scholarly journals CTIM-24. AUTOLOGOUS CD34+ ENRICHED HEMATOPOIETIC PROGENITOR CELLS GENETICALLY MODIFIED FOR HUMAN INTERFERON-α2, ARE WELL TOLERATED & RAPIDLY ENGRAFT IN PATIENTS WITH GLIOBLASTOMA MULTIFORME (TEM-GBM_001 STUDY)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii38-ii38
Author(s):  
Gaetano Finocchiaro ◽  
Bernhard Gentner ◽  
Marica Eoli ◽  
Farina Francesca ◽  
Elena Anghileri ◽  
...  
Keyword(s):  
Disease Progression ◽  
Ex Vivo ◽  
Genetically Modified ◽  
Conditioning Regimen ◽  
Gene Promoter ◽  
Human Interferon ◽  
Open Label ◽  
Antitumor Effects ◽  
Open Label Phase ◽  
Interferon Α2

Abstract GBM with an unmethylated MGMT gene promoter is associated with very poor prognosis. A subset of tumor associated macrophages expressing the angiopoietin receptor Tie2 (TEMs) can be genetically modified for local & tumor restricted release of interferon-α2 (IFN). IFN has antitumor effects, inhibits angiogenesis & modulates the immune system. Temferon consists of autologous HSPCs transduced ex-vivo with an LVV encoding an IFN gene & expression control sequences for TEMs. TEM-GBM is an open-label, Phase I/IIa study (Part A: 3x3x3 dose escalation; Part B: n=12), & Temferon (single dose) is given to patients with first diagnosis of GBM & unmethylated MGMT promoter. Part A 3rd cohort is ongoing & completes dosing in September 2020. Eight patients completed screening; one patient died (disease progression) before Temferon was administered. Six patients received Temferon (3 women, 3 men, mean age 52.3 years). Cohort 1 received Temferon 0.5x106 cells/kg & Cohort 2, 1x106 cells/kg. Neutropenia & thrombocytopenia occurred as expected following conditioning & hematologic recovery (HR) occurred median D+13. Transduced PBMCs were identified by vector copy number (VCN) on myeloid cells at HR & at later timepoints. In general, a dose-ordered increase in VCN was observed (mean VCN D+30 CD14+ Cohort 1: 0.094, cohort 2: 0.125); 1 patient in each cohort had low VCNs. VCN remained detectable up to recent follow up visits (≤ D+180). No dose-limiting toxicities have been reported. Four SAEs occurred in 3 patients who received Temferon (pneumonia, pulmonary embolism, febrile neutropenia, fatigue) but these events were not attributed to Temferon, resolved, & may have been related to the conditioning regimen (carmustine & thiotepa). Disease progression has been confirmed in 3 patients who received Temferon. These preliminary results indicate feasibility of engrafting a pre-determined fraction of Temferon cells in the bone marrow of GBM patients without, so far, causing dose-limiting toxicity.

scholarly journals P05.02 A phase I/IIa dose escalation study evaluating the safety and efficacy of autologous CD34+ enriched hematopoietic progenitor cells genetically modified for human interferon-α2 in patients with GBM and an unmethylated MGMT promoter (TEM-GBM-001)

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii34-iii34
Author(s):  
B Gentner ◽  
F Ciceri ◽  
F DiMeco ◽  
F Legnani ◽  
M Eoli ◽  
...  
Keyword(s):  
Phase I ◽  
Poor Prognosis ◽  
Conditioning Regimen ◽  
Gene Promoter ◽  
Human Interferon ◽  
Interferon Α ◽  
Antitumor Effects ◽  
Dose Escalation Study ◽  
Mgmt Promoter

Abstract BACKGROUND Glioblastoma (GBM) remains the most common malignant primary brain tumor in adults. Most patients with GBM & an unmethylated O-6-methylguanine-DNA methylase (MGMT) gene promoter, have a poor prognosis with approximately 20% of patients surviving to 2 years. Poor prognosis is likely related to a number of factors including a highly immunosuppressive tumor microenvironment (TME). The TME in GBM is mainly composed of tumor associated macrophages (TAMs) & microglia. A subset of tumor-infiltrating macrophages characterized by expression of the angiopoietin receptor Tie2 (TEMs) have features of M2-TAMs, promote tumor angiogenesis & are infrequently found in normal organs. Tie2 is significantly upregulated upon homing to tumors. Gene therapy technology has allowed TEMs to be used as carriers for the local and tumor restricted release of interferon-α (IFN). IFN has antitumor effects, inhibits angiogenesis & modulates the immune system. Cell-based delivery of IFN into the TME by TEMs is expected to provide efficacy, taking advantage of pleiotrophic anti-tumor effects & avoiding tolerability issues associated with systemic IFN treatment. MATERIAL AND METHODS We are currently conducting a Phase I/IIa clinical study in Milan to evaluate this therapeutic approach (Temferon) in 21 patients with GBM & unmethylated MGMT promoter (EudraCT Number 2018- 001404-11). The study recruits & follows up patients at a specialist neurosurgical & neuro-oncology unit (INCB); administration of Temferon & hematological follow up takes place at a specialist hematology & bone marrow transplantation unit at OSR. Potentially eligible patients are identified immediately after first surgical resection of GBM once the MGMT promoter methylator status is known. Once screening procedures have been completed, harvesting of HSPCs occurs followed by 6 weeks of radiotherapy. Patients receive a non-myeloablative conditioning regimen consisting of BCNU & thiotepa. This is followed by administration of non-manipulated HSPCs and Temferon. In-patient monitoring occurs until hematological recovery. Thereafter, regular follow-up of patients occurs up to 2 years (+720 days) and patients will be invited to participate in a long term follow-up study lasting an additional 6 years. RESULTS In Part A of the study, 3 cohorts of 3 patients will receive escalating doses of Temferon. On completion of Part A, a single dose of Temferon will be selected to be studied in a further 12 patients in Part B. Criteria for study eligibility are the same for both Part A and Part B. In the event that GBM disease progression occurs, patients will be managed with second line therapies including second surgery, TMZ, BCNU, fotemustine or any other approved therapy for GBM. Patient recruitment for Part A is ongoing with the first dose of Temferon administered in July 2019.

scholarly journals TEM-GBM: An Open-Label, Phase I/IIa Dose-Escalation Study Evaluating the Safety and Efficacy of Genetically Modified Tie-2 Expressing Monocytes to Deliver IFN-α within Glioblastoma Tumor Microenvironment

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2844-2844
Author(s):  
Bernhard Gentner ◽  
Gaetano Finocchiaro ◽  
Francesca Farina ◽  
Marica Eoli ◽  
Capotondo Alessia ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Phase I ◽  
Transgene Expression ◽  
Ex Vivo ◽  
Conditioning Regimen ◽  
Open Label ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Open Label Phase ◽  
D 12

Abstract Background: We developed a macrophage-based treatment relying on ex vivo transduction of autologous hematopoietic stem and progenitor cells (HSPC) to express immune-payloads within the TME. Our ATMP (Temferon) targets IFN-a, an immune-modulatory molecule counteracting also neo-angiogenesis and tumor growth, to a subset of Tie2-expressing, tumor-infiltrating macrophages known as TEMs. Materials and Methods: TEM-GBM is an open-label, Phase I/IIa dose-escalation study evaluating safety and efficacy of Temferon in up to 21 newly diagnosed glioblastoma patients with unmethylated MGMT promoter. Key eligibility criteria include age 18-70 years, ECOG 0-1 and KPS >70%, and adequate cardiac, renal, hepatic and pulmonary function. Important exclusion criteria include the presence of active autoimmune disease or receipt of any oral or parenteral chemotherapy or immunotherapy within 2 years of screening. Autologous CD34+ HSPC are mobilized with lenograstim and plerixafor, collected by apheresis, purified and transduced ex vivo with a 3 rd generation lentiviral vector encoding for IFN-a2. Transgene expression is confined to TEMs by the Tie2 promoter and post-transcriptional regulation by microRNA-126 thus achieving tumor specificity. The study evaluates safety and biological activity of Temferon in 7 cohorts of three patients each, where escalating doses of Temferon are co-administered with a fixed CD34+ cell dose of non-manipulated supporter cells following a sub-myeloablative conditioning regimen (Thiotepa + BCNU or + Busulfan). The primary endpoints for this study are: Engraftment of Temferon over the first 90 DaysThe proportion of patients achieving hematologic recovery by Day +30 from ASCTShort-term tolerability of Temferon; stable blood counts and absence of cytopenias, absence of significant organ toxicities (> grade 2); absence of Replication Competent Lentivirus The figure below reports the TEM-GBM study design. Results: As of 28th June 2021, 18 patients have been enrolled; 15 received Temferon (D+0) with follow-up of 30 - 697 days. There was rapid engraftment and hematological recovery after the conditioning regimen. Median neutrophil and platelet engraftment occurred at D+13 and D+12 for patients in cohort 1-3 and D+16 and D+15 for patients assigned to cohort 4 and 5, respectively. Temferon-derived differentiated cells, as determined by the presence of vector genomes in the DNA of peripheral blood and bone marrow cells, were found within 14 days post treatment and persisted subsequently, albeit at lower levels (up to 18 months). Very low concentrations of IFNa were detected in the plasma (average 7.8 pg/ml at D+30; baseline < LLOQ) and in the cerebrospinal fluid (average 1.6 pg/ml at D+30; baseline < LLOQ), suggesting tight regulation of transgene expression. Seven deaths occurred: six at D+241, +322, +340, +402, +478, +646 after Temferon administration due to disease progression, and one at D+60 due to complications following the conditioning regimen. Nine patients had progressive disease (PD; range D-12 to +239). SAEs include infections, venous thromboembolism, brain abscess, hemiparesis, GGT elevation and poor performance status compatible with autologous stem cell transplantation, concomitant medications and PD. Four patients underwent second surgery. These recurrent tumors had gene-marked cells present and increased expression of IFN-responsive gene signatures compared to diagnosis, indicative of local IFNa release by TEMs. In one patient, a stable lesion (as defined by MRI) had a higher proportion of T cells and TEMs within the myeloid infiltrate and an increased IFN-response signature than in a progressing lesion. The T-cell immune repertoire changed with evidence for expansion of tumor-associated clones. Tumor microenvironment characterization by scRNA and TCR sequencing is ongoing. Conclusion: These interim results show that Temferon is generally well tolerated by patients, with no dose limiting toxicities identified to date. The results provide initial evidence of Temferon's potential to activate the immune system and reprogram the tumor microenvironment (TME), as predicted by preclinical studies. Figure 1 Figure 1. Disclosures Naldini: Genenta Science: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: Founder.

scholarly journals IMMU-01. TEM-GBM: AN OPEN-LABEL, PHASE I/IIA DOSE-ESCALATION STUDY EVALUATING THE SAFETY AND EFFICACY OF GENETICALLY MODIFIED TIE-2 EXPRESSING MONOCYTES TO DELIVER IFN-A WITHIN GLIOBLASTOMA TUMOR MICROENVIRONMENT

2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv4-iv4
Author(s):  
Gaetano Finocchiaro ◽  
Marica Eoli ◽  
Bernhard Gentner ◽  
Alessia Capotondo ◽  
Elena Anghileri ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Conditioning Regimen ◽  
Tumor Type ◽  
Open Label ◽  
Dose Escalation Study ◽  
Differentiated Cells ◽  
Open Label Phase ◽  
Concomitant Medications ◽  
General Physical ◽  
Post Transcriptional Regulation

Abstract Temferon is a macrophage-based treatment relying on ex-vivo transduction of autologous HSPCs to express immune-payloads within the TME. Temferon targets the immune-modulatory molecule IFN-a, to a subset of tumor infiltrating macrophages known as Tie-2 expressing macrophages (TEMs) due to the Tie2 promoter and a post-transcriptional regulation layer represented by miRNA-126 target sequences. As of 31st May 2021, 15-patients received Temferon (D+0) with follow-up of 3 – 693 days. After conditioning neutrophil and platelet engraftment occurred at D+13 and D+13.5, respectively. Temferon-derived differentiated cells, as determined be the number of vector copy per genome, were found within 14 days post treatment and persisted albeit at lower levels up to 18-months. Very low concentrations of IFN-a in the plasma (8.7 pg/ml-D+30) and in the CSF (1.6 pg/ml-D+30) were detected, suggesting tight regulation of transgene expression. Five-deaths occurred at D+322, +340, +402, +478 and +646 due to PD, and one at D+60 due to complications following the conditioning regimen. Eight-patients had progressive disease (range: D-11 to +239) as expected for this tumor type. SAEs include GGT elevation (possibly related to Temferon) and infections, venous thromboembolism, brain abscess, hemiparesis, seizures, anemia and general physical condition deterioration, compatible with ASCT, concomitant medications and PD. Four-patients underwent 2ndsurgery. Recurrent tumors had gene-marked cells and increased expression of ISGs compared to first surgery, indicative of local IFNa release by TEMs. In one patient, a stable lesion had a higher proportion of T cells and TEMs within the myeloid infiltrate and an increased ISGs than in the progressing lesion, detected in the same patient. Tumor-associated clones expanded in the periphery. TME characterization by scRNA and TCR-sequencing is ongoing. To date, Temferon is well tolerated, with no DLTs identified. The results provide initial evidence of Temferon potential to activate the immune system of GBM patients, as predicted by preclinical studies.

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.

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.

A phase I-IIa study of genetically modified Tie-2 expressing monocytes in patients with glioblastoma multiforme (TEM-GBM Study).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2532-2532
Author(s):  
Gaetano Finocchiaro ◽  
Bernhard Gentner ◽  
Francesca Farina ◽  
Alessia Capotondo ◽  
Marica Eoli ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Phase I ◽  
Transgene Expression ◽  
Bone Marrow Cells ◽  
Lentiviral Vector ◽  
Ex Vivo ◽  
Genetically Modified ◽  
Conditioning Regimen ◽  
Poor Performance Status ◽  
Tumor Type

2532 Background: Genetically modified cell-based therapies are relevant in immuno-oncology due to their potential for tumor specificity & potential durability. We developed a cell-based treatment, Temferon, relying on ex-vivo transduction of autologous HSPCs to express therapeutic payloads within the tumor microenvironment. Temferon targets IFNa to Tie-2 expressing macrophages (TEMs). Methods: TEM-GBM is an open-label, Phase I/IIa dose-escalation study evaluating safety & efficacy of Temferon in up to 21 newly diagnosed patients with glioblastoma & unmethylated MGMT promoter. Autologous HSPCs are transduced ex-vivo with a lentiviral vector encoding for IFNa. The transgene expression is confined to TEMs due to the Tie2 promoter & the post-transcriptional regulation by miRNA-126. Results: As of January 17 2021, 15 patients have been enrolled; 9 received Temferon (D+0) with follow-up of 61 – 559 days. There was rapid engraftment & hematological recovery after the conditioning regimen. Median neutrophil & platelet engraftment occurred at D+13 & D+12, respectively. Temferon-derived differentiated cells, as determined by the presence of vector genomes in the DNA of peripheral blood & bone marrow cells, were found within 14 days post treatment & persisted subsequently, albeit at lower levels (up to 18 months). We also detected very low concentrations of IFNa in the plasma (median 5pg/ml at D+30; baseline < LLOQ) & in the cerebrospinal fluid, suggesting tight regulation of transgene expression. Three deaths occurred: two at D+343 & +402 after Temferon administration due to disease progression, & one at D+60 due to complications following the conditioning regimen. Seven patients had progressive disease (PD; range D+27-239) as expected for this tumor type. SAEs include infections, venous thromboembolism, brain abscess, hemiparesis, GGT elevation & poor performance status compatible with autologous stem cell transplantation, concomitant medications & PD. Four patients underwent second surgery. These recurrent tumors had gene-marked cells present & increased expression of IFN-responsive gene signatures compared to diagnosis, indicative of local IFNa release by TEMs. In one patient a stable lesion (as defined by MRI) had a higher proportion of T cells & TEMs within the myeloid infiltrate & an increased IFN-response signature than in a progressing lesion. The T-cell immune repertoire changed with evidence for expansion of tumor-associated clones. Tumor microenvironment characterization by scRNA & TCR sequencing is ongoing. Conclusions: Our interim results show that Temferon is well tolerated by patients, with no dose limiting toxicities identified to date. The results provide initial evidence of Temferon potential to modulate the TME of GBM patients, as predicted by preclinical studies. Clinical trial information: NCT03866109.

scholarly journals Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study

2021 ◽  
Author(s):  
Nuria Carrillo ◽  
May C. Malicdan ◽  
Petcharat Leoyklang ◽  
Joseph A. Shrader ◽  
Galen Joe ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Clinical Efficacy ◽  
Muscle Disease ◽  
Secondary Outcome ◽  
Phase 2 ◽  
Open Label ◽  
Safety And Efficacy ◽  
Gne Myopathy ◽  
Open Label Phase

Abstract Purpose To evaluate the safety and efficacy of N-acetylmannosamine (ManNAc) in GNE myopathy, a genetic muscle disease caused by deficiency of the rate-limiting enzyme in N-acetylneuraminic acid (Neu5Ac) biosynthesis. Methods We conducted an open-label, phase 2, single-center (NIH, USA) study to evaluate oral ManNAc in 12 patients with GNE myopathy (ClinicalTrials.gov NCT02346461). Primary endpoints were safety and biochemical efficacy as determined by change in plasma Neu5Ac and sarcolemmal sialylation. Clinical efficacy was evaluated using secondary outcome measures as part of study extensions, and a disease progression model (GNE-DPM) was tested as an efficacy analysis method. Results Most drug-related adverse events were gastrointestinal, and there were no serious adverse events. Increased plasma Neu5Ac (+2,159 nmol/L, p < 0.0001) and sarcolemmal sialylation (p = 0.0090) were observed at day 90 compared to baseline. A slower rate of decline was observed for upper extremity strength (p = 0.0139), lower extremity strength (p = 0.0006), and the Adult Myopathy Assessment Tool (p = 0.0453), compared to natural history. Decreased disease progression was estimated at 12 (γ = 0.61 [95% CI: 0.09, 1.27]) and 18 months (γ = 0.55 [95% CI: 0.12, 1.02]) using the GNE-DPM. Conclusion ManNAc showed long-term safety, biochemical efficacy consistent with the intended mechanism of action, and preliminary evidence clinical efficacy in patients with GNE myopathy.

Safety of trastuzumab emtansine (T-DM1) in HER2-positive advanced breast cancer (BC) patients (pts): Primary results from KAMILLA study cohort 1.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1033-1033
Author(s):  
Carlos H. Barrios ◽  
Rachel Wuerstlein ◽  
Antonio Anton ◽  
Suzette Delaloge ◽  
Filippo Montemurro ◽  
...  
Keyword(s):  
Disease Progression ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Study Cohort ◽  
Primary Analysis ◽  
Her2 Positive ◽  
Open Label ◽  
Metastatic Setting ◽  
Open Label Phase ◽  
Grade 3

1033 Background: KAMILLA is a single-arm, open-label, phase 3b safety study of T-DM1 in pts with HER2-positive advanced BC from 278 sites in 40 countries. We report the primary analysis of the first study cohort (N = 2003). Methods: Pts with HER2-positive, locally advanced or metastatic BC (locally confirmed) with progression after prior treatment with chemotherapy and a HER2-directed agent for metastatic BC or within 6 mo of completing adjuvant therapy were enrolled. Pts received T-DM1 3.6 mg/kg every 3 wks until unacceptable toxicity, withdrawal, or disease progression. The primary outcome was safety. Results: A total of 2002 pts were treated (median age 55 yrs, range, 26–88). Most pts had a baseline ECOG score of 0 (n = 1110, 55.4%) or 1 (n = 775, 38.7%), and 1232 (61.5%) had ER and/or PR positive tumors. Median time since initial BC diagnosis was 5 yrs (range, 0–53). Most pts had received ≥2 prior lines of therapy (0–1 prior lines: 29.7%; ≥2: 66.0%); 1855 (92.8%) received prior targeted therapy in the locally advanced/metastatic setting. Median T-DM1 exposure was 5.6 mo (range, 0–46). Adverse events (AEs) were reported in 93.0% (n = 1862). Serious AEs occurred in 21.3% (n = 427), most commonly vomiting (17, 0.8%), pneumonia (16, 0.8%), anemia (13, 0.6%), and pyrexia (13, 0.6%). Grade ≥3 AEs occurred in 40.8% (n = 816), most commonly anemia (60, 3.0%), thrombocytopenia (55, 2.7%), and fatigue (50, 2.5%). Additional AEs of grade ≥3 (multiple individual items grouped) were thrombocytopenia/platelet count decrease (74, 3.7%), hepatic disorders (139, 6.9%), and hemorrhage (46, 2.3%). Grade 5 AEs occurred in 2.2% (n = 45). Treatment discontinuation was most often due to disease progression (1495, 78.1%). Median progression-free survival was 8.3 (95% CI: 8.0–9.7), 6.5 (5.6–8.0), 5.9 (5.6–8.1), 5.6 (5.0–5.9), and 5.6 (5.4–6.6) mo in pts with 0–1, 2, 3, 4, and 5+ prior lines of therapy. Median overall survival was 27.2 mo (95% CI: 25.5–28.7). Conclusions: KAMILLA isthe largest (to date) cohort of T-DM1 treated pts and these data are consistent with safety and efficacy seen in prior randomized studies, thereby supporting T-DM1 as therapy for previously treated HER2-positive advanced BC pts. Clinical trial information: NCT01702571.

Interim safety analysis of the DANTE trial: Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma—A randomized, open-label phase II trial of the German Gastric Group at the AIO and SAKK.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4549-4549
Author(s):  
Nils Homann ◽  
Sylvie Lorenzen ◽  
Michael Schenk ◽  
Peter C. Thuss-Patience ◽  
Eray Goekkurt ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Clinical Stage ◽  
Locally Advanced ◽  
Safety Analysis ◽  
Open Label ◽  
Serious Adverse Events ◽  
Open Label Phase

4549 Background: The DANTE study evaluates atezolizumab in the perioperative treatment of locally advanced, potentially resectable gastric or GEJ adenocarcinoma in combination with perioperative FLOT. Here, we report the protocol-defined interim safety analysis. Methods: DANTE is a multinational, prospective, multicenter, randomized, investigator-initiated, open label phase II trial. Patients (pts) with locally advanced, potentially resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N-positive) without distant metastases are enrolled. Pts are randomized 1:1 to 4 pre-operative 2-week cycles of FLOT followed by surgery and 4 additional cycles of FLOT plus atezolizumab at 840 mg every 2 weeks, followed by a total of 8 additional cycles of atezolizumab at 1200 mg every 3 weeks as monotherapy (arm A) or FLOT alone (arm B). Primary endpoint is time to disease progression or relapse after surgery (PFS/DFS). Results: Recruitment started in Sep 2018; by Feb 2020, a total of 175 pts have been randomized. This analysis is based on the first 40 pts (20 pts in each arm). The pts had a median age of 62 y and 75% of pts had an ECOG PS of 0 in both arms. The cohort was well balanced in terms of tumor location and clinical stage. 5% of the 40 patients (overall 7.4% of 175 pts enrolled) showed microsatellite instability. 90% of pts enrolled completed all pre-operative cycles in each arm. Total number of adverse events with relation to study treatment was 154 in arm A and 148 in arm B. Total number of serious adverse events (SAE; related or not) was 16 in Arm A and 14 in arm B. 20% of pts in each arm had an SAE due to perioperative morbidity. No surgical mortality was observed. 18 and 19 pts proceeded to operation in arms A and B, respectively. Premature treatment discontinuation occurred in 2 pts in each arm: disease progression (1) and deterioration of general health condition (1) in arm A; and pts’ wish (1) and death (1) in arm B. Median hospitalization time was 15 days in arm A and 16 days in arm B. Conclusions: Perioperative atezolizumab plus FLOT is feasible and safe. The study continues recruitment. Clinical trial information: NCT03421288 .

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

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