scholarly journals Bintrafusp alfa (M7824) a bifunctional fusion protein targeting TGF-β and PD-L1: results from a phase 1 expansion cohort in patients with recurrent glioblastoma

2021 ◽  
Author(s):  
Mustafa Khasraw ◽  
Michael Weller ◽  
David Lorente ◽  
Kathryn Kolibaba ◽  
Chee Khoon Lee ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Disease Control ◽  
Protein Targeting ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Complete Response ◽  
Recurrent Glioblastoma ◽  
Open Label ◽  
Bifunctional Fusion Protein ◽  
Expansion Cohort

Abstract Background For patients with recurrent glioblastoma (rGBM), there are few options following treatment failure with radiotherapy plus temozolomide. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 antibody blocking PD-L1. Methods In this phase 1, open-label expansion cohort, (NCT02517398), patients with rGBM that progressed after radiotherapy plus temozolomide received bintrafusp alfa 1200 mg Q2W until disease progression, unacceptable toxicity, or trial withdrawal. Response was assessed per RANO criteria. The primary endpoint was disease control rate (DCR); secondary endpoints included safety. Results As of August 24, 2018, 35 patients received bintrafusp alfa for a median of 1.8 (range, 0.5-20.7) months. Eight patients (22.9%) experienced disease control as assessed by an independent review committee: 2 had a partial response, 4 had stable disease, and 2 had non–complete response /non–progressive disease. Median progression-free survival (PFS) was 1.4 (95% CI, 1.2-1.6) months; 6- and 12-month PFS rates were 15.1% and 11.3%, respectively. Median overall survival (OS) was 5.3 (95% CI, 2.6-9.4) months; 6- and 12-month OS rates were 44.5% and 30.8%, respectively. The DCR (95% CI) was 66.7% (22.3-95.7%) for patients with IDH-mutant GBM (n=6) and 13.8% (3.9-31.7%) for patients with IDH–wild-type GBM (n=29). Disease control was seen regardless of PD-L1 expression. Twenty-five patients (71.4%) experienced treatment-related adverse events (grade ≥3; 17.1% [n=6]). Conclusions The percentage of patients achieving disease control and the manageable safety profile may warrant further investigation of bintrafusp alfa in GBM.

scholarly journals ATIM-16. PHASE 1 STUDY RESULTS OF M7824 (MSB0011359C), A BIFUNCTIONAL FUSION PROTEIN TARGETING TGF- AND PD-L1, AMONG PATIENTS WITH RECURRENT GLIOBLASTOMA (rGBM)

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi4-vi4
Author(s):  
Mustafa Khasraw ◽  
Michael Weller ◽  
David Lorente Estelles ◽  
Kathryn Kolibaba ◽  
Chee Lee ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Protein Targeting ◽  
Phase 1 ◽  
Recurrent Glioblastoma ◽  
Phase 1 Study ◽  
Study Results ◽  
Bifunctional Fusion Protein

scholarly journals Hypofractionated Stereotactic Re-Irradiation with Pembrolizumab and Bevacizumab in Patients with Recurrent High Grade Gliomas: Results from a Phase 1 Study

2020 ◽  
Author(s):  
Solmaz Sahebjam ◽  
Peter A Forsyth ◽  
Nam D Tran ◽  
John A Arrington ◽  
Robert Macaulay ◽  
...  
Keyword(s):  
Phase 1 ◽  
Progression Free Survival ◽  
Complete Response ◽  
Recurrent Glioblastoma ◽  
High Grade ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
High Grade Gliomas ◽  
Grade 3 ◽  
Recommended Phase Ii Dose

Abstract Background Radiotherapy may synergize with programmed death 1 (PD-1)/PD-1 ligand (PD-L1) blockade. The purpose of this study was to determine the recommended Phase II dose, safety/tolerability, and preliminary efficacy of combining pembrolizumab, an anti-PD-1 monoclonal antibody, with hypofractionated stereotactic irradiation (HFSRT) and bevacizumab in patients with recurrent high grade gliomas (HGGs). Methods Eligible subjects with recurrent glioblastoma or anaplastic astrocytoma were treated with pembrolizumab (100 or 200 mg based on dose level Q3W) concurrently with HFSRT (30 Gy in 5 fractions) and bevacizumab 10 mg/kg Q2W. Results Thirty two patients were enrolled (bevacizumab naïve, n = 24; bevacizumab resistant, n = 8). The most common treatment-related adverse events (TRAEs) were proteinuria (40.6%), fatigue (25%), increased alanine aminotransferase (25%), and hypertension (25%). TRAEs leading to discontinuation occurred in 1 patient who experienced a grade 3 elevation of aspartate aminotransferase. In the bevacizumab naïve cohort, twenty patients (83%) had a complete response (CR) or partial response (PR). The median overall survival (OS) and progression-free survival (PFS) were 13.45 months (95% CI: 9.46-18.46) and 7.92 months (95% CI: 6.31-12.45), respectively. In the bevacizumab resistant cohort, PR was achieved in 5 patients (62%). Median OS was 9.3 months (95% CI: 8.97-18.86) with a median PFS of 6.54 months (95% CI: 5.95-18.86). The majority of patients (20/26 pts; 77%) had tumor-cell/tumor-microenvironment PD-L1 expression <1%. Conclusions The combination of HFSRT with pembrolizumab and bevacizumab in patients with recurrent HGG is generally safe and well tolerated. These findings merit further investigation of HFSRT with immunotherapy in HGGs.

M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with heavily pretreated CRC: Preliminary results from a phase I trial.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 764-764 ◽  
Author(s):  
Scott Kopetz ◽  
Alexander I. Spira ◽  
Michael Wertheim ◽  
Edward Kim ◽  
Benjamin R. Tan ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Transforming Growth Factor ◽  
Molecular Subtype ◽  
Phase 1 ◽  
Unmet Need ◽  
Primary Objective ◽  
Open Label ◽  
Programmed Death ◽  
Heavily Pretreated ◽  
Bifunctional Fusion Protein

764 Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which plays a key role in tumor immunosuppression, may enhance the response to programmed death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs). M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, which serves as a TGF-β “trap.” We report results in patients (pts) with heavily pretreated colorectal cancer (CRC), an area of high unmet need since these pts no longer respond to standard therapies. Methods: In this expansion cohort of the ongoing, phase 1, open-label trial NCT02517398, pts with heavily pretreated (≥3rd line) advanced CRC receive M7824 1200 mg q2w until confirmed progressive disease (PD), unacceptable toxicity or trial withdrawal. The primary objective is best overall response (BOR) per RECIST v1.1; secondary objectives include safety/tolerability. Results: As of 28 June 2017, 32 heavily pretreated pts with advanced CRC (87.5% had ≥3 prior therapies) received M7824 for a median duration of 7.1 (range: 2-38) weeks; 2 pts remained on treatment. Among the 29 evaluable pts, 1 had a confirmed partial response (PR; ongoing at 8 months), 1 had stable disease (SD) and 27 had PD as BOR per independent read. The pt with a PR had CRC that was microsatellite stable (MSS), consensus molecular subtype (CMS) 4, KRAS mutant (mt) and PD-L1+; this pt had the highest tumor cell PD-L1 expression in our cohort (20%; PD-L1 expression was generally low among the other 24 pts with available results). 4 pts (12.5%) experienced 5 different grade 3 treatment-related adverse events (AEs; adrenal insufficiency, anemia, blood bilirubin increased, enteritis [leading to discontinuation] and fatigue); there were no grade ≥4 treatment-related AEs or treatment-related deaths. Conclusions: In heavily pretreated pts with advanced CRC, 1 pt (MSS, CMS 4, KRAS mt and PD-L1+) had a durable PR, 1 had SD and 27 had PD as BOR. M7824 showed a manageable safety profile. Updated data – including PD-L1, TGF-β and CMS results – will be presented. A study in pts with CMS 4 is in preparation. Clinical trial information: NCT02517398.

scholarly journals PL3.5 Efficacy and safety of selinexor in recurrent glioblastoma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii3-iii4 ◽  
Author(s):  
A B Lassman ◽  
P Y Wen ◽  
M van den Bent ◽  
S R Plotkin ◽  
A Walenkamp ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Complete Response ◽  
Median Number ◽  
Recurrent Glioblastoma ◽  
Treatment Modalities ◽  
Efficacy And Safety ◽  
Open Label ◽  
Partial Responder

Abstract BACKGROUND New treatment modalities are needed for recurrent glioblastoma (rGBM). Selinexor is a novel, oral selective inhibitor of nuclear export which forces nuclear retention of tumor suppressor proteins including p53 and p27, leading to apoptosis. We previously reported interim results showing tolerability, preliminary efficacy, and blood-brain barrier penetration in a surgical cohort (N=8). We now report updated results following completion of accrual to non-surgical cohorts (N=68). MATERIALS AND METHODS This is an open-label, multicenter, phase 2 study of selinexor monotherapy. Patients (pts) not undergoing surgery for measurable rGBM per response assessment neuro-oncology criteria (RANO) were enrolled in one of 3 arms encompassing different dosing schedules of selinexor (50 mg/m2 [~ 85 mg] BIW, 60 mg BIW, and 80 mg QW). Treatment was continuous, although cycles were defined as 28 days and response was assessed every other cycle by MRI. Prior treatment with radiotherapy and temozolomide was required and prior bevacizumab was exclusionary. The primary endpoint was 6-month progression free survival (6mPFS) rate, calculated by the Kaplan-Meier method. RESULTS 76 pts were enrolled; 24, 14 and 30 pts on doses of ~85 mg BIW, 60 mg BIW, and 80 mg QW, respectively. Median age was 56 years (range 21–78). Median number of prior treatments was 2 (range 1–7) At the end of the 6 cycles, 30.2% pts on 80 mg QW were free from progression. The 6mPFS rate on 80 mg QW was 18.9%. Best RANO-defined responses (assessed locally) among 26 evaluable pts on 80 mg QW included 1 complete response, 2 partial responses, 7 stable disease, and 16 with progressive disease. Complete and partial responses were durable: the complete and a partial responder remain on selinexor for 393 and 1093 days respectively, as of the cut-off date. Median duration of response was 10.8 months. The most common related adverse events (all grades) in pts on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (42%/64%/63%), leukopenia (38%/7%/43%), fatigue (71%/71%/47%), neutropenia (29%/14%/33%), decreased appetite (46%/71%/27%), and thrombocytopenia (67%/29%/23%). CONCLUSION Selinexor demonstrated efficacy, with durable responses and disease stabilization in rGBM. Based on the favorable efficacy and safety profile, selinexor at a dose of 80 mg QW is recommended for further development in rGBM.

A phase Ib study of xentuzumab plus abemaciclib and fulvestrant in patients (pts) with advanced hormone receptor-positive (HR+), HER2-negative breast cancer (BC) with visceral or non-visceral disease.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1057-1057
Author(s):  
Douglas Yee ◽  
Patricia LoRusso ◽  
Marie Paule Sablin ◽  
Aleix Prat ◽  
Agostina Stradella ◽  
...  
Keyword(s):  
Disease Control ◽  
Progression Free Survival ◽  
Neutralizing Antibody ◽  
Standard Of Care ◽  
Complete Response ◽  
Dose Finding ◽  
Open Label ◽  
Hormone Receptor Positive ◽  
Recommended Phase Ii Dose ◽  
Visceral Disease

1057 Background: Cyclin-dependent kinase (CDK) 4 & 6 inhibitors plus endocrine therapy (ET) are standard of care for advanced HR+ BC. Combining xentuzumab, an insulin-like growth factor (IGF) ligand-neutralizing antibody, with ET and everolimus, suggested progression-free survival (PFS) benefit in pts with advanced HR+ BC and non-visceral disease. Activation of the IGF pathway leads to an increase in cyclin D1, providing a rationale for combining IGF and CDK4 & 6 inhibition. This prospective, open-label study is investigating xentuzumab plus abemaciclib, a CDK4 & 6 inhibitor, with fulvestrant. In dose-finding cohorts, the recommended phase II dose (RP2D) was determined as xentuzumab 1000 mg weekly intravenously plus abemaciclib 150 mg every 12h orally (Q12h). Here, we report preliminary data on disease control rate (DCR) from two expansion cohorts in pts with advanced HR+ BC with visceral (D1) or non-visceral disease (D2). Methods: Postmenopausal women with advanced/metastatic HR+ BC that had progressed on or after ET (including adjuvant ET) were enrolled. Pts could not have received >1 line of ET or any chemotherapy for metastatic disease. No prior CDK4 & 6 inhibitor therapy was permitted. Pts had to have ≥1 documented visceral metastasis in D1 and no visceral metastases in D2. Pts received xentuzumab weekly plus abemaciclib Q12h (at RP2D) plus fulvestrant 500 mg per label. Protocol primary endpoint was PFS rate at 18 months (mos). Secondary endpoints included DCR (complete response [CR], partial response [PR] and non-CR/non-progressive disease [PD] or stable disease [SD] lasting ≥24 weeks [wks]). Results: In D1/D2, 33/31 pts were treated: median age 60/53 years. 19 pts in D2 had bone-only, non-measurable disease. At data cut-off (Jan 2021), median treatment duration was 7.5/9.2 mos in D1/D2; 40 pts remain on treatment. In D1, DCR was 64%: 17 (52%) pts had PR and 4 (12%) had SD lasting ≥24 wks. In D2, DCR was 55%: 5 (16%) pts had PR, 10 (32%) had non-CR/non-PD lasting ≥24 wks and 2 (7%) had SD lasting ≥24 wks. Median duration of disease control was 10.9 mos in each cohort. Some pts had not reached 24 wks; full DCR data will be presented. Most common AEs are shown in the table (≥33% all-grade in either cohort). No hypo/hyperglycemia was reported. Conclusions: Xentuzumab plus abemaciclib and fulvestrant demonstrated encouraging disease control in pts with advanced HR+ BC with visceral and non-visceral disease. The safety profile was manageable, and consistent with the known profiles of the three agents. Clinical trial information: NCT03099174 .[Table: see text]

Efficacy and safety of selinexor in recurrent glioblastoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2005-2005 ◽  
Author(s):  
Andrew B. Lassman ◽  
Patrick Y. Wen ◽  
Martin J. Van Den Bent ◽  
Scott Randall Plotkin ◽  
Anna Maria Elisabeth Walenkamp ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Progression Free Survival ◽  
Complete Response ◽  
Median Number ◽  
Recurrent Glioblastoma ◽  
Treatment Modalities ◽  
Efficacy And Safety ◽  
Open Label ◽  
Nuclear Retention ◽  
Disease Stabilization

2005 Background: New treatment modalities are needed for recurrent glioblastoma (rGBM). Selinexor (SEL) is a novel, oral selective inhibitor of nuclear export which forces nuclear retention of tumor suppressor proteins including p53 and p27, leading to apoptosis. We previously reported interim results showing tolerability, preliminary efficacy, and blood-brain barrier penetration in a surgical cohort (N = 8). We now report updated results following completion of accrual to non-surgical cohorts (N = 68). Methods: This is an open-label, multicenter, phase 2 study of SEL monotherapy. Patients (pts) not undergoing surgery for measurable rGBM (per RANO) were enrolled in one of 3 arms encompassing different dosing schedules. Treatment was continuous, although cycles were defined as 28 days and response was assessed every other cycle by MRI. Prior treatment with radiotherapy and temozolomide was required and prior bevacizumab was exclusionary. The primary endpoint was 6-month progression free survival (6mPFS) rate, calculated by the Kaplan Meier method. Results: A total of 76 pts were enrolled. Median age was 56 years (range 21-78). Median number of prior treatments was 2 (range 1-7). At the end of the 6 cycles, 30.2% patients on 80 mg QW were free from progression. The 6mPFS rate on 80 mg QW was 15.1%. Best RANO-defined responses (assessed locally) among 26 evaluable pts on 80 mg QW included 1 complete response, 2 partial responses, 7 stable disease, and 16 with progressive disease. Median duration of response was 10.8 months. The most common related adverse events in pts on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (42%/64%/60%), leukopenia (38%/7%/43%), fatigue (71%/71%/43%), neutropenia (29%/14%/33%), decreased appetite (46%/71%/27%), and thrombocytopenia (67%/29%/23%). Conclusions: SEL demonstrated efficacy, with durable responses and disease stabilization in rGBM. Based on the favorable efficacy and safety profile, SEL at a dose of 80 mg QW is recommended for further development in rGBM. Clinical trial information: NCT01986348. [Table: see text]

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