A phase II, open label, randomized controlled trial of nivolumab plus ipilimumab with stereotactic radiotherapy versus ipilimumab plus nivolumab alone in patients with melanoma brain metastases (ABC-X Trial).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS9600-TPS9600 ◽  
Author(s):  
Maria Gonzalez ◽  
Angela M. Hong ◽  
Matteo S. Carlino ◽  
Victoria Atkinson ◽  
Wei Wang ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Stereotactic Radiotherapy ◽  
Controlled Trial ◽  
Tumour Response ◽  
Previous Treatment ◽  
Open Label ◽  
Absolute Increase ◽  
Significance Level ◽  
Melanoma Brain Metastases ◽  
Treatment Naïve

TPS9600 Background: Nivolumab combined with ipilimumab is active in melanoma brain metastases, with intracranial response rates > 55% and durable survival in treatment naïve patients (pts) (Long GV et al Lancet Onc 2018; Tawbi H et al NEJM 2018). We seek to determine if the addition of stereotactic radiotherapy (SRS) results in improved intracranial outcomes. Methods: This is a multisite, open-label, phase 2 trial in systemic treatment-naïve pts with melanoma brain metastases. Pts must have ≥1 asymptomatic brain metastases that are ≥5mm and ≤40mm as per modified RECIST 1.1, on gadolinium-enhanced MRI, and no history of previous treatment with SRS. Eligible pts are randomly assigned to either receive nivolumab plus ipilimumab with SRS or nivolumab plus ipilimumab alone. Nivolumab (1mg/kg) and ipilimumab (3mg/kg) are given every 3 weeks for 4 doses. Following induction, 480mg nivolumab is given every 4 weeks until progression, unacceptable toxicity, or a maximum of 2 years. SRS is administered as single fraction of 16-22Gy, or hypofractionated for larger lesions (24-27Gy in 3 fractions), within 7 days of immunotherapy commencement. Pts will be evaluated for intracranial and extracranial tumour response, and overall response, every 6 weeks to week 24 and 12 weekly thereafter until overall disease progression or death. The primary endpoint is neurologic specific survival (NSS) at 12 months. Secondary endpoints include intracranial response rate, intracranial PFS, overall PFS, overall progression free survival, overall survival, neurocognitive function and incidence of radiation necrosis. 109 patients in each cohort (218 total) will achieve > 80% power at the significance level (alpha) of 0.10 to detect a minimum absolute increase of 9% in the NSS rate at 12 months. Clinical trial information: NCT03340129.

Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): Randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9508-9508
Author(s):  
Georgina V. Long ◽  
Victoria Atkinson ◽  
Serigne Lo ◽  
Alexander David Guminski ◽  
Shahneen Kaur Sandhu ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Braf Inhibitor ◽  
Local Therapy ◽  
Leptomeningeal Disease ◽  
Open Label ◽  
Phase 2 Study ◽  
Melanoma Brain Metastases ◽  
Secondary Endpoints ◽  
Local Brain ◽  
Clinical Trial Information

9508 Background: Preliminary data from the ABC (76 pts) and CheckMate 204 (94 pts) trials showed that nivo and nivo+ipi have activity in active melanoma brain metastases, with durable responses in a subset of pts. Here, we report updated 5-yr data from all pts enrolled on the ABC trial (NCT02374242). Methods: This open-label ph2 trial enrolled 3 cohorts of pts with active melanoma brain mets naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014-Apr 2017. Pts with asymptomatic brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3Wx4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets i) that failed local therapy, ii) with neuro symptoms and/or iii) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥wk12. Key secondary endpoints were IC PFS, overall PFS, OS, & safety. Results: A total of 76 pts (med f/u 54 mo) were enrolled; median age 59y, 78% male. For cohorts A, B and C: elevated LDH 51%, 58% and 19%; V600BRAF 54%, 56% and 81%; prior BRAFi 23%, 24%, 75%. Efficacy and toxicity are shown in the table. There were no treatment-related deaths. 1/17 deaths in cohort A & 4/16 in cohort B were due to IC progression only. Conclusions: Nivo monotherapy and ipi+nivo are active in melanoma brain mets, with durable responses in the majority of patients who received ipi+nivo upfront. A study of upfront ipi+nivo+/-SRS is underway (NCT03340129). Clinical trial information: NCT02374242. [Table: see text]

scholarly journals EP-1226 Survival in patients with melanoma brain metastases treated by stereotactic radiotherapy

2019 ◽  
Vol 133 ◽  
pp. S676
Author(s):  
S. Lambert ◽  
A. Huchet ◽  
R. Trouette ◽  
V. Karahissarlian ◽  
C. Pouypoudat ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Stereotactic Radiotherapy ◽  
Melanoma Brain Metastases

First-line durvalumab plus platinum-etoposide in extensive-stage (ES)-SCLC (CASPIAN): Impact of brain metastases on treatment patterns and outcomes.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9068-9068
Author(s):  
Yuanbin Chen ◽  
Luis G. Paz-Ares ◽  
Mikhail Dvorkin ◽  
Dmytro Trukhin ◽  
Niels Reinmuth ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Cranial Irradiation ◽  
Prophylactic Cranial Irradiation ◽  
Treatment Patterns ◽  
First Line ◽  
Open Label ◽  
Treatment Naïve ◽  
Extensive Stage ◽  
Post Hoc ◽  
The Brain

9068 Background: In the Phase 3, randomized, open-label CASPIAN study, first-line durvalumab (D) added to etoposide plus either cisplatin or carboplatin (EP) significantly improved OS vs EP alone (HR 0.73 [95% CI 0.59–0.91]; p = 0.0047) in pts with ES-SCLC at the planned interim analysis. Here we describe treatment patterns and outcomes for pts according to brain metastases. Methods: Treatment-naïve pts (WHO PS 0/1) with ES-SCLC received 4 cycles of D 1500 mg + EP q3w followed by maintenance D 1500 mg q4w until disease progression (PD) or up to 6 cycles of EP q3w and optional prophylactic cranial irradiation (PCI; investigator’s discretion). Pts with either asymptomatic or treated and stable brain metastases were eligible. Brain imaging was suggested for pts with suspected brain metastases, but was not mandated at screening or during treatment. The primary endpoint was OS. Analysis of OS and PFS in pt subgroups with and without brain metastases was prespecified. Other analyses in these subgroups were post hoc. Data cutoff: Mar 11, 2019. Results: At baseline, 28 (10.4%) of 268 pts in the D + EP arm and 27 (10.0%) of 269 pts in the EP arm had known brain metastases; of these, only 3 pts (~11% of those with baseline brain metastases) in each arm received radiotherapy (RT) to the brain prior to study entry. D + EP consistently improved OS vs EP in pts with or without known brain metastases at baseline (HR 0.69 [95% CI 0.35–1.31] and 0.74 [0.59–0.93], respectively); PFS was also consistently improved with D + EP regardless of the presence or not of baseline brain metastases (HR 0.73 [0.42–1.29] and 0.78 [0.64–0.95]). Among pts without known brain metastases at baseline, similar proportions developed new brain metastases at first PD in the D + EP (20/240; 8.3%) and EP arms (23/242; 9.5%), despite 19 (7.9%) pts in the EP arm having received PCI. Overall, 48 of 268 (17.9%) and 49 of 269 (18.2%) pts in the D + EP and EP arms received RT to the brain subsequent to study treatment; rates remained similar across the D + EP and EP arms regardless of baseline brain metastases (11 of 28 [39.3%] and 11 of 27 [40.7%] pts with known baseline brain metastases, compared to 37 of 240 [15.4%] and 38 of 242 [15.7%] pts without known baseline brain metastases). Conclusions: In CASPIAN, OS and PFS outcomes were improved with D + EP vs EP regardless of baseline brain metastases, consistent with the ITT analyses. Rates of new brain metastases at first PD were similar between arms, although PCI was permitted only in the control arm. Rates of subsequent RT to the brain were also similar in both arms. Clinical trial information: NCT03043872.

scholarly journals Pragmatic randomised controlled trial of very early etanercept and MTX versus MTX with delayed etanercept in RA: the VEDERA trial

2020 ◽  
Vol 79 (4) ◽  
pp. 464-471 ◽  
Author(s):  
Paul Emery ◽  
Sarah Horton ◽  
Raluca Bianca Dumitru ◽  
Kamran Naraghi ◽  
Désirée van der Heijde ◽  
...  
Keyword(s):  
Randomised Controlled Trial ◽  
Controlled Trial ◽  
Power Doppler ◽  
Treat To Target ◽  
Symptom Duration ◽  
First Line ◽  
Open Label ◽  
Remission Rates ◽  
Treatment Naïve ◽  
Randomised Controlled

ObjectivesWe sought to confirm in very early rheumatoid arthritis (ERA) a much greater superiority (30%) of first-line etanercept+methotrexate (ETN+MTX) over treat-to-target MTX (MTX-TT) than previously reported in ERA (14%); and explore whether ETN following initial MTX secures a comparable response to first-line ETN+MTX.MethodsPragmatic, open-label, randomised controlled trial of treatment-naïve ERA (≤12 months symptom), Disease Activity Score 28 joint (DAS28)-erythrocyte sedimentation rate (ESR) ≥3.2, rheumatoid factor (RF)+/−anticitrullinated peptide antibody (ACPA) positive or ultrasound power Doppler (PD) if RF and ACPA negative. Subjects were randomised 1:1 to ETN+MTX; or MTX-TT, escalated to ETN if week 24 DAS28-ESR ≥2.6 and intramuscular corticosteroid at protocolised time points. Primary endpoint of week 48 DAS28ESR remission with clinical and imaging secondary endpoints.ResultsWe randomised 120 patients, 60 to each arm (71% female, 73% RF/84% ACPA positive, median (IQR) symptom duration 20.3 (13.1, 30.8) weeks; mean (SD) DAS28 5.1 (1.1)). Remission rates with ETN+MTX and MTX-TT, respectively, were 38% vs 33% at week 24; 52% vs 38% at week 48 (ORs 1.6, 95% CI 0.8 to 3.5, p=0.211). Greater, sustained DAS28-ESR remission observed with ETN+MTX versus MTX-TT (42% and 27%, respectively; p=0.035). PD was fully suppressed by week 48 in over 90% in each arm. Planned exploratory analysis revealed OR 2.84, 95% CI 0.8 to 9.6) of achieving remission after 24 weeks of ETN administered first line compared with administered post-MTX.ConclusionsCompared with remission rates typically reported with first-line tumour necrosis factor inhabitor+MTX versus MTX-TT, we did not demonstrate a larger effect in very ERA. Neither strategy conferred remission in the majority of patients although ultrasound confirmed local inflammation suppression. Poorer ETN response following failure of MTX-TT is also suggested.Trial registration numberNCT02433184

Ipilimumab and radiation in patients with unresectable melanoma brain metastases: A multicenter, open label, phase-2, Spanish Melanoma Group (GEM) study (NCT-2013-001132-22).

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 9546-9546 ◽  
Author(s):  
Jose A. Lopez-Martin ◽  
Ana M. Arance ◽  
Luis De La Cruz-Merino ◽  
Ana Illescas ◽  
Izazkun Valduvieco ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Phase 2 ◽  
Open Label ◽  
Melanoma Brain Metastases ◽  
Open Label Phase

scholarly journals Ledipasvir/sofosbuvir with or without ribavirin for 8 or 12 weeks for the treatment of HCV genotype 4 infection: results from a randomised phase III study in Egypt

Gut ◽  
2018 ◽  
Vol 68 (4) ◽  
pp. 721-728 ◽  
Author(s):  
Gamal Shiha ◽  
Gamal Esmat ◽  
Mohamed Hassany ◽  
Reham Soliman ◽  
Mohamed Elbasiony ◽  
...  
Keyword(s):  
Previous Treatment ◽  
Phase Iii ◽  
Open Label ◽  
Genotype 4 ◽  
Hcv Genotype ◽  
Multicentre Phase ◽  
Highly Effective ◽  
Treatment Naïve ◽  
Phase Iii Study ◽  
To Receive

ObjectiveWe evaluated the efficacy and safety of ledipasvir/sofosbuvir alone and with ribavirin for 8 and 12 weeks in Egyptian patients with and without cirrhosis, who were infected with hepatitis C virus (HCV) genotype 4, including those who had failed previous treatment with sofosbuvir regimens.DesignIn this open-label, multicentre, phase III study, treatment-naive patients were randomised to receive 8 or 12 weeks of ledipasvir/sofosbuvir±ribavirin. Interferon treatment-experienced patients were randomised to receive 12 weeks of ledipasvir/sofosbuvir±ribavirin, while sofosbuvir-experienced or ledipasvir/sofosbuvir-experienced patients received 12 weeks of ledipasvir/sofosbuvir+ribavirin. Randomisation was stratified by cirrhosis status. The primary endpoint was sustained virological response 12 weeks post-treatment (SVR12).ResultsWe enrolled 255 patients from four centres in Egypt. Among treatment-naive patients, SVR12 rates were 95% and 90% for those receiving 8 weeks of ledipasvir/sofosbuvir alone and with ribavirin, respectively, and 98% for those receiving 12 weeks of ledipasvir/sofosbuvir both alone and with ribavirin. Among interferon-experienced patients, SVR rates were 94% for those receiving 12 weeks of ledipasvir/sofosbuvir and 100% for those receiving 12 weeks of ledipasvir/sofosbuvir plus ribavirin. All patients previously treated with sofosbuvir regimens who received ledipasvir/sofosbuvir plus ribavirin achieved SVR12. The most common adverse events, headache and fatigue, were more common among patients receiving ribavirin.ConclusionAmong non-cirrhotic treatment-naive patients with HCV genotype 4, 8 weeks of ledipasvir/sofosbuvir±ribavirin was highly effective. Twelve weeks of ledipasvir/sofosbuvir±ribavirin was highly effective regardless of presence of cirrhosis or prior treatment experience, including previous treatment with sofosbuvir or ledipasvir/sofosbuvir.Trial registration numberNCT02487030.

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