Immunomodulatory switch maintenance therapy in metastatic colorectal carcinoma: The phase III IMPALA study.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS785-TPS785 ◽  
Author(s):  
David Cunningham ◽  
Werner Scheithauer ◽  
Alfredo Zurlo ◽  
Ramon Salazar ◽  
Michel Ducreux ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Primary Endpoint ◽  
Immune Cell ◽  
Immune Monitoring ◽  
Phase Iii ◽  
Induction Treatment ◽  
Impact Study ◽  
Open Label ◽  
Double Blind ◽  
To Receive

TPS785 Background: The Toll-like receptor 9 agonist MGN1703 was compared to placebo in 59 metastatic CRC (mCRC) patients with disease control after standard induction chemotherapy in the double-blind randomized phase 2 IMPACT study. MGN1703 showed a superior effect over placebo, with a hazard ratio (HR) for the primary endpoint “PFS on maintenance” of 0.55 (p = 0.041) by local assessment and 0.56 (p = 0.070) by independent radiological review. Exploratory PFS analyses identified patients with objective RECIST response, normalized CEA and presence of activated NKT cells at the end of induction treatment to benefit the most from MGN1703. The OS evaluation showed a HR of 0.40 (median 24.5 vs. 15.1 months) for patients with RECIST response after induction therapy. Furthermore, at time of IMPACT study closure, 4 MGN1703 patients were still without progressive disease and continued treatment in compassionate use. As of August 2015, 3 patients were still receiving MGN1703 treatment in excess of three years (47-55 months), with 2 objective responses ongoing over 46 months. Methods: The international, multicenter, open-label phase 3 IMPALA study is conducted in collaboration with the AIO, TTD and GERCOR cooperative groups. In IMPALA, mCRC patients having achieved an objective tumor response following any type of first line induction therapy are randomized to receive MGN1703 switch maintenance monotherapy in the experimental arm or local standard of care in the control arm. In case of relapse, patients will reintroduce induction treatment whenever feasible, with those in the experimental arm continuing to receive MGN1703 therapy in the weeks without infusional chemotherapy. The primary endpoint of the study will be OS. Secondary endpoints include PFS, response rates, safety, and QoL in selected centers. Induction treatment, CEA and activated NKT at baseline are stratification factors and will be prospectively assessed. All randomized patients take part in a comprehensive immune monitoring plan evaluating cytokines and chemokines in serum and the activation status of immune cell populations. Recruitment started in September 2014 and the study is expected to recruit 540 patients within 24 months in 8 European countries. Clinical trial information: NCT02077868.

IMPALA, a randomized phase III study in patients with metastatic colorectal carcinoma: Immunomodulatory maintenance therapy with TLR-9 agonist MGN1703.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. TPS791-TPS791 ◽  
Author(s):  
David Cunningham ◽  
Alfredo Zurlo ◽  
Ramon Salazar ◽  
Michel Ducreux ◽  
Tom Samuel Waddell ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Immune Cell ◽  
Cox Regression ◽  
Objective Response ◽  
Phase Iii ◽  
Induction Treatment ◽  
Self Administration ◽  
Open Label ◽  
Response To Chemotherapy ◽  
To Receive

TPS791 Background: The potent TLR-9 agonist MGN1703, a synthetic DNA-based immunomodulator, was compared to placebo in metastatic colorectal cancer (mCRC) patients with disease control after standard induction chemotherapy +/- bevacizumab in the phase II IMPACT trial and showed a superior effect with a hazard ratio for the primary endpoint PFS on maintenance of 0.55 (p=0.041) by local investigator assessment and 0.56 (p=0.070) by independent radiological review. In the MGN1703 arm 3 objective responses were observed, two of them appearing as late as 9 months after the start of treatment. At time of study closure 4 MGN1703 patients were still without progressive disease and continued treatment by self-administration in a compassionate use setting. Exploratory Cox regression and ROC analyses suggested a potential predictive role at baseline for normal CEA, objective response to prior chemotherapy and presence of activated NKT-cells. Methods: The pivotal IMPALA study has been designed to confirm these data and started to enroll patients with smaller tumor burden after a good response to chemotherapy, as best candidates to receive a maintenance treatment with immunotherapy. IMPALA is a randomized, international, multicenter, open-label phase III trial that will include 540 patients from 120 centers with the collaboration of the AIO, TTD, and GERCOR cooperative groups and is currently recruiting patients. In this study mCRC patients with an objective tumor response following any first line induction therapy will be randomized to MGN1703 monotherapy maintenance or local standard of care. At time of relapse, patients will reintroduce the induction treatment whenever feasible, with those in the experimental arm continuing to receive MGN1703 in the weeks without chemotherapy. Patients will also be stratified by CEA level and activated NKT at baseline. The primary endpoint of the study will be overall survival. Secondary endpoints include PFS, response rates, safety, and QoL in selected centers. All patients will be evaluated for cytokines and chemokines in serum and the activation status of various immune cell populations. Clinical trial information: NCT02077868.

scholarly journals Oral levosimendan in amyotrophic lateral sclerosis: a phase II multicentre, randomised, double-blind, placebo-controlled trial

2019 ◽  
Vol 90 (10) ◽  
pp. 1165-1170 ◽  
Author(s):  
Ammar Al-Chalabi ◽  
Pamela Shaw ◽  
P Nigel Leigh ◽  
Leonard van den Berg ◽  
Orla Hardiman ◽  
...  
Keyword(s):  
Heart Rate ◽  
Amyotrophic Lateral Sclerosis ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Iii ◽  
Open Label ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Lateral Sclerosis

ObjectiveTo evaluate the efficacy and safety of oral levosimendan in patients with amyotrophic lateral sclerosis (ALS). This phase II, randomised, double-blind, placebo-controlled, crossover, three-period study with 6 months open-label follow-up enrolled adults with ALS and sitting slow vital capacity (SVC) 60%–90 % of predicted from 11 sites in four countries.MethodsPatients received levosimendan 1 mg daily, 1 mg two times a day or placebo during three 14-day crossover periods and levosimendan 1–2 mg daily during open-label follow-up. Primary endpoint was sitting SVC; secondary endpoints included supine SVC, ALS Functional Rating Scale-Revised (ALSFRS-R), tolerability and safety.ResultsOf 66 patients randomised, 59 contributed to the double-blind results and 50 entered open-label follow-up. Sitting SVC was not significantly different between the treatments. In post hoc analysis using period-wise baselines, supine SVC favoured levosimendan over placebo, estimated mean differences from baseline being −3.62% on placebo, +0.77% on levosimendan 1 mg daily (p=0.018) and +2.38% on 1 mg two times a day (p=0.001). Headache occurred in 16.7% of patients during levosimendan 1 mg daily (p=0.030), 28.6% during 1 mg two times a day (p=0.002) and 3.3% during placebo. The respective frequencies for increased heart rate were 5.1% (p=0.337), 18.5% (p=0.018) and 1.7%. No significant differences between the treatments were seen for other adverse events.ConclusionsLevosimendan did not achieve the primary endpoint of improving sitting SVC in ALS. Headache and increased heart rate were increased on levosimendan, although it was otherwise well tolerated. A phase III study to evaluate the longer term effects of oral levosimendan in ALS is ongoing.

Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial.

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA10008-LBA10008 ◽  
Author(s):  
George D. Demetri ◽  
Peter Reichardt ◽  
Yoon-Koo Kang ◽  
Jean-Yves Blay ◽  
Heikki Joensuu ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Controlled Trial ◽  
Performance Status ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Double Blind Study ◽  
Open Label ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Multikinase Inhibitor

LBA10008 Background: Oral multikinase inhibitor regorafenib (REG) demonstrated substantial activity in a phase II trial in pts with GIST after failure of both IM and SU (J Clin Oncol. 2011; 29:606s; abstr 10007). This phase III, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of REG for this unmet clinical need. Methods: Eligible pts had metastatic and/or unresectable GIST, objective failure of both prior IM and SU (progressive disease [PD] on, or intolerance to, IM and PD on SU), ≥1 measurable lesion, ECOG performance status 0 or 1. Pts were randomized 2:1 to receive best supportive care plus either REG 160 mg po once daily (3 wks on/1 wk off) or placebo (PL). The primary endpoint was progression-free survival (PFS) (modified RECIST 1.1, independent central review). Secondary endpoints included overall survival (OS), disease control rate (DCR, defined as rate of partial response [PR] plus stable disease [SD] lasting for ≥12 wks), response rate and duration, safety and correlative genotype analyses. At time of PD, pts were eligible for unblinding and crossover to open-label REG. Results: Between Jan and Aug of 2011, 234 pts were screened; 199 were randomized (REG: 133, PL: 66). Pts were stratified at randomization according to number of prior systemic therapies and geographical region. Baseline characteristics were balanced between the two arms. The primary endpoint was met: median PFS was 4.8 months for REG vs. 0.9 months for PL. Hazard ratio for PFS was 0.27 (95% CI, 0.18-0.39), p<0.0001. PFS rates at 3 and 6 months were 60% and 38% for REG vs. 11% and 0% for PL. DCR was 53% (REG) vs. 9% (PL).The HR for OS was 0.77 (p=0.20) with 85% PL pts having crossed over to REG. The most common > grade 3 treatment-emergent AEs in the REG arm during double-blind study were hypertension (28%), hand-foot skin reaction (21%), and diarrhea (8%). Conclusions: This randomized trial demonstrated that REG significantly improved PFS and DCR in pts with advanced GIST after failure of at least prior IM and SU. REG was well tolerated, with AEs as expected for this class and manageable with dose modifications.

Everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET): Updated results of a randomized, double-blind, placebo-controlled, multicenter phase III trial (RADIANT-3).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 158-158 ◽  
Author(s):  
M. H. Shah ◽  
T. Ito ◽  
C. Lombard-Bohas ◽  
E. M. Wolin ◽  
E. Van Cutsem ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Controlled Trial ◽  
Somatostatin Analogs ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Open Label ◽  
Double Blind ◽  
Phase Ii Studies ◽  
The Impact ◽  
Patient Subgroups

158 Background: There is an unmet medical need for effective treatments for patients with advanced pNET. Systemic therapies for advanced pNET are limited both by toxicity and efficacy. Everolimus, an oral mTOR inhibitor, has shown promising antitumor activity in 2 phase II studies, leading to further investigation in the largest phase III randomized controlled trial completed in pNET patients. Methods: Patients with advanced low- or intermediate-grade pNET were randomly assigned to everolimus 10 mg/d orally + best supportive care (BSC; n = 207) or placebo + BSC (n = 203). Long-acting somatostatin analogs (SSAs) were permitted as BSC during the study. The primary endpoint was progression free survival (PFS). At progression (RECIST), patients could be unblinded and those randomly assigned to placebo were offered open-label everolimus. Results: Compared with placebo, everolimus reduced the risk of progression by 65% and increased median PFS by more than 6 months, from 4.6 to 11.0 months (HR = 0.35; 95% CI: 0.27-0.45; p < 0.0001), by investigator review (primary endpoint). Median PFS by central review was consistent (HR = 0.34; 95% CI: 0.26 to 0.44; p < 0.001] in favor of everolimus. Eighteen-month PFS estimates were 34% for everolimus (95% CI: 26-43) vs 9% (95% CI: 4-16) for placebo. Everolimus demonstrated a significant PFS benefit across all patient subgroups according to baseline characteristics and prior SSA use. Prior SSA use was 49% in the everolimus arm and 50% in the placebo arm. Updated analyses of the impact of concomitant SSA will be reported. The most common drug-related adverse events were stomatitis, rash, diarrhea, fatigue, and infections (primarily upper respiratory); most were grade 1 or 2. Stomatitis (6.9% vs 0%), anemia (6% vs 0%), and hyperglycemia (5% vs 2%) were the most common grade 3-4 events. Conclusions: Everolimus significantly prolonged PFS compared with placebo in patients with advanced pNET in this large phase III clinical trial. This benefit was seen across all patient subgroups. Treatment resulted in a significant 6.4-month prolongation in median PFS. Everolimus had an acceptable and predictable safety profile. [Table: see text]

RAINFALL: A randomized, double-blind, placebo-controlled phase III study of cisplatin (Cis) plus capecitabine (Cape) or 5FU with or without ramucirumab (RAM) as first-line therapy in patients with metastatic gastric or gastroesophageal junction (G-GEJ) adenocarcinoma.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 5-5 ◽  
Author(s):  
Charles S. Fuchs ◽  
Kohei Shitara ◽  
Maria Di Bartolomeo ◽  
Sara Lonardi ◽  
Salah-Eddin Al-Batran ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Primary Endpoint ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Phase Iii ◽  
First Line ◽  
Double Blind ◽  
Double Blind Placebo ◽  
To Receive ◽  
Line Chemotherapy

5 Background: Ramucirumab, a VEGFR-2 IgG1 human monoclonal antibody, is the only biologic with proven efficacy as both a single-agent and in combination with paclitaxel in the second-line treatment of G-GEJ adenocarcinoma. RAINFALL (NCT02314117) is a global, double-blind, placebo-controlled randomized clinical trial addressing the hypothesis that adding ramucirumab to first-line Cis plus Cape or 5-fluorouracil (5FU) produces significant clinical benefit. Methods: Metastatic G-GEJ cancer patients eligible for first-line chemotherapy with ECOG performance status 0-1 were randomized 1:1 to receive either RAM (8 mg/kg iv D1, D8) or placebo (PL), every 21d. All patients received Cape (or 5FU)+Cis. Cis was given for up to 6 cycles. Cape+RAM/placebo was continued until progressive disease, toxicity or other discontinuation criteria. The primary endpoint was progression-free survival (PFS) for the first 508 patients; overall survival (OS) for ITT population was a powered secondary endpoint. Results: 645 patients were randomized to receive RAM+Cape/Cis (n=326) or PL+Cape/Cis (n=319). PFS was significantly prolonged in patients treated with RAM+Cape/Cis versus PL+Cape/Cis (HR, 0.75; 95% CI 0.61–0.94; p=0.011; median, 5.7 vs 5.4 mos), meeting the primary endpoint. There was no survival benefit for patients treated with RAM+Cape/Cis versus PL+Cape/Cis (HR, 0.96; 95% CI 0.80–1.16; p=0.68; median, 11.2 vs 10.7 mos). ORR in the ITT population was 41.1% in the RAM arm (95% CI 35.8–46.4) and 36.4% (95% CI 31.1–41.6) in the PL arm. Grade ≥3 adverse events in ≥10% of patients in the RAM arm were: neutropenia (26.3% RAM; 27.0% PL), anemia (12.1% RAM; 14.0% PL), and hypertension (9.9% RAM; 1.6% PL). No new safety signals were observed. Conclusions: In treatment-naïve patients with metastatic G-GEJ adenocarcinoma, the addition of ramucirumab to first-line chemotherapy conferred a significant 25% reduction in the risk of disease progression or death in the primary endpoint of PFS; however, ramucirumab was not associated with an improved OS. Clinical trial information: NCT02314117.

Bortezomib (Velcade)-Melphalan-Prednisone (VMP) Versus Velcade- Thalidomide-Prednisone (VTP) in Elderly Untreated Multiple Myeloma Patients: Which Is the Best Partner for Velcade: An Alkylating or An Immunomodulator Agent?

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 651-651 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Albert Oriol ◽  
Joaquín Martínez ◽  
Ma Teresa Cibeira ◽  
Raquel de Paz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Time ◽  
Induction Therapy ◽  
Response Rate ◽  
Haematological Toxicity ◽  
Phase Iii ◽  
Induction Treatment ◽  
Induction Phase ◽  
Weekly Schedule ◽  
To Receive

Abstract Melphalan – Prednisone (MP) has been the Standard of care for elderly multiple myeloma patients in the past 40 years. However, bortezomib and thalidomide-based combinations have demonstrated to improve the efficacy in terms of both response rate and time to events as compared to MP. In two recent Phase II and phase III trials we have shown (Mateos et al. Blood 2006; San Miguel JF et al. EHA 2008) that the combination VMP is highly effective, but it remains to be elucidated which agent is the optimal partner for bortezomib: an alkylating or an immunomodulatory drug. In order to answer this question in April 2006, Spanish Myeloma Group (PETHEMA/GEM) activated a phase III trial comparing VMP versus VTP in untreated MM patients older than 65 years. Patients in the VMP arm received intravenous bortezomib 1.3 mg/m2 twice weekly (days 1, 4, 8, 11; 22, 25, 29 and 32) for one 6-week cycle (8 doses per cycle), followed by once weekly (days 1, 8, 15 y 22) for five 5-week cycles (4 doses per cycle) in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1–4 of each cycle. Patients in the VTP arm received the same bortezomib and prednisone regimen, but instead of melphalan they received continuous thalidomide at dose of 100 mg daily. For both groups, treatment continued for a maximum of 6 cycles (31 weeks) unless disease progression or unacceptable treatment-related toxicity occurred. The primary endpoint was overall response rate (ORR) after induction therapy and secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), time to and duration of response, and safety. As of July 30, 2008, 246 out of 260 planned patients have been included in the study and 167 are evaluables for response to induction therapy and adverse events (AEs). Efficacy and toxicity analyses were performed on an intention-to-treat basis. 80 patients were randomly assigned to receive VMP and 87 to receive VTP. Regarding baseline characteristics, including cytogenetic abnormalities, no significant differences were observed in both arms. No significant differences were observed in response rate: ≥ PR in 78% of patients in VMP and VTP groups respectively, with a CR rate of 18% vs 23% (p=NS) and CR/nCR of 38% vs 32% (P= NS). Only one patient prgressed under induction treatment in each arm. Median time to first response was similar in both arms (1,6 months) and there were not differences in the median time to achieve CR (4,4 vs 4,9 months). Regarding haematological toxicity, VMP resulted in higher incidence of ≥G3 neutropenia (34% vs 19%; p=0,009) and thrombocytopenia (21% vs 9%; p=0,01); in contrast, 157 related non-hematological AEs occurred in VTP arm vs 133 in VMP arm (p<0,005); and they were ≥G3 in 32% vs 25% (p=0,04). The most relevant toxicities included: ≥G3 cardiac toxicity reported in 7% of patients receiving VTP vs 0% in VMP arm; the incidence of ≥G3 thromboembolic events was 3,4% in VTP arm and <1% in VMP arm; finally, 15% of patients in VTP arm developed ≥G3 peripheral neuropathy and 9% in VMP arm. No significant differences were reported in other non-hematologic toxicities, including infections despite the higher incidence of neutropenia in VMP arm. Treatment discontinuation due to AEs was required in 8 patients in VMP arm and in 16 patients in VTP arm (p=0,08). Five patients in VMP arm and 7 in VTP group died during the induction phase due to AEs. In summary this initial analysis indicates that there are no significant differences in terms of efficacy between VMP and VTP, while the incidence of non-hematological AEs, specially cardiac events, was higher in the VTP arm, resulting in more serious AEs and treatment discontinuations.. These data suggest that thalidomide may not be the partner of choice for combination with bortezomib and other IMIDs such as lenalidomide should be explored. In addition, our data indicate that the modified VMP regimen used in this trial (weekly schedule after cycle 1 and only six cycles) is well tolerated although the CR rate is lower than in the VISTA trial.

Randomized phase III trial of imatinib (IM) rechallenge versus placebo (PL) in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) after failure of at least both IM and sunitinib (SU): RIGHT study.

2013 ◽  
Vol 31 (18_suppl) ◽  
pp. LBA10502-LBA10502 ◽  
Author(s):  
Yoon-Koo Kang ◽  
Min-Hee Ryu ◽  
Baek-Yeol Ryoo ◽  
Hyun Jin Kim ◽  
Jong Jin Lee ◽  
...  
Keyword(s):  
Disease Control ◽  
Primary Endpoint ◽  
Performance Status ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Open Label ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Advanced Gist

LBA10502 Background: To palliate and prolong disease control after failure of all available treatment in advanced GIST, resumption of IM dosing has been commonly practiced based on evidence of rapid GIST progression after discontinuation of all TKIs. We evaluated the efficacy of IM rechallenge in pts with advanced GIST following failure of all TKIs. Methods: Eligible pts had metastatic and/or unresectable GIST with prior benefit from first-line IM (defined as disease control for > 6 months), progressive disease (PD) on first-line IM, PD on or intolerance to SU, and ECOG performance status 0-3. Pts were randomized 1:1 to receive best supportive care with either IM 400 mg po once daily or PL. At the time of PD, pts were unblinded and allowed to cross-over to open-label IM. The primary endpoint was progression-free survival (PFS) determined by blinded external radiology review according to RECIST v1.0. Secondary endpoints included overall survival (OS), time to progression, disease control rate (DCR) at 12 weeks, and safety. Results: Between July 2010 and January 2013, 81 pts were randomized (IM: 41, PL: 40) at a single Korean center. All baseline characteristics were balanced between the arms and 40% of pts received ≥ 3 prior TKIs. The planned final analysis in March 2013 demonstrated that the primary endpoint was met, with significantly greater PFS for pts randomized to IM vs. PL : 1.8 vs. 0.9 months, respectively (p=0.002), hazard ratio (HR) 0.45 (95% CI, 0.27-0.76). DCR at 12 weeks was 32% for IM vs. 5% for PL (p=0.003). With 92.5 % of PL pts rapidly crossing over to IM, median OS was 8.2 months for IM vs. 7.5 months for PL (HR of 0.99, p=0.982). The most common treatment-emergent AEs (> grade 3) during double-blind period in the IM arm included anemia (29%), fatigue (10%), and hyperbilirubinemia (7%). Conclusions: Rechallenge of IM significantly improves PFS and DCR in pts with advanced GIST after failure of at least IM and SU, likely by continuous kinase inhibition of the bulk of disease clones which retain IM sensitivity. However, TKI-resistant clones continue to progress leading to relatively brief duration of benefit. Clinical trial information: NCT01151852.

OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial

Cephalalgia ◽  
2010 ◽  
Vol 30 (7) ◽  
pp. 793-803 ◽  
Author(s):  
SK Aurora ◽  
DW Dodick ◽  
CC Turkel ◽  
RE DeGryse ◽  
SD Silberstein ◽  
...  
Keyword(s):  
Adverse Events ◽  
Chronic Migraine ◽  
Primary Endpoint ◽  
Burden Of Illness ◽  
Phase Iii ◽  
Open Label ◽  
Double Blind ◽  
Episode Frequency ◽  
Open Label Phase ◽  
Prophylaxis Therapy

Objectives: This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine. Methods: The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U–195 U; n = 341) or placebo ( n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24. Results: No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (−5.2 vs. −5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days ( p = .006) and migraine days ( p = 0.002). OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few subjects discontinued due to adverse events. Conclusions: There was no between-group difference for the primary endpoint, headache episodes. However, significant reductions from baseline were observed for onabotulinumtoxinA for headache and migraine days, cumulative hours of headache on headache days and frequency of moderate/severe headache days, which in turn reduced the burden of illness in adults with disabling chronic migraine.

A randomized, double-blind, multicenter, phase III study of fosnetupitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving doxorubicin-cyclophosphamide/epirubicin-cyclophosphamide (AC/EC) based highly emetogenic chemotherapy: CONSOLE-BC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 12094-12094
Author(s):  
Junji Tsurutani ◽  
Kazuo Matsuura ◽  
Kenichi Inoue ◽  
Yuko Tanabe ◽  
Tetsuhiko Taira ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Study Drug ◽  
Complete Response ◽  
Nausea And Vomiting ◽  
Phase Iii ◽  
Pivotal Phase ◽  
Double Blind ◽  
History Of ◽  
Neurokinin 1 ◽  
To Receive

12094 Background: Fosnetupitant (FN) is a phosphorylated pro-drug of netupitant that has high binding affinity and selectivity for the neurokinin 1 receptor and a long half-life of 70 h. Recent studies have reported that fosaprepitant (FA) has a risk for developing injection site reactions (ISRs) in patients with breast cancer who receive doxorubicin-cyclophosphamide/epirubicin-cyclophosphamide (AC/EC)-based treatments. Previous studies have shown that FN may have a low risk of ISRs and could potentially address this unmet medical need. The present study (JapicCTI-194691) was intended to evaluate the safety profile, including ISRs, of FN in patients receiving AC/EC treatment. For exploratory purposes, we set the FA group as the exploratory arm. A separate pivotal phase 3 study (JapicCTI-194611) was conducted to verify the efficacy and safety of FN compared with FA in patients receiving cisplatin-based chemotherapy. Methods: Patients scheduled to receive AC/EC were randomly assigned 1:1 to receive FN 235 mg or FA 150 mg in a double-blind manner, in combination with intravenous palonosetron (PALO) 0.75 mg and dexamethasone (DEX) 9.9 mg on day 1. The stratification factors were age class ( < 55 years vs. ≥55 years) and site. The primary endpoint was the incidence of treatment-related adverse events (TRAEs) of FN. In addition, the ISRs were investigated as secondary endpoints. Efficacy outcomes were also evaluated as secondary endpoint. Results: Between April 2019 and March 2020, total 102 patients were enrolled in the study. Fifty-two patients were randomized to the FN group and 50 to the FA group, and all of them were treated with the study drug and evaluated for safety. The baseline characteristics were generally balanced, except for the history of motion sickness (54.9% vs. 44.9%) and non-smokers (78.4% vs. 63.3%) in the FN and FA groups, respectively, which are considered as risk factors for chemotherapy-induced nausea and vomiting. The primary endpoint, the incidence of TRAEs was 21.2% (n = 11) (95% CI 11.1% – 34.7%) in the FN group, which was similar to that in the FA group [22.0% (n = 11) (95% CI 11.5% - 36.0%) ]. Any cause or treatment-related ISRs were observed in 5.8% (n = 3) and 0% (n = 0), respectively, in the FN group and 26.0% (n = 13) and 10.0% (n = 5), respectively, in the FA group. The overall (0–120 h) complete response (no emetic event and no rescue medication) rate standardized by age category was 45.9% (n = 23) in the FN group and 51.3% (n = 25) in the FA group. Conclusions: The safety of FN in combination with PALO and DEX was favorable. Risk of ISR by FN was quite low in the AC/EC setting. Clinical trial information: JapicCTI-194691.

Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid-Induced Constipation and Cancer

2017 ◽  
Vol 35 (34) ◽  
pp. 3859-3866 ◽  
Author(s):  
Nobuyuki Katakami ◽  
Toshiyuki Harada ◽  
Toru Murata ◽  
Katsunori Shinozaki ◽  
Masakazu Tsutsumi ◽  
...  
Keyword(s):  
Phase Iii ◽  
Controlled Study ◽  
Open Label ◽  
Double Blind ◽  
Once Daily ◽  
Spontaneous Bowel Movement ◽  
Patients With Cancer ◽  
End Point ◽  
Μ Opioid Receptor ◽  
To Receive

Purpose Opioid-induced constipation (OIC) is a frequent and debilitating adverse effect (AE) of opioids—common analgesics for cancer pain. We investigated the efficacy and safety of a peripherally acting μ-opioid receptor antagonist, naldemedine (S-297995), for OIC, specifically in patients with cancer. Patients and Methods This phase III trial consisted of a 2-week, randomized, double-blind, placebo-controlled study (COMPOSE-4) and an open-label, 12-week extension study (COMPOSE-5). In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned on a 1:1 basis to receive once-daily oral naldemedine 0.2 mg or placebo. The primary end point was the proportion of spontaneous bowel movement (SBM) responders (≥ 3 SBMs/week and an increase of ≥ 1 SBM/week from baseline). The primary end point of COMPOSE-5 was safety. Results In COMPOSE-4, 193 eligible patients were randomly assigned to naldemedine (n = 97) or placebo (n = 96). The proportion of SBM responders in COMPOSE-4 was significantly greater with naldemedine than with placebo (71.1% [69 of 97 patients] v 34.4% [33 of 96 patients]; P < .0001). A greater change from baseline was observed with naldemedine than with placebo in the frequency of SBMs/week (5.16 v 1.54; P < .0001), SBMs with complete bowel evacuation/week (2.76 v 0.71; P < .0001), and SBMs without straining/week (3.85 v 1.17; P = .0005). In COMPOSE-4, more patients treated with naldemedine than with placebo reported treatment-emergent AEs (TEAEs) (44.3% [43 of 97 patients] v 26.0% [25 of 96 patients]; P = .01); in COMPOSE-5, 105 (80.2%) of 131 of patients reported TEAEs. Diarrhea was the most frequently reported TEAE in COMPOSE-4 (19.6% [19 of 97 patients] v 7.3% [seven of 96 patients] with naldemedine v placebo) and COMPOSE-5 (18.3% [24 of 131 patients] with naldemedine). Naldemedine was not associated with signs or symptoms of opioid withdrawal and had no notable impact on opioid-mediated analgesia. Conclusion Once-daily oral naldemedine 0.2 mg effectively treated OIC and was generally well tolerated in patients with OIC and cancer.

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