverse events. Discussion: We are conducting an intervention study to investigate the safety and efficacy of durvalumab treatment in patients with NSCLC ineligible for stage III chemoradiotherapy following radiation monotherapy.

Comparison of neoadjuvant 6 vs 8 cycles of docetaxel/doxorubicin/cyclophosphamide (TAC) in patients early responding to TACx2-the GEPARTRIO Study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 576-576 ◽  
Author(s):  
G. Von Minckwitz ◽  
J. Blohmer ◽  
P. Vogel ◽  
C. Hanusch ◽  
H. Eidtmann ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Breast Conservation ◽  
Sensory Neuropathy ◽  
Early Response ◽  
Moderate Increase ◽  
Open Label ◽  
Non Invasive ◽  
Hand Foot Syndrome ◽  
Secondary Endpoints ◽  
Pathologic Complete Remission

576 Background: Primary breast cancer (BC) patients (P) with early response to neoadjuvant TACx2 (75mg/m, 50 mg/m, 500 mg/m, day 1, q21, supported with (pegylated) G-CSF and epoetin) experience a high pathologic complete remission (pCR) rate after further TACx4 (von Minckwitz et al, Ann Oncol 2005) compared to patients without early response (SABCS 2005, Abst 38). We compared prolongation to 8 cycles of TAC with conventional 6 cycles TAC in the chemosensitive subgroup. Methods: P with operable (T 2 cm by palpation) or locally advanced (T4 or N3, M0) BC were treated with TACx2. If tumor reduction was exceeding 50% according to breast ultrasound, P were randomized to receive either 4 or 6 additional cycles. Endpoints were pCR-rate (no invasive and no non-invasive residuals) (primary), sonographic response before surgery, breast conservation rate, safety and compliance (secondary). To detect an increase in pCR-rate from 20 to 26%, 606 evaluable patients were requested for each arm (α=0.05, β=0.2, one-sided). Results: 2106 P were recruited into the multi-centre, prospective, open-label, randomized GEPARTRIO-trial within 36 months. 1400 P with an early response to TACx2 were randomized with the last patient having surgery in Dec 05. Median clinical tumor size was 4.0 (1.0 - 30.0) cm at study entry. A planned safety and blinded efficacy interim analysis was performed on the first 600 patients (306 TACx6, 294 TACx8). Main toxicities (grade I-IV %TACx6 vs %TACx8) were: anemia (91 vs 93), thrombopenia (39 vs 49), neutropenia (65 vs 75), febrile neutropenia (10 vs 16), infection (29 vs 30), vomiting (42 vs 44), diarrhea (59 vs 52), stomatitis (66 vs 67), conjunctivitis (51 vs 57), allergic reactions (20 vs 14), edema (40 vs 47), asthenia (90 vs 93), hand-foot-syndrome (25 vs 28), nail (43 vs 50), dyspnea (33 vs 37), sensory neuropathy (51 vs 61). Treatment was discontinued early in 165 P (31.0%), 53 (19.8%) P during TACx6 and 112 (42.3%) P during TACx8. Overall pCR was reported in 102 (17.0%) of these patients. Conclusions: TACx8 is associated with moderate increase in toxicity and treatment discontinuations compared to TACx6. Final results on the primary and secondary endpoints will be presented. [Table: see text]

Safety of bevacizumab in patients with metastases to the central nervous system

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2007-2007 ◽  
Author(s):  
U. P. Rohr ◽  
S. Augustus ◽  
S. F. Lasserre ◽  
P. Compton ◽  
J. Huang
Keyword(s):  
Brain Metastases ◽  
Locally Advanced ◽  
Safety Information ◽  
Safety Data ◽  
Clinical Signs ◽  
Metastatic Breast ◽  
Tumor Type ◽  
Cns Metastases ◽  
Open Label ◽  
Background Rate

2007 Background:. The background rate of CNS hemorrhage (CH) in cancer patients with brain metastases not receiving bevacizumab (BV) treatment is 5%-29%, depending on tumor type. Patients with CNS metastases were routinely excluded from most BV late-stage clinical trials, following the occurrence of CH in one hepatocellular carcinoma patient with occult CNS metastasis in a BV phase I trial. In this particular tumour type, up to 87.5% has been reported as a background rate of CH without BV use. Available safety information in BV-treated patients with CNS metastases has been reviewed to determine whether the exclusion of these patients from trials is still justified. Methods: A retrospective exploratory analysis was conducted using safety data from three datasets: A.) 13 randomized controlled phase II or III trials (RCTs); B.) Two ongoing open-label trials MO19391 (ATHENA) and MO19390 (SAIL). While patients with known CNS metastases, based on imaging or clinical signs and symptoms, were excluded from trial in A and B datasets, patients who were found to have CNS lesions had either unrecognized CNS metastases at study entry or had developed these during the trial.; C.) 2 ongoing open-label studies AVF3752g and AVF3671g in patients with NSCLC, where inclusion of patients with treated CNS metastases was allowed. Incidence of CH in patients with brain metastases was quantified in each dataset. Results: A.) In 13 RCTs, with a total of 8443 patients with locally advanced, unresectable, or metastatic breast, renal, pancreatic, colorectal cancer, or NSCLC, brain metastases were identified in 187 patients (91 in BV-arms and 96 in control arm). Three of 91 (3.29%) BV-treated patients developed grade 4 CH, and one in 96 patients in the control arm (1.04%) developed grade 5 CH; B.) In open-label studies no CH was reported in 68 patients with CNS metastases, out of 3,252 patients enrolled. C.) In two studies in patients with treated CNS metastases, one subject in 83 (1.2%) BV treated patients developed a grade 2 CH. Conclusions: In this retrospective review, the rates of CH in BV-treated patients with CNS metastases is low, and appears consistent with historical rates of CH in these patient populations. Ongoing trials are expected to provide additional data regarding the risk of CH in patients with primary and metastatic CNS tumors. [Table: see text]

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