scholarly journals Intrathecal treatment trial of rituximab in progressive MS: results after a 2-year extension

2020 ◽  
Author(s):  
Joakim Bergman ◽  
Joachim Burman ◽  
Tommy Bergenheim ◽  
Anders Svenningsson
Keyword(s):  
Bacterial Meningitis ◽  
Disease Progression ◽  
Walking Speed ◽  
Progressive Multiple Sclerosis ◽  
Ventricular Catheter ◽  
Open Label ◽  
Frontal Horn ◽  
Open Label Phase ◽  
The Right

Abstract Objectives To evaluate the effect of intrathecally (IT) delivered rituximab as a therapeutic intervention for progressive multiple sclerosis (PMS) during a 3-year follow-up period. Methods Participants of a 1-year open-label phase 1b study of IT delivered rituximab to patients with PMS were offered extended treatment with follow-up for an additional 2 years. During the extension phase, treatment with 25 mg rituximab was administered every 6 months via a subcutaneous Ommaya reservoir connected to the right frontal horn with a ventricular catheter. Results Mild to moderate vertigo and nausea occurred in 4 out of 14 participants as temporary adverse events associated with IT rituximab infusion. During the entire 3-year period, two cases of low-virulent bacterial meningitis occurred, which were successfully treated. Walking speed deteriorated significantly during the study. Conclusions IT administration of rituximab via a ventricular catheter was well tolerated. Considering the meningitis cases, the risk of infection was not negligible. The continued loss of walking speed indicates that IT rituximab was not able to stop disease progression. Classification of evidence This study provides class IV evidence that intraventricularly administered rituximab in progressive MS is associated with a risk for bacterial meningitis and does not halt disease progression. EU Clinical Trial Register EudraCT; 2008-002626-11 and 2012-000721-53

Intrathecal treatment trial of rituximab in progressive MS

Neurology ◽  
2018 ◽  
Vol 91 (20) ◽  
pp. e1893-e1901 ◽  
Author(s):  
Joakim Bergman ◽  
Joachim Burman ◽  
Jonathan D. Gilthorpe ◽  
Henrik Zetterberg ◽  
Elena Jiltsova ◽  
...  
Keyword(s):  
Progressive Multiple Sclerosis ◽  
Intrathecal Administration ◽  
Control Group ◽  
Csf Biomarkers ◽  
Ventricular Catheter ◽  
Frontal Horn ◽  
Severe Infections ◽  
Phase 1B ◽  
The Right

ObjectivesTo perform a phase 1b assessment of the safety and feasibility of intrathecally delivered rituximab as a treatment for progressive multiple sclerosis (PMS) and to evaluate the effect of treatment on disability and CSF biomarkers during a 1-year follow-up period.MethodsThree doses of rituximab (25 mg with a 1-week interval) were administered in 23 patients with PMS via a ventricular catheter inserted into the right frontal horn and connected to a subcutaneous Ommaya reservoir. Follow-ups were performed at 1, 3, 6, 9, and 12 months.ResultsMild to moderate vertigo and nausea were common but temporary adverse events associated with intrathecal rituximab infusion, which was otherwise well tolerated. The only severe adverse event was a case of low-virulent bacterial meningitis that was treated effectively. Of 7 clinical assessments, only 1 showed statistically significant improvement 1 year after treatment. No treatment effect was observed during the follow-up period among 6 CSF biomarkers.ConclusionsIntrathecal administration of rituximab was well tolerated. However, it may involve a risk for injection-related infections. The lack of a control group precludes conclusions being drawn regarding treatment efficacy.ClinicalTrials.gov identifierNCT01719159.Classification of evidenceThis study provides Class IV evidence that intrathecal rituximab treatment is well tolerated and feasible in PMS but involves a risk of severe infections.

Neoadjuvant treatment of locally advanced GIST: Results of APOLLON, a prospective, open label phase II study in KIT- or PDGFRA-positive tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10031-10031 ◽  
Author(s):  
Peter Hohenberger ◽  
Claus Langer ◽  
Clemens Martin Wendtner ◽  
Werner Hohenberger ◽  
Annette Pustowka ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Adjuvant Treatment ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Progression Rate ◽  
Open Label ◽  
Open Label Phase ◽  
Prospective Phase

10031 Background: Imatinib may significantly downstage the metastatic GIST. This prospective, phase II, open-label trial of neoadjuvant imatinib evaluated the overall tumor response and progression rate of disease in locally advanced, non-metastic patients. Methods: Inclusion criteria were: KIT (n=39) or PDFRA (n=6) positive GIST, proven by biopsy and IHC. Tumors had to be locally advanced, potentially resectable, M0. Patients received 400 mg of imatinib daily (KIT exon 9 mutations: twice daily) for 6 months, in the absence of disease progression or unacceptable toxicity. At two months 18F-FDG-PET examination was performed to assess response in paralle to CT imaging. Adjuvant treatment postoperatively was not part of the study protocol (CST1571-BDE43, NCT00112632). Median follow-up is 36 months in 39 patients. Results: From 7/2005 to 10/ 2009, 41 patients (16f, 25 m, mean age 54 yrs) were recruited to the trial with an average tumor size of 10.8 cm. One patient died from myocardial infarction 3 weeks after start of treatment, all other patients completed the protocol. In two patients dose reduction/interruption due to toxicity was required. 34/41 patients underwent resection of the tumor after a median of 200 d (range 57-394), while two patients had to be operated early due to disease progression. R0 resections were performed in 30/34 patients, two patients showed M1 disease at resection. Five patients showed developed progression postop., resulting in a PFS rate at 3 years of 85.2%. No patient has died so far from the disease. Conclusions: Neoadjuvant treatment with imatinib for six months is a safe treatment in patients with locally advanced disease. The extent of the operation can be significantly downsized after pretreatment. Despite the fact that no adjuvant treatment was foreseen, the progression-free rate at 3 years postoperatively is promising.

scholarly journals DIPG-35. BIOLOGICAL MEDICINE FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) ERADICATION: RESULTS OF THE THREE ARM BIOMARKER-DRIVEN RANDOMIZED BIOMEDE 1.0 TRIAL

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii293-iii294
Author(s):  
Jacques Grill ◽  
Gwenael Le Teuff ◽  
Karsten Nysom ◽  
Klas Blomgren ◽  
Darren Hargrave ◽  
...  
Keyword(s):  
Disease Progression ◽  
Stereotactic Biopsy ◽  
Diagnostic Yield ◽  
Steering Committee ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Open Label ◽  
Pten Loss ◽  
Multi Stage ◽  
Open Label Phase ◽  
Biological Medicine

Abstract Despite 50 years of clinical trials, no improvement of survival has been observed in DIPG and most children die within 2 years of diagnosis. Only radiotherapy transiently controls disease progression. The study was conceived as a randomized multi-arm multi-stage program. It started with an open-label phase-II trial comparing three drugs (everolimus, dasatinib, erlotinib) combined with irradiation, allocated according to the presence of their specific targets (PTEN-loss, EGFR-overexpression) defined with a stereotactic biopsy after central confirmation of the diagnosis (presence of histone H3K27M mutation or loss of K27 trimethylation). Targeted therapies were started concomitantly with radiotherapy and were continued until disease progression. No biopsy-related death was reported and diagnostic yield was excellent, with only 5 non-informative biopsies. Biopsy excluded the diagnosisof DIPG in 8% of the cases. At the 3rd interim analysis, based on 193 randomized patients, the IDMC concluded that the study was unlikely to show a difference of OS between the 3 drugs even if 250 patients would be randomized. The median OS from the time of diagnosis was 11.9, 10.5 and 10 months for everolimus, dasatinib and erlotinib. Treatment was discontinued due to toxicity in 2%, 13%, and 15%, respectively. BIOMEDE shows the feasibility of biologically-driven treatment in DIPG on a large international scale. Based on the better toxicity profile and the slightly better efficacy, although not statistically significant, the steering committee proposed that everolimus should be used as the control arm for the next BIOMEDE 2.0 trial.

scholarly journals Re‐treatment with radium‐223: 2‐year follow‐up from an international, open‐label, phase 1/2 study in patients with castration‐resistant prostate cancer and bone metastases

The Prostate ◽  
2019 ◽  
Vol 79 (14) ◽  
pp. 1683-1691 ◽  
Author(s):  
Oliver Sartor ◽  
Daniel Heinrich ◽  
Neil Mariados ◽  
Maria José Méndez Vidal ◽  
Daniel Keizman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Phase 1 ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Castration Resistant ◽  
Radium 223 ◽  
Open Label Phase

scholarly journals Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: a single-arm, open-label, phase 2 trial

2020 ◽  
Vol 8 (1) ◽  
pp. e000798
Author(s):  
Lu Xie ◽  
Jie Xu ◽  
Xin Sun ◽  
Wei Guo ◽  
Jin Gu ◽  
...  
Keyword(s):  
Pulmonary Metastases ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Trial ◽  
Open Label Phase ◽  
High Grade Osteosarcoma

BackgroundResults of our previous study showed high objective response but short-term activity of apatinib in advanced osteosarcoma. We aimed to investigate the activity of apatinib in combination with camrelizumab in patients with inoperable high-grade osteosarcoma progressing after chemotherapy.MethodsThis open-label, phase 2 trial was conducted at Peking University People’s Hospital. We enrolled patients with advanced osteosarcoma progressed after chemotherapy. Patients received 500 mg apatinib orally once daily plus 200 mg camrelizumab by intravenous infusion every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) and clinical benefit rate at 6 months, which were based on RECIST V.1.1.Results43 patients were enrolled between January 25 and September 4, 2018. With median follow-up time of 48.3 (Q1, Q3, 30.6, 66.6) weeks, 13 (30.23%, 95% CI 17.2%, 40.1%) of 43 patients were progression free at 6 months and the 6-month PFS rate was 50.9% (95% CI 34.6%, 65.0%). Until final follow-up, the objective response rate was 20.9% (9/43) and two patients with durable disease control were observed. Patients with programmed cell death 1 ligand-1 (PD-L1) tumor proportion score ≥5% and pulmonary metastases tended to have a longer PFS in comparison to the others (p=0.004 and 0.017, respectively). Toxic effects led to dose reductions, or interruptions, or both in 24 (55.8%) of 43 patients and permanent discontinuation in 4 (9.3%) patients. There were no treatment-related deaths.ConclusionsAlthough the combination of apatinib and camrelizumab seemed to prolong PFS in comparison to single agent apatinib in treating advanced osteosarcoma, it did not reach the prespecified target of 6-month PFS of 60% or greater. Overexpression of PD-L1 and the presence of pulmonary metastases only were associated with longer PFS.Trial registration numberNCT03359018.

scholarly journals Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study

Leukemia ◽  
2020 ◽  
Vol 34 (7) ◽  
pp. 1875-1884 ◽  
Author(s):  
Nizar J. Bahlis ◽  
Meletios A. Dimopoulos ◽  
Darrell J. White ◽  
Lotfi Benboubker ◽  
Gordon Cook ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Open Label ◽  
Refractory Multiple Myeloma ◽  
Open Label Phase ◽  
Intent To Treat ◽  
Line Of Therapy

Abstract In POLLUX, daratumumab (D) plus lenalidomide/dexamethasone (Rd) reduced the risk of disease progression or death by 63% and increased the overall response rate (ORR) versus Rd in relapsed/refractory multiple myeloma (RRMM). Updated efficacy and safety after >3 years of follow-up are presented. Patients (N = 569) with ≥1 prior line received Rd (lenalidomide, 25 mg, on Days 1–21 of each 28-day cycle; dexamethasone, 40 mg, weekly) ± daratumumab at the approved dosing schedule. Minimal residual disease (MRD) was assessed by next-generation sequencing. After 44.3 months median follow-up, D-Rd prolonged progression-free survival (PFS) in the intent-to-treat population (median 44.5 vs 17.5 months; HR, 0.44; 95% CI, 0.35–0.55; P < 0.0001) and in patient subgroups. D-Rd demonstrated higher ORR (92.9 vs 76.4%; P < 0.0001) and deeper responses, including complete response or better (56.6 vs 23.2%; P < 0.0001) and MRD negativity (10–5; 30.4 vs 5.3%; P < 0.0001). Median time to next therapy was prolonged with D-Rd (50.6 vs 23.1 months; HR, 0.39; 95% CI, 0.31–0.50; P < 0.0001). Median PFS on subsequent line of therapy (PFS2) was not reached with D-Rd versus 31.7 months with Rd (HR, 0.53; 95% CI, 0.42–0.68; P < 0.0001). No new safety concerns were reported. These data support using D-Rd in patients with RRMM after first relapse.

scholarly journals Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long‐term follow‐up of the randomized, open‐label, phase 3 CheckMate 025 trial

Cancer ◽  
2020 ◽  
Vol 126 (18) ◽  
pp. 4156-4167 ◽  
Author(s):  
Robert J. Motzer ◽  
Bernard Escudier ◽  
Saby George ◽  
Hans J. Hammers ◽  
Sandhya Srinivas ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Advanced Renal Cell Carcinoma ◽  
Open Label ◽  
Phase 3 ◽  
Open Label Phase ◽  
Long Term Follow Up

Follow-Up Results of a Prospective, Multicenter, Open-Label Study of Oral Fludarabine Phosphate in Patients with Previously Untreated B-CLL.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2128-2128
Author(s):  
Jean-Francois Rossi ◽  
A. Van Hoof ◽  
K. De Boeck ◽  
S. A. Johnson ◽  
D. Bron ◽  
...  
Keyword(s):  
Disease Progression ◽  
Median Time ◽  
Response Rate ◽  
Time To Progression ◽  
Open Label ◽  
Overall Response ◽  
Fludarabine Phosphate ◽  
Duration Of Response ◽  
Grade 3

Abstract The IV formulation of fludarabine phosphate is an effective treatment in patients with B-cell chronic lymphocytic leukemia (B-CLL), yielding overall response rates of 60% to 80%. An oral formulation of fludarabine phosphate has been developed. In a previously published multicenter, open-label, phase II clinical trial, 81 previously untreated B-CLL patients received 10-mg tablets of fludarabine phosphate (Fludara® oral) 40 mg/m2/day for 5 days, repeated every 4 weeks. The primary endpoint of the trial was response rate, and secondary endpoints included safety and quality of life assessments. Of 81 patients (mean age, 61.2 years; range, 30–75 years) with previously untreated B-CLL, 81.5% were classified as Binet stage B or C. The overall response rate (complete response [CR] + partial response [PR]) using National Cancer Institute (NCI) criteria was 80.2% (12.3% CR and 67.9% PR) and the median time to progression was 841 days (range, 28–1,146 days) (Rossi JF, et al. J Clin Oncol2004;22:1260–1267). The most frequently reported grade 3/4 adverse event was myelosuppression: WHO grade 3/4 hematologic toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%). This analysis reports on the long-term follow-up of this cohort during the period from November 2001 to November 2004. Of the 74 patients eligible for the survival analysis, 61 were also assessed for duration of response using NCI criteria: 9 CR (14.8%) and 52 PR (82.2%). During the 3-year follow-up period, 22 (29.7%) patients did not progress. For those who progressed, median time to progression was 29.7 months, and median duration of response was 22.9 months. In 41 (80.4%) of these patients, an increase in circulating lymphocytes was reported as evidence of disease progression. In 23 patients (45.1%), an increase in the sum of the products of at least 2 lymph nodes and/or appearance of new palpable nodes was reported as evidence of disease progression. During the indicated follow-up period, 37 patients (50%) received subsequent treatment. Twelve patients (16.2%) died during the follow-up period: 7 patients (58.3%) due to disease progression, 3 patients (25.0%) due to adverse events, and 2 patients (16.7%) due to other causes. Results from this study suggest that oral fludarabine phosphate is clinically effective and well tolerated by patients with previously untreated B-CLL. Moreover, these data demonstrate that oral fludarabine phosphate achieves response rates and duration of response comparable to those achieved with first-line fludarabine phosphate IV therapy.

Planned survival analysis from KEYNOTE-045: Phase 3, open-label study of pembrolizumab (pembro) versus paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer (UC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4501-4501 ◽  
Author(s):  
Dean F. Bajorin ◽  
Ronald De Wit ◽  
David J. Vaughn ◽  
Yves Fradet ◽  
Jae-Lyun Lee ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Standard Of Care ◽  
Open Label ◽  
Phase 3 ◽  
Prior Therapy ◽  
Open Label Phase ◽  
Duration Of Response ◽  
Combined Positive Score ◽  
Ecog Ps

4501 Background: Second-line chemotherapies (chemo) for advanced UC have limited clinical benefit (OS, 7-9 mo). Data from the open-label, phase 3 KEYNOTE-045 study (NCT02256436) showed significantly longer OS with pembro v chemo (median, 10.3 v 7.4 mo; hazard ratio [HR], 0.73; P = 0.002) in recurrent, advanced UC. Data from a planned survival analysis are presented. Methods: Pts had histologically or cytologically confirmed UC, progression after platinum, ECOG PS 0-2, measurable disease (RECIST v1.1), and ≤2 lines of systemic therapy. Pts were randomly assigned 1:1 to pembro 200 mg Q3W or investigator’s choice of paclitaxel 175 mg/m2 Q3W, docetaxel 75 mg/m2 Q3W, or vinflunine 320 mg/m2 Q3W. Primary efficacy end points were OS and PFS (RECIST v1.1, blinded central review). ORR (RECIST v1.1, blinded central review) was a secondary end point. Results: 542 pts were enrolled (pembro, 270; chemo, 272). Baseline characteristics were generally similar between arms. As of Jan 18, 2017, median follow-up was 18.5 mo (range, 14.2-26.5). Median OS was significantly longer with pembro v chemo (10.3 v 7.4 mo; HR, 0.70; P < 0.001), and significance was maintained regardless of PD-L1 expression as measured by combined positive score (HR: CPS < 1%, 0.84; CPS ≥1%, 0.59; CPS < 10%, 0.76; CPS ≥10%, 0.57). OS benefit with pembro v chemo was seen regardless of age, ECOG PS, prior therapy, liver metastases, histology, and choice of chemo. The 18-mo OS rate (95% CI) was 36.1% (30.1%-42.0%) with pembro v 20.5% (15.2%-25.8%) with chemo (KM estimate). PFS was not different between arms. ORR was higher with pembro v chemo (21.1% v 11.0%), and median (range) duration of response was longer (not reached [1.6+-20.7+ mo] v 4.4 mo [1.4+-20.3]). 69% (pembro) v 36% (chemo) of responses lasted ≥12 mo. Fewer pts experienced a treatment-related AE with pembro v chemo (any grade, 61.3% v 90.2%; grade ≥3, 16.5% v 49.8%). Conclusions: The OS benefit and superior safety profile of pembro over chemo are maintained with longer follow-up. Combined, these results support the potential of pembro as a new standard of care for patients with UC who previously received platinum. Clinical trial information: NCT02256436.

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