scholarly journals PDCT-16. A PHASE I STUDY OF SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) WITH TEMSIROLIMUS IN CHILDREN WITH NEWLY DIAGNOSED OR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi186-vi187
Author(s):  
Soumen Khatua ◽  
Joya Chandra ◽  
Vidya Gopalakrishnan ◽  
Leena Ketonen ◽  
Michael Johnson ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Phase I ◽  
Dose Escalation ◽  
Survival Data ◽  
Progressive Disease ◽  
Maximum Tolerated Dose ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Pontine Glioma ◽  
Phase Ii Studies

Abstract Diffuse intrinsic pontine glioma (DIPG) in children remains essentially incurable with a median survival of 12 months. Radiation therapy is currently the standard treatment modality. To date chemotherapy or biologic agents have had no meaningful increase in survival. Data from biopsied DIPG showed the PI3K/AKT/mTOR pathway as a major oncogenic player. Thus targeting these pathways with mTOR inhibitors could hold promise. Genomic and epigenetic insights have shown the role of histone deacetylase (HDAC) in these tumors. Both temsirolimus (mTOR inhibitor) and SAHA (HDAC inhibitor) are well described in pediatric clinical trials with an established maximum tolerated dose (MTD) for phase II studies. This is the first ongoing phase I multi-targeted therapeutic study, in pediatric DIPG, using SAHA and temsirolimus in a combinatorial approach, targeting the key oncogenic pathway and molecules (NCT02420613 currently recruiting). Patients with a performance score of 50 or greater, with newly diagnosed (Stratum I), or progressive (stratum II) DIPG will be eligible. Biopsy is not mandatory. A standard 3 + 3 design is being used for this study. 1 dose escalation and 2 dose de-escalations are permitted beyond the starting dose level. In stratum I patients receive radiation therapy concurrently with vorinostat on the days of radiation, followed by adjuvant therapy with vorinostat and temsirolimus for 10 cycles if they do not have progressive disease. In stratum II patients receive vorinostat and temsirolimus for 12 cycles (28 day cycle), if they do not have progressive disease. Correlative studies evaluating histone acetylation, phosphorylated 70S6K and Akt are being performed. Currently 5 patients have been enrolled, and the study is at the dose escalation level with no dose limiting toxicity (DLT) seen so far. Safety, adverse effects, biological correlatives, and clinical outcomes will be reported once study is completed.

A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG)

2020 ◽  
Vol 149 (3) ◽  
pp. 511-522
Author(s):  
Mariko DeWire ◽  
Christine Fuller ◽  
Trent R. Hummel ◽  
Lionel M. L. Chow ◽  
Ralph Salloum ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Phase I ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Pontine Glioma

scholarly journals Phase I study of TrasGEX, a glyco-optimised anti-HER2 monoclonal antibody, in patients with HER2-positive solid tumours

ESMO Open ◽  
2018 ◽  
Vol 3 (4) ◽  
pp. e000381 ◽  
Author(s):  
Walter Fiedler ◽  
Herbert Stoeger ◽  
Antonella Perotti ◽  
Guenther Gastl ◽  
Jens Weidmann ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Dose Escalation ◽  
Progressive Disease ◽  
Antitumour Activity ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Her2 Positive ◽  
Dose Escalation Study ◽  
Phase Ii Studies

PurposeTrasGEX is a second-generation monoclonal antibody of trastuzumab, glyco-optimised to enhance antibody-dependent cellular cytotoxicity while fully retaining trastuzumab’s antigen-binding properties to human epidermal growth factor receptor 2 (HER2). A phase I dose-escalation study was conducted to establish the optimal TrasGEX dose and regimen for phase II studies and to define the safety, pharmacokinetics (PK) and preliminary antitumour activity of TrasGEX.Patients and methodsA total of 37 patients with advanced HER2-positive carcinomas and progressive disease received TrasGEX intravenously every 3 weeks until disease progression in doses of 12–720 mg in a three-plus-three dose escalation design, including an expansion cohort at the highest dose.ResultsNo dose limiting toxicity was observed, and no maximum tolerated dose was reached. Drug-related adverse events were mainly infusion-related reactions occurring during the first infusion in 51% of patients; all but two were mild-to-moderate. Compared with trastuzumab, the PK parameters were dose dependent, with a mean terminal half-life (t1/2) of 263±99 hours for the 720 mg dose. Clinical benefit in 15 out of 30 (50%) evaluable patients included one ongoing complete response, two partial remissions lasting 16 and 77 weeks and disease stabilisation (SD) in 12 patients lasting a median (range) of 17 (7–26) weeks; three of them had SD of 24, 25 and 26 weeks, respectively.ConclusionTrasGEX was safe, well-tolerated and showed antitumour activity in 50% of evaluable patients, all with progressive disease at study entry. Infusions at an interval of 2–3 weeks should achieve clinically relevant trough levels for future studies (NCT01409343).

scholarly journals EPCT-06. A PHASE I STUDY OF MULTI-TARGETED THERAPY IN NEWLY DIAGNOSED OR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii304-iii305
Author(s):  
Muhammad Baig ◽  
Jason Johnson ◽  
Sumit Gupta ◽  
Zsila Sadighi ◽  
Wafik Zaky ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Maintenance Therapy ◽  
Phase I ◽  
Phase I Study ◽  
Diffusion Tensor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Pontine Glioma ◽  
Dose Limiting Toxicity

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) constitutes 80% of pediatric brain stem tumors with a median survival of 12 months. The PI3K/AKT/mTOR pathway is a key oncogenic driver of this tumor. Targeting the chromatin dysregulation through HDAC inhibition, demonstrated benefit in vivo and vitro studies. We completed the first study as a multi-targeted therapy using SAHA and temsirolimus in pediatric DIPG. METHODS After receiving institutional IRB approval, we enrolled 6 patients on this phase I study using a 3 + 3 statistical design. Patients were divided into stratum 1 and stratum 2, based on newly diagnosed or relapsed DIPG respectively. Stratum I patients received radiation therapy concurrently with vorinostat, followed by maintenance therapy with vorinostat and temsirolimus for 10 cycles (28 day cycle), while in stratum II patients received vorinostat and temsirolimus for 12 cycles. Neuroimaging including diffusion tensor imaging were evaluated where feasible. RESULTS Three patients were enrolled in each of the stratum. One patient in stratum 1 completed therapy, 2 other demonstrated progressive disease (PD) after 4th and 1st cycle of maintenance therapy respectively. In stratum 2 all patients progressed 2 months after the start of therapy. However no dose-limiting toxicity (DLT) was noted. The patient in stratum 1 who completed therapy, remained free of PD 21 months after diagnosis with continued improvements in the volume of enhancing and T2 hyperintense disease. CONCLUSION Although no significant benefit was seen as compared to historical controls during this study, no dose limiting toxicity was noticed with this treatment.

scholarly journals Correction to: A phase I/II study of gemcitabine during radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma

2017 ◽  
Vol 136 (1) ◽  
pp. 219-220
Author(s):  
Sophie E. M. Veldhuijzen van Zanten ◽  
Fatma E. El‑Khouly ◽  
Marc H. A. Jansen ◽  
Dewi P. Bakker ◽  
Esther Sanchez Aliaga ◽  
...  
Keyword(s):  
Phase I ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Pontine Glioma

A humanized antibody against CD40 (SGN-40) is well tolerated and active in non-Hodgkin’s lymphoma (NHL): Results of a phase I study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7534-7534 ◽  
Author(s):  
A. Forero-Torres ◽  
R. R. Furman ◽  
J. D. Rosenblatt ◽  
A. Younes ◽  
K. Harrop ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Dose Escalation ◽  
Phase I Study ◽  
Cell Function ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Cell Transplant ◽  
Humanized Antibody ◽  
Phase Ii Studies

7534 Background: CD40 is a member of the TNF receptor family and is widely expressed on hematologic malignancies of B-cell origin. SGN-40 is a humanized antibody against CD40 with effector cell function and mild agonistic activity. Preclinical toxicity studies and efficacy data supported initiation of a multi-institutional phase I study to test the safety, pharmacokinetics, immunogenicity, and efficacy of SGN-40 in patients with relapsed NHL. Methods: Cohorts of 3–6 pts were treated weekly with a maximum dose of 2, 3, or 4 mg/kg/wk SGN-40. A dose escalation schedule is used such that patients receive 1 mg/kg on D1 and D4, 2 mg/kg on D8, and higher doses on weeks 3–5. Responding patients may receive a second cycle. Further dose escalation up to 8 mg/kg is planned. Results: 16 pts have been treated with multiple histologic subtypes: follicular (1), marginal zone (MZL; 1), mantle cell (4), and diffuse large B-cell (DLBCL; 10). One patient (2 mg/kg) developed a reversible Grade 3 unilateral conjunctivitis and ipsilateral loss of visual acuity. No other dose limiting toxicity has been observed up to 4 mg/kg. Preliminary pharmacokinetic data suggest that the antibody has a relatively short half-life, perhaps reflecting a route of elimination or binding that is not saturated at current doses. Two partial responses have been observed at 3 mg/kg (1 MZL, 1 DLBCL) and one partial response has been observed at 4 mg/kg dose (DLBCL relapsed after autologous stem cell transplant with small volume tumor). Conclusions: Using an intra-patient dose escalation schedule, SGN-40 has been well-tolerated at doses up to 4 mg/kg/wk. Further dose-escalation is ongoing to determine the maximum tolerated dose. Three objective responses have been seen, including two in patients with extensively treated aggressive disease. Correlative studies are underway measuring soluble CD40, cytokine release, effect of FcR polymorphisms, and SGN-40-induced immunogenicity. Given the favorable tolerability and activity, phase II studies in NHL are planned. [Table: see text]

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